PHARMACOTHERAPY SELF-ASSESSMENT PROGRAM

New!
PSAP Series
2022–2024
Available for BCPS recertification credits

PSAP Release Release Date Posttest Deadline ACPE Deadline

Cardiology January 18, 2022 July 15, 2022 January 18, 2025

Current Issues in Pharmacotherapy May 16, 2022 November 15, 2022 May 16, 2025

Behavioral Health September 15, 2022 March 15, 2023 September 15, 2025

Endocrinology and Nephrology January 17, 2023 July 17, 2023 January 17, 2026

Critical Care and Emergency May 15, 2023 November 15, 2023 May 15, 2026
Medicine

Pulmonary and Gastrointestinal September 15, 2023 March 15, 2024 September 15, 2026
Diseases

Infectious Diseases January 16, 2024 July 15, 2024 January 16, 2027

Hematology and Oncology May 15, 2024 November 15, 2024 May 15, 2027

Neurology and Chronic Conditions September 16, 2024 March 17, 2025 September 16, 2027

Series Editor Series Editor

Cynthia A. Sanoski, Daniel M. Witt,
Pharm.D., FCCP, Pharm.D., FCCP,
BCPS BCPS

For purchase information, visit www.accp.com/store

®
 IMPORTANT INFORMATION ON THE RELEASE OF
PSAP 2022 Book 1 (Cardiology)
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PSAP 2022 Book 1 (Cardiology)

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ISBN-13s: 978-1-952291-37-1 (print); 978-1-952291-38-8 (eBook)

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Pharmacotherapy
Self-Assessment
Program
TABLE OF CONTENTS
Cardiology I�������������������������������������������������������������������������� 1
Cardiology I Panel ������������������������������������������������������������������������������ 3
Heart Failure with Reduced Ejection
Fraction
By Ralph J. Riello III, Pharm.D., BCPS
Introduction ���������������������������������������������������������������������������������������� 7
HF Updates According to the 2021 Expert Consensus
Decision Pathway ������������������������������������������������������������������������������ 9
Optimizing GDMT ���������������������������������������������������������������������������� 15
Inotropic Therapy������������������������������������������������������������������������������ 17
Advanced Therapeutic Modalities ������������������������������������������������ 21
Heart Failure with Preserved Ejection Fraction �������������������������� 23
Conclusion ���������������������������������������������������������������������������������������� 25
References ���������������������������������������������������������������������������������������� 25
Self-Assessment Questions������������������������������������������������������������ 29
Drug-Induced Cardiovascular Disease
By Katherine Aymond, Pharm.D., BCPS, BCCP
Introduction �������������������������������������������������������������������������������������� 33
Chemotherapy and Immunotherapy-Induced Cardiotoxicity ������ 33
Other Agents of Cardiotoxicity ������������������������������������������������������ 42
Conclusion ���������������������������������������������������������������������������������������� 51
References ���������������������������������������������������������������������������������������� 51
Self-Assessment Questions������������������������������������������������������������ 53
Cardiology II ���������������������������������������������������������������������� 57
Cardiology II Panel���������������������������������������������������������������������������� 59
Peripheral Arterial Disease
By Anastasia L. Armbruster, Pharm.D., FACC, BCPS, BCCP
Introduction �������������������������������������������������������������������������������������� 63
Diagnosis ������������������������������������������������������������������������������������������ 65
Pharmacotherapy in Patients with PAD ���������������������������������������� 66
Symptomatic Management ������������������������������������������������������������ 71
Critical Limb Ischemia �������������������������������������������������������������������� 72
Acute Limb Ischemia ���������������������������������������������������������������������� 73
Conclusion ���������������������������������������������������������������������������������������� 75
References ���������������������������������������������������������������������������������������� 76
Self-Assessment Questions������������������������������������������������������������ 79
Antithrombotic Therapy in Cardiac
Interventions
By Stephanie Dwyer Kaluzna, Pharm.D., BCCP;
and Jaclynne Gowen, Pharm.D., BCCP
Percutaneous Coronary Intervention �������������������������������������������� 83
Use of P2Y 12 Inhibitor in Percutaneous Coronary
Intervention �������������������������������������������������������������������������������������� 85
PSAP 2022 Book 1 • Cardiology
Triple Antithrombotic Therapy�������������������������������������������������������� 98
Antithrombotic Therapy in Transcatheter Aortic Valve
Implantation ������������������������������������������������������������������������������������ 103
Antithrombotic Therapy in MitraClip ������������������������������������������� 105
Conclusion �������������������������������������������������������������������������������������� 107
References �������������������������������������������������������������������������������������� 108
Self-Assessment Questions�����������������������������������������������������������111
Cardiology III�������������������������������������������������������������������� 115
Cardiology III Panel����������������������������������������������������������������������117
Management of Atrial Fibrillation
By Amy L. Lehnert, Pharm.D., BCPS, BCCP
Introduction�������������������������������������������������������������������������������������� 121
Definitions���������������������������������������������������������������������������������������� 122
Mechanisms������������������������������������������������������������������������������������ 122
Diagnostic Criteria�������������������������������������������������������������������������� 125
Clinical Management of AF������������������������������������������������������������ 125
Contemporary Strategies for Stroke Prevention������������������������ 138
Contemporary Strategies for Rhythm Control���������������������������� 141
AF Management in Special Populations�������������������������������������� 148
Conclusion �������������������������������������������������������������������������������������� 149
References �������������������������������������������������������������������������������������� 149
Self-Assessment Questions���������������������������������������������������������� 152
Non-Statin Therapy for Dyslipidemia
By Nicholas W. Carris, Pharm.D., BCPS; and Kevin Cowart,
Pharm.D., MPH, BCACP, CDCES
Introduction�������������������������������������������������������������������������������������� 157
Populations Likely to Benefit from Non-Statin Therapy������������ 158
Non-Statin Agents for Dyslipidemia �������������������������������������������� 166
Emerging Non-Statin Therapies: Medications
in the Pipeline���������������������������������������������������������������������������������� 172
Implementing Non-Statin Therapy ���������������������������������������������� 173
Conclusion �������������������������������������������������������������������������������������� 174
References �������������������������������������������������������������������������������������� 174
Self-Assessment Questions���������������������������������������������������������� 177
Cardiology IV ������������������������������������������������������������������ 181
Cardiology IV Panel������������������������������������������������������������������������ 183
Interactive Case: Hyperlipidemia
Management for Special Populations
By Glenn Herrington, Pharm.D., AACC, BCCP, BCPS, CDCES;
and Daniel M. Riche, Pharm.D., FCCP, CLS, ASH-CHC
Interactive Case: Hyperlipidemia Management
for Special Populations������������������������������������������������������������������ 187
Hyperlink to activity������������������������������������������������������������������������ 188
Self-Assessment Questions���������������������������������������������������������� 191
iii Table of Contents
Interactive Case: Anticoagulation in Special
Populations
By Allison E. Burnett, Pharm.D., CACP; and Kelly M. Rudd,
Pharm.D., FCCP, BCPS, CACP
Interactive Case: Anticoagulation in Special Populations�������� 195
Hyperlink to activity������������������������������������������������������������������������ 196
Self-Assessment Questions����������������������������������������������������������202
Interactive Case: Cardiovascular Diseases
in Pregnancy
By Lindsey Federle, Pharm.D., BCCP, BCPS
Interactive Case: Cardiovascular Diseases in Pregnancy ��������207
Hyperlink to activity������������������������������������������������������������������������208
Self-Assessment Questions���������������������������������������������������������� 210

PSAP 2022 Book 1 • Cardiology iv Table of Contents

Cardiology I
Cardiology I Panel

Series Editors: Drug-Induced Cardiovascular Disease

Cynthia A. Sanoski, Pharm.D., FCCP, BCPS Author
Department Chair Katherine Aymond, Pharm.D., BCPS, BCCP
Associate Professor of Pharmacy Practice
Clinical Assistant Professor
Thomas Jefferson University
School of Clinical Sciences
Philadelphia, Pennsylvania
University of Louisiana Monroe
Daniel M. Witt, Pharm.D., FCCP, BCPS Clinical Pharmacy Specialist - ICU
Professor and Chair Department of Pharmacy
Department of Pharmacotherapy University Medical Center New Orleans
Assistant Dean of Clinical Affairs New Orleans, Louisiana
University of Utah College of Pharmacy
Salt Lake City, Utah Reviewers
Barbara S. Wiggins, Pharm.D., MBA, FCCP,
Faculty Panel Chair: FACC, FNLA, BCPS, BCCP, BCCCP, CLS
Craig J. Beavers, Pharm.D., FCCP, FACC, FAHA, BCCP, Clinical Pharmacy Specialist - Cardiology
BCPS-AQ Cardiology, CACP Department of Pharmacy
Director of Cardiovascular Services Medical University of South Carolina
Baptist Health Paducah Affiliate Professor
Cardiovascular Clinical Pharmacist Medical University of South Carolina School of Pharmacy
Department of Pharmacy Services Charleston, South Carolina
UK Healthcare Susan M. Smith, Pharm.D., BCPS
Assistant Adjunct Professor
Associate Professor of Pharmacy
Department of Pharmacy Practice and Science
School of Pharmacy
University of Kentucky College of Pharmacy
Wingate University
Paducah, Kentucky
Wingate, North Carolina

Heart Failure with Reduced Ejection

Fraction
Author
Ralph J. Riello III, Pharm.D., BCPS
Clinical Pharmacy Specialist, Clinical & Translational
Research
Department of Internal Medicine
Yale University School of Medicine
New Haven, Connecticut

Reviewers
Stormi E. Gale, Pharm.D., BCPS, BCCP
Assistant Professor
Department of Pharmacy Practice and Science
University of Maryland School of Pharmacy
Baltimore, Maryland
Nilam R. Naik, Pharm.D., BCPS, CACP
Clinical Pharmacy Specialist
VA Tennessee Valley Healthcare System
Nashville, Tennessee
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Consultancies: Anastasia Armbruster (ACC/AHA Joint Committee Clinical Practice Guidelines); Jessica Bente (ACCP); Allison
Burnett: Consultancies (Anticoagulation Forum; National Certification Board for Anticoagulation Providers; Global Strategies);
Jessie L. Dunne (Pulmonary Hypertension Association); Nancy M. Nix (Pharmacosmos); Daniel M. Riche (Novo Nordisk; Merck;
AstraZeneca); Ralph J. Riello III (AstraZeneca; Johnson & Johnson); Sara Vazquez (Anticoagulation Forum);

Stock Ownership:

Royalties: Allison Burnett (Wolters-Kluwer); Daniel M. Riche (McGraw-Hill); Honoraria (Merck); Sara Vazquez (UpToDate)

Grants: Anastasia Armbruster (ACCP); Jessica Bente (New Jersey Society of Health-System Pharmacists); Gregory Castelli
(American Board of Family Medicine); Kevin Cowart (University of South Florida Taneja College of Pharmacy); Ralph J. Riello
III (AstraZeneca)

Honoraria: Anastasia Armbruster (AstraZeneca); John Bucheit (Association of Diabetes Care & Education Specialists); Nancy M.
Nix (Coherus; Pfizer; AstraZeneca); Ralph J. Riello III (Alexion; AstraZeneca; Janssen)

Other:

Nothing to disclose: Katherine Aymond, Eugene N. Bush, Nicholas W. Carris, Stephanie Dwyer Kaluzna, Lindsey Federle, Beth-
any A. Ford, Stormi E. Gale, Jaclynne R. Gowen, Glenn Herrington, Christine Ji, Amy L. Lehnert, Nilam R. Naik, Brenda Pahl, Joel
J. Peterson, A. Joshua Roberts, Kelly M. Rudd, Ashley Schenk, Susan M. Smith, Elisabeth M. Wang, Toby C. Trujillo, Barbara Wig-
gins, Leslie Wooten, Eman El Sayed Younis

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Cardiology II – 0217-0000-22-003-H01-P, 6.0 contact hours; Cardiology III – 0217-0000-22-004-H01-P, 5.0 contact hours; and
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Heart Failure with Reduced Ejection
Fraction
By Ralph J. Riello III, Pharm.D., BCPS

Reviewed by: Stormi E. Gale, Pharm.D., BCPS, BCCP; and Nilam R. Naik, Pharm.D., BCPS, CACP

LEARNING OBJECTIVES

1. Distinguish phenotypic, structural, and functional classifications of heart failure to assess the stage of illness and delay
disease progression.
2. Justify the incorporation of recently approved pharmacologic therapies for heart failure with reduced ejection fraction
(HFrEF) into evidence-based therapies consistent with the American College of Cardiology’s 2021 Expert Consensus
Decision Pathway.
3. Develop a pharmacologic treatment plan for HFrEF that optimizes the use of traditional guideline-directed medical therapy.
4. Evaluate the role of inotropic agents and advanced therapeutic modalities available for patients with stage D heart failure.
5. Assess the potential benefit of pharmacologic therapies with recently expanded indications and promise for treatment
of heart failure with preserved ejection fraction.

ABBREVIATIONS IN THIS CHAPTER
ACC/AHA American College of Cardiology/
American Heart Association
ACEI Angiotensin-converting enzyme
inhibitor
ARB Angiotensin receptor blocker
CKD Chronic kidney disease
ECDP Expert Consensus Decision
Pathway
eGFR Estimated glomerular filtration rate
GDMT Guideline-directed medical therapy
HF Heart failure
HFimpEF Heart failure with improved
ejection fraction
HFmrEF Heart failure with mildly reduced
ejection fraction
HFpEF Heart failure with preserved ejec-
tion fraction
HFrEF Heart failure with reduced ejection
fraction
HFSA Heart Failure Society of America
HHF Hospitalization for heart failure
JHFS Japanese Heart Failure Society
LVEF Left ventricular ejection fraction
MRA Mineralocorticoid receptor
antagonist
NT-proBNP N-terminal fragment B-type
natriuretic peptide
INTRODUCTION
Epidemiology and Public Health Burden of Heart
Failure
Heart failure (HF) is a staggering public health burden in the United
States, affecting individual patients, caregivers, clinicians, and health
care systems across the country. Nearly 1 million new cases of HF are
diagnosed each year, amounting to a national prevalence of about 6
million Americans aged 20 years or older (Virani 2021). Although con-
temporary health policy efforts aim to improve care efficiency and
delay the progression of disease, the aging population is projected
to drive a 46% increase in HF prevalence by 2030, which will affect
more than 8 million adults, or 3.0% of the general population (Gerber
2015). Heart failure is evenly proportioned between HF with reduced
ejection fraction (HFrEF) and HF with preserved ejection fraction
(HFpEF), with 53% of patients having impaired systolic function and
the remaining 47% having preserved systolic function. However, gen-
der and racial disparities persist in HF consistent with cardiovascu-
lar disease as a whole: Black men are more commonly hospitalized
with HFrEF at 70% and white women at 59%; those two groups consti-
tute the highest proportion of HFpEF hospitalizations (Virani 2021).
Despite long-standing availability of lifesaving pharmacotherapies,
there remains a pervasive underutilization of evidence-based HFrEF
medications, whereas only limited disease-modifying treatment
options are available for patients with HFpEF (Greene 2018). Con-
sequently, the 5-year mortality rate of overall HF rivals most of the
major malignancies—at 52.6%—whereas 1-year mortality reaches a
strikingly high 29.6% (Gerber 2015).

PSAP 2022 Book 1 • Cardiology 7 Heart Failure with Reduced Ejection Fraction
 RAAS Renin-angiotensin-aldosterone system
SGLT2 Sodium-glucose cotransporter 2
T2DM Type 2 diabetes mellitus
Table of other common abbreviations.
BASELINE KNOWLEDGE STATEMENTS
Readers of this chapter are presumed to be familiar
with the following:
• General understanding of the pathophysiologic
derangements leading to heart failure
• Knowledge of the American College of Cardiology/
American Heart Association staging system and
the New York Heart Association functional classifi-
cation of heart failure
• Familiarity with traditional pharmacologic
therapies indicated for HFrEF, including angiotensin-
converting enzyme inhibitors, angiotensin receptor
blockers, β-blockers, and mineralocorticoid recep-
tor antagonists
Table of common laboratory reference values
ADDITIONAL READINGS
The following free resources have additional back-
ground information on this topic:
• Maddox TM, Januzzi JL, Allen LA, et al. 2021 Update
to the 2017 ACC Expert Consensus Decision
Pathway for Optimization of Heart Failure
Treatment: Answers to 10 Pivotal Issues About
Heart Failure With Reduced Ejection Fraction:
A Report of the American College of Cardiology
Solution Set Oversight Committee. J Am Coll
Cardiol 2021;77:772-810.
• Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/
AHA/HFSA focused update of the 2013 ACCF/AHA
guideline for the management of heart failure: a
report of the American College of Cardiology/
American Heart Association Task Force on Clinical
Practice Guidelines and the Heart Failure Society
of America. Circulation 2017;136:e137-61.
• McDonagh TA, Metra M, Adamo M, et al. 2021 ESC
guidelines for the diagnosis and treatment of acute
and chronic heart failure: developed by the Task
Force for the Diagnosis and Treatment of Acute
and Chronic Heart Failure of the European Society
of Cardiology (ESC) with the special contribution of
the Heart Failure Association (HFA) of the ESC.
Eur Heart J 2021;42:3599-726.
• Neu R, Leonard MA, Dehoorne ML, et al. Impact of
pharmacist involvement in heart failure transition
of care. Ann Pharmacother 2020;54:239-46.
PSAP 2022 Book 1 • Cardiology
In addition to alarming rates of morbidity and mortality,
HF consistently ranks as the costliest condition in the United
States, with expenditures totaling $30.7 billion—two-thirds
of which is attributable to direct medical costs (Heidenreich
2013). Because of the 30-day rehospitalization rate of 18.2%
among Medicare beneficiaries with HF, much of the cost bur-
den disproportionately affects acute-care facilities (Virani
2021). The tremendous strain HF exerts on health care insti-
tutions across the country has influenced payment reform to
incentivize improved coordination of HF care delivery at the
system level. Though significant health policy advancements
have been made during the past decade, little or no improve-
ment in hospital readmission rates or 30-day mortality has
yet been realized. It is therefore imperative that a standard-
ized approach to the risk stratification, diagnosis, and staging
of HF progression be adopted so as to more readily identify
patients appropriate for implementation of disease-modify-
ing pharmacotherapy and advanced therapeutic modalities.
Distinguishing Between the Different
Definitions and Classifications of Heart Failure
Previous definitions of HF were highly ambiguous and incon-
sistent across varying platforms, with indiscriminate focus
on hemodynamic parameters, pathophysiologic aspects,
and other clinical diagnostic features. Patients, clinicians,
and investigators facing an unclear picture of HF despite
the growing epidemiologic burden of disease underscore
the importance of an updated, standardized characteriza-
tion of the illness. A recently proposed universal definition
as set forth by the Heart Failure Society of America (HFSA),
the Heart Failure Association of the European Society of Car-
diology (HFA-ESC), and the Japanese Heart Failure Society
(JHFS) describes HF as clinical syndrome with a specific con-
stellation of symptoms and structural or functional cardiac
abnormalities known to be associated with HF. Those cardinal
symptoms include dyspnea, fluid retention or edema, fatigue,
and intolerance of daily-life activities. The physical presen-
tation of HF must be further corroborated by the presence
of elevated biomarkers or objective evidence of cardiogenic
congestion. More specifically, elevated B-type-natriuretic-
peptide levels of 35 or more or 100 or more pg/mL or N-terminal
fragment proBNP (NT-proBNP) of 125 or more or 300 or more
pg/mL for the ambulatory or hospital setting, respectively,
must be present alongside confirmatory signs of HF captured
by means of diagnostic modalities such as chest radiogra-
phy, echocardiography, or right heart catheterization (Boz-
kurt 2021). Notably, natriuretic peptide thresholds endorsed
by the HFSA/HFA-ESC/JHFS for HF diagnosis—although
consistent with clinical practice guidelines—may have lower
specificities in patients with advanced age, atrial fibrillation,
or chronic kidney disease (CKD).
Beyond an updated definition of disease, new categories of
HF according to left ventricle ejection fraction (LVEF) were also
recently developed (Table 1). Both HFrEF and HFpEF remain
8 Heart Failure with Reduced Ejection Fraction

Table 1. Universal Classification of HF According
to LVEF
HFSA/HFA-ESC/
JHFS classification LVEF
HFrEF ≤40%
HFmrEF 41% – 49%
HFpEF ≥50%
HFimpEF Baseline ≤40%, a ≥10-point
increase from baseline and a
second measurement of >40%
HFimpEF = heart failure with improved ejection fraction;
HFmrEF = heart failure with mildly reduced ejection frac-
tion; HFpEF = heart failure with preserved ejection fraction;
HFrEF = heart failure with reduced ejection fraction; HFSA/
HFA-ESC/JHFS = Heart Failure Society of America/Heart
Failure Association of the European Society of Cardiology/
Japanese Heart Failure Society; LVEF = left ventricular
ejection fraction.
Information from: Bozkurt B, Coats AJS, Tsutsui H, et al.
Universal definition and classification of heart failure: a
report of the Heart Failure Society of America, Heart
Failure Association of the European Society of Cardiology,
Japanese Heart Failure Society and Writing Committee of
the Universal Definition of Heart Failure. J Card Fail 2021;
27:P387-413.
defined as LVEF 40% or less and 50% or more, respectively.
However, the dichotomy of LVEF above or below the traditional
40% threshold has been expanded to include HF with mildly
reduced EF (HFmrEF), which distinguishes transitional patients
with LVEFs of 41% – 49% and which represents an underinves-
tigated subgroup that comprises up to 20% of patients with HF
(Bozkurt 2021). Previously referred to as having midrange HF,
patients with HFmrEF overlap the characteristics of both HFrEF
and HFpEF—but they may be more likely to benefit from neuro-
hormonal antagonism than would patients with preserved EF.
Although HFmrEF may indicate early signs of deteriorating sys-
tolic dysfunction, this classification can also reflect recovering
EF—typically in the setting of adherence to disease-modifying
therapy. Therefore, periodic echocardiography assessment is
recommended as a way of monitoring trends in LVEF overtime
and can meaningfully inform response to therapy. To more spe-
cifically define the phenomenon, a new category was created
to characterize patients with HF who also have LVEFs from
which they have indeed recovered. Heart failure with improved
EF (HFimpEF) represents such patients with a positive trajec-
tory phenotype. Patients with HFimpEF have baseline LVEFs of
40% or less, but they experience a 10-or-more-point increase
in systolic function, with a subsequent measurement of more
than 40% (Bozkurt 2021).
Proposed revisions to stages in the development and
progression of HF also extend further than only an updated
PSAP 2022 Book 1 • Cardiology
disease description and new LVEF categories. The original
American College of Cardiology/American Heart Associa-
tion (ACC/AHA) staging system that described HF was based
entirely on symptoms and the unidirectional absence or pres-
ence of structural heart disease. Although it may be widely
known among clinicians, the ACC/AHA platform does not
incorporate the evolving role of biomarkers in disease pro-
gression, nor does it exhibit strong association with prog-
nosis or quality of life. The recent HFSA/HFA-ESC/JHFS
classification of HF revises the previous ACC/AHA staging
system to address the prior approach’s gaps and limitations
and to enhance patient and public understanding and adop-
tion (Bozkurt 2021). The revised HFSA/HFA-ESC/JHFS stag-
ing platform recognizes HF as a continuum of illness with
corresponding clinical trajectories as patients move from
at risk of HF to pre-HF or de novo HF to more-advanced dis-
ease. The New York Heart Association’s (NYHA’s) functional
classification of HF offers a complementary understand-
ing of a patient’s ACC/AHA or HFSA/HFA-ESC/JHFS stage
by describing symptomatic severity as it affects limitations
on the activities of daily life (Table 2). Unlike the ACC/AHA
staging system, the NYHA scale is a bidirectional functional
assessment and exhibits strong correlation with mortality as
well as health-related quality of life. Pharmacists should be
become familiar with both HFSA/HFA-ESC/JHFS staging and
NYHA classifications so as to become able to identify appro-
priate pharmacotherapy commensurate with illness sever-
ity to delay disease progression, reduce mortality risk, and
improve quality of life.
HF UPDATES ACCORDING TO THE
2021 EXPERT CONSENSUS DECISION
PATHWAY
Biomarker Considerations
In addition to providing practical guidance to integrate
recently approved pharmacotherapeutic classes into the
care of patients with HFrEF, recent recommendations also
highlight the importance of the routine incorporation of bio-
markers into clinical practice as well as management strat-
egies for common comorbid conditions (Maddox 2021).
The natriuretic peptide system is a central counterregula-
tory process directly compensatory to HF pathophysiology.
In response to ventricular wall stretch caused by high intra-
cardiac filling pressures, atrial natriuretic peptide and BNP
get synthesized and then released from cardiac myocytes.
These neurohormones promote diuresis, natriuresis, and
vasodilation while also inhibiting both the sympathetic ner-
vous system and the renin-angiotensin-aldosterone system
(RAAS). B-type natriuretic peptide and its inactive proteolytic
fragment, NT-proBNP, are the two most well-characterized
biomarkers in HF. Specifically, clinical practice guidelines
confer a Class I recommendation to measure serum BNP or
NT-proBNP concentrations in order to establish or exclude a
9 Heart Failure with Reduced Ejection Fraction
 Table 2. Comparison of Structural and Functional Classifications of HF Development and Progression

HFSA/HFA-ESC/JHFS Universal Definition

ACC/AHA HF Staging System and Classification of HF NYHA Functional Classification
Stage Description Stage Description Class Description

A Patients at high risk At risk Patients at risk of HF but without No associated N/A
of developing HF but current or prior symptoms or functional
without structural heart signs of HF and without structural, class
disease (e.g., HTN, biomarker, or genetic markers of heart
DM, CAD, metabolic disease (e.g., HTN, CVD, DM, obesity,
syndrome) known exposure to cardiotoxins,
cardiomyopathy history)

B Patients with structural Pre-HF Patients without current or prior No associated N/A
heart disease but no symptoms or signs of heart failure functional
signs or symptoms of but having evidence of one of the class
HF (prior MI, low EF, following: structural heart disease
no symptoms) (LVH, valvular heart disease, chamber
enlargement, etc.), abnormal cardiac
function (reduced LV or RV systolic
function, increased filling pressures,
etc.), elevated natriuretic peptide
levels (or elevated cardiac troponin
levels after cardiotoxin exposure)

C Patients with structural HF Patients with current or prior I No limitations of

heart disease and symptoms and/or signs of HF caused physical activity
current or previous by structural and/or functional cardiac
II Slight limitation of
symptoms (low EF, abnormalities
physical activity
HF signs/symptoms)
III Marked limitation
of physical activity

D Patients with symptoms Advanced Severe symptoms and/or signs of HF IV Unable to carry
despite maximal medical HF at rest, recurrent hospitalizations on any physical
therapy (end-stage HF) despite GDMT, refractory to or activity without
intolerant of GDMT requiring discomfort
advanced therapies

CAD = coronary artery disease; CVD = cardiovascular disease; DM = diabetes mellitus; EF = ejection fraction; GDMT = guideline-
directed medical therapy; HF = heart failure; HTN = hypertension; LV = left ventricle; LVH = left ventricular hypertrophy; MI = myocar-
dial infarction; N/A = not applicable; NYHA = New York Heart Association; RV = right ventricle.
Information from: Bozkurt B, Coats AJS, Tsutsui H, et al. Universal definition and classification of heart failure: a report of the Heart
Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and
Writing Committee of the Universal Definition of Heart Failure. J Card Fail 2021;27:P387-413.

clinical diagnosis of HF, evaluate illness severity, and eluci-
date overall prognosis (Yancy 2017). Elevated natriuretic pep-
tide concentrations in an ambulatory patient with HFrEF, for
example, may be suggestive of an imminent risk of decom-
pensation requiring intravenous diuretics and further escala-
tion of care—particularly if levels are acutely increased from
baseline.
Not only do natriuretic peptide levels play a prominent role
in HF diagnosis and staging, but they also inform prognosis,
determine risk stratification, and have more recently been
applied to assess responsiveness to guideline-directed med-
ical therapy (GDMT). This is because BNP and NT-proBNP
concentrations typically get decreased by evidence-based
pharmacotherapy proportional to their magnitude of clinical
benefit. Conversely, patients with HFrEF whose natriuretic
peptide levels fail to improve despite adherence to GDMT
may be considered nonresponders, implying poor prognosis
and advanced illness. In the Guiding Evidence Based Therapy
Using Biomarker Intensified Treatment in HF trial, patients
with HFrEF who achieved goal NT-proBNP levels of less than

PSAP 2022 Book 1 • Cardiology 10 Heart Failure with Reduced Ejection Fraction
1,000 pg/mL were associated with significant reverse ventric-
ular remodeling, improved LVEF, and fewer adverse events
after 1 year —independent of management strategy (Daubert
2019). Moreover, the Prospective Study of Biomarkers,
Symptom Improvement and Ventricular Remodeling During
Entresto Therapy for Heart Failure Study demonstrated that
both the rapidity and robustness of NT-proBNP reductions
after angiotensin- receptor–neprilysin-inhibitor (ARNI) initi-
ation were associated with corresponding improvements in
reverse remodeling as well as the odds of HF hospitalization
or death (Januzzi 2020). Consequently, routine monitoring
of natriuretic peptide concentrations serves as a useful risk
assessment and treatment responsiveness tool. However,
specific natriuretic-peptide-level targets as treatment goals
are not currently endorsed by guidelines (Maddox 2021).
When using biomarkers to aid in clinical decision-making
around intensification of GDMT, careful consideration must
be given to assay interpretation for patients prescribed sacu-
bitril/valsartan. Mechanistically—because of its inhibitory
effect on neprilysin, a neutral endopeptidase responsible
for BNP degradation—the sacubitril component of ARNI may
cause concentrations of BNP to moderately increase and
thereby further delay a return to baseline levels. And because
NT-proBNP is not a substrate for neprilysin, however, it may
be preferable to BNP as a monitoring parameter in the con-
text of ARNI treatment (Maddox 2021). Pharmacists engaged
in biomarker monitoring in the acute- or ambulatory-care
context should inform HF-treatment providers of this unique
interaction and then guide interpretation as needed.
Comorbidity Management in HF
Although HF is the leading individual cause of hospitalization
in the United States, the presence of either cardiovascular
or noncardiac comorbidities significantly increases the risk
of further complications (Virani 2021). Multiple Class I and
III antiarrhythmics used for control of atrial and ventricular
arrhythmias, for example, are contraindicated in HF because
of their negative inotropic or proarrhythmic effects. In addi-
tion, widely prescribed oral hypoglycemics for type 2 diabe-
tes mellitus (T2DM)—such as thiazolidinediones often cause
edema, which can precipitate HF symptoms. Even OTC med-
ications such as NSAIDs or nasal decongestants like phenyl-
ephrine and pseudoephedrine can worsen HF (Pagell 2016).
Guideline-directed medical therapy for HFrEF now also neces-
sitates the use of four concomitant medication classes—all
of which lower blood pressure. Therefore, prudent prescrib-
ing for patients with HF and comorbid conditions must be
exercised so as to prevent polypharmacy and avoid medica-
tion-related adverse events.
Iron Deficiency
Iron deficiency—characterized by a ferritin of less than 100
ng/mL or 100–300 ng/mL with transferrin saturation of less
than 20%—is estimated to affect approximately half of all
PSAP 2022 Book 1 • Cardiology
patients with HFrEFs. The condition is independently asso-
ciated with poor prognosis, reduced quality of life, and dimin-
ished exercise capacity irrespective of concomitant anemia
(von Haehling 2019). Impaired oxygen delivery to tissue in
patients with anemia precipitates neurohormonal and hemo-
dynamic derangements that may overlap and exacerbate
symptoms of HF like fatigue and dyspnea. Although screen-
ing for reversible causes of anemia is essential in a routine
baseline evaluation for HF, the etiology is often complex and
multifactorial. Functional iron deficiency caused by inflam-
mation in the setting of chronic illness is not well understood,
but it is important to know that lower ferritin thresholds for
diagnosis apply to individuals without chronic conditions.
Decreased dietary iron intake and reduced ferrous absorp-
tion in the edematous gut wall are likely contributory, but
more-complex mechanisms related to iron sequestration
have also been identified. It is important to correct iron defi-
ciency in patients with HF, and therefore, pharmacists must
carefully consider the iron formulation, route of administra-
tion, and dosing regimen.
Enteral iron preparations are poorly absorbed, often cause
many unpleasant GI side effects, and require up to 6 months
to replenish iron stores. The IRON-5 and IRONOUT-HF stud-
ies investigated the impact of ferrous sulfate and iron poly-
saccharide, respectively, but failed to demonstrate any
functional impact on peak oxygen consumption in patients
with iron-deficient HFrEF (von Haehling 2019). Intravenous
iron avoids many of the drawbacks associated with oral sup-
plementation and appears to hold more promising clinical
benefit. Short-term exposure with parenteral ferric carboxy-
maltose in the FAIR-HF and CONFIRM-HF trials improved
NYHA class performance and 6-minute walk-test perfor-
mance. Ferric carboxymaltose was associated with a lower
HF hospitalization risk in CONFIRM-HF, but the study was
underpowered for assessment of clinical end points. Still,
the 2017 ACC/AHA/HFSA guideline preferentially endorsed
intravenous iron replacement in NYHA class II to IV HF with
concomitant deficiency (Yancy 2017). Subsequently, the Ran-
domised, Double-Blind Placebo Controlled Trial Comparing
the Effect of Intravenous Ferric Carboxymaltose on Hospital-
isations and Mortality in Iron Deficient Patients Admitted for
Acute Heart Failure (AFFIRM-AHF) study demonstrated a 26%
relative risk reduction in total HF hospitalizations with ferric
carboxymaltose compared with placebo (217 [48.9%] vs. 294
[53.5%]; HR 0.74; 95% CI, 0.58–0.94, p=0.013) when initiated
before discharge in clinically stabilized patients with iron-
deficient acute HF with LVEFs of less than 50% after 1 year of
follow-up (Ponikowski 2020). It is notable that ferric carboxy-
maltose was dosed at 500–2000 mg based on body weight
and hemoglobin; patients who were persistently deficient
received additional doses at weeks 6, 12, and 24 if needed.
The ongoing FAIR-HF2, HEART-FID, and IRONMAN trials are
expected to further inform the role of parenteral iron repletion
11 Heart Failure with Reduced Ejection Fraction
on clinical end points for patients with iron-deficient HF (clin-
icaltrials.gov).
Chronic Kidney Disease
The heart and kidney maintain saltwater homeostasis and
regulate blood pressure by way of interdependent neurohor-
monal mechanisms that are critical to the function of either
organ alone. Cardiorenal disease is, unsurprisingly, a preva-
lent manifestation of comorbid illness among patients with
HF, because approximately half also suffer from CKD and vice
versa (Virani 2021). Not only does CKD worsen an already poor
prognosis of HF, but also mortality increases proportionally
to the degree of coexistent renal insufficiency. It is import-
ant to note that randomized control trials establishing lifesav-
ing pharmacotherapy for HFrEF have consistently excluded
patients with severe renal dysfunction. Furthermore, this
complex but common cohort is less likely to be prescribed
GDMT compared with patients without kidney disease (Hein
2019). Many of the guideline-recommended medications for
HF may affect kidney function, often necessitating renal
dose adjustments and close monitoring. For example, RAAS
inhibitors can potentiate the risk of hyperkalemia or precip-
itate acute kidney injury. Consequently, initial ARNI dosing
should be reduced to 24/25 mg twice daily if estimated glo-
merular filtration rate (eGFR) is less than 30 mL/minute/1.73
m2, whereas mineralocorticoid receptor antagonists (MRAs)
are not recommended for use unless eGFR is more than
30 mL/minute/1.73 m2 and serum potassium is less than
5 mEq/L (Yancy 2017).
Hyperkalemia is a well-established adverse medication
reaction to RAAS inhibition that worsens with kidney disease
and acts as a common barrier to the initiation or uptitration
of GDMT (Maddox 2021). Beyond diet modifications to reduce
potassium intake, novel potassium-binding resins such as
patiromer sorbitex calcium and sodium zirconium cyclosili-
cate are now indicated for management of acute and chronic
hyperkalemia. Adjunctive use of patiromer is associated with
improved MRA utilization in patients with chronic HF and histo-
ries of hyperkalemia, but the impact on other RAAS inhibitors
is not yet known (Pitt 2011). The ongoing DIAMOND, LIFT, and
OPERA-HF trials should serve to (1) further define the roles of
newer-generation potassium-binding resins to more broadly
prevent hyperkalemia while enabling GDMT optimization and
(2) clarify any potential benefit in HF outcomes (clinicaltrials.
gov). Consideration of those agents in treating comorbid HF
and CKD should include attention to binding interactions
with other concurrent medications, GI discomforts, magne-
sium derangements with patiromer, and edema caused by
increased sodium load with sodium zirconium cyclosilicate
(Hein 2019). Until the role of novel potassium binders in HF
is better understood, individualized selection of specific
GDMT agents that may confer lower comparable levels of
hyperkalemia or acute renal insufficiency risk such as ARNI
or a sodium-glucose cotransporter 2 (SGLT2) inhibitor may
PSAP 2022 Book 1 • Cardiology
be warranted (Riello 2021). Finerenone, a novel nonsteroidal
MRA, has also demonstrated cardiorenal benefits, with a low
incidence of hyperkalemia-related treatment discontinuation
(1.2%–2.3%) in diabetic kidney disease studies FIDELIO-DKD
and FIGARO-DKD (Pitt 2021; Bakris 2020). Recently, finere-
none received regulatory approval to reduce the risk of sus-
tained eGFR decline, end-stage renal disease, cardiovascular
death, nonfatal myocardial infarction, and HF hospitalization
in patients with comorbid CKD. The potential benefit of finere-
none is being investigated in HFpEF as well by way of active
enrollment of patients in the ongoing FINEARTS-HF trial (clin-
icaltrials.gov).
It is important that SGLT2 inhibitors be considered con-
traindicated in severe renal impairment per the prescribing
label—but for a lack of A1C-lowering efficacy in diabetes man-
agement not explicitly because of safety concerns or rela-
tionship to nondiabetic indications. The SGLT2 inhibitors
have been safely studied in patients with eGFRs as low as 20
mL/minute/1.73 m2 for HF or CKD and have received corre-
sponding label updates. For example, dapagliflozin recently
received expanded regulatory approval to reduce the risk of
kidney function decline, kidney failure, cardiovascular death,
and hospitalization for HF on the basis of the DAPA-CKD
trial (Heerspink 2020). In this study of patients with eGFRs
of 25–75 mL/minute/1.73 m2 and urinary albumin-to-creati-
nine ratios of 200–5000, dapagliflozin improved cardiorenal
outcomes, including all-cause mortality independent of dia-
betes status after a median 2.4 years of follow-up compared
with placebo. The ongoing EMPA-Kidney trial is anticipated
to corroborate those beneficial effects with empagliflozin in
patients with broader ranges of renal impairment inclusive of
eGFR 20–90 mL/minute/1.73 m2 (clinicaltrials.gov).
Diabetes
Among the most commonly encountered comorbidities for
patients with HF, T2DM requires a strategic multidisciplinary
approach to optimal management of both conditions simulta-
neously. Uncontrolled hyperglycemia typically leads to isch-
emic HF through atherosclerotic or hypertensive mechanisms
but can also precipitate a diabetic cardiomyopathy that often
manifests as diastolic dysfunction and, eventually, HFpEF
(Jia 2018). Consequently, the presence of T2DM increases the
risk of developing incident HF more than twofold among the
general population; also, poor glycemic control significantly
increases HF hospitalization risk and decreases overall sur-
vival among patients with established disease (Dunlay 2019).
Despite the substantial risk of cardiovascular compli-
cations in patients with T2DM, many commonly prescribed
glucose-lowering agents have failed to consistently demon-
strate improvements in macrovascular outcomes. And several
antihyperglycemics have even demonstrated safety concerns
related to HF. Thiazolidinediones as a class are known to carry
an FDA boxed warning with regard to causing or exacerbat-
ing HF, and dipeptidyl peptidase 4 (DPP4) inhibitors alogliptin
12 Heart Failure with Reduced Ejection Fraction
and saxagliptin received regulatory precautions for increased
HF hospitalization risk. Other conventional oral hypoglyce-
mics like sulfonylureas and glinides have (1) only limited pro-
spective evidence to support their safety in the treatment of
HF and (2) mixed findings in observational studies (Dunlay
2019). In consideration of the more-consistent cardiorenal
benefits demonstrated by SGLT2 inhibitors and glucagonlike
peptide 1 (GLP-1) receptor agonists across multiple robust
cardiovascular outcome trials, the most-recent American Dia-
betes Association guidelines recommend preferential use of
these agents for patients who have T2DM with established
atherosclerotic cardiovascular disease (ASCVD) or multiple
cardiac risk factors (ADA 2020). Additional preference should
be given to SGLT2 inhibitors specifically proven to reduce the
risk of worsening HF and cardiovascular death in patients
with diabetic HF—particularly those with HFrEF (Das 2020).
Several GLP-1 receptor agonists have demonstrated
reductions in major adverse cardiovascular events among
patients with T2DM and established ASCVD or multiple
high-risk features. In the 9340-patient LEADER trial, liraglu-
tide significantly reduced the primary composite outcome
of cardiovascular death, nonfatal myocardial infarction, and
stroke compared with placebo after 3.8 years of median
follow-up (Marso 2016a). Both of the smaller, SUSTAIN-6 and
PIONEER 6 trials comparing injectable and oral semaglutide
with placebo, respectively, were underpowered to determine
superiority; however, each formulation was associated with
similar reductions in the primary three-point composite end
point (Husain 2019; Marso 2016b). Neither exenatide nor lix-
isenatide in the EXSCEL and ELIXA trials, respectively, demon-
strated statistically significant reductions in cardiovascular
outcomes compared with placebo. Weekly injections of dula-
glutide compared with placebo in 9901 patients with T2DM
predominantly at high cardiovascular risk improved the risk
of cardiovascular death, nonfatal myocardial infarction, and
stroke in the REWIND trial (Gerstein 2019). Notably, REWIND
was the only GLP-1 receptor agonist cardiovascular safety
study thus far to prespecify urgent HF visits as a secondary
outcome—though no differences versus placebo were found.
The benefit of most GLP-1 agonists appears to be driven by a
reduction in cardiovascular death; a discernible impact on HF
events has yet to be observed for GLP-1 agonists in patients
who have T2DM and various cardiovascular-risk profiles. The
limited evidence for GLP-1 receptor agonists in patients with
HF but without diabetes has been largely neutral, with one
notable exception. The FIGHT trial—which evaluated liraglu-
tide compared with placebo in 300 recently decompensated
patients with HF irrespective of T2DM diagnosis—did not
determine any benefit for a variety HF-related outcomes and
functional status; however, a nonsignificant trend toward a
numerically increased risk of death or HF hospitalization was
identified (HR 1.30; 95% CI, 0.92–1.83, p=0.14) throughout the
6-month study duration (Margulies 2016). And that risk was
higher (HR 1.54; 95% CI, 0.97–2.46, p=0.07) among patients
PSAP 2022 Book 1 • Cardiology
with HFrEF and T2DM. And because GLP-1 agonists exhibit
positive chronotropic effects that consistently increase
heart rate by 5–10 beats/minute, precaution should be taken
when used in patients with diabetes and HFrEF—particu-
larly patients who may not be optimally prescribed β-blocker
therapy.
The first antihyperglycemic-medication class to demon-
strate cardiorenal benefits among patients with T2DM at
high cardiovascular risk consisted of the SGLT2 inhibitors.
The EMPA-REG OUTCOME trial randomized 7020 patients
with T2DM and established ASCVD to empagliflozin or pla-
cebo, evaluating three-point major adverse cardiovascular
events as the primary composite end point. After a median
follow-up period of 3.1 years, empagliflozin lowered the risk
of the primary outcome by a striking 38%; HF hospitalizations
by 35%; and all-cause mortality by 32% (Zinman 2015). The
subsequent, CANVAS clinical trial program integrated results
of canagliflozin across two placebo-controlled studies inclu-
sive of 10,142 patients, with about 65% having prior ASCVD
and with the remainder at only high cardiovascular risk (Neal
2017). The larger proportion of patients under primary pre-
vention likely contributed to the achievement of a significant
reduction in the same three-point composite end point of
empagliflozin but not the individual component of cardiovas-
cular death alone. Further, the CANVAS trial was complicated
by a signal for increased risk of lower-limb amputations—par-
ticularly of the toe or metatarsal in patients with advanced dia-
betes who were not otherwise observed in other canagliflozin
studies to date (Perkovic 2019). The largest SGLT2-inhibitor
cardiovascular safety study—DECLARE-TIMI 58—enrolled
the smallest proportion of patients with T2DM, established
ASCVD at 40.6%, and, consequently, did not demonstrate
improvement in the same three-point composite outcome
(Wiviott 2018). However, given the consistent reduction in
HHF demonstrated by prior SGLT2-inhibitor trials, the study
oversight committee amended the protocol to incorporate an
additional primary end point of cardiovascular death or hos-
pitalization for HF. Compared with placebo, dapagliflozin sig-
nificantly reduced the right of this composite end point (4.9%
vs. 5.8%; HR 0.83; 95% CI, 0.73–0.95; p=0.005)—predomi-
nantly because of a reduction in HF hospitalizations. Despite
an enrollment of 8246 patients with diabetes and established
ASCVD, ertugliflozin did not improve the risk of major adverse
cardiovascular events compared with placebo in the VER-
TIS-CV trial (Cannon 2020). In alignment with prior SGLT2-in-
hibitor trials, only HF hospitalizations were significantly
reduced with ertugliflozin. A dual SGLT1 and SGLT2 receptor
antagonist—sotagliflozin—is currently being considered for
regulatory approval. In SCORED—a recent, 10,584-patient car-
diovascular outcomes study of patients with comorbid T2DM
and CKD and with or without albuminuria—sotagliflozin sig-
nificantly reduced its amended coprimary composite end
point of cardiovascular death, HF hospitalizations, and urgent
HF visits (HR 0.74; 95% CI, 0.63–0.88; p<0.001) (Bhatt 2021a).
13 Heart Failure with Reduced Ejection Fraction
In the subsequent, SOLOWIST-WHF trial, which enrolled 1222
patients with T2DM and recent hospitalizations for worsen-
ing HF, sotagliflozin also produced the same primary com-
posite outcome (51.0% vs. 76.3%; HR 0.67; 95% CI, 0.52–0.85;
p<0.001) compared with placebo (Bhatt 2021). Early termina-
tions of the trials—caused by loss of sponsor funding and the
advent of the COVID-19 pandemic—may have encumbered the
ability to detect differences in individual components of the
primary outcome. However, a pooled analysis of both studies
suggests the benefits of sotagliflozin may apply to patients
with diabetes and HF irrespective of LVEF, including HFmrEF
and HFpEF (Bhatt 2021b).
New Evidence-Based Medications for HFrEF
SGLT2 Inhibitors
The use of SGLT2 inhibitors for cardiovascular-risk reduction
in patients with T2DM has been part of consensus practice
for the past few years, but their emerging role as the fourth
pillar of HFrEF GDMT has been demonstrated only recently
(Maddox 2021). By promoting glucosuria through a block-
ade of sodium and glucose reabsorption in the proximal
tubule of the nephron, SGLT2 inhibitors lower glucose. Their
mechanism for cardiorenal protection is not well understood
but appears to be multifactorial and related principally to
(1) hemoconcentration, (2) osmotic diuresis and natriuresis,
(3) arterial pressure and stiffness reduction, and (4) efficient
myocardial ketone metabolism—all of them independent of
hyperglycemia (Zelniker 2020).
The first landmark randomized, controlled trial to establish
the benefit of SGLT2 inhibitors beyond T2DM investigated the
role of dapagliflozin in patients with HFrEF. In the DAPA-HF
study, dapagliflozin reduced the risk of the primary composite
end point of worsening HF or cardiovascular death compared
with placebo in 4744 patients with HFrEF and with or without
diabetes (16.3% vs. 21.2%; HR 0.74; 95% CI, 0.65–0.85) after
18.2 months of median follow-up (McMurray 2019). Unlike the
previous, DECLARE-TIMI 58 study, dapagliflozin also signifi-
cantly reduced the risk of key secondary end points, includ-
ing cardiovascular death (9.5% vs. 11.5%; HR 0.82; 95% CI,
0.69–0.98) and all-cause mortality (11.6% vs. 13.9%; HR 0.83;
95% CI, 0.71–0.97). Based on the landmark findings from the
DAPA-HF study, dapagliflozin received expanded regulatory
approval to reduce the risk of death or HF hospitalization
among patients with HFrEF irrespective of the presence or
absence of T2DM. The EMPEROR-Reduced trial corroborated
the benefits of SGLT2 inhibitors in patients with HFrEF and
diabetes and patients with HFrEF but without diabetes alike.
In the study, empagliflozin significantly reduced the primary
composite outcome of HF hospitalization or cardiovascular
death (19.4% vs. 24.7%; HR 0.75; 95% CI, 0.65–0.86) among
3730 patients with HFrEF compared with placebo after a
median 16 months (Packer 2020). This benefit appeared to
be largely influenced by the effect on HF hospitalizations, as
PSAP 2022 Book 1 • Cardiology
neither cardiovascular death (10% vs. 10.8%; HR, 0.92; 95% CI,
0.75-1.12) nor overall mortality (10.1% vs. 10.7%; HR, 0.92; 95%
CI, 0.62-1.19) achieved statistically significant differences.
An ensuing meta-analysis of both pivotal trials, however, did
indeed suggest the benefits of dapagliflozin and empagli-
flozin consistently improved a host of cardiorenal outcomes
in HFrEF patients independent of T2DM (Zannad 2020).
The immense benefit of SGLT2 inhibitors in patients with
or without diabetes is anticipated to rapidly increase overall
prescribing rates, warranting practical considerations for rou-
tine incorporation into the HF armamentarium. It is import-
ant to note that the doses of dapagliflozin and empagliflozin
studied for HFrEF were the same, 10-mg once-daily regimen.
Dosing of empagliflozin should be increased to 25 mg only if
additional glucose lowering is desired—for example, in uncon-
trolled comorbid T2DM. Hemoglobin A1C reduction is unlikely
to occur in advanced kidney disease, but cardiorenal bene-
fits appear to be maintained if eGFR is 25 or more or 20 or
more mL/minute/1.73 m2 with dapagliflozin and empagli-
flozin, respectively. Nondiabetic patients—and even dia-
betic patients not concomitantly prescribed a sulfonylurea
or insulin therapy—rarely experience hypoglycemic events
from an SGLT2 inhibitor alone. To avoid ketosis, however,
(1) SGLT2 inhibitors should be held 3 days before major sur-
gery in patients with T2DM and (2) confirmed modifiable risk
factors for ketoacidosis should be resolved before reinitiat-
ing. In addition, fluctuating clinical features such as renal
function, volume status, and nutritional intake should be eval-
uated before routine inpatient continuation of chronic therapy
or new initiation in hospitalized patients across therapeutic
indications. Dose reductions of concurrent loop diuretic ther-
apy may be warranted over time for patients prescribed an
SGLT2 inhibitor—especially if blood pressure is tenuous or
indicative of intravascular volume contraction. Although gen-
ital mycotic infections are the most common adverse reac-
tions to SGLT2 inhibitors—occurring predominantly in women
and uncircumcised males—proper personal hygiene may mit-
igate risk. If treatment is required, topical or systemic anti-
fungal therapy typically alleviates discomfort. Urinary tract
infections occur less often but may be more likely to occur in
patients with histories of pyelonephritis, kidney stones, uret-
eral stenting, or indwelling urinary catheters.
sGC Modulators
The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic
guanosine monophosphate (cGMP) pathway regulates vaso-
dilation and myocardial demand via smooth muscle relax-
ation. In HF, inadequate cardiac output and decreased NO
bioavailability result in compensatory vasoconstriction and
reduced cGMP generation. Organic nitrate supplementation
activates NO-sGC-cGMP but is limited by tachyphylaxis and
may contribute to oxidative stress. Novel oral sGC activators
stimulate cGMP synthesis, enhance sGC sensitivity to NO,
and promote vasodilation independent of NO or heme.
14 Heart Failure with Reduced Ejection Fraction
 Vericiguat is the first sGC activator approved to reduce the
risk of cardiovascular death, hospitalization for heart failure
(HHF), and outpatient intravenous diuretics in symptomatic
patients with chronic HF and LVEFs of less than 45%. Despite
recent regulatory approval, vericiguat initially disappointed
in the phase II, dose-finding Soluble Guanylate Cyclase
Stimulation in Heart Failure with Reduced Ejection Fraction
(SOCRATES-REDUCED) trial (Gheorghiade 2015). The SOCRA-
TES-REDUCED trial randomized 456 clinically stable patients
with chronic heart failure recently hospitalized for HF and
with LVEFs of less than 45% to either placebo or one of four
oral vericiguat doses ranging from 1.25 to 10 mg daily for 12
weeks. Although vericiguat was well tolerated, the primary
end point of change in NT-proBNP was no different from that
of placebo. The phase III Vericiguat Global Study in Subjects
with Heart Failure with Reduced Ejection Fraction (VICTORIA)
trial, however, achieved its primary composite end point of
cardiovascular death or first HHF (Armstrong 2020). In the
VICTORIA study, 5050 patients with NYHA II–IV HF and LVEFs
of less than 45% on optimal medical therapy were randomized
to receive vericiguat to a target 10 mg or placebo. Driven pri-
marily by a reduction in HHF, vericiguat modestly reduced the
risk of the primary outcome (37.9% vs. 40.9%; HR 0.90; 95% CI,
0.83–0.98; p=0.02) after a median 10.8 months of follow-up.
Neither symptomatic hypotension nor syncope occurs more
often with vericiguat.
In light of guideline preference for ARNI and the addition
of SGLT2 inhibitors to GDMT, vericiguat’s place in therapy
should be reserved for patients with advanced HFrEF and
Table 3. Evidence-Based Dosing Guidance for HFrEF Medications
Starting Dose
ACEI (Class I; LOE A)
Captopril 6.25 mg TID
Enalapril 2.5 mg BID
Lisinopril 2.5–5 mg
Ramipril 1.25–2.5 mg
Trandolapril 0.5–1 mg
ARB (Class I; LOE A)
Candesartan 4–8 mg
Losartan 50 mg
Valsartan 40 mg BID
ARNI (Class I; LOE B)
Sacubitril/Valsartan 24/26–49/51 mg
PSAP 2022 Book 1 • Cardiology
recent decompensation despite optimal therapy for whom an
additional branded medication does not cause undue finan-
cial burden. Further benefit may also be derived in patients
with low circulating biomarker levels, including cGMP, NO, and
BNP, although this precision-medicine approach to vericiguat
therapy requires further elucidation to support routine con-
sideration. Because of the exclusion of patients prescribed
long-acting nitrates and NO donors from the VICTORIA trial,
however, it is unclear how the combination of vasodilatory
therapies would be tolerated or would affect clinical outcomes
(Armstrong 2020). Therefore, the traditional, vasodilatory com-
bination of isosorbide dinitrate and hydralazine still remains
strongly preferred to vericiguat for African American patients
with HFrEF as a compulsory add-on to GDMT (Maddox 2021).
OPTIMIZING GDMT
For decades, the original, evidence-based pillars of GDMT
for HFrEF have included RAAS inhibitors and sympathetic
nervous system antagonists from three primary pharmaco-
logic categories: angiotensin-converting-enzyme inhibitors
(ACEIs) or angiotensin receptor blockers (ARBs), β-block-
ers, and MRA. Despite long-standing availability, widespread
affordability, and robust evidence to support the strongest
possible guideline recommendations for use in all patients
with stage C HFrEF, less than 25% of eligible patients are pre-
scribed all three medication classes in contemporary practice
(Greene 2018). Furthermore, a dismal 1% of those patients are
simultaneously titrated to target doses proven to extend sur-
vival in pivotal clinical trials (Table 3).
Mean Total Daily Dose
Target Dose Achieved in Clinical Trials
50 mg TID 122.7 mg
10–20 mg BID 16.6 mg
20–40 mg 32.5–35 mg
10 mg 7.7 mg
4 mg 2.5 mg
32 mg 24 mg
150 mg 129 mg
160 mg BID 254 mg
97/103 mg BID 375 mga
(continued)
15 Heart Failure with Reduced Ejection Fraction
 Table 3. Evidence-Based Dosing Guidance for HFrEF Medications  (continued)

Mean Total Daily Dose

Starting Dose Target Dose Achieved in Clinical Trials

β-Blockers (Class I; LOE A)

Bisoprolol 1.25 mg 10 mg 8.6 mg

Carvedilol 3.125 mg BID 25 mg BID for weight <85 kg 37 mg

50 mg BID for weight ≥85 kg

Carvedilol CR 10 mg 80 mg Not studied

Metoprolol succinate 12.5–25 mg 200 mg 159 mg

MRA (Class I; LOE A)

Eplerenone 25 mg QD 50 mg 42.6 mg

Spironolactone 12.5–25 mg 25-50 mg 26 mg

sGC Modulatorsb

Vericiguat 2.5 mg QD 10 mg 8.9 mg

SGLT2 Inhibitor b

Dapagliflozin 10 mg 10 mg Not reported

Empagliflozin 10 mg 10 mg Not reported

Vasodilators (Class I; LOE A)

Hydralazine 25 mg TID 75 mg TID Not studied

Isosorbide dinitrate 20 mg TID 40 mg TID Not studied

Fixed-dose combination hydralazine/ 20/37.5 mg TID 40/75 mg TID 90 mg/175 mg

isosorbide dinitratec

If Channel Inhibitor (Class IIA; LOE B)

Ivabradine 2.5–5 mg BID Titrate to HR 50–60 bpm 13 mg

Maximum dose 7.5 mg BID

Total daily dose of both individual sacubitril/valsartan components described in the PARADIGM-HF trial.
a

b
Both sGC modulators and SGLT2I became recently approved for HFrEF, but only SGLT2Is are endorsed in updated Expert
Consensus Decision Pathways as GDMTs.
c
The ACC/AHA/HFSA guideline considers either the fixed-dose combination or the separate combination of isosorbide dinitrate and
hydralazine appropriate for GDMT for HFrEF in self-described Black patients, but it is important to note that these
recommendations do not include isosorbide mononitrate.
ACC = American College of Cardiology; ACEI = angiotensin-converting-enzyme inhibitor; AHA = American Heart Association;
ARB = angiotensin receptor blocker; ARNI = angiotensin receptor–neprilysin inhibitor; BID = twice daily; bpm = beats per minute;
GDMT = guideline-directed medical therapy; HFrEF = heart failure with reduced ejection fraction; HFSA = Heart Failure Society of
America; HR = heart rate; LOE = level of evidence; MRA = mineralocorticoid receptor antagonist; QD = once daily; sGC = soluble
guanylate cyclase; SGLT2i = sodium-glucose cotransporter-2 inhibitor.
Information from: Maddox TM, Januzzi JL, Allen LA, et al. 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for
Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction:
A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2021;77:772-810.

Because ARNI preference and SGLT2 inhibitor incorpo-
ration into GDMT became endorsed only more recently by
guidelines and expert consensus statements, adoption of
these newer therapies represents an immediately impact-
ful quality improvement opportunity. For example, just 2%
of patients with HFrEF and comorbid T2DM are currently
treated with SGLT2 inhibitors—with prescribing rates for
patients without diabetes presumably even lower (Vadugana-
than 2020). Plus, positioning SGLT2 inhibitors as the fourth
pillar of GDMT for HFrEF management may reduce cumula-
tive mortality risk by 73%, thereby preventing one death for
every 3.9 patients treated over 2 years (Bassi 2020). All four
disease-modifying therapeutic classes have early, incremen-
tal, and additive benefits when used as quadruple therapy,

PSAP 2022 Book 1 • Cardiology 16 Heart Failure with Reduced Ejection Fraction
yet they remain woefully underutilized at present for a multi-
tude of reasons.
Barriers to optimal medication titration are indeed multi­
faceted but most often include patient-specific factors
such as abnormal kidney function, hyperkalemia, hypoten-
sion, pill burden, or out-of-pocket expenses—particularly in
the incorporation of more-recently-approved therapies such
as ARNI and SGLT2 inhibitors (Maddox 2021). Provider- and
health-system-related impediments to the implementation of
established GDMT may also play a role. Clinical inertia, siloed
care, poor interprovider communication, and lack of familiar-
ity with highly complex HF regimens are among the chief con-
tributing nonpatient factors. Therefore, routine integration of
pharmacists into collaborative, multidisciplinary-care path-
ways dedicated to HF management are critical to optimizing
GDMT and promoting medication adherence.
Sequence of Initiation and Titration
The fundamental principle of HF care is to prioritize the
use of GDMT to derive the greatest potential benefit. For
all patients with HFrEF, this now includes quadruple ther-
apy with ARNI, evidence-based β-blockers, MRA, and SGLT2
inhibitors (Maddox 2021). In addition, the combination of
hydralazine and isosorbide dinitrate is also first-line therapy
for all self-identified African Americans, and ivabradine may
be considered second-line for select HFrEF patients in sinus
rhythm (Figure 1).
Conventional sequencing of GDMT was cumbersome and
protracted, typically requiring at least 6 months to reach tar-
get doses while also necessitating a trial period of ACEI or ARB
before transitioning to ARNI (Yancy 2017). Although more-
recent guideline recommendations endorse preference for
ARNI initiation in de novo HFrEF, transitioning stable patients
on ACEIs or ARBs is still a commonly encountered clini-
cal scenario. Patients on equivalent ACEIs that total a daily
dose of more than 10 mg of enalapril can begin sacubitril/
valsartan 49/51 mg twice daily after a 36-hour washout
period. The same dose of sacubitril/valsartan is also recom-
mended for patients on an equivalent total daily dose of more
than 160 mg of valsartan. Patients on fewer ACEI/ARB equiva-
lents and who have eGFRs of less than 30 mL/minute/1.73 m2
are recommended for initiation with sacubitril/valsartan
24/26 mg twice daily.
Within 1 or 2 weeks of initiation, GDMT begins to reduce
the risk of cardiovascular death, HHF, and urgent HF visits,
and based on that, treatment should begin immediately in
stable patients (Packer 2021). Deferring optimal medical ther-
apy reduces the likelihood of ever initiating GDMT and there-
fore may also result in preventable harm. Opportunities to
initiate and uptitrate GDMT in the hospital setting or during
the vulnerable, postdischarge period should not be missed.
Furthermore, because target doses of each medication are
associated with the best possible outcomes, titration to
these dosing thresholds should be attempted until reached or
PSAP 2022 Book 1 • Cardiology
maximally tolerated. Subtarget dosing still confers a magni-
tude of benefit—precluding the need to achieve target doses
before initiating other disease-modifying therapy. Previous
intolerance should not obviate future titration attempts in the
absence of contraindications. Furthermore, tolerability may
be improved by initiating GDMT at lower starting doses or by
staggering individual agents—particularly ARNI and β-block-
ers (Greene 2021). Simultaneous initiation of MRA and SGLT2
inhibitors, however, requires no or minimal titration and rarely
precipitates adverse effects.
Recent guidelines endorse ARNI initiation to be concurrent
with β-blocker therapy, followed by adding MRA and SGLT2
inhibitors 2–4 weeks later (Maddox 2021). With continual
potassium, creatinine, and vital sign monitoring, doses of
each medication can be increased on a biweekly basis until
goal or maximal tolerated dose is achieved. More-intensive
approaches to GDMT optimization support synchronized ini-
tiation of all four foundational therapies at once, completing
titration to target doses as soon as 3 weeks (Greene 2021).
Alternative sequencing strategies propose simultaneous
initiation of β-blockers and SGLT2 inhibitors first, followed
by ARNI and MRA within 4 weeks thereafter (McMurray
2021). Uniquely, uptitration to target doses with this model
occurs only after quadruple therapy has been established.
A thorough understanding of medication-specific factors—
including mechanism of action, common adverse effects,
and routine monitoring parameters—is key to successful
titration of GDMT to target dosing (Table 4). Irrespective of
the particular pathway chosen, an individualized approach
that prioritizes both the timely initiation and the optimization
of GDMT must also coincide with close clinical assessment
and consideration of patient-specific barriers to medication
titration.
INOTROPIC THERAPY
The term inotropic therapy refers broadly to pharmacologic
treatments that improve cardiac contractility. Although clin-
ically useful for acute treatment of cardiogenic shock with
low cardiac output, inotropes are associated with adverse
outcomes when used for chronic HF. Despite a multitude
of attempts, short-term improvements in hemodynamics or
surrogate measures of cardiac performance with inotropic
agents have not translated into longer-term morbidity bene-
fits and have even increased mortality (Ahmad 2019). How-
ever, initial investigation of inotropic therapy was conducted
before incorporation of β-blockers and cardiac resynchro-
nization therapy or implantable cardioverter-defibrillator
devices (CRT/ICD) into routine practice. Given the growing
population of patients with end-stage HF, the high cost of
ventricular-assist devices, and the organ shortage facing car-
diac transplantation, interest in the development of novel and
safe inotropes possessing unique mechanisms of action has
been reinvigorated after a substantial hiatus.
17 Heart Failure with Reduced Ejection Fraction
 At risk of HF (Stage A) Pre-HF (Stage B) Disease Prevention

• Risk Factor Management • Manage Structural Cardiac Disease

• Diabetes • MI → BB, DAPT, Statin
• Hypertension • MI with EF ≤35% → ACEI/ARB, BB, DAPT, MRA, Statin
• Hyperlipidemia • NICM → ACEI/ARB, BB

HF (Stage C) Initiate/Optimize GDMT

Comorbidity
• Elevated BNP or recent HHF → ARNI, MRA
HFpEF management,
• HTN → ACEI/ARB
Diuretics, SGLT2Ia

NYHA II-IV
• eGFR ≥20–30 → SGLT2Id
• eGFR ≥30 & K ≤5 → MRA

NYHA I–IV (EF ≤40%)

NYHA III or IV
HFrEF ACEI/ARB/ARNIb
• AA on GDMT → HYDISDN
AND BBc

NYHA II or III (EF ≥35%)

• HR ≥70, max BB → Ivabradine

Advanced HF (Stage D) Durable MCS, Palliation, Symptom Control

• Cardiac transplantation
• Inotropic therapy
• LVAD implantation

Figure 1. Treatment algorithm for HF.

a
Empagliflozin reduced the risk of cardiovascular death or HHF among patients with HFpEF.
b
ARNI is preferred to ACEI or ARB as first-line therapy. Prior ACEI/ARB tolerance is not required.
c
Evidence-based β-blockers include bisoprolol, carvedilol, and metoprolol succinate. Though also recommended, carvedilol CR was
approved on the basis of pharmacokinetic equivalence.
d
Empagliflozin if eGFR is 20–29 or more mL/minute/1.73 m2. Either dapagliflozin or empagliflozin if eGFR is 30 or more mL/minute/1.73 m2.
AA = African American; ACEI = angiotensin-converting-enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin
receptor–neprilysin inhibitor; BB = β-blocker; CRT = cardiac resynchronization therapy; DAPT = dual antiplatelet therapy; EF = ejection
fraction; eGFR = estimated glomerular filtration rate; GDMT = guideline-directed medical therapy; HF = heart failure; HFpEF = heart
failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; HHF = hospitalization for heart failure;
HR = heart rate; HTN = hypertension; HYD-ISDN = hydralazine-isosorbide dinitrate; ICD = implantable cardioverter-defibrillator;
K = potassium; MCS = mechanical circulatory support; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist;
NICM = nonischemic cardiomyopathy; NYHA = New York Heart Association; SGLT2I = sodium-glucose cotransporter 2 inhibitor.
Information from: Maddox TM, Januzzi JL, Allen LA, et al. 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for
Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction:
A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2021;77:772-810.

PSAP 2022 Book 1 • Cardiology 18 Heart Failure with Reduced Ejection Fraction
 Table 4. HF Therapies: Mechanism of Action, Adverse Effects, and Monitoring

Drug Class Mechanism of Action Adverse Effects Monitoring Parameters

ACEI Inhibit ACE, reducing Ang I conversion to Ang II • Acute kidney injury • BP
• Angioedema • K
• Cough • SCr
• Hyperkalemia
• Hypotension

ARB Antagonize Ang II type 1 receptor • Acute kidney injury • BP

• Angioedema • K
• Hyperkalemia • SCr
• Hypotension

ARNI Inhibit neprilysin, potentiating natriuretic peptide • Acute kidney injury • BP

activity Antagonize Ang II type 1 receptor • Angioedema • K
• Cough • NT-proBNP
• Hyperkalemia • SCr
• Hypotension

β-Blockers Antagonize β-adrenergic receptor and potentially • Bradycardia • BP

α-adrenergic activity • Dizziness • HR
• Hypotension

Digoxin Inhibit Na/K ATPase pump, increasing intracellular • Bradycardia • BP

Na and Ca influx, improving impaired baroreceptor • Confusion • Digoxin level
reflex and renal Na reabsorption, and inhibiting • Dizziness • HR
sympathetic activity • Nausea
• Visual disturbances
• Vomiting

Hydralazine Direct arteriole vasodilation • Dizziness • BP

• Headache
• Hypotension

If Channel Selective sinoatrial node funny-channel-current- • Bradycardia • BP

Inhibitors flow disruption • Hypotension • HR
• Phosphenes

Isosorbide Increase cGMP concentration, relaxing vascular • Dizziness • BP

dinitrate smooth muscle • Headache
• Hypotension

Loop Diuretics Inhibit Na reabsorption in ascending loop of Henle • Dizziness • BP

• Continual urination • Urine output
• Hypotension • Volume status
• Muscle cramps • Weight
• Thirst

MRA Antagonize mineralocorticoid receptor, blocking • Gynecomastia • BP

aldosterone (spironolactone) • K
• Hyperkalemia • SCr

sGC Modulators Increase cGMP concentration, relaxing vascular • Anemia • BP

smooth muscle • Hypotension • CBC

SGLT2I Antagonize Na-glucose cotransporter in proximal • Acute kidney injury • A1C

tubule, reducing renal glucose reabsoprtion • Dyslipidemia • BP
• Genital mycotic • Glucose
infection • SCr
• Hypoglycemia • Volume status
• Ketoacidosis
• Urinary tract infection

(continued)

PSAP 2022 Book 1 • Cardiology 19 Heart Failure with Reduced Ejection Fraction
 Table 4. HF Therapies: Mechanism of Action, Adverse Effects, and Monitoring  (continued)

ACEI = angiotensin-converting enzyme inhibitor; Ang I = angiotensin I; Ang II = angiotensin II; ARB = angiotensin receptor blocker;
ARNI = angiotensin receptor–neprilysin inhibitor; BP = blood pressure; Ca = calcium; CBC = complete blood count; HF = heart failure;
HR = heart rate; K = potassium; MRA = mineralocorticoid receptor antagonist; Na = sodium; NT-proBNP = N terminal fragment B-type
natriuretic peptide; SCr = serum creatinine; sGC = soluble guanylate cyclase; SGLT2I = sodium-glucose cotransporter-2 inhibitor.

Because of both lack of demonstrated benefit and potential
for harm, the current role of conventional inotropic agents—
chiefly dobutamine, and milrinone—is limited to patients with
advanced HF refractory to GDMT for either palliation or as
bridge therapy to mechanical circulatory support or cardiac
transplant in eligible patients (Yancy 2013). Dobutamine—a
β-agonist—and milrinone—a phosphodiesterase-3 inhibitor—­
directly improve cardiac contractility and provide varying
degrees of vasodilation through activity in the peripheral vas-
culature. Dobutamine reduces systemic vascular resistance
at lower doses but exerts a largely neutral impact on vascular
tone at higher doses because of a counterbalance of α1 and
β2 receptor affinity. Although milrinone provides more-bal-
anced inodilation across the dosing spectrum, it is eliminated
renally, and given its comparably longer half-life, it may accu-
mulate in kidney injury. Milrinone does avoid direct adrener-
gic agonism, which may be advantageous for patients with
HF-prescribed concomitant β-blocker therapy. Both agents
are highly arrhythmogenic, however, which necessitates

Patient Care Scenario

A 56-year-old African American woman with a medical his-
tory significant for T2DM (A1C = 7.4% on metformin), CKD
stage 3 (baseline SCr 1.3; eGFR 45 mL/minute/1.73 m2),
and HFrEF (LVEF = 33%) was hospitalized for shortness
of breath and fluid overload consistent with an acute
decompensation requiring intravenous diuretics. During
the hospital stay, her home losartan 100 mg daily was
changed to sacubitril/valsartan 97/103 mg twice daily;
home metoprolol succinate continued at 200 mg daily;
and she was newly started on spironolactone 50 mg daily.
During a visit to the HF disease management clinic
2 weeks after discharge, she reports somewhat tolerating
the new medication regimen aside from a few headaches,
fatigue, and episodes of lightheadedness. A basic met-
abolic panel from the clinic is unremarkable. Her HR is
72 beats/minute, and blood pressure is 105/75 mm Hg.
A repeat echocardiogram revealed her LVEF was remain-
ing around baseline at 34%. What is best to recommend
for this patient?

ANSWER
The sequencing of initiation and uptitration of GDMT
for HFrEF is a common but complex clinical problem
facing contemporary HF management. Before SGLT2
inhibitors’ demonstrations of cardiovascular mortal-
ity and HHF benefit when added on to ACEI/ARB/ARNI,
β-blocker, and MRA, the combination of hydralazine and
isosorbide dinitrate would be indicated as part of GDMT
for self-identified Black patients given the 43% rela-
tive reduction in mortality observed in the A-HeFT trial.
Current guidance recommends African American patients
with HFrEF be prescribed this combination after GDMT
has been adjusted to target or maximally tolerated doses.
This patient’s GDMT regimen was titrated to goal during
the hospital stay. Although her systolic blood pressure is
only on the lower end of normal, she is already experienc-
ing side effects likely attributed to low blood pressure.
The combination of hydralazine and isosorbide dinitrate
often causes headache and dizziness but reduces sys-
tolic and diastolic blood pressure by only 1.9 and 2.4
mm Hg, respectively; SGLT2 inhibitors reduce systolic
blood pressure by about the same magnitude or less.
Given her concomitant CKD and T2DM with an A1C above
goal, there are compelling indications for initiation of an
SGLT2 inhibitor such as dapagliflozin or empagliflozin to
reduce the risk of cardiorenal complications and thereby
preserve kidney function. To date, no heterogeneity by
ethnicity or race has been identified in SGLT2 inhibitor
studies. Prioritizing the initiation of both the combina-
tion of hydralazine and isosorbide dinitrate as well as the
SGLT2 inhibitor studied in HF would be consistent with
the 2021 ACC Expert Consensus Decision Pathway and
should be individualized to the patient’s comorbid condi-
tions and tolerance for additional GDMT that may further
lower blood pressure.

1. Maddox TM, Januzzi JL, Allen LA, et al. 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart
Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction: A Report of the American College
of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2021;77:772-810.
2. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med
2004;351:2049-57.
3. Morris AA, Testani JM, Butler J. Sodium-glucose cotransporter-2 inhibitors in heart failure: racial differences and a potential for reduc-
ing disparities. Circulation 2021;143:2329-31.

PSAP 2022 Book 1 • Cardiology 20 Heart Failure with Reduced Ejection Fraction
careful monitoring and use of minimal effective doses to alle-
viate symptomatic congestion.
Palliative HF Care
Although successful implementation and titration of GDMT
substantially improve survival, HF remains a debilitating and
progressive disease with a poor overall prognosis. Therefore,
palliative care is strongly recommended for all patients with
advanced HF in order to improve quality of life (Yancy 2013).
Despite those recommendations and robust evidence for
improved patient-centered health outcomes, palliative care
is a persistently underutilized service that is rarely offered
to patients with HF (Diop 2017). A comprehensive palliative-­
care plan should be integrated early in HF management and
include intensive symptomatic relief, detailed end-of-life pref-
erences, and access to caregiver support. Even in advanced
HF, GDMT may be useful to extend life and avoid hospitaliza-
tion. Diuretic agents, however, are more critical to achieve
immediately control of symptoms of congestion and should
be continued through hospice to end of life (Maddox 2021).
Home infusions of dobutamine or milrinone should also be
considered for palliation to improve functional status, though
patients with end-stage HF may become (1) inotrope depen-
dent as their conditions worsen and (2) unable to wean with-
out deterioration. As patients with HF transition toward
comfort care, discontinuation of life-sustaining inotropes
or neurohormonal antagonists may be prudent. These com-
plex treatment decisions should be individualized to reflect a
patient’s wishes in concert with a palliative-care consultant.
Investigational Therapies
Omecamtiv Mecarbil
Omecamtiv mecarbil selectively activates cardiac myosin to
promote conformational change of the physiologic, weakly
bound myosin-ATP intermediate state to a stronger, actin-
bound, force-producing state to stimulate myosin phosphate
release. This mechanism is thought to enhance the duration
and force of each systolic contraction without affecting myo-
cardial energetics. Because omecamtiv acts directly on the
sarcomere, it avoids certain potentially problematic calcium-­
related proarrhythmic effects observed with other inotro-
pes like digoxin, dobutamine, milrinone, and levosimendan
(Psotka 2019).
The Global Approach to Lowering Adverse Cardiac Out-
comes Through Improving Contractility in Heart Failure
(GALACTIC-HF) trial recently compared pharmacokinetically
guided dosing of omecamtiv mecarbil with placebo in 8256
patients with symptomatic chronic HF and LVEFs of 35% or
less (Teerlink 2021). After a median follow-up period of 21.8
months, the primary composite outcome of HHF, urgent HF
visit, or cardiovascular death occurred significantly less
often with omecamtiv (37.0% vs. 39.1%; HR 0.92; CI 0.86–
0.99; p=0.03). It is important to note that that difference was
PSAP 2022 Book 1 • Cardiology
driven by HHF and urgent-care visits; cardiovascular death
alone was not affected (19.6% vs. 19.4%; HR 1.01; CI 0.92–
1.11). Potentially related to increased contractility, patients
with severely depressed LVEFs of 28% or less appeared to
derive greater benefit than did patients with systolic dysfunc-
tions of more than 28%. A modest quality-of-life improvement
in the Kansas City Cardiomyopathy Questionnaire was also
observed for patients recruited in the hospital but not in the
ambulatory-care setting. Although NT-proBNP decreased by
10% at week 24, omecamtiv increased cardiac troponin levels
4 ng/L higher. Despite that finding, cardiac ischemic and ven-
tricular arrhythmia events were similar to placebo.
Omecamtiv mecarbil awaits regulatory review, but its
place in therapy within the expanding HFrEF treatment
landscape deserves further clarification. Based on GALAC-
TIC-HF, recently decompensated patients with poor systolic
functions may stand to benefit the most. Omecamtiv may
also be especially useful when hypotension or renal insuffi-
ciency limits the initiation or titration of GDMT as well as in
patients with advanced or end-stage HF who may not be can-
didates for continuous inotrope infusions. Given that plasma
concentration-guided dosing of omecamtiv mecarbil was
used in clinical trials, it is likely that pharmacists will play a
crucial role in its future use and monitoring.
ADVANCED THERAPEUTIC
MODALITIES
CRT/ICD Devices
Ventricular arrhythmias are common complications of HF
and are of concern. Arrhythmogenesis is often multifac-
torial because of increased sympathetic tone, underlying
ischemic heart disease or myocardial scarring, conduction
delays, electrolyte abnormalities, and drug-induced arrhyth-
mias. Although GDMT may reverse cardiac remodeling and
lower arrhythmia risk, up to half of all patients with HF still
die from sudden cardiac death precipitated by a ventricular
tachyarrhythmia (Virani 2021). Implantable cardiac devices
consist of an electronic generator and lead wires, typically
placed by way of a minimally invasive procedure in a cardiac
catheterization or electrophysiology laboratory. Leads are
inserted into a peripheral vein and guided toward the heart,
one end attaching to the generator and the other terminat-
ing in cardiac tissue itself. The generator is powered by lith-
ium batteries, which can last up to 10 years before requiring
replacement, at which time the device must be accessed
from a tunneled pocket under the skin of the chest well.
Device pocket hematomas are rare but major risks of mor-
bidity, necessitating cautious periprocedural anticoagulation
management. Subcutaneous systems are alternatives to the
traditional transvenous approach, featuring an entirely extra-
cardiac implantation procedure that avoids many of the com-
mon perioperative complications of conventional devices.
21 Heart Failure with Reduced Ejection Fraction
 Implantable cardioverter-defibrillators (ICDs) detect and
terminate ventricular dysrhythmias by way of single- or
dual-chamber defibrillator leads capable of electronic-shock
delivery. A biventricular ICD, also known as a cardiac resyn-
chronization therapy (CRT) device, consists of a right-ven-
tricular defibrillator lead as well as an added, left-ventricular
pacing lead. The CRT devices optimize the atrioventricular
interval through the coronary sinus, thereby coordinating
contraction between and within both ventricles. Implantation
of either cardiac device has been shown to improve outcomes
among patients with HFrEF for both primary and secondary
arrhythmia prevention. Primary-prevention ICD placement
should be considered for patients with HFrEF and persistently
reduced LVEFs of 35% or less despite at least three optimally
dosed GDMTs (see Figure 1). For this indication, ICD therapy
reduced all-cause mortality by more than 50% during a 5-year
study period compared with conventional medical therapy in
patients with LVEFs of 30% or less, histories of myocardial
infarction, and inducible ventricular tachyarrhythmia (Moss
1996). A subsequent study of 1232 similar patients recruited
without requiring invasive electrophysiological testing found
that defibrillator implantation reduced all-cause mortality by
31% after only 20 months of average follow-up (Moss 2002).
Among NYHA Class II or III patients with LVEFs of 35% or less
of either ischemic or nonischemic etiology, preventive ICD
therapy reduced all-cause mortality by 23% compared with
amiodarone after a median 45.5 months of follow-up (Bardy
2005). Cardiac resynchronization therapy should be consid-
ered in symptomatic patients with EFs of 35% or less in sinus
rhythm with QRS durations of 120 msec or greater. Although
CRT alone initially did not improve survival in 1520 patients
with advanced HF and QRS intervals of at least 120 msec,
the combination of CRT with a pacemaker-defibrillator did
reduce the risk of death by 36% compared with optimal phar-
macologic therapy (Bristow 2004). A subsequent CRT trial
did, however, demonstrate improved survival as well as echo-
cardiography findings, symptoms, and quality of life in 813
patients with advanced HF because of systolic dysfunction
and cardiac dyssynchrony compared with standard pharma-
cologic therapy (Cleland 2005). Implantation of an implant-
able cardioverter-defibrillator for secondary prevention has
also been shown to reduce mortality risk by 20%–30% and is
indicated for survivors of sudden cardiac arrest or those with
syncopes from or histories of presumed sustained ventricu-
lar arrhythmia. It is important to note that patients at NYHA
stage IV have not been shown to benefit from ICD placement
and should be considered only if awaiting heart transplanta-
tion. In addition, to avoid inappropriate shocks that may be
inconsistent with goals of care, clinicians must also disable
cardiac devices in patients with HF who are transitioning to
hospice care.
Antiarrhythmic medications variably affect the defibril-
lation threshold of an ICD. Defibrillation threshold refers to
the lowest amount of energy necessary to successfully
PSAP 2022 Book 1 • Cardiology
defibrillate an arrhythmia with a view to restore normal sinus
rhythm. Amiodarone, lidocaine, and nondihydropyridine cal-
cium channel blockers can potentially raise the defibrillation
threshold and thereby require higher voltage or risk defibril-
lation failure and subsequent shocks. Contrastingly, β-block-
ers as well as sotalol or dofetilide may lower the defibrillation
threshold. These agents can also slow the rate of ventricu-
lar tachycardia to below rate-sensing cutoff programming,
thereby misfiring an appropriate ICD shock opportunity
(Lampert 2013). Amiodarone plus β-blockers appears to be
more effective than sotalol to prevent device shocks—but at
the expense of more-adverse pulmonary and thyroid events
as well as bradycardia (Connolly 2006). Drug–device inter-
actions represent an important component of CRT/ICD man-
agement, and pharmacists are uniquely qualified and well
positioned to inform providers and patients so as to avoid
adverse events and improve quality of life.
Remote Hemodynamic Monitoring
Development of remote patient monitoring accelerated
because of the 2019 coronavirus pandemic, thereby lever-
aging the accessibility and convenience of electronic, tele-
health, or mobile technology to manage and monitor disease
outside traditional health care facilities. Remote patient
monitoring debuted in the area of HF almost 3 decades ago,
when a multidisciplinary telephonic monitoring and follow-­
up program reduced the rehospitalization rate by more
than 50% (Rich 1995). However, subsequent large, prospec-
tive, multicenter investigations of more-advanced remote
patient-monitoring interventions—including implantable car-
diac electronic devices, thoracic bioimpedance or dielectric
sensing systems, and wearable hemodynamic sensors—have
failed to demonstrate any benefit and were not cost-effective
(Dickinson 2018). One notable exception is the CardioMEMS
implantable pulmonary artery pressure-monitoring system,
which received FDA approval in 2014 based on an analysis
of long-term ongoing follow-up from the CardioMEMS Heart
Sensor Allows Monitoring of Pressure to Improve Outcomes
in NYHA Class III Heart Failure Patients (CHAMPION) trial.
The CHAMPION trial was a prospective multicenter, single-
blind study of 550 patients with NYHA III HF who had had
recent HHFs in the past year and were randomized to receive
wireless implantable pulmonary artery pressure monitors
compared with usual care (Abraham 2011). After a mean of 15
months follow-up, the CardioMEMS device had reduced the
primary end point of HHF by 37% (158 vs. 254; HR 0.763; 95%
CI, 0.52–0.77; p<0.0001). Because HF decompensation is typ-
ically preceded by days to weeks of asymptomatic intracar-
diac and pulmonary artery pressure elevations, patients who
were managed with hemodynamic data from the CardioMEMS
device were more likely to have GDMT titration performed as
well as to receive real-time diuretic dose adjustments before
symptoms of congestion developed. Adverse event rates
were consistent with those of right-heart catheterization
22 Heart Failure with Reduced Ejection Fraction
but better than other permanent implants such as CRT/ICD.
Based largely on reductions in HHF, CardioMEMS was asso-
ciated with a comprehensive health care cost reduction of
$13,190 per year per patient implanted with the device (Desai
2017). A postapproval CardioMEMS single-arm observational
study demonstrated even greater benefits in all-cause hos-
pitalizations across HF subgroups, including patients with
HFpEF (Shavelle 2020). A pre-COVID-19-pandemic analysis of
the recent Haemodynamic-Guided Management of HF study
suggested a possible benefit on mortality and total HF events
based on hemodynamic-guided management through the
CardioMEMS monitoring system (Lindenfeld 2021). Pharma-
cists participating in remote hemodynamic-monitoring pro-
grams may be able to optimize GDMT or guide diuretic dose
titrations to prevent HHF and reduce total cost of care.
LVAD and Cardiac Transplantation
Patients with advanced HF refractory to GDMT should be
considered for advanced therapeutic modalities such as
definitive therapy, including durable mechanical circulatory
support with left ventricular assist devices (LVADs) or refer-
rals for orthotopic heart transplantation (see Figure 1). Car-
diac transplantation is the only curative treatment for HF
and has a median donor graft survival of more than 12 years.
However, the paucity of suitable organ donors renders heart
transplantation an epidemiologically insignificant therapeu-
tic strategy when compared with the growing need of poten-
tial stage D recipients. Therefore, to extend life with improved
functional status, the implantation of an LVAD may be use-
ful as a bridge to transplantation or used as destination ther-
apy in those not eligible for transplantation. End-of-life goals
and individualized, patient-specific characteristics should be
reviewed thoroughly in consideration of advanced therapeu-
tic modalities. For example, pulmonary hypertension is a sig-
nificant contraindication to transplantation but not for LVAD
candidacy. Conversely, patients with severe right ventricular
failure are suboptimal LVAD candidates but may experience
better transplantation outcomes. Other LVAD precautions
include history of recurrent infections, untreated aortic regur-
gitation, older age, and high frailty index. Anticoagulation with
warfarin to an INR goal of 2–3 is currently recommended to
prevent LVAD thrombosis for all available devices. Alternative
anticoagulation strategies with newer-generation VADs that
have magnetically suspended propulsion systems are cur-
rently under investigation, potentially obviating the need for
anticoagulation altogether, which may significantly reduce
complications if pump thrombosis risk can be minimized.
HEART FAILURE WITH PRESERVED
EJECTION FRACTION
Despite accounting for approximately half of the overall HF
population and conferring a comparably high mortality risk,
HFpEF has historically lacked even a single evidence-based
pharmacologic treatment option offering an observable
PSAP 2022 Book 1 • Cardiology
impact on overall prognosis (Virani 2021). Traditionally
characterized by a crude categorization of LVEF of 50% or
more, HFpEF actually represents a heterogenous subpop-
ulation of HF with a multitude of distinct pathophysiologic
phenotypes inherently more complex than classification by
diastolic dysfunction alone (Riello 2021). Impaired left ven-
tricular relaxation is a common hallmark sign of HFpEF, but
it may be caused by a host of interdependent factors such
as cardiometabolic disease and systemic inflammation, obe-
sity and epicardial adipose accumulation, myocardial isch-
emia and fibrosis, and arterial and vascular rigidity (Obokata
2020). Although active development of disease-modifying
pharmacotherapy for HFpEF has remained unsuccessful for
several decades, recent emerging research and regulatory
expansion suggest that this area of tremendous need may
soon establish more-definitive treatment—and with measur-
able benefit beyond symptomatic control and comorbidity
management.
Angiotensin- Receptor–Neprilysin-Inhibitor
Given its landmark success in HFrEF and encouraging mul-
tifactorial impact on several compensatory neurohormonal
pathways thought to be at least partially shared with HFpEF,
patients, clinicians, and investigators were hopeful that ARNI
may be among the first medications to show a clear and con-
sistent benefit in HFpEF. The Prospective Comparison of
ARNI with ARB Global Outcomes in HF with Preserved Ejec-
tion Fraction (PARAGON-HF) study randomized 4796 symp-
tomatic patients with LVEFs of 50% or more and elevated
NT-proBNP to sacubitril/valsartan 97/103 mg twice daily or
valsartan 160 mg twice daily (Solomon 2019). Although ARNI
reduced the primary composite end point of cardiovascular
death and HHF by 13%, it narrowly missed statistical signifi-
cance after a median 35 months of follow-up (894 vs. 1009;
HR 0.87; 95% CI, 0.75–1.01; p=0.059). The fragility index of this
result required a net difference of only seven events to reach
a p value of less than 0.05 (Solomon 2021). Furthermore, had
urgent HF visits—which were collected prospectively and
adjudicated independently—been incorporated into the pri-
mary composite outcome, as with other contemporary HFpEF
trials, PARAGON-HF would have indeed achieved its end point
(HR 0.86; 95% CI, 0.75–0.99; p=0.040). There was significant
heterogeneity of the trial findings between two prespecified
subgroups—including hypothesis-generating observations
of more-favorable effects with ARNI in those with LVEFs of
45% to 57%. as well as in women compared with men. Nota-
bly, ARNI was also associated with an improvement in the
exploratory renal composite outcome of death from kid-
ney failure, end-stage renal disease, and an eGFR decrease
of 50% or more from baseline (1.4% vs. 2.7%; HR 0.50; 95%
CI, 0.33–0.77). It was important that fewer patients random-
ized to sacubitril/valsartan also discontinued the study drug
and had SCr elevations of 2.0 or more mg/dL or any elevated
23 Heart Failure with Reduced Ejection Fraction
serum potassium but did experience more hypotension and
angioedema.
In consideration of the totality of evidence—particu-
larly across the spectrum of LVEF consistent with PARA-
DIGM-HF—the FDA Cardiovascular and Renal Drugs Advisory
Committee voted to approve an expanded ARNI indication “to
reduce the risk of cardiovascular death and hospitalization
for heart failure in patients with chronic heart failure,” with
no specific LVEF cutoff (Solomon 2021). Although the merits
of the largely unprecedented regulatory decision to expand
ARNI labeling to support use in HFpEF despite a neutral trial
finding are contentious, it may be reasonable to consider
sacubitril/valsartan for female patients with HFpEF as well
as those with EFs of 57% or less who are at low risk of symp-
tomatic hypotension.
Mineralocorticoid Receptor Activation
Mineralocorticoid receptor activation is associated with
sodium retention, potassium loss, endothelial dysfunction,
vascular inflammation, myocardial fibrosis, and hypotrophy
central to the pathophysiology of HFrEF and is shared, at
least in part, by HFpEF. Therefore, the use of MRA to manage
diastolic dysfunction in HFpEF was once a promising ther-
apeutic target that initially disappointed when studied rig-
orously. The Treatment of Preserved Cardiac Function with
an Aldosterone Antagonist Trial (TOPCAT) was a large mul-
ticenter, double-blind, placebo-controlled trial that evalu-
ated the effect of spironolactone on morbidity and mortality
in 3445 patients with HFpEF (Pitt 2014). The primary com-
posite end point of cardiovascular death, HHF, and resusci-
tated cardiac arrest was similar between treatment arms
(18.6% vs. 20.4%; HR 0.89; 95% CI, 0.77–1.04; p=0.14) after
a mean follow-up of 3.3 years, as were cardiovascular mor-
tality and aborted cardiac arrest individually. Rates of HHF,
however, were significantly lower with spironolactone (12.0%
vs. 14.2%; HR 0.83; 95% CI, 0.69–0.99; p=0.04). Furthermore,
hyperkalemia and renal failure were also more common in
spironolactone-treated patients. Interestingly, a post hoc
analysis of TOPCAT revealed significant geographic dis-
parities with regard to the primary outcome between study
sites in North America and South America (27.3% vs. 31.8%;
HR 0.82; 95% CI, 0.69–0.98; p=0.26) compared with those in
eastern Europe (9.3% vs. 8.4%; HR 1.10; 95% CI, 0.79–1.51;
p=0.576) (Pfeffer 2015). About half of all patients enrolled in
TOPCAT were recruited from Russia and Georgia, experienc-
ing curiously low event rates consistent with a healthier study
population not necessarily suffering from HFpEF. In addition
to these regional biases, serum concentrations of the active
spironolactone metabolite, canrenone, were undetectable
in 30% of participants from Russia versus only 3% from the
United States and Canada (de Denus 2017). These findings
suggest, at a minimum, that lack of study drug adherence as
well as other potential protocol violations may have occurred
disproportionately outside the Americas. Current guidelines
PSAP 2022 Book 1 • Cardiology
recommend consideration of an MRA for patients with HFpEF
and LVEFs or more than 45%, elevated BNPs, and recent hos-
pitalizations within the past year to reduce the risk of sub-
sequent HHF (see Figure 1). Much like the recent ARNI label
expansion, the same FDA Cardiovascular and Renal Drugs
Advisory Committee also voted that the totality of evidence
from TOPCAT was compelling enough to support a broader
indication for spironolactone inclusive of at least patients
with HFmrEF up to LVEFs of 55% – 57%. However, a formal
label expansion request has yet to be submitted to the FDA
for consideration.
Another recently approved MRA, finerenone, is currently
being investigated in the ongoing FINEARTS-HF trial for a
potential impact on the primary composite end point of car-
diovascular death, HHF, or urgent HF visits in HFpEF (clini-
caltrials.gov). About 5550 patients with LVEFs of 40% or
more, NYHA II–IV symptoms, elevated NT-proBNPs, struc-
tural heart disease, and recent HF events will be randomized
in either an ambulatory or an acute-care setting to receive
finerenone 40 mg once daily or matching placebo. Should
finerenone demonstrate an impact similar to that in the FIDE-
LIO-DKD and FIGARO-DKD trials in the area of cardiorenal end
points among patients with nondiabetic HFpEF, it may be the
first MRA to definitively mitigate morbidity and mortality risk
beyond HFrEF.
SGLT2 Inhibitors
Sodium-glucose cotransporter 2 inhibitors have consistently
demonstrated cardiorenal outcome benefits among patients
with HFrEF and patients with CKD independent of T2DM. Nota-
bly, several pivotal cardiovascular safety studies of patients
with T2DM at high cardiovascular risk—such as EMPA-REG,
CANVAS, and DECLARE-TIMI 58—did not distinguish comor-
bid HF subpopulations by ejection fraction. Cardiovascu-
lar outcome trials with pretrial ejection fraction information
available like VERTIS CV, SCORED, and SOLOIST suggest
a benefit of HHF among patients with comorbid T2DM and
HFpEF but remain unproven in nondiabetic HFpEF. Given that
diabetic cardiomyopathy can manifest as either systolic or
diastolic function, independent trials were necessary to con-
firm the hypothesis-generating benefits of SGLT2 inhibitors
for both HFrEF and HFpEF. Based on the landmark findings of
DAPA-HF and EMPEROR-Reduced, dapagliflozin and empagli-
flozin are now considered part of quadruple GDMT for HFrEF;
however, only empagliflozin has yet completed its HFpEF trial
to date (Maddox 2021).
The Empagliflozin Outcome Trial in Patients with Chronic
Heart Failure (EMPEROR-Preserved) trial randomized 5988
patients with LVEFs of more than 40%, NYHA II–IV symptoms
for 3 months or more before enrollment, elevated NT-proBNPs,
and either structural heart disease or recent HHF to empagli-
flozin 10 mg once daily or placebo for a median 26.2 months
of treatment. Empagliflozin significantly reduced the risk of
the primary composite end point of cardiovascular death or
24 Heart Failure with Reduced Ejection Fraction
HHF (13.8% vs. 17.1%; HR 0.79; 95% CI, 0.69–0.90; p<0.001),
driven predominantly by a 29% lower risk of hospitalization
(Anker 2021). Although there was a nonsignificant 9% lower
risk of cardiovascular death with empagliflozin (HR 0.91; 95%
CI, 0.76–1.09), overall mortality was neutral (HR 1.00; 95% CI,
0.87–1.15). It is important to note that those benefits were
consistent among patients with or without diabetes; however,
an attenuation appeared to be observed in patients with the
highest ejection fractions (Anker 2021). Adverse events more
commonly experienced with empagliflozin than with pla-
cebo included uncomplicated UTI and hypotension. Although
the high rate of treatment discontinuation (23%) was similar
between arms, that discontinuation may have notably mini-
mized the effect size of empagliflozin on cardiovascular and
all-cause mortalities (Drazner 2021). The Dapagliflozin Evalu-
ation to Improve the Lives of Patients with Preserved Ejection
Fraction Heart Failure (DELIVER) trial is a similar interna-
tional, randomized, placebo-controlled HFpEF study eval-
uating the impact of dapagliflozin 10 mg once daily on the
primary composite end point of cardiovascular death, HHF,
or urgent HF visits after about 39 months of follow-up (clini-
caltrials.gov). To date, the DELIVER study has recruited 6263
ambulatory or hospitalized patients with LVEFs greater than
40%, evidence of structural heart disease, NYHA II–IV func-
tional status for 6 weeks or more before enrollment, and ele-
vated NT-proBNPs. It is anticipated that the results of both
trials will establish SGLT2 inhibitors as constituting the first
medication class to offer indisputable cardiovascular out-
come benefits among patients with HFpEF.
CONCLUSION
Four classes of disease-modifying therapeutics proven to
reduce cardiovascular mortality and prevent HF hospitaliza-
tions are now available for patients with HFrEF. The medica-
tions—ARNIs, β-blockers, MRAs, and, most recently, SGLT2
inhibitors—are all supported by robust clinical trial evidence
as well as the strongest possible guideline recommendation
compelling their use. Nonetheless, HF remains the costliest
condition in the United States, with a 5-year mortality rate
comparable to most of the major malignancies. One of the
most critical reasons for that is the abysmal uptake of evi-
dence-based pharmacotherapy across the country. Recent
guidance on pathways for initiation, titration, and sequencing
of GDMT as well as how to address barriers to medication opti-
mization provides a framework for closing that gap in care.
The integration of pharmacists into multidisciplinary care
teams dedicated to this endeavor represents a necessary step
toward optimal GDMT implementation, promotes best possi-
ble patient outcomes, and ensures medication adherence.
Furthermore, recent recognition of the increasing prevalence
and heterogeneity of HFpEF, without any definitive therapies
to mitigate its formidable morbidity and mortality, has rein-
vigorated clinical investigators and regulatory agencies alike
to establish safe and effective therapies for this unmet need.
PSAP 2022 Book 1 • Cardiology
Practice Points
Clinical pharmacists must overcome many barriers in
their optimizations of pharmacotherapies for patients
with HF. As new strategies to better inform implemen-
tation of GDMT for HFrEF and promising therapeutics
for HFpEF loom on the horizon, new guideline rec-
ommendations as well as expanded indications for
existing medications continuously evolve contempo-
rary practice:
• The HFSA/HFA-ESC/JHFS recently proposed a universal
definition of HF and updated standardized HF classifi-
cations and staging beyond LVEF and structural cardiac
disease.
• Patients with HF should be routinely assessed and treated
for common comorbidities such as iron deficiency, CKD,
and T2DM to improve quality of life and reduce cardiorenal
complications.
• Dapagliflozin and empagliflozin have recently been
shown to improve cardiovascular death rates and HF
hospitalizations—independent of diabetes status—among
patients with HFrEF.
• Clinicians should ensure that patients with HFrEF are
receiving quadruple therapy with a RAAS inhibitor—
preferably, ARNI—in combination with a β-blocker, an MRA,
and now also an SGLT2 inhibitor.
• GDMT for HFrEF should be titrated to maximally tolerated
doses from randomized, controlled trials but not at the
expense of initiating all four disease-modifying agents.
• Optimization of evidence-based therapy should occur every
2 weeks during hospitalization for HFrEF and when patients
are outpatients so as to achieve GDMT within 3–6 months
of diagnosis.
• Despite arguably neutral HFpEF trials, ARNI and spirono-
lactone recently received regulatory support for expanded
use in patients with LVEFs greater than 40%.
• SGLT2 inhibitors may represent the first medication class
in HFpEF to definitively improve cardiovascular mortality
and HF hospitalizations.
Although ARNI and MRA recently received regulatory support
for expanded indications in HFpEF, SGLT2 inhibitors have
now become the only pharmacologic treatment options with
clear potential to significantly improve cardiorenal outcomes
for patients with HF, irrespective of ejection fraction or diabe-
tes status. Given the pervasive underutilization of GDMT in
patients with HFrEF, as new therapeutics emerge and prove
beneficial for HFpEF, pharmacists must ensure the same
latency to optimize that evidence-based treatment not also
affect HFpEF.
REFERENCES
Abraham WT, Adamson PB, Bourge RC, et al. Wireless
pulmonary artery haemodynamic monitoring in chronic
heart failure: a randomised controlled trial. Lancet
2011;377:658-66.
ADA (American Diabetes Association). 10. Cardiovascular
disease and risk management: Standards of Medical Care
in Diabetes 2021. Diabetes Care 2021 44:S125-S50.
25 Heart Failure with Reduced Ejection Fraction
Ahmad T, Miller PE, McCullough M, et al. Why has positive
inotropy failed in chronic heart failure? Lessons learned
from prior inotrope trials. Eur J Heart Fail 2019;21:1064-78.
Anker S, Butler J, Filippatos G, et al. Empagliflozin in patients
with chronic heart failure with preserved ejection fraction.
N Engl J Med 2021;doi:10.1056/NEJMoa2107038
Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in
patients with heart failure with reduced ejection fraction.
N Engl J Med 2020;382:1883-93.
Bakris GL, Agarwal R, Anker S, et al. Effect of finerenone
on chronic kidney disease outcomes in type 2 diabetes.
N Engl J Med 2020;383:2219-29.
Bardy GH, Lee JL, Mark DB, et al. Amiodarone or an implant-
able cardioverter-defibrillator for congestive heart failure.
N Engl J Med 2005;352:225-7.
Bassi NS, Ziaeian B, Yancy CW, et al. Association of optimal
implementation of sodium-glucose cotransporter 2 inhib-
itor therapy with outcome for patients with heart failure.
JAMA Cardiol 2020;5:948-51.
Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients
with diabetes and chronic kidney disease. N Engl J Med
2021a;384:129-39.
Bhatt DL, Szarek M, Steg GP, et al. Sotagliflozin in patients
with diabetes and recent worsening heart failure. N Engl
J Med 2021b;384:117-28.
Bozkurt B, Coats AJS, Tsutsui H, et al. Universal definition
and classification of heart failure: a report of the Heart
Failure Society of America, Heart Failure Association of
the European Society of Cardiology, Japanese Heart Fail-
ure Society and Writing Committee of the Universal Defini-
tion of Heart Failure. J Card Fail 2021;27:P387-413.
Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchro-
nization therapy with or without an implantable defibril-
lator in advanced chronic heart failure. N Engl J Med
2004;350:2140-50.
Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular
outcomes with ertugliflozin in type 2 diabetes. N Engl J
Med 2020;383:1425-35.
Cleland JGF, Daubert JCC, Erdmann E, et al. The effect of
cardiac resynchronization on morbidity and mortality in
heart failure. N Engl J Med 2005;352:1539-49.
Connolly SJ, Dorian P, Roberts RS, et al. Comparison of
beta-blockers, amiodarone plus beta-blockers, or sotalol
for prevention of shocks from implantable cardioverter
defibrillators: the OPTIC study: a randomized trial.
JAMA 2006;295:165-71.
Das SR, Everett BM, Birtcher KK, et al. 2020 Expert Consen-
sus Decision Pathway on novel therapies for cardiovascu-
lar risk reduction in patients with type 2 diabetes: a report
of the American College of Cardiology Solution Set Over-
sight Committee. J Am Coll Cardiol 2020;76:1117-45.
Daubert MA, Adams K, Yow E, et al. NT-proBNP goal achieve-
ment is associated with significant reverse remodelings
PSAP 2022 Book 1 • Cardiology
and improved clinical outcomes in HFrEF. J Am Coll
Cardiol HF 2019;7:158-168.
de Denus S, O’Meara E, Desai AS, et al. Spironolactone
metabolites in TOPCAT: new insights into regional varia-
tion. N Engl J Med 2017; 376:1690-2.
Desai AS, Bhimaraj A, Bharmi R, et al. Ambulatory hemo-
dynamic monitoring reduces heart failure hospitaliza-
tions in “real-world” clinical practice. J Am Coll Cardiol
2017;69:2357-65.
Dickinson MG, Allen LA, Albert NA, et al. Remote monitoring
of patients with heart failure: a white paper from the Heart
Failure Society of America Scientific Statements Commit-
tee. J Cardiac Fail 2018;24:682-94.
Diop MS, Rudolph JL, Zimmerman KM, et al. Palliative care
interventions for patients with heart failure: a systematic
review and meta-analysis. J Palliat Med 2017;20:84-92.
Drazner MH. SGLT2 inhibition in heart failure with a pre-
served ejection fraction – a win against a formidable foe.
N Engl J Med 2021;doi:10.1056/NEJMed2113008
Dunlay SM, Givertz MM, Aguilar D, et al. Type 2 diabetes
mellitus and heart failure: a scientific statement from the
American Heart Association and the Heart Failure Society
of America. Circulation 2019;140:e294-e324.
Gerber Y, Weston SA, Redfield MM, et al. A contemporary
appraisal of the heart failure epidemic in Olmsted
County, Minnesota, 2000 to 2010. JAMA Intern Med 2015;
175:996–1004.
Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide
and cardiovascular outcomes in type 2 diabetes (REWIND):
a double-blind, randomised placebo-controlled trial.
Lancet 2019;394:121-30.
Gheorghiade M, Greene SJ, Butler J, et al. Effect of vericig-
uat, a soluble guanylate cyclase stimulator, on natriuretic
peptide levels in patients with worsening chronic heart
failure and reduced ejection fraction: the SOCRATES-­
REDUCED randomized trial. JAMA 2015;314:2251-62.
Greene SJ, Butler J, Albert NM, et al. Medical therapy
for heart failure with reduced ejection fraction: the
CHAMP-HF registry. J Am Coll Cardiol 2018;72:351-66.
Greene SJ, Butler J, Fonarow GC. Simultaneous or rapid
sequence initiation of quadruple medical therapy for heart
failure—optimization therapy with the need for speed.
JAMA Cardiol 2021;6:743-4.
Heerspink HJL, Stefansson BV, Correa-Rotter R, et al.
Dapagliflozin in patients with chronic kidney disease.
N Engl J Med 2020;383:1436-46.
Heidenreich PA, Albert NM, Allen LA, et al; on behalf of the
American Heart Association Advocacy Coordinating Com-
mittee; Council on Arteriosclerosis, Thrombosis and Vas-
cular Biology; Council on Cardiovascular Radiology and
Intervention; Council on Clinical Cardiology; Council on
Epidemiology and Prevention; Stroke Council. Forecast-
ing the impact of heart failure in the United States: a pol-
icy statement from the American Heart Association. Circ
Heart Fail 2013;6:606-19.
26 Heart Failure with Reduced Ejection Fraction
Hein AM, Scialla JJ, Edmonston D, et al. Medical manage-
ment of heart failure with reduced ejection fraction in
patients with advanced renal disease. JACC Heart Fail
2019;7:371-82.
Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglu-
tide and cardiovascular outcomes in patients with type 2
diabetes. N Engl J Med 2019;381:841-51.
Januzzi JL, Camacho A, Pina IL, et al. Reverse cardiac
remodeling and outcome after initiation of sacubitril/
valsartan. Circ Heart Fail 2020;13:e006946.
Jia G, Hill MA, Sowers JR. Diabetic cardiomyopathy: an
update of mechanisms contributing to this clinical entity.
Circ Res 2018;122:624-38.
Lampert R. Managing with pacemakers and implantable
cardioverter defibrillators. Circulation 2013;128:1576-85.
Lindenfeld J, Zile MR, Desai AS, et al. Haemodynamic-guided
management of heart failure (GUIDE-HF): a randomised
controlled trial. Lancet 2021;398:991-1001.
Maddox TM, Januzzi JL, Allen LA, et al. 2021 Update to the
2017 ACC Expert Consensus Decision Pathway for Opti-
mization of Heart Failure Treatment: Answers to 10 Piv-
otal Issues About Heart Failure With Reduced Ejection
Fraction: A Report of the American College of Cardiol-
ogy Solution Set Oversight Committee. J Am Coll Cardiol
2021;77:772-810.
Margulies KB, Hernandez AF, Redfield MM, et al. Effects
of liraglutide on clinical stability among patients with
advanced heart failure and reduced ejection fraction: a
randomized clinical trial. JAMA 2016;316:500-8.
Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardio-
vascular outcomes in patients with type 2 diabetes. N Engl
J Med 2016b;375:1834-44.
Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide
and cardiovascular outcomes in type 2 diabetes. N Engl
J Med 2016a;375:311-22.
McMurray JJV, Packer M. How should we sequence the
treatments for heart failure and a reduced ejection frac-
tion? A redefinition of evidence-based medicine. Circula-
tion 2021;143:875-7.
McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin
in patients with heart failure and reduced ejection frac-
tion. N Engl J Med 2019;381:1995-2008.
Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with
an implanted defibrillator in patients with coronary dis-
ease at high risk for ventricular arrhythmia. N Engl J Med
1996;335:1933-40.
Moss AJ, Wojciech Z, Hall J, et al. Prophylactic implantation
of a defibrillator in patients with myocardial infarction and
reduced ejection fraction. N Engl J Med 2002;346:877-83.
Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and
cardiovascular and renal events in type 2 diabetes. N Engl
J Med 2017;377:644-57.
PSAP 2022 Book 1 • Cardiology
Obokata M, Reddy YNV, Borlaug BA. Diastolic dysfunction
and heart failure with preserved ejection fraction: under-
standing mechanisms by using noninvasive methods.
JACC Cardiovasc Imagining 2020;13:245-57.
Packer M, Anker SD, Butler J, et al. Cardiovascular and renal
outcomes with empagliflozin in heart failure. N Engl J Med
2020;383:1413-24.
Packer M, Anker SD, Butler J, et al. Effect of empagliflozin
on the clinical stability of patients with heart failure and a
reduced ejection fraction. Circulation 2021;143:326-36.
Pagell RL, O’Bryant CL, Cheng D, et al. Drugs that cause or
exacerbate heart failure: a scientific statement from the
American Heart Association. Circulation 2016;134:e32-69.
Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin in renal
outcomes in type 2 diabetes and nephropathy. N Engl J
Med 2019;380:2295-306.
Pfeffer MA, Claggett B, Assmann SF, et al. Regional variation
in patients and outcomes in the Treatment of Preserved
Cardiac Function Heart Failure with an Aldosterone Antag-
onist (TOPCAT) trial. Circulation 2015;131:34-42.
Pitt B, Anker SD, Bushinsky DA, et al. Evaluation of the
efficacy and safety of RLY5016, a polymeric potassium
binder, in a double-blind, placebo-controlled study in
patients with chronic heart failure (the PEARL-HF) trial.
Eur Heart J 2011;32:820-8.
Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular events
with finerenone in kidney disease and type 2 diabetes.
N Engl J Med 2021;doi:10.1056/NEJMoa2110956
Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for
heart failure with preserved ejection fraction. N Engl J
Med 2014;370:1383-92.
Ponikowski P, Kirwan BA, Anker SD, et al. Ferric carboxymalt-
ose for iron deficiency at discharge after acute heart fail-
ure: a multicentre, double-blind, randomised, controlled
trial. Lancet 2020; 396(10266):1895-1904.
Psotka MA, Gottlieb SS, Francis GS, et al. Cardiac calcit-
ropes, myotropes, and mitotropes: JACC review topic of
the week. J Am Coll Cardiol 2019;73:2345-53.
Rich MW, Beckham V, Wittenberg C, et al. A multidisci-
plinary intervention to prevent the readmission of elderly
patients with congestive heart failure. N Engl J Med
1995;333:1190-5.
Riello RJ, Pitt B. ARNI and MRA combination in PARAGON-
HF: odd couple or dynamic duo? JACC Heart Fail 2021;
9:25-7.
Shavelle DM, Desai AS, Abraham WT, et al. Lower rates of.
heart failure and all-cause hospitalizations during pulmo-
nary artery pressure-guided therapy for ambulatory heart
failure: one-year outcomes from the CardioMEMS post-­
approval study. Circ Heart Fail 2020;13:229-38.
Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin-­
neprilysin inhibition in heart failure with preserved
ejection fraction. N Engl J Med 2019;381:1609-20.
27 Heart Failure with Reduced Ejection Fraction
Solomon SD, McMurray JJV. Making the case for an
expanded indication for sacubitril/valsartan in heart
failure. J Card Fail 2021;27:693-5.
Teerlink JR, Diaz R, Felker GM, et al. Cardiac myosin activa-
tion with omecamtiv mecarbil in systolic heart failure.
N Engl J Med 2021;384:105-16.
Vaduganathan M, Fonarow GC, Green SJ, et al. Contempo-
rary treatment patterns and clinical outcomes of comor-
bid diabetes mellitus and HFrEF: the CHAMP-HF registry.
JACC Heart Fail 2020;8:459-80.
Virani SS, Alonso A, Aparicio HJ, et al; on behalf of the
American Heart Association Council on Epidemiology and
Prevention Statistics Committee and Stroke Statistics
Subcommittee. Heart disease and stroke statistics—2021
update: a report from the American Heart Association.
Circulation 2021;143:e254-e743.
von Haehling S, Ebner N, Evertz R, et al. Iron deficiency in
heart failure: an overview. JACC Heart Fail 2019;7:36-46.
Wiviott SD, Raz I, Bonaca MP, et al.; for the DECLARE-TIMI 58
Investigators. Dapagliflozin and cardiovascular outcomes
in type 2 diabetes. N Engl J Med 2018;377:644-57.
PSAP 2022 Book 1 • Cardiology
Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA
focused update of the 2013 ACCF/AHA guideline for the
management of heart failure: a report of the American Col-
lege of Cardiology/American Heart Association Task Force
on Clinical Practice Guidelines and the Heart Failure Soci-
ety of America. J Am Coll Cardiol 2017;70:776-803.
Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guide-
line for the management of heart failure: a report of the
American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines.
J Am Coll Cardiol 2013;62:e147-e239.
Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in
patients with heart failure with reduced ejection fraction:
a meta-analysis of the EMPEROR-Reduced and DAPA-HF
trials. Lancet 2020;396:819-29.
Zelniker TA, Braunwald E. Mechanisms of cardiorenal effects
of sodium-glucose cotransporter 2 inhibitors: JACC state-
of-the-art review. J Am Coll Cardiol 2020;75:422-34.
Zinman B, Wanner C, Lachin JM, et al.; for the EMPA-REG
OUTCOME Investigators. Empagliflozin, cardiovascular
outcomes, and mortality in type 2 diabetes. N Engl J Med
2015;373:2117-28.
28 Heart Failure with Reduced Ejection Fraction
Self-Assessment Questions
Questions 1–3 pertain to the following case.
Q.E., a 57-year-old white woman with a medical history sig-
nificant for breast cancer, completed a 6-cycle regimen of
chemotherapy including doxorubicin, docetaxel, and cyclo-
phosphamide less than 1 week ago. She feels fatigued, which
her oncologist attributes to the recent chemotherapy. Out
of an abundance of caution, Q.E. is referred to a cardiolo-
gist who performs a laboratory assessment and ECHO that
resulted in an NT-proBNP of 390 pg/mL [reference range <125
pg/mL] and a left ventricular ejection fraction (LVEF) of 58%
and no identifiable abnormalities. Q.E. denies any symptoms
of heart failure (HF) and reports being able to complete her
normal activities of daily life without limitations.
1. Which one of the following best evaluates Q.E. with
respect to the Heart Failure Society of America (HFSA),
Heart Failure Association of the European Society of
Cardiology (HFA-ESC), and the Japanese Heart Fail-
ure Society (JHFS) staging system and New York Heart
Association (NYHA) functional classification?
A. At risk for HF and NYHA Class I
B. At risk for HF with no accompanying NYHA
classification
C. Pre-HF and NYHA Class I
D. Pre-HF with no accompanying NYHA classification
2. During her annual follow-up visit to the cardiologist,
Q.E. had a repeat ECHO and laboratory assessment that
reported a LVEF of 38% and NT-proBNP of 1670 pg/mL
[reference range <125 pg/mL]. Over the past month, she
reports being unable to walk up a flight of stairs with-
out assistance, frequent breaks due to dyspnea while
brushing her teeth or collecting the mail, and requiring
2-3 pillows propped in a chair to sleep a few times per
week. Which one of the following best categorizes Q.E.
according to the HFSA/HFA-ESC/JHFS staging system
and NYHA functional classification?
A. HF and NYHA Class II
B. HF and NYHA Class III
C. Advanced HF and NYHA Class III
D. Advanced HF and NYHA Class IV
3. Based on Q.E.’s presentation, laboratory, and ECHO find-
ings, the cardiologist diagnoses her with HF and pre-
scribes an ARNI and β-blocker that same visit. Q.E. is
referred to a HF disease management clinic to optimize
the rest of her guideline-directed medical therapy regi-
men and titrate to target dosing. After 6 months of consis-
tent follow-up visits in the clinic, a repeat ECHO reports
an LVEF of 49%. According to the HFSA/HFA-ESC/JHFS
PSAP 2022 Book 1 • Cardiology
Updated Universal Definition of HF, which one of the fol-
lowing best evaluates Q.E.’s category of HF?
A. HF with reduced ejection fraction (HFrEF)
B. HF with mildly reduced ejection fraction (HFmrEF)
C. HF with improved ejection fraction (HFimpEF)
D. HF with preserved ejection fraction (HFpEF)
4. About 4 months ago, a 68-year-old white man was hos-
pitalized for an anterior wall myocardial infarction com-
plicated by left ventricular systolic dysfunction. At
discharge, he was prescribed the following medications:
aspirin 81 mg daily, atorvastatin 80 mg daily, carvedilol
12.5 mg twice daily, sacubitril/valsartan 49/51 mg twice
daily, spironolactone 25 mg daily, and ticagrelor 90 mg
twice daily. During a post-discharge follow-up visit today,
the patient’s LVEF as measured via ECHO has improved
from 25% to 32% since the last hospital assessment. His
laboratory results are within normal limits. He is euvole-
mic, normotensive, and reports only slight limitations of
physical activity. Which one of the following is best to
recommend for this patient?
A. Increase carvedilol to 25 mg twice daily.
B. Increase spironolactone to 50 mg daily.
C. Start empagliflozin 10 mg daily.
D. Increase sacubitril/valsartan to 97/103 mg twice
daily.
5. A 55-year-old white man (weight 214 lb) is admitted to
the hospital with acutely decompensated HF requiring
inotropic support. Echocardiogram shows LVEF 42%,
moderate functional mitral regurgitation, and dilated left
ventricle. The patient’s medical history is significant for
hyperlipidemia and idiopathic dilated cardiomyopathy.
His condition stabilizes and he is resumed on his home
regimen of bumetanide 2 mg daily, carvedilol 12.5 mg
twice daily, eplerenone 25 mg daily, lisinopril 20 mg daily,
and rosuvastatin 10 mg daily. A basic metabolic panel is
unrevealing aside from a Hgb of 11.2 g/dL. The patient is
clinically stable other than complaints of feeling fatigued
and inability to participate in physical therapy. He exhib-
its no clinical signs of bleeding, so the medical resident
begins to work up the cause of his anemia. Iron studies
return with a serum ferritin 115 ng/mL and transferrin sat-
uration 18% [reference range 20%-50%]. Which one of the
following is best to recommend to correct this patient’s
iron-deficiency anemia?
A. Ferric carboxymaltose 500 mg IV once
B. Ferrous sulfate 200 mg Monday, Wednesday, Friday
for 3 months
C. Iron dextran 1,000 mg IV once
D. Iron sucrose 200 mg IV every other day for 5 doses
29 Heart Failure with Reduced Ejection Fraction
Questions 6 and 7 pertain to the following case.
I.M. is a 56-year-old white man with a medical history signif-
icant for uncontrolled diabetes and hypertension. He denies
taking any medications and has been lost to follow-up with
his primary care provider. I.M. presents to the ED with diffi-
culty breathing due in the setting of volume overload with
8 kg weight gain in the past week. His laboratory results
are unremarkable except Na: 130 mEq/L, K 4.9 mEq/L, SCr
2.5 mg/dL (baseline 1.1 mg/dL), and NT-proBNP 11,000 pg/mL
[reference range >300 pg/mL]. Cardiology is consulted and an
ECHO is performed, revealing severely impaired systolic func-
tion with an LVEF of 22%. I.M.’s vital signs are blood pressure
of 149/88 mm Hg, HR 98 beats/minute, respiratory rate of 24
breaths/minute, and oxygen saturation of 97% on room air.
I.M. is admitted to the telemetry floor for management.
6. The admitting resident is undecided about which medi-
cation to start first for I.M.’s acute heart failure manage-
ment. Which one of the following is best to recommend
for I.M.?
A. Eplerenone
B. Furosemide
C. Metoprolol succinate
D. Sacubitril/valsartan
7. After being stabilized, I.M. is initiated on the following
medication regimen: eplerenone 25 mg daily, furose-
mide 40 mg daily, metoprolol succinate 100 mg daily,
and sacubitril/valsartan 49/51 mg twice daily. His vital
signs have improved to 124/82 mm Hg, heart rate 62
beats/minute, respiratory rate 19 breaths/minute, and
oxygen saturation 99% on room air. A repeat laboratory
assessment is unrevealing except for a SCr of 1.4 mg/dL.
Which one of the following is best to recommend to opti-
mize I.M.’s guideline-directed medical therapy?
A. Add dapagliflozin 10 mg daily.
B. Increase eplerenone to 50 mg daily.
C. Increase metoprolol succinate to 150 mg daily.
D. Increase sacubitril/valsartan to 97/103 mg twice
daily.
Questions 8 and 9 pertain to the following case.
J.T. is a 72-year-old white man with a medical history signif-
icant for diabetes (A1C 6.8%), CKD stage 4 (baseline SCr 1.3
mg/dL) and HFrEF (LVEF 34%). His home drugs include aspi-
rin 81 mg daily, carvedilol 25 mg twice daily, dapagliflozin 10
mg daily, furosemide 20 mg daily, losartan 100 mg daily, met-
formin 1,000 mg twice daily, rosuvastatin 20 mg daily, and spi-
ronolactone 25 mg daily. J.T. is clinically stable but appears
overly dry on examination and has had a limited appetite and
complains of thirst. His laboratory results within normal lim-
its except for an eGFR 22 mL/min/1.73 m2.
8. During a visit with J.T.’s primary care provider, dapagli-
flozin and furosemide were both discontinued due to
PSAP 2022 Book 1 • Cardiology
concerns for his renal function. Which one of the follow-
ing is best to recommend for J.T.?
A. Continue without dapagliflozin.
B. Initiate empagliflozin at 10 mg daily.
C. Initiate empagliflozin at 25 mg daily.
D. Reinitiate dapagliflozin at 5 mg daily.
9. Three months later, J.T. is following-up in the HF disease
management clinic. He is euvolemic with an eGFR 30 mL/
min/1.73 m2 and reports adherence to all previous med-
ications including an SGLT2 inhibitor. Which one of the
following is best to recommend regarding optimization
of J.T.’s guideline-directed medical therapy?
A. Increase losartan to 150 mg daily.
B. Switch losartan to sacubitril/valsartan 49/51 mg
twice daily with a 36-hour washout.
C. Switch losartan to sacubitril/valsartan 49/51 mg
twice daily without a 36-hour washout.
D. Increase spironolactone to 50 mg daily.
10. A 47-year-old African American man (weight 176 lb) with
no medical insurance has a medical history significant
for drug and alcohol use disorder, hypertension, and
HFrEF (LVEF 31%). He endorses good adherence to his
medications and has been stable on a previous regimen
of carvedilol 25 mg twice daily, furosemide 20 mg daily,
lisinopril 40 mg daily, and spironolactone 50 mg daily.
On the patient’s last visit to the HF disease management
clinic, however, he was switched from lisinopril to sacu-
bitril/valsartan 49/51 mg twice daily. Although he has
been tolerating ARNI well, he is about to run out of his
30-day free supply provided by a manufacturer coupon
and expresses concerns that he lacks prescription insur-
ance and cannot afford subsequent refills. The cardiol-
ogist transitions him back to lisinopril after a 36-hour
washout period. Which one of the following is best to
recommend to optimize this patient’s guideline-directed
medical therapy?
A. Reinitiate sacubitril-valsartan at 97/103 mg twice
daily.
B. Initiate dapagliflozin 10 mg daily.
C. Initiate isosorbide dinitrate 20 mg and hydralazine
37.5 mg three times daily.
D. Increase lisinopril to 80 mg daily.
11. A 72-year-old white man (weight 168 lb) has a medical
history significant for advanced HF (LVEF 21%) with
LVAD implantation 2 years prior. He is referred to the pal-
liative care service to discuss goals of care. His home
drugs include bumetanide 4 mg daily, carvedilol 25 mg
twice daily, dapagliflozin 10 mg daily, eplerenone 50 mg
daily, ivabradine 7.5 mg twice daily, sacubitril/valsartan
97/103 mg twice daily, and warfarin 6 mg daily. Despite
this regimen, the patient is unable to perform any phys-
ical activities without significant discomfort and is
30 Heart Failure with Reduced Ejection Fraction
 predominantly bed bound. He does not wish to undergo
surgery and wants to “live comfortably” to see his grand-
children graduate high school in 6 months. Which one of
the following is best to recommend for this patient?
A. Start digoxin 125 mcg daily, goal 0.5-0.9 ng/mL.
B. Initiate home infusion of dobutamine 7.5 mcg/kg/
min.
C. Initiate home infusion of milrinone 0.125 mcg/kg/min.
D. Discontinue GDMT and transition to hospice.
12. A 57-year-old white man (weight 215 lb) with a medical
history significant for HFpEF (LVEF 55%; NYHA Class III),
well-controlled hypertension, and CKD stage 3 (base-
line SCr 1.2 mg/dL; eGFR 57 mL/min/1.73 m2) arrives
to the HF diuretic clinic with symptoms of congestion
for the first time in the last year. The nurse practitioner
in the clinic administers intravenous bumetanide 4 mg
then performs a medication reconciliation, noting per-
tinent home drugs to include amlodipine 10 mg daily,
bumetanide 2 mg daily as needed, ferrous sulfate 325
mg every other day, losartan 50 mg daily, multivitamin
with B-complex, and rosuvastatin 20 mg daily. Which
one of the following is best to recommend to optimize
this patient’s HF regimen?
A. Increase bumetanide 4 mg daily.
B. Start spironolactone 25 mg daily.
C. Start empagliflozin 10 mg daily.
D. Switch losartan to sacubitril/valsartan 24/26 mg
twice daily.
13. A 61-year-old African American woman (weight 159 lb)
was newly diagnosed with HFmrEF (LVEF 44%) after
a hospitalization for myocardial infarction. Her medi-
cal history includes diabetes (A1C = 7.0%). The patient’s
home drugs include aspirin 81 mg daily, clopidogrel 75
mg daily, empagliflozin 10 mg daily, furosemide 20 mg
daily as needed, metformin 1000 mg twice daily, metop-
rolol succinate 100 mg daily, rosuvastatin 20 mg daily,
and sacubitril/valsartan 97/103 mg twice daily. Pertinent
laboratory results include K 4.0 mEq/L, SCr 1.1 mg/dL,
and eGFR 65 mL/min/1.73 m2. The patient complains of
increased swelling in her feet and legs with a 4-lb weight
gain over the last few days which she self-medicated with
furosemide. She reports more limitations with physical
PSAP 2022 Book 1 • Cardiology
activity than normal lately. She can no longer walk the
length of the local track without losing her breath and
sleeps in a chair upright once per week. Which one of the
following is best to recommend for this patient?
A. Increase empagliflozin to 25 mg daily.
B. Start isosorbide dinitrate 20 mg and hydralazine
37.5 mg three times daily.
C. Start spironolactone 25 mg daily.
D. Start vericiguat 2.5 mg daily.
Questions 14 and 15 pertain to the following case.
C.H. is a 68-year-old white woman (weight 148 lb) with newly
diagnosed with HFpEF (LVEF 54%) and a medical history sig-
nificant for hypertension and diabetes (A1C 7.4%). Her current
medication regimen includes atorvastatin 40 mg daily, chlor-
thalidone 12.5 mg daily, furosemide 20 mg daily as needed,
and metformin 1000 mg twice daily. C.H.’s blood pressure
is 128/84 mm Hg and heart rate 65 beats/minute. A labora-
tory assessment for today’s visit includes pertinent results
of NT-proBNP 750 pg/mL [reference range >125 pg/mL], K 4.5
mEq/L, SCr 1.2, and eGFR 61 mL/min/1.73 m2.
14. Which one of the following is best to recommend to man-
age C.H.’s comorbidities?
A. Start empagliflozin 10 mg daily.
B. Start liraglutide 0.6 mg subcutaneous daily.
C. Start sitagliptin 25 mg daily.
D. Increase chlorthalidone to 25 mg daily.
15. Three months later, C.H. returns for a follow-up appoint-
ment. Since her last appointment, she has been hos-
pitalized for acute decompensated HF and required
intravenous diuretics. Her vital signs during today’s visit
are blood pressure 141/88 mm Hg, heart rate 75 beats/
minute, and pertinent laboratory results of NT-proBNP is
1220 pg/mL [reference range >125 pg/mL], K 4.9 mEq/L,
SCr 1.5, and eGFR 29 mL/min/1.73 m2. Which one of the
following is best to recommend for C.H.’s HFpEF?
A. Start irbesartan 150 mg daily.
B. Start nebivolol 5 mg daily.
C. Start sacubitril/valsartan 24/26 mg twice daily.
D. Start spironolactone 25 mg daily.
31 Heart Failure with Reduced Ejection Fraction
Learner Chapter Evaluation: Heart Failure with Reduced Ejection Fraction

As you take the posttest for this chapter, also evaluate the 8. The teaching and learning methods used in the chapter
material’s quality and usefulness, as well as the achievement were effective.
of learning objectives. Rate each item using this 5-point scale: 9. The active learning methods used in the chapter were
effective.
• Strongly agree
10. The learning assessment activities used in the chapter
• Agree
were effective.
• Neutral
• Disagree 11. The chapter was effective overall.
• Strongly disagree 12. The activity met the stated learning objectives.
13. If any objectives were not met, please list them here.
1. The content of the chapter met my educational needs.
2. The content of the chapter satisfied my expectations.
3. The author presented the chapter content effectively.
OTHER COMMENTS
4. The content of the chapter was relevant to my practice 14. Please provide any specific comments related to any
and presented at the appropriate depth and scope. perceptions of bias, promotion, or advertisement of
commercial products.
5. The content of the chapter was objective and balanced.
15. Please expand on any of your above responses, and/or
6. The content of the chapter is free of bias, promotion, and
provide any additional comments regarding this chapter:
advertisement of commercial products.
7. The content of the chapter was useful to me.

PSAP 2022 Book 1 • Cardiology 32 Heart Failure with Reduced Ejection Fraction
Drug-Induced Cardiovascular Disease
By Katherine Aymond, Pharm.D., BCPS, BCCP

Reviewed by Barbara S. Wiggins, Pharm.D., MBA, FCCP, FACC, FNLA, BCPS, BCCP, BCCCP, CLS; and Susan M. Smith, Pharm.D., BCPS

LEARNING OBJECTIVES

1. Develop a treatment plan to monitor for cardiotoxicities associated with cancer therapies.
2. Apply cardio-oncology knowledge to prevent toxicities in patients with cancer.
3. Evaluate an individual patient’s pharmacotherapy to distinguish drug-induced cardiovascular disease.
4. Develop a treatment plan for managing ventricular arrhythmias.
5. Account for potential cardiotoxicities when designing an individualized pharmacotherapy plan.

INTRODUCTION
ABBREVIATIONS IN THIS CHAPTER
The FDA is responsible for regulating drug safety through a series
CNI Calcineurin inhibitor
of pre- and postmarketing surveillance. Over 2 million reports were
CV Cardiovascular
provided in 2020 to the FDA using the Adverse Event Reporting Sys-
CVD CV disease
tem, including drug-induced diseases (fda.gov). The database serves
HF Heart failure
as the FDA’s postmarketing safety surveillance system and is eval-
ICI Immune checkpoint inhibitor
uated by clinical reviewers to identify new safety concerns. These
RAAS Renin-angiotensin-aldosterone
regulations contribute to labeling changes, boxed warnings, precau-
system
tions, and contraindications. Although the U.S. drug approval pro-
SNS Sympathetic nervous system
cess does not allow approval until efficacy and safety are shown in
TdP Torsades de pointes
clinical trials, identification of all possible adverse effects remains a
VEGF Vascular endothelial growth factor
challenge. Rare adverse effects that present as an unrelated condi-
VT Ventricular tachycardia
tion are particularly difficult to recognize. Serious adverse effects,
Table of other common abbreviations. especially those that induce disease, should be readily recognized
by a pharmacist to minimize patient harm. Several classes of medi-
cations have been identified as causing or worsening cardiovascular
disease (CVD). Although these medication classes span a wide array
of pharmacotherapy, agents used in the treatment of oncologic dis-
ease have been implicated in recent years.

CHEMOTHERAPY AND IMMUNOTHERAPY-

INDUCED CARDIOTOXICITY
Medical advances in recent decades in the diagnosis and treatment
of cancer have altered the survivability and morbidity previously
associated with this often-terminal disease. The newly defined field
of cardio-oncology targets CVD as an important cause of death in
many cancer survivors. Many treatment modalities, both old and
new, have cardiotoxicities that can further contribute to the progno-
sis of a patient with cancer. Risk stratification, prevention, identifi-
cation, and treatment of these toxicities can vastly improve patient
care. This timeline spans from cancer prevention strategies and diag-
nosis through survivorship and includes the collaboration of both
cardiology and oncology specialists (Barac 2015).

PSAP 2022 Book 1 • Cardiology 33 Drug-Induced Cardiovascular Disease

Mechanisms and Clinical Manifestations
Cardiotoxicity encompasses a wide range of pathophysiologic
processes, including arrhythmias, hyper/hypotension, heart
failure (HF), and myocardial ischemia. Possible mechanisms
for cardiotoxicity include both direct and indirect effects to
the CV system. Direct effects include myocardial cell injury by
the chemotherapeutic or immunotherapeutic agent, resulting
in myocardial dysfunction. Indirect effects encompass a wide
array of mechanisms including endothelial dysfunction, isch-
emia caused by thrombosis, and hemodynamic alterations.
Molecular pathophysiology is not well understood for some
agents and is beyond the scope of this chapter.
The effects of cancer-related treatment can range in sever-
ity and persistence, occurring acutely, subacutely, or chron-
ically. Acute and subacute effects often occur between
therapy initiation and can last up to weeks after therapy
completion. These effects may include arrhythmias, acute
coronary syndromes, pericardial disease, or myocardial dys-
function (Florescu 2013). Chronic effects may occur any time
after therapy completion and are typically associated with
systolic or diastolic dysfunction leading to HF (Florescu 2013).
A variety of cardiotoxicities exist that can manifest depend-
ing on the offending chemotherapeutic or immune-modulating
agent. Arrhythmias, which include both supraventricular (atrial
fibrillation) and ventricular (QT prolongation), occur directly
through chronotropy or indirectly through inflammation.
Hypertension can coexist in patients with cancer before diag-
nosis and can be exacerbated by inhibition of angiogenesis, a
common target for immunotherapies. Angiogenesis, the devel-
opment of new blood vessels, plays a critical role in growth of
BASELINE KNOWLEDGE STATEMENTS
Readers of this chapter are presumed to be familiar
with the following:
• General knowledge of various cardiovascular
diseases (CVDs)
• Proposed mechanisms of medications known to
cause CVD
• General knowledge of management of various CVDs
• General knowledge of mechanisms of action of
oncologic agents
Table of common laboratory reference values
ADDITIONAL READINGS
The following resource has additional information on
this topic:
• Page RL II, O’Bryant CL, Cheng D, et al. Drugs that
may cause or exacerbate heart failure. A scientific
statement from the American Heart Association.
Circulation 2016;134:1-38.
PSAP 2022 Book 1 • Cardiology
solid tumors. Antiangiogenic targets cause a decrease in nitric
oxide production, increasing vasoconstriction and peripheral
vascular resistance and thereby increasing arterial blood pres-
sure (Florescu 2013). Heart failure is one of the most common
and earliest-described cardiotoxicities with diagnostic crite-
ria. Chemotherapeutic agents are intended to cause apoptosis
and necrosis, suppress growth or angiogenesis, or affect cell
repair mechanisms in cancer cells. However, these intended
effects can also damage healthy cardiac cells in the myocar-
dium, leading to cardiotoxicity. Proposed mechanisms vary by
agent, with some direct and indirect postulations, but many
remain unknown (Yeh 2009).
Agents of Toxicity
Anthracyclines
Classified as cytostatic antibiotics, anthracyclines—includ-
ing doxorubicin, daunorubicin, epirubicin, and idarubicin—are
used to treat several solid tumor and hematologic malignan-
cies (Octavia 2012). Anthracycline-induced cardiomyopathy
was first identified in the 1960s and presents as a hypoki-
netic heart progressing to eventual HF. Several risk factors
increase the risk of cardiotoxicity, including age older than 65,
preexisting heart disease or known CV risk factors, and prior
or concurrent chest irradiation. Risk also increases with the
use of other cardiotoxic chemotherapeutic agents (Cardinale
2020). The mechanisms of toxicity remain unclear for anthra-
cyclines. It has been hypothesized that the cardiomyocyte is
the main cellular target within the heart. Possible generation
of reactive oxygen species through several mechanisms and
reduction in antioxidant levels induce myocyte damage. This
oxidative stress induces apoptosis of the cardiomyocyte,
leading to cardiomyopathy (Octavia 2012).
Anthracycline-induced cardiomyopathy is classified by
time of onset, including acute, subacute, and chronic. Chronic
cardiomyopathy, characterized by late-onset HF, is the most
common cardiomyopathy, occurring at a rate of 1.6%–5%.
Late-onset HF is defined as occurring at least 1 year after
treatment completion, up to decades later. Acute toxicity is
rare but is seen immediately after infusion and is reversible.
Findings of both subacute and chronic toxicity include dilated
cardiomyopathy. Anthracyclines are dosed on the basis of
body surface area, and the risk of HF increases with cumula-
tive dosing. Toxicity is dose-dependent, with higher rates of
dysfunction occurring with higher cumulative dose therapy
of doxorubicin greater than 250 mg/m2 or epirubicin greater
than 600 mg/m2 during a lifetime.
Human Epidermal Growth Factor
Receptor 2 Inhibitors
Human epidermal growth factor 2 (HER2) receptors pro-
mote cell proliferation and are overexpressed in around 25%
of breast cancers. Expression of the HER2 receptor causes
an aggressive breast cancer associated with a high risk of
recurrence and reduced survival. Human epidermal growth
34 Drug-Induced Cardiovascular Disease
factor receptors are also found on the cardiomyocyte. Inhibi-
tion of the HER2 receptor in cardiomyocytes results in abnor-
mal growth and repair, leading to contractile dysfunction
and impaired myocyte survival (Yeh 2009). Trastuzumab is a
humanized monoclonal antibody for the HER2 receptor and
is FDA approved for the treatment of HER2-positive breast
cancers. Although trastuzumab-associated cardiotoxicity
can occur with monotherapy, the risk increases dramatically
with the addition of an anthracycline-based regimen, regard-
less of lifetime cumulative anthracycline dose. Trastuzumab-
associated cardiotoxicity is most associated with a decrease
in left ventricular ejection fraction (LVEF) that can progress
to severe HF (Copeland-Halperin 2019).
Literature cites the overall incidence of HER2-positive
breast cancer in up to 25% of patients when trastuzumab is
used in combination with anthracyclines and as low as 2%
for monotherapy (Yeh 2009). Much like anthracyclines, other
risk factors have also been linked to increased risk, includ-
ing advanced age, preexisting CVD, and obesity (Copeland-
Halperin 2019; Yeh 2009). Other anti-HER2 therapies have
since come onto the market, including lapatinib and pertu-
zumab, both of which have increased rates of adverse cardiac
events, but less often than trastuzumab (Jerusalem 2019;
Choi 2017; Swain 2013). A potential risk of cardiotoxicity is
associated with these newer medications; however, experi-
ence is currently limited, and long-term data are needed. Cau-
tion should be exercised when prescribing anti-HER2 agents
to patients with preexisting CVD.
Vascular Endothelial Growth Factor Inhibitors
Vascular endothelial growth factor (VGEF) inhibitors target
angiogenesis, which is essential for tumor growth. Vascular
Patient Care Scenario
A 45-year-old woman with a medical history of refractory
multiple myeloma, hypertension, and smoking presents at
the clinic with new-onset shortness of breath, dyspnea on
exertion, lower extremity pitting edema, and inability to
complete household tasks over the past several weeks. The
team begins a workup for potential diagnoses, including
ANSWER
It is important to perform a thorough medication his-
tory to determine which medications she has previously
been treated with. The pharmacist should specifically ask
about chemotherapy, immunotherapy, preventive treat-
ments, and radiation that may have been used to treat
her cancer. This information will help identify whether
any of these treatments are a likely cause of the drug-in-
duced CVD contributing to her current condition, such as
anthracycline-induced cardiotoxicity, VEGF inhibitor car-
diotoxicity, or corticosteroid-induced hypertension. If
1. Alexandre J, Cautela J, Ederhy S, et al. Cardiovascular toxicity related to cancer treatment: a pragmatic approach to the American and
European cardio-oncology guidelines. J Am Heart Assoc 2020;9:e018403.
PSAP 2022 Book 1 • Cardiology
endothelial growth factor inhibitors include bevacizumab for
the treatment of colorectal cancers and non–small cell lung
cancer and sunitinib for metastatic renal cell carcinoma. Tox-
icity of VEGF inhibitors affects both cardiac and vascular
function and includes hypertension, arterial thromboembo-
lism (particularly myocardial infarctions [MIs]), cardiac isch-
emia, and cardiac dysfunction. Hypertension incidence is as
high as 35% in some reported clinical trials (Yeh 2009).
The mechanism by which bevacizumab causes hyperten-
sion remains unclear. Hypotheses include decreased pro-
duction of nitric oxide through VGEF inhibition. Nitric oxide
regulates vascular tone through vasodilation, and abnormal-
ities in this system remain a target for many CV therapies.
Other hypotheses include alterations in the renin-angio-
tensin system and cholesterol emboli syndrome. The anti-
angiogenesis effects of VEGF inhibitors can also contrib-
ute to endothelial cell dysfunction and cause defects within
the endothelium, activating the clotting cascade. In addition,
decreased production of nitric oxide can contribute to throm-
boembolic events through prostacyclin pathways. Heart
failure associated with bevacizumab is possibly related to
uncontrolled hypertension, resulting in progressive contrac-
tile dysfunction and eventual cardiac failure (Yeh 2009).
BCR-ABL Kinase Inhibitors
BCR-ABL kinase inhibitors are a subset of tyrosine kinase
inhibitors. These targeted cancer therapies are designed to
inhibit tyrosine kinase signaling pathways, leading to anti-
tumorigenesis and anti-angiogenesis activity. BCR-ABL path-
way activation results in inhibition of apoptosis in chronic
myeloid leukemia, allowing chronic myeloid leukemia cells to
evade the body’s natural response (Chen 2008). All approved
HF, pulmonary embolism, and chronic obstructive pulmo-
nary disease exacerbation. During your discussion with
the primary physician, the team asks whether any medi-
cations could be causing the patient’s symptoms. What
strategy would be best to recommend for this patient?
drug-induced CVD is suspected, the pharmacist should
investigate the temporal association between the intro-
duction of the drug in question and symptom onset,
factoring in baseline information, if available. In addi-
tion, other causative factors should be excluded.
Discontinuation of the drug in question may be recom-
mended if a specific drug-induced CVD is suspected and
alternative therapy can be used. Referral to a cardio-on-
cologist should be provided.
35 Drug-Induced Cardiovascular Disease
agents are active against BCR-ABL, but with unpredictable
levels of potency and activity for other kinases (Aghel 2017).
Agents in this class—including imatinib, dasatinib, nilotinib,
bosutinib, and ponatinib—provide “on-target” toxicity to the
intended cancer cells contributing to apoptosis and anti-
proliferation pathways. “Off-target” toxicities also occur at
unintended cell lines with kinase pathways, such as the car-
diomyocyte, resulting in dysfunction (Chen 2008). The vari-
able potency and activity therefore lead to different safety
profiles for each agent. The detailed mechanism for each
agent is beyond the scope of this chapter.
Cardiotoxicity for the BCR-ABL kinase inhibitor class of
drugs encompasses several different pathologies, including,
but not limited to, edema, hypertension, hypotension, arrhyth-
mias, QTc prolongation, pericardial effusions, and left ventric-
ular dysfunction. The most cardiotoxic agent in this class is
the third-generation agent ponatinib. Ponatinib is responsi-
ble for both adverse vascular effects and cardiotoxicities.
Ponatinib’s lack of selectivity for cancer cell kinases has led
to significant cardiotoxicity through several pathways in the
cardiomyocyte. Ponatinib’s inhibition results in impaired sur-
vival of the cardiomyocyte, resulting in loss of cells and car-
diac dysfunction (Singh 2020). The vascular effects were
noted in preclinical trials, with an excess of events noted in a
long-term follow-up trial. Several serious occlusive events—
including coronary artery occlusions, MIs, cerebrovascu-
lar occlusions, peripheral arterial occlusions, and venous
thromboembolisms – led to suspension of ponatinib’s FDA
approval in October 2013. However, the suspension was lifted
with added monitoring, and a boxed warning was added to the
prescribing information in December 2013 because ponatinib
is the only treatment for patients with chronic myeloid leuke-
mia who have a T3151 mutation (Singh 2020).
Immune Checkpoint Inhibitors
Immune checkpoint inhibitors (ICIs) encompass several dif-
ferent drugs that have transformed the management of var-
ious cancers. Checkpoint pathways are innate mechanisms
within the human body to control immune responses. Two pro-
teins are considered checkpoint proteins – cytotoxic T-lym-
phocyte-associated protein 4 and programmed cell death
protein 1 – and are found on the surface of cytotoxic T cells.
Immune checkpoint inhibitors prevent binding of receptors
and ligands and inhibit signaling pathways used by cancer
cells to evade T cell–mediated death in normal immune func-
tion. Six ICIs are FDA approved for the treatment of advanced
malignant cancers, including first-to-market agents ipilim-
umab, nivolumab, and pembrolizumab for the treatment of
unresectable or metastatic melanoma.
Several toxicities are associated with ICIs and are called
immune-related adverse effects. Modulation of immune func-
tion through T-cell activity affects several organ systems in
the body and can range from mild, allowing for treatment
continuation, to severe, resulting in death. The most lethal
PSAP 2022 Book 1 • Cardiology
toxicity is myocarditis, occurring at a rate of 1%–2% with an
associated mortality of 27%–46% (Michel 2019). Conduc-
tion abnormalities from myocarditis include complete heart
block, supraventricular tachycardias, and ventricular tachy-
cardias (VTs), with VTs leading to sudden death (Brahmer
2018). Inflammation can also lead to progressive loss of left
ventricular function, resulting in HF. Development of myo-
carditis is typically observed in the subacute phase within
1 month of initiation. The exact mechanism remains unde-
fined. Other cardiotoxicities noted in the literature include
Takotsubo syndrome, pericarditis, and acute coronary syn-
dromes. Both Takotsubo syndrome and pericarditis are sec-
ondary pathologies associated with several kinds of cancers;
therefore, evaluation of these patients should include careful
elimination of other causes. The pathogenesis of acute cor-
onary syndrome in patients using ICIs is hypothesized to be
mediated by existing plaque disruption (Michel 2019).
Ibrutinib
Ibrutinib is a first-in-class agent inhibiting Bruton tyrosine
kinase, which is responsible for the growth and proliferation
of B-cell cancers. Ibrutinib is an effective first-line treatment
for chronic lymphocytic leukemia. Although ibrutinib was pre-
viously considered well tolerated, recent meta-analyses have
shown an increased risk of atrial fibrillation at a rate of 3.3 up
to 5.77 per 100 person-years (More 2020; Ganatra 2018). In
addition, other cardiotoxicities can occur, including ventricu-
lar arrhythmias and hypertension.
The mechanism of pathogenesis is not well understood. It
is postulated that Bruton tyrosine kinase is expressed in car-
diac tissue, particularly in the atria, and may play a role during
stress conditions (Ganatra 2018).
Ibrutinib-associated atrial fibrillation should be man-
aged in accordance with the most recent American College
of Cardiology (ACC) guidelines. Rate control with β-blockers
is preferred as initial treatment. Calcium channel blockers,
verapamil, and diltiazem should be avoided because of drug-
drug interactions. Treatments for rhythm control can be dis-
cussed with the patient if rate control is inadequate or the
patient is hemodynamically unstable, and no drug-drug inter-
actions exist (Alexandre 2020).
Ibrutinib-associated atrial fibrillation together with cancer-­
associated thromboembolism poses a complex challenge for
clinicians to balance the efficacy and safety of anticoagula-
tion. New-onset atrial fibrillation associated with malignancy
has an increased risk of thromboembolism and HF. Cancer
is a well-defined thromboembolic risk factor, and clinical tri-
als have often excluded patients with active malignancy.
In a large retrospective cohort, new-onset atrial fibrillation
after a cancer diagnosis was associated with higher rates
of HF and thromboembolism (Hu 2013). In patients with can-
cer with new-onset atrial fibrillation, an increasing CHADS2
score (greater than 4) was associated with higher mortality
but not increased rates of thromboembolism (Hu 2013). In
36 Drug-Induced Cardiovascular Disease
 Patient Care Scenario
A 45-year-old woman (weight 80 kg) has a medical his- A. Discontinue ibrutinib and refer her to a cardiologist.
tory that includes hypertension and chronic lymphocytic B. Administer intravenous diltiazem 10 mg once and
leukemia. She presents at the ED in atrial fibrillation. She initiate a systemic heparin infusion.
has concerns about dizziness, with heart rate 130 beats/ C. Administer intravenous metoprolol 5 mg once.
minute and blood pressure 130/84 mm Hg. Her SCr is 1.2
D. Administer intravenous amiodarone 150 mg once
mg/dL. Her current medications include ibrutinib 420 mg
followed by continuous infusion and apixaban 5 mg
once daily and lisinopril 10 mg daily. Which one of the
twice daily.
following is best to recommend to manage this patient’s
atrial fibrillation?

ANSWER
Rate control with β-blockers is preferred in patients
with atrial fibrillation on ibrutinib (Answer C is correct).
Rate control with non-dihydropyridine calcium chan-
nel blockers is contraindicated because diltiazem is a
CYP 3A4 inhibitor and will increase toxicity of ibrutinib.
In addition, this patient’s CHA 2DS2-VASc score is 2 and
does not qualify her for anticoagulation under current
guideline recommendations. When ibrutinib is one of the
only options for cancer, therapy should be continued and
referral for evaluation should be made to a cardio-oncol-
ogist. Initiating rhythm control would be inappropriate in
this patient as rate control is preferred first line for hemo-
dynamically stable patients (Answer A, Answer B, and
Answer D are incorrect).

1. Imbruvica (ibrutinib). Package insert. Janssen Biotech, July 2019.

2. Alexandre J, Cautela J, Ederhy S, et al. Cardiovascular Toxicity Related to Cancer Treatment: A Pragmatic Approach to the American and
European Cardio-Oncology Guidelines. J Am Heart Assoc 2020;9:e018403.
3. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management
of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical
Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons [published correction appears
in Circulation. 2019 Aug 6;140(6):e285]. Circulation. 2019;140(2):e125-e151.

addition, newer stroke risk estimators such as CHA 2DS2VASc
have been shown to underestimate the risk of thromboembo-
lism (D’Souza 2018). This highlights that stroke risk assess-
ment tools should be interpreted with caution in patients with
cancer and that decisions to use anticoagulation should be
individualized.
Anticoagulation selection for ibrutinib-associated atrial
fibrillation is challenging because of the many drug-drug
interactions with commonly used medications. Ibrutinib is
metabolized by CYP3A4 and CYP2D6. According to the pack-
age insert, ibrutinib is a weak inducer of CYP3A4 and inhibits
P-glycoprotein (P-gp) (Imbruvica 2019). Increased bleeding
risk has been identified with the use of ibrutinib because of
effects on platelet signaling pathways and thrombocytope-
nia. Choice of anticoagulant remains controversial. Oral Xa
inhibitors have clinically insignificant CYP3A4 interactions
with ibrutinib. Warfarin is also an option; however, it has
been shown to increase major hemorrhage. Warfarin remains
desirable because of its monitoring ability to ensure adequate
anticoagulation. Dabigatran is a major substrate for P-gp and
is contraindicated. Careful consideration for thromboem-
bolic risk and bleeding should be weighed for each patient,
allowing for shared decision-making (Ganatra 2018).
American Society of Clinical Oncology
Guidelines
The ACC and American Heart Association (AHA) describe
HF as a progressive disease that starts with risk factor
identification, with risk factors including chemotherapy expo-
sure and its related toxicities. Developed in 2016, the Ameri-
can Society of Clinical Oncology (ASCO) guidelines address
cardiac dysfunction in adult cancer survivors. The advisory
group sought to answer five questions that address (1) risk
categorization, (2) prevention before initiation of chemo-
therapy, (3) prevention during chemotherapy, (4) monitoring
during chemotherapy, and (5) monitoring after chemotherapy
(Armenian 2016). Risk categorization should be addressed in
all patients regardless of their treatment phase.
The guideline authors chose to focus on the develop-
ment of systolic rather than diastolic impairment because of
the lack of data available to distinguish management in the
respective patient populations. Systolic cardiac impairment
presents as a decrease in the LVEF and can be symptomatic
or asymptomatic. Other cardiotoxicities such as coronary
artery disease or pericardial and valvular pathophysiology
are not discussed.
In 2018, ASCO in partnership with the National Comprehen-
sive Cancer Network published an additional practice guide-
line focused specifically on immune-related adverse effects
related to patients using ICIs. This guideline discusses man-
agement of all immune-related adverse effects associated with
ICI therapy in all major organ systems, including CV. The guide-
line aims to answer the broad question, “How should clinicians
manage immune-related adverse effects in adult patients with
cancer treated with immune checkpoint blockade antibodies?”
(Brahmer 2018). Recommendations are not graded as usually

PSAP 2022 Book 1 • Cardiology 37 Drug-Induced Cardiovascular Disease

found in the guidelines; rather, recommendations represent a
Box 1. Risk Factors for CVD
consensus opinion, with dissent noted in the text.
The guideline recognizes the most common CV toxicities Modifiable Risk Factors
Diabetes
as myocarditis, pericarditis, arrhythmias, impaired ventricu-
Dietary intake
lar function with HF, and vasculitis. The guideline also details Dyslipidemia
recommendations for venous thromboembolism manage- Hypertension
ment. The authors note that although CV toxicities are not the Physical inactivity
most common toxicity associated with ICIs, they are associ- Premature CVD in a first-degree relative:
ated with significant morbidity and mortality. Cardiotoxicities • < 55 yr in male relative
are noted for all agents within the class, but data are limited • < 65 yr in female relative
to case reports and small case series, encompassing less Tobacco use
than 0.1% of patients (Brahmer 2018). Nonmodifiable Risk Factors
Age:
Prevention
• Males ≥ 45 yr
Risk of cardiac dysfunction includes both treatment- • Females ≥ 55 yr
specific risk factors and non–treatment-related modifiers Sex
of risk. Patients treated with high-dose anthracyclines are • Male
at increased risk of developing cardiotoxicity. Lower doses • Post-menopausal women
of anthracyclines combined with trastuzumab in addition to
CVD = cardiovascular disease.
CV risk factors also increase a patient’s risk of cardiac dys-
Information from: Arnett DK, Blumenthal RS, Albert MA,
function. Older age contributes to this increased risk, with et al. 2019 ACC/AHA guideline on the primary preven-
patients 65 and older implicated most often. Common CV risk tion of cardiovascular disease: a report of the American
factors and comorbidities contribute to the overall cardiac College of Cardiology/American Heart Association
health of the patient with cancer, and the presence of such Task Force on Clinical Practice Guidelines. Circulation
risk factors can contribute to cardiotoxicities. Two or more 2019;140:e596-e646.
modifiable risk factors such as obesity, hypertension, diabe-
tes, dyslipidemia, and smoking increase the risk of HF. Pres-
selection of agents, type and stage of cancer, and efficacy of
ence of compromised heart function at baseline substantially
other available treatments.
increases the risk of further dysfunction. Patients with bor-
There are no strategies to prevent the development of car-
derline low ejection fractions (EFs), a history of MI, or mod-
diotoxicity before initiation of these specific agents. Baseline
erate valvular heart disease are all considered compromised.
monitoring helps identify ineligible candidates for therapy
These risk modifiers should be considered before initiating
and serves as a comparator during treatment. Consensus
specific cardiotoxic therapies such as anthracyclines or tras-
and expert opinion suggest avoidance of therapies with the
tuzumab (Armenian 2016).
potential to cause cardiotoxicity if an alternative treatment is
Before initiation of potential cardiotoxic therapies, the
available. Comprehensive assessment of the patient before
AHA recommends a cardio-oncologic evaluation for patients
initiation is also recommended (Armenian 2016).
using anthracyclines, HER2 inhibitors, VEGF inhibitors, ibru-
Risk of cardiotoxicity during drug administration can be
tinib, and certain BCR-ABL inhibitors. Patients using ponati-
minimized by actively managing modifiable risk factors. Anth-
nib and nilotinib should be referred for evaluation, whereas
racycline-induced cardiomyopathy can be managed using
users of imatinib, bosutinib, and dasatinib need be referred
several strategies. Dexrazoxane interferes with free radical
only if they are at very high CV risk (Box 1) (Alexandre 2020).
generation and is cardioprotective against anthracycline-in-
Cardio-oncologic evaluation is only necessary in patients
duced cardiotoxicity. Dexrazoxane can be administered
using ICIs if they have cardiotoxic effects after initiation. The
before anthracycline infusions and has shown significant risk
AHA recommends that a cardio-oncologic evaluation include
reduction for acute HF in patients receiving high-dose anth-
CV imaging and testing together with a physician visit. This
racyclines (Cardinale 2020). Benefit in lower-dose anthracy-
cardio-oncologic evaluation includes ECG, lipid panel, trans-
cline regimens has not been determined; therefore, they are
thoracic echocardiogram including LVEF measurements,
not commonly used in clinical practice (Armenian 2016). Dex-
active management of modifiable cardiac risk factors, and
razoxane should be considered to prevent cardiotoxicity in
encouragement of a heart-healthy lifestyle, including diet
patients who have advanced metastatic breast cancers with
and exercise counseling. Baseline cardiac biomarkers such
cumulative anthracycline doses greater than 250 mg/m2 of
as high-sensitivity troponin I, BNP, and N-terminal pro–brain
doxorubicin and greater than 600 mg/m2 of epirubicin (Arme-
natriuretic peptide (NT-proBNP) may also be useful before
nian 2016). Using continuous infusion dosing rather than bolus
initiating therapy (Koutsoukis 2018). If baseline abnormali-
dosing of anthracyclines has also decreased cardiotoxicity.
ties are detected, careful consideration should be placed on

PSAP 2022 Book 1 • Cardiology 38 Drug-Induced Cardiovascular Disease

Liposomal formulations of doxorubicin are also associated
with decreased risk. These three strategies show benefit in the
setting of high cumulative dosing of anthracyclines but are of
unknown benefit in patients receiving lower dosing regimens.
Use of angiotensin-converting enzyme (ACE) inhibitors,
β-blockers, and angiotensin receptor blockers (ARBs) as pro-
phylaxis for cardiomyopathy has been explored in recent
years. One early study showed that early initiation of enal-
april in patients with elevated troponin (“troponin triggered”)
receiving high-dose anthracyclines prevented a decrease
in LVEF (Cardinale 2006). Most trials evaluating the effects
of standard HF therapies as prevention for chemotherapy-
induced toxicities have included small sample sizes with
short-term follow-ups. Since publication of the 2016 ASCO
guidelines, several randomized control trials and meta-
analyses have been conducted and published; however,
results continue to show mixed benefit (Table 1).
Results of the CECCY trial, published in 2018, showed no
difference in the rate of LVEF decrease among patients with
HER2-negative breast cancer prophylactically treated with
carvedilol compared with placebo (14.5% vs. 13.5%, p=1.0)
(Avila 2018). After publication of CECCY, a meta-analysis
concluded that β-blockers preserved LVEF by almost 4%.
The population was mixed but mainly included patients with
breast cancer and excluded the use of ACE inhibitors and
trastuzumab (Shah 2019).

Table 1. Summary of Trials Evaluating ACE Inhibitor, ARB, or β-Blocker Prophylaxis for Anthracycline-Induced Cardiotoxicity
Since 2016 ASCO Guideline Publication

Study/Design Treatment Outcome Results Conclusion

Avila 2018 Carvedilol vs. placebo Prevention of ≥ 10% LVEF 14.5% vs. 13.5% (p=1.0) No benefit
CECCY trial reduction

Shah 2019 β-Blocker vs. placebo Final LVEF -3.84 mean difference β-Blocker associated
Meta-analysis with preservation of EF
by almost 4%

Cardinale 2018 Enalapril prevention Troponin elevation above 23% vs. 26% (p=0.50) No benefit between
ISCO-1 trial vs. troponin-triggered threshold strategies
enalapril

Georgakopoulos Metoprolol vs. Occurrence of clinical or No clinical symptoms Coadministration of

2019 enalapril vs. placebo subclinical cardiotoxicity of HF metoprolol or enalapril
offers no benefit

Słowik 2020 Ramipril vs. placebo Occurrence of cardiotoxicity 6.3% vs. 18.5% (p=0.15) No benefit on LVEF
defined by biomarkers or
decrease 10% of LVEF

Lee 2021 Candesartan vs. Decrease in LVEF > 10% 4.9% vs. 8.6% vs. 18.6% Candesartan may be
carvedilol vs. placebo within 6 mo of therapy (p=0.022 for candesartan effective in preventing
vs. placebo, p=0.145 for early decrease in LVEF
carvedilol vs. placebo)

Lin 2021 ACE inhibitors/ARBs Change in LVEF -3.16 mean difference ACE inhibitors and ARBs
Meta-analysis vs. controls reduced cardiotoxicity
by preserving LVEF

CECCY = Carvedilol Effect in Preventing Chemotherapy-Induced Cardiotoxicity; ISCO = International CardioOncology Society-One
(trial); LVEF = left ventricular ejection fraction.
Information from: Avila MS, Ayub-Ferreira SM, de Barros Wanderley MR Jr, et al. Carvedilol for Prevention of Chemotherapy-Related
Cardiotoxicity: The CECCY Trial. J Am Coll Cardiol. 2018;71(20):2281-2290, Shah P, Garris R, Abboud R, et al. Meta-Analysis Comparing
Usefulness of Beta Blockers to Preserve Left Ventricular Function During Anthracycline Therapy. Am J Cardiol. 2019;124(5):789-794,
Cardinale D, Ciceri F, Latini R, et al. Anthracycline-induced cardiotoxicity: A multicenter randomised trial comparing two strategies for
guiding prevention with enalapril: The International CardioOncology Society-one trial. Eur J Cancer. 2018;94:126-137, Georgakopoulos
P, Kyriakidis M, Perpinia A, et al. The role of metoprolol and enalapril in the prevention of doxorubicin-induced cardiotoxicity in
lymphoma patients. Anticancer Res 2019;39:5703-7; Słowik A, Jagielski P, Potocki P, et al. Anthracycline-induced cardiotoxicity
prevention with angiotensin-converting enzyme inhibitor ramipril in women with low-risk breast cancer: results of a prospective
randomized study. Kardiol Pol 2020;78:131-7; Lee M, Chung WB, Lee JE, et al. Candesartan and carvedilol for primary prevention of
subclinical cardiotoxicity in breast cancer patients without a cardiovascular risk treated with doxorubicin. Cancer Med 2021;10:
3964-73; Lin H, Liang G, Wu Y, et al. Protective effects of ACEI/ARB on left ventricular function in anthracycline-induced chronic
cardiotoxicity: a meta-analysis of randomized controlled trials. Cardiology 2021;146:469-80.

PSAP 2022 Book 1 • Cardiology 39 Drug-Induced Cardiovascular Disease

 The role of renin-angiotensin system inhibition has been
explored in several trials. The ISCO-1 trial conducted in Italy
randomly assigned patients to receive enalapril prophylacti-
cally (“prevention” arm) or after an increase in troponin (tropo-
nin-triggered arm). The primary outcome of troponin elevation
occurred in 23% in the prevention groups and 26% in the tro-
ponin-triggered group (p=0.50), showing that ACE inhibitor
treatment may only be necessary in patients with troponin
elevation rather than prophylactic use (Cardinale 2018).
Investigators sought to define the long-term benefits of
prophylactic therapy with metoprolol or enalapril in patients
with lymphoma treated with anthracycline-based regimens.
Patients were randomly assigned to placebo, metoprolol, or
enalapril open label and followed for 10 years. The primary
outcome of clinical or subclinical cardiotoxicity did not differ
between the three groups at the 3- or 10-year mark. Like previ-
ous trials, improvements in diastolic dysfunction were noted
in the metoprolol group (Georgakopoulos 2019).
Investigators prospectively studied treatment with ramipril
shortly before chemotherapy in young women with no CV risk
factors newly diagnosed with breast cancer. They randomly
assigned patients to ramipril or placebo and estimated the
LVEF at baseline. The primary outcome was a combination
of increased concentrations of troponin or NT-proBNP and a
decrease in LVEF of more than 10%. There were no significant
differences between the groups. The authors concluded that
relatively healthy young women with breast cancer would
likely not benefit from ACE inhibitor therapy (Słowik 2020).
Other investigators sought to determine whether ARB or
β-blocker therapy would mitigate the risk of left ventricular
dysfunction early in the treatment of healthy patients with
breast cancer taking anthracyclines. This was a post hoc
analysis of the SAVE HEART trial to evaluate the effects of
candesartan or carvedilol compared with a control group,
which was omitted from the initial analysis. The primary
outcome was early doxorubicin-induced subclinical cardio-
toxicity (DISC) defined by development within 6 months of
chemotherapy. Doxorubicin-induced subclinical cardiotoxic-
ity was defined by an LVEF decrease of greater than 10% or
below 50% at follow-up. Candesartan significantly reduced
the incidence of early DISC compared with control (4.9% vs.
18.6%, p=0.022). The authors concluded that low-dose can-
desartan had a lower incidence of early DISC in patients with
breast cancer with no CV risk (Lee 2021).
Investigators conducted a meta-analysis of randomized
controlled trials using ACE inhibitors and ARBs prophylacti-
cally to prevent anthracycline-induced cardiotoxicity. They
included seven trials using change in LVEF as their end
point. They found that use of prophylactic renin-angiotensin-
aldosterone system (RAAS) inhibition better preserved LVEF,
with a mean difference of -3.16% (p=0.02). They concluded
that although there were only a few clinical trials and partic-
ipants, use of ACE inhibitors or ARBs reduced cardiotoxicity
associated with anthracyclines (Lin 2021).
PSAP 2022 Book 1 • Cardiology
Current guideline recommendations do not include the use
of prophylactic ACE inhibitors, ARBs, or β-blockers for anth-
racycline- or trastuzumab-treated patients because of lack of
consistent evidence and need for larger and longer clinical tri-
als. However, as evidenced by meta-analyses, early β-blocker
treatment potentially has short-term beneficial effects in pre-
serving LVEF and is reasonable to consider (Blanter 2019).
Prophylactic use of ACE inhibitors or ARBs has shown mod-
est changes in LVEF, but further, large-scale studies are
needed (Lin 2021).
Diagnosis and Treatment
Initial Evaluation
Neither the frequency of monitoring nor its effect on out-
comes is defined for patients at risk of cardiotoxicity.
Frequent symptom monitoring in all patients exposed to car-
diotoxic anticancer agents should occur throughout treat-
ment and follow-up. Patients who have previously received
anthracycline therapy should be considered for echocardi-
ography within 1 year of therapy completion. Patients with
evidence of structural heart disease on echocardiography,
including left ventricular dysfunction, hypertrophy, valvular
disease, or left ventricular dilation, regardless of symptoms,
should be staged using classifications set forth by the ACC
and AHA guidelines for HF management. Referral to a cardiol-
ogist should occur for stages B, C, and D (NCCN 2021).
Anthracycline-induced cardiotoxicity is defined by a
decrease in LVEF of at least 10% from baseline with an overall
decrease of less than 50%. In cardio-oncology, toxicities are
further classified as type I or type II. Type I is considered irre-
versible, as seen with anthracycline use. Type II is associated
with targeted therapies and is considered reversible.
Imaging and Monitoring
Patients noted to be at high risk of CVD should undergo more
frequent monitoring while receiving cardiotoxic chemother-
apeutic agents. Routine surveillance for all patients should
include a careful history and a complete physical examina-
tion at each visit. Referral to a cardio-oncologist is also rec-
ommended for further evaluation. Alternative treatments
should be considered for patients experiencing symptoms
at any time during therapy while weighing the risk-benefit
(Domercant 2016). Echocardiography should be performed
for patients experiencing symptoms to rule in or out HF symp-
tomology. Electrocardiograms should be obtained in patients
experiencing arrhythmias.
Follow-up and Treatment
Interruption of chemotherapy for toxicities may be necessary,
depending on the severity. Treatment for each specific toxic-
ity does not differ from that for patients without cancer. For
example, patients found to have a decrease in LVEF with signs
and symptoms of HF should be treated in accordance with
the ACC and AHA guidelines. Clinicians must also carefully
40 Drug-Induced Cardiovascular Disease
 Table 2. Summary of Specific Chemotherapeutic Agents and Prevention or Mitigation Strategies for Cardiotoxicities

Associated
Agent/Class Cardiotoxicity Prevention or Mitigation Strategies Other Pearls

Anthracyclines Cardiomyopathy All dosing: Do not initiate for LVEF < 40%
HF • Cardio-oncologic evaluation at baseline, end of unless no other effective
treatment, 6 mo, 1 yr, and 2 yr treatment available
• Baseline BNP, troponin
• Optimal management of CV risk factors
High dose:
• Consider dexrazoxane
• Additional cardio-oncologic evaluation before
each cycle
• Troponin at the end of each cycle
Low dose:
• Troponin at the end of each cycle if risk factors
present
CV symptoms or positive troponin:
• Cardio-oncologic evaluation

HER2 inhibitors Cardiomyopathy • Cardio-oncologic evaluation at baseline, every Do not initiate for LVEF < 40%
Trastuzumab HF 3 mo during treatment, end of treatment, 6 mo, unless no other effective
1 yr and 2 yr treatment available
• Baseline BNP, troponin
• Optimal management of CV risk factors
• Troponin after each cycle if risk factors present
CV symptoms or positive troponin:
• Cardio-oncologic evaluation

VEGF inhibitors Hypertension • Cardio-oncologic evaluation at baseline, every

Myocardial ischemia 3 mo for 1 yr, every 6 mo during treatment
LV dysfunction • Optimal management of CV risk factors
QTc prolongation • Home BP monitoring
Arterial thromboem-
bolic events

BCR-ABL kinase Atherosclerosis • Cardio-oncologic evaluation at baseline, every Nilotinib carries a boxed
inhibitors PAD 3 mo for 1 yr, and every 6 mo during treatment warning for QT prolongation
ACS for ponatinib and nilotinib and high-risk patients and sudden death. Ponatinib
Stroke taking imatinib, bosutinib, and dasatinib has been associated with
Pericardial effusion • Optimal management of CV risk factors severe arterial thrombotic
Pulmonary artery • Home BP monitoring for ponatinib and nilotinib events during treatment.
hypertension • PAD screening and ankle-brachial index with
QTc prolongation Doppler of lower extremities at baseline for
nilotinib and every 6 mo if at high risk, for both
ponatinib and nilotinib

ICIs Immune-related • ECG and troponin at baseline, within 48 hr of Grading (G) levels 1–4
myocarditis each administration, and if symptomatic G1: Abnormal testing
Pericarditis • Cardio-oncologic evaluation if positive troponin (biomarkers or ECG)
Supraventricular or ECG abnormal G2: G1 + mild symptoms
arrhythmias G3: G1 + symptoms with mild
ACS activity
Takotsubo G4: Moderate to severe
syndrome decompensation, life
threatening
Permanently discontinue ICIs
for all grades of cardiotoxicity

(continued)

PSAP 2022 Book 1 • Cardiology 41 Drug-Induced Cardiovascular Disease

 Table 2. Summary of Specific Chemotherapeutic Agents and Prevention or Mitigation Strategies for Cardiotoxicities
(continued)

Ibrutinib AF • Cardio-oncologic evaluation at baseline, every AF most likely in the first

Ventricular 3 mo for 1 yr, and every 6 mo during treatment 30 days
arrhythmias • Home BP monitoring
HF • Symptomatic patients monitored with Holter
Hypertension ECG

ACS = acute coronary syndromes; AF = atrial fibrillation; BP = blood pressure; HF = heart failure; ICI = immune checkpoint inhibitor;
LV = left ventricular; PAD = peripheral arterial disease; VEGF = vascular endothelial growth factor.
Information from: Alexandre J, Cautela J, Ederhy S, et al. Cardiovascular toxicity related to cancer treatment: a pragmatic approach
to the American and European cardio-oncology guidelines. J Am Heart Assoc 2020;9:e018403; Brahmer JR, Lacchetti C, Schneider
BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American
Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018;36:1714-68.

weigh other patient-specific factors such as drug-drug inter-

actions, laboratory assessments (for hematologic abnormal- Table 3. Medications Associated with Drug-Induced
ities), and patient outcomes. Table 2 summarizes prevention Sinus Bradycardia and AV Nodal Blockade
and mitigation strategies.
Sinus AV Nodal
Medication Bradycardia Blockade
OTHER AGENTS OF CARDIOTOXICITY Adenosine X X
Arrhythmias
Amiodarone X X
Supraventricular Arrhythmias β-Blockers X X
Sinus Bradycardia and Atrioventricular Nodal
Clonidine X
Blockade
Dexmedetomidine X
Sinus bradycardia is defined as a heart rate less than 60
beats/minute. Dysfunction of the sinoatrial (SA) node, which Digoxin X X
is responsible for the automaticity of the heart, can also Dronedarone X
result in sinus “pauses” or sinus arrest. Atrioventricular (AV)
Ivabradine X X
nodal blockage occurs when electrical impulses do not prop-
agate from the atria and ventricles. Blockade is described Non-DHP CCB X X
as first, second, or third degree on the basis of severity and Propafenone X X
characteristics. First-degree AV block is a delay in conduc-
tion resulting in a lengthened PR interval by 0.2 seconds. AV = atrioventricular; non-DHP CCB = non-dihydropyridine
Second-degree AV block is exhibited by a lack of conduction calcium channel blocker.

of some impulses between the atria and the ventricle, result-
ing in a “dropped” beat. Third-degree AV block, or complete
heart block, is exhibited by no association between atria and
ventricular beats.
Several mechanisms can cause drug-induced sinus bra-
dycardia, including SA node automaticity inhibition, slow SA
node conduction, or prolonged repolarization of the SA node.
Atrioventricular block can be caused by AV node conduction
inhibition or prolonged repolarization of the AV node. In addi-
tion, activation or inhibition of sympathetic and parasympa-
thetic nervous systems can affect conduction. Drugs that
affect the action potentials – including calcium channel and
sodium channel inhibitors – may also cause sinus bradycar-
dia and/or AV block. Table 3 lists these medications. Other
mechanisms for consideration include drug overdose, drug
Information from: Wiggins BS, Lehner AL. Drug-induced
cardiovascular disease. In: Jackevicius C, Patterson JH,
eds. Cardiology Self-Assessment Program, 2020 Book 1.
Critical Care Cardiology. American College of Clinical
Pharmacy, 2020:93-119.
accumulation because of decreased elimination or metab-
olism, and synergistic or additive effects of combining drug
therapies.
Prevention of sinus bradycardia and AV nodal blockage
is imperative. Careful monitoring of heart rate is required in
those with first-degree heart block but is not a contraindica-
tion to initiation. In patients with known second- or third-de-
gree heart block without pacemakers, nodal-blocking agents
should be avoided. Medications should also be adjusted for

PSAP 2022 Book 1 • Cardiology 42 Drug-Induced Cardiovascular Disease

 Table 4. Drug-Specific Management of Severe Bradycardia/AV Nodal Blockade

Medication Treatment Options General Approach

β-Blocker/ GI decontamination with activated charcoal Severely symptomatic:

non-DHP CCBs Supportive therapies • Initiate all treatments simultaneously
• IV fluid bolus Mildly symptomatic:
• Calcium chloride IV (up to 3 g total) • Initiate in succession, depending on
• Vasopressors PRN response
HDIE • Atropine + IV fluid bolus
• Regular insulin 1 unit/kg bolus + 0.5- to 1-unit/kg/hr • Glucagon
infusion • Calcium chloride IV
• PRN dextrose 50% 50 mL • Vasopressors
Glucagon 5 mg IV push, 2- to 5-mg/hr infusions • HDIE
Refractory shock: Consider lipid emulsion 20% 100-mL bolus • Lipid emulsions

Digoxin Digoxin-immune Fab (antigen-binding fragments) (DigiFab/ Fab administered to patients with life-
Digibind) threatening or hemodynamically
• Dosing based on acute vs. chronic ingestion unstable arrhythmias, hyperkalemia,
AND evidence of end-organ dysfunction from
• Steady-state serum digoxin concentration hypoperfusion (e.g., renal failure)
OR
• Number of tablets ingested

CCB = non-dihydropyridine calcium channel blocker; HDIE = high-dose insulin/euglycemia; IV = intravenous(ly); PRN = as needed.
Information from: Schult RF, Acquisto NM, Toxicology of cardiovascular drugs. In: Jackevicius C, Patterson JH, eds. Cardiology Self-
Assessment Program, 2020 Book 1. Critical Care Cardiology. American College of Clinical Pharmacy, 2020:67-92; Oliphant CS.
Drug-induced cardiovascular disease and drugs to avoid in CV disease. In: Updates in Therapeutics®: Cardiology Pharmacy
Preparatory Review Course. American College of Clinical Pharmacy 2018:273-300.

renal and hepatic impairment and applicable drug interac-
tions to ensure accumulation does not occur.
Symptomatic bradyarrhythmias can be mitigated by
decreasing or discontinuing the causative agent. If symp-
tomatic relief is not provided with this measure or symp-
toms require hospitalization, a temporary pacemaker may
be required while awaiting drug clearance. If there is underly-
ing dysfunction of the AV node, permanent pacemaker place-
ment may be warranted. In severe cases, atropine may be
administered at a dose of 1 mg every 3–5 minutes (maximum
stimulate the sympathetic nervous system (SNS) can cause
these supraventricular arrhythmias (Table 5). Because of
the uncommon nature of supraventricular arrhythmias, pre-
ventive measures are unclear. Management should include
Table 5. Medications Causing AF or Atrial Flutter and
Mechanism
Medication Mechanism

dose 3 mg). If atropine is ineffective, a continuous infusion of Adenosine Shorten atrial

epinephrine intravenously should be initiated at a dose refractory period
of 2–10 mcg/minute or dopamine intravenously at 2–10 Albuterol, alcohol, dobutamine, SNS stimulation
mcg/kg/minute to maintain adequate blood pressures. Table dopamine, theophylline
4 summarizes drug overdose–specific treatments.
Levothyroxine, liothyronine, Hyperthyroidism
thyroid, amiodarone
Atrial Fibrillation/Atrial Flutter Ivabradine Unknown
Atrial fibrillation is a rapid irregularly irregular supraventricu- Bisphosphonates
lar arrhythmia caused by multiple ectopic impulses originat-
ing from the atria and not the SA node. Electrocardiographic SNS= sympathetic nervous system
characteristics include an absence of P waves. In contrast, Information from: Oliphant CS. Drug-induced cardiovascular
the ECG pattern of AF has discernable P waves that produce disease and drugs to avoid in CV disease. In: Updates in
a sawtooth-like pattern. Therapeutics: Cardiology Pharmacy Preparatory Review
Course. American College of Clinical Pharmacy,
Atrial fibrillation and flutter are not typically drug induced, 2018:273-300.
but medications that shorten the atrial refractory period or

PSAP 2022 Book 1 • Cardiology 43 Drug-Induced Cardiovascular Disease

discontinuation of potentially causative agents. If the arrhyth-
mia persists, patients should be treated according to current
AHA or ACC guideline recommendations.
Ventricular Arrhythmias
Monomorphic VT
Monomorphic VT originates from ectopic focus in the ven-
tricles causing ventricular depolarization. Monomorphic VT
is defined by a regular wide QRS complex with a rate greater
than 100 beats/minute, with a uniform and stable morphol-
ogy. Monomorphic VT is described as sustained or unsus-
tained, with unsustained monomorphic VT terminating
within less than 30 seconds. Monomorphic VT can be related
to medication use or other CV or metabolic causes. Non–
medication-related risk factors include structural heart dis-
ease, depressed left ventricular function (EF less than 40%),
and electrolyte depletion, particularly magnesium, potas-
sium, and calcium. Diagnosis of drug-induced VT requires
careful consideration of the patient’s medication history,
elimination of CV pathophysiology, and differentiation from
previous episodes, if any. Vaughan Williams class Ic anti-
arrhythmics are commonly implicated in drug-induced VT
because their inhibition of sodium channels results in reduc-
tion in ventricular conductivity (Table 6).
Table 6. Medications Associated with Monomorphic
Ventricular Tachycardia
Medication Mechanism
Digoxin Sodium-potassium-adenosine
triphosphate pump inhibition,
resulting in increased
intracellular calcium
Amiodarone, disopyramide, Sodium channel inhibition
flecainide, procainamide,
propafenone
Amphetamines, cocaine. SNS stimulation
dobutamine, dopamine,
terbutaline
Milrinone, theophylline PDE inhibition preventing
breakdown of cAMP,
causing increased
intracellular calcium and
ventricular ectopic activity
Adenosine, regadenoson SNS stimulation
Myocardial ischemia
PDE = phosphodiesterase; SNS = sympathetic nervous
system.
Information from: Oliphant CS. Drug-induced cardiovascular
disease and drugs to avoid in CV disease. In: Updates in
Therapeutics: Cardiology Pharmacy Preparatory Review
Course. American College of Clinical Pharmacy, 2018:
273-300.
PSAP 2022 Book 1 • Cardiology
Heart failure with reduced EF is a risk factor for VT; there-
fore, class Ic antiarrhythmics are contraindicated. Class Ia
and Ic should be avoided in coronary artery disease. Digoxin
should be dose adjusted in patients with renal impairment
and closely monitored during acute kidney injury. Concen-
trations above 2 ng/mL are considered toxic. Monitor for
potential drug-drug interactions when initiating new antiar-
rhythmics. Maintain normal electrolyte concentrations and
consider closer monitoring during periods of GI illnesses
such as excessive vomiting or diarrhea.
If VT occurs, discontinue the potential offending medica-
tion. Direct cardioversion may be necessary to restore sinus
rhythm if the patient is hemodynamically unstable. If the
patient is hemodynamically stable, management includes
intravenous antiarrhythmics from several classes such as
adenosine, procainamide, amiodarone, or sotalol.
Torsades de Pointes
Torsades de pointes (TdP) or polymorphic VT comes from the
French phrase meaning “twisting of the points.” Torsades de
pointes is the result of prolongation of the ventricular action
potential, evidenced on ECG as QTc prolongation. Torsades de
pointes is potentially life threatening, and quick recognition
is critical to prevent deterioration to ventricular fibrillation.
Torsades de pointes can be congenital or acquired. Acquired
TdP is often a result of medications that lengthen the rela-
tive refractory period. Lengthening of the refractory period
can occur with decreases in outward current or increases in
inward current during repolarization.
There are several risk factors for TdP (Box 2). Prolongation
of the QTc is a crucial step in TdP development. Onset can
be variable, coinciding with the peak of the drug, or delayed
as the drug accumulates. The risk of TdP increases when the
QTc interval is prolonged over 500 milliseconds. Table 7 lists
commonly associated medications.
Box 2. Risk Factors for Drug-Induced
Torsades de Pointes
• Additive effect of > 1 agent used in combination
• Advanced age
• Bradycardia
• Depressed left ventricular ejection fraction
• Elevated drug concentration (alterations in metabolism
or excretion)
• Female sex
• Hypomagnesemia, hypokalemia
• QTc > 500 ms
ms = milliseconds.
Information from: Wiggins BS, Lehner AL. Drug-induced car-
diovascular disease. In: Jackevicius C, Patterson JH, eds.
Cardiology Self-Assessment Program, 2020 Book 1. Critical
Care Cardiology. American College of Clinical Pharmacy,
2020:93-119.
44 Drug-Induced Cardiovascular Disease
 Table 7. Medications with Known Risk of Drug-Induced Torsades de Pointes

Drug Class Agents

Antiarrhythmics Amiodarone, disopyramide, dofetilide, dronedarone, flecainide, ibutilide, procainamide,

propafenone, quinidine, sotalol

Antidepressants Citalopram, escitalopram

Antiemetics Chlorpromazine, domperidone, droperidol, ondansetron

Antimicrobials Azithromycin, clarithromycin, ciprofloxacin, erythromycin, fluconazole, levofloxacin,

moxifloxacin, pentamidine

Antipsychotics Haloperidol, thioridazine

Chemotherapeutics Arsenic trioxide, oxaliplatin, vandetanib

Opioid agonists Methadone

Information from: Wiggins BS, Lehner AL. Drug-induced cardiovascular disease. In: Jackevicius C, Patterson JH, eds. Cardiology
Self-Assessment Program, 2020 Book 1. Critical Care Cardiology. American College of Clinical Pharmacy, 2020:93-119.

Torsades de pointes can be prevented through early recog- Volume Retention

nition of risk factors and careful monitoring. A baseline ECG
should be obtained, when feasible, and a repeat ECG should
be obtained when the medication has reached steady state.
Use of prolonging agents should be avoided if the baseline
ECG reveals a QTc interval greater than 450 milliseconds.
Contributing medications should be discontinued if the QTc
exceeds 500 milliseconds. A full medication profile review
helps elucidate synergistic effects of several QTc-prolongat-
ing medications. Normal potassium and magnesium con-
centrations should be maintained, and closer monitoring
during GI illnesses, such as vomiting or diarrhea, should be
considered.
Management of TdP relies on distinguishing polymorphic
VT from monomorphic morphology. Unstable patients should
be treated with defibrillation. Administration of intravenous
magnesium has been reported to terminate TdP and is admin-
istered at a dose of 1–2 g over 15 minutes. Figure 1 summa-
rizes TdP management.
Hypertension
Hypertension was the leading cause of death worldwide in
2010. Almost one-half of all U.S. adults have hypertension,
and only one-fourth of cases are under control (CDC 2020).
Drug-induced hypertension can be caused by use or with-
drawal of a medication and is often overlooked as a poten-
tial cause of resistant hypertension. Hypertension is often
preventable and reversible. A careful medication history
including OTC and herbal supplements is necessary to iden-
tify potential sources of drug-induced hypertension. Causes
include volume retention, sympathomimetic activation, and
direct vasoconstriction. In addition, abrupt withdrawal of
β-blockers and centrally acting α-agonists can cause rebound
hypertension.
Arterial blood pressure is regulated under normal conditions
by the RAAS in the kidneys. Through signaling pathways, hor-
mone release, and sensed changed in pressure and flow, the
body can adapt by regulating intravascular volume. Inter-
action with the RAAS leading to volume retention occurs
for several common classes. These adverse effects can be
unwanted and lead to harmful effects in certain patient pop-
ulations. Commonly implicated drug classes include NSAIDs,
sex hormones, and corticosteroids.
Nonsteroidal Anti-inflammatory Drugs
The availability of several NSAIDs OTC makes this drug class
a common offender of drug-induced hypertension. Nonsteroi-
dal anti-inflammatory drugs inhibit cyclooxygenase (COX)-1
and COX-2, causing a reduction in prostaglandin synthesis.
Prostaglandins have vasodilatory and natriuretic effects.
Nonsteroidal anti-inflammatory drugs increase sodium and
water retention and activate the RAAS. Prolonged NSAID use
can result in an increase in blood pressure by an average of
5 mm Hg. Naproxen, piroxicam, and ibuprofen have the high-
est increases (Lovell 2017). However, low-dose aspirin has
almost no effect on blood pressure.
Nonsteroidal anti-inflammatory drugs also reduce the effi-
cacy of RAAS inhibitor agents, β-blockers, and diuretics used
for the treatment of preexisting hypertension. Alternative
agents such as calcium channel blockers and centrally act-
ing agents can be used in patients who cannot discontinue
NSAID therapy.
Sex Hormones
Oral contraceptives containing estrogen can activate the
RAAS by increasing the production of angiotensinogen,
resulting in volume retention. Higher doses of estrogen than

PSAP 2022 Book 1 • Cardiology 45 Drug-Induced Cardiovascular Disease

 Torsades de pointes

Discontinue offending agent(s)

Correct electrolytes (K+, Mg2+, Ca2+)

Hemodynamically Hemodynamically
unstable stable

Defibrillation Magnesium sulfate

1–2 g IV over 15 min

TdP recurrence

TdP with bradycardia TdP with no

or precipitated by bradycardia or does
pauses in rhythm not appear to be
precipitated by
pauses in the rhythm

Isoproterenol 2- to 10-mcg/min
continuous IV infusion
OR TdP recurrence Defibrillation
Temporary transvenous
overdrive pacing

Figure 1. Management of drug-induced torsades de pointes.

IV = intravenous(ly); TdP = torsades de pointes.
Information from: Tisdale JE. Ventricular arrhythmias. In: Tisdale JE, Miller DA, eds. Drug-Induced Diseases: Prevention, Detection,
and Management. American Society of Health-System Pharmacists, 2018:523-67.

previously used have a more pronounced effect; however,
increases in blood pressure can occur with newer, lower dos-
ing strategies. Hormone therapy from contraception supplies
higher concentrations of estrogen and progestin than nor-
mally detected. In contrast, doses of exogenous hormones
given to postmenopausal women for the prevention of meno-
pausal symptoms are lower than what is found in vivo during
menopause. Although estrogen replacement therapy in both
populations of women results in a higher risk of CV events,
drug-induced hypertension is uncommon in postmenopausal
women. The incidence of hypertension in patients taking oral
contraceptives is about 5% (Lovell 2017).
Testosterone causes fluid retention through androgen
receptor agonism, which stimulates erythropoietin. Increases
in blood volume through polycythemia lead to edema from
sodium and water retention. Testosterone is a known modu-
lator and regulator of metabolic functions, including choles-
terol synthesis and heart function. Testosterone deficiency
leads to metabolic syndrome, resulting in hypertension. How-
ever, replacement in hypogonadal men has been shown to
decrease blood pressure by an average of 23 mm Hg systolic
and 16 mm Hg diastolic (Francomano 2014).
Corticosteroids
Corticosteroids include both mineralocorticoids and glu-
cocorticoids, with mineralocorticoid activity implicated in
drug-induced hypertension through sodium and water reten-
tion. Steroids that have greater mineralocorticoid activ-
ity (i.e., hydrocortisone and fludrocortisone) have a greater
effect on blood pressure. However, other steroids can have

PSAP 2022 Book 1 • Cardiology 46 Drug-Induced Cardiovascular Disease

mineralocorticoid activity at higher doses (7.5 mg/day or
more of prednisone equivalents). Twenty percent of patients
who use corticosteroids have hypertension, with elevations
of as much as 15 mm Hg at cortisol doses of 80–200 mg
(Kassel 2015). Some studies suggest that CV risk is more pro-
nounced at higher steroid doses than during long treatment
durations (Lovell 2017).
Sympathomimetic Activation
Decongestants
Pseudoephedrine and phenylephrine are both available OTC
for nasal congestion. Pseudoephedrine and phenylephrine
work by activating the SNS through α1-adrenergic receptors,
causing peripheral vasoconstriction. Phenylephrine doses of
45 mg can increase systolic pressures by 20 mm Hg (Lovell
2017). Many formulations co-formulated with acetamino-
phen pose an additional concern because coadministration
increases the bioavailability of phenylephrine. Pseudoephed-
rine also causes a dose-dependent increase in blood pres-
sure, though the clinical implications are unclear. Increases
in both normotensive patients and patients with hypertension
were less than 2 mm Hg. Decongestants should be used with
caution in patients with hypertension; however, they are gen-
erally considered safe.
Psychostimulants
Sympathetic stimulation from medications used for atten-
tion-deficit/hyperactivity disorder increases the norepi-
nephrine in the presynaptic terminal, activating adrenergic
receptors, leading to vasoconstriction. Data in the pediat-
ric population show that stimulants increase diastolic blood
pressure and heart rate, but not systolic blood pressure (Kas-
sel 2015). The AHA recommends blood pressure and heart
rate monitoring within 1–3 months after initiation. Follow-up
monitoring should occur every 6–12 months and more often
during periods of titration or weaning (Vetter 2008).
Caffeine
Caffeine causes an increase in blood pressure by activat-
ing the SNS, increasing catecholamine release, and blocking
circulating adenosine, responsible for coronary vasodila-
tion (Lovell 2017). One meta-analysis found that acute con-
sumption of 200–300 mg of caffeine caused an increase of
8.14 mm Hg in systolic blood pressure within the first several
hours. Drinking caffeine (coffee) for 2 weeks did not appear
to raise participants’ blood pressure (Mesas 2011). Long-term
effects of drinking caffeine are unknown, but drinking caf-
feine was not associated with worse outcomes.
Cocaine
Like other psychostimulants, cocaine increases norepineph-
rine at the synapse, resulting in sympathetic stimulation of
α-adrenergic receptors in the periphery but also β-adrenergic
PSAP 2022 Book 1 • Cardiology
receptors in the heart. The resultant effect is hypertension
from peripheral vasoconstriction, tachycardia, and increased
contractility. Cocaine causes a dose-dependent increase in
blood pressure as well as other effects depending on route of
administration (Lovell 2017).
Antidepressants and Antipsychotics
Several antidepressants and antipsychotics have been iden-
tified as potentially contributing to drug-induced hyperten-
sion. Bupropion, a dopamine reuptake inhibitor, is associated
with elevations in supine blood pressure while causing
orthostatic hypotension. Risk of hypertension is increased
in patients using transdermal nicotine patches for smoking
cessation.
Tricyclic antidepressants were some of the first antidepres-
sants to be used. Each drug in this class works similarly by pre-
venting reuptake of serotonin and norepinephrine. However,
tricyclic antidepressants have unintended adverse effects
because of receptor selectivity. Some members of this class
have anticholinergic, antihistaminic, and α1-adrengeric recep-
tor activity. Tricyclic antidepressants should be reserved for
patients who cannot be treated with newer-generation antide-
pressants (Kassel 2015).
Monoamine oxidase inhibitors are associated with eleva-
tions in blood pressure with ingestion of tyramine-rich foods.
Possible mechanisms by which hypertension occurs include
metabolism to amphetamine. Monoamine oxidase inhibi-
tors should only be used in patients who are refractory to or
unable to take first-line therapies (Kassel 2015).
Venlafaxine, a serotonin and norepinephrine reuptake
inhibitor, causes hypertension at doses greater than 300 mg/
day. Doses should be limited in patients and additional agents
added on if symptoms are uncontrolled at maximum doses.
Venlafaxine’s enantiomer, desvenlafaxine, also causes eleva-
tions in blood pressure, particularly in those with preexisting
CVD (Kassel 2015).
Direct Vasoconstriction
Calcineurin inhibitors (CNIs) tacrolimus and cyclosporine
are immunosuppressive agents used for the prevention of
solid organ transplant rejection together with several other
conditions. Because there are no alternatives to therapy,
adverse effects must be managed. Drug-induced hyperten-
sion occurs through several pathways. Calcineurin inhibitors
decrease the production of nitric oxide, resulting in inhibi-
tion of vasodilation. In addition, SNS stimulation causes
sodium retention. It appears that cyclosporine more com-
monly causes drug-induced hypertension and that effects
are dose related (Lovell 2017). Management of CNI-induced
hypertension can be through dose reduction or addition of
antihypertensives. Expert opinion suggests reducing the CNI
dose by 25% for stage 1 hypertension and 50% for stage 2.
47 Drug-Induced Cardiovascular Disease
Dihydropyridine calcium channel blockers are the preferred
antihypertensive because of their lack of drug interactions
and mechanism. Dihydropyridine calcium channel blockers
are particularly beneficial in kidney transplant recipients by
causing vasodilation in both the afferent and efferent arteri-
oles (Claus 2018).
Miscellaneous/Other
Erythropoiesis-stimulating agents epoetin alfa and darbep-
oetin alfa are FDA approved to treat anemia for a variety of
pathologies, including chronic kidney disease and HIV, and as
an adjunct to chemotherapy. Hypertension occurs in about
20%–30% of patients, developing in the subacute treatment
phase. Several different mechanisms exist, including increase
in blood viscosity, RAAS activation, and increased vasocon-
striction through decreased nitric oxide synthesis. If discon-
tinuing the medication is not feasible, several strategies can
be used to lower the blood pressure. In patients with chronic
kidney disease, volume removal may prove helpful. Addition
of diuretics and antihypertensives to control the blood pres-
sure elevation can also be considered. Patients taking eryth-
ropoiesis-stimulating agents should have their doses lowered
or discontinued when no longer indicated. Blood pressure
should be monitored throughout therapy (Claus 2018).
Hypotension
Hypotension, defined as blood pressure less than 90/60 mm
Hg, can often result from over-intensification of an antihyper-
tensive regimen or as an unintended adverse effect because
of receptor selectivity. Hypotension is potentially problematic
in older adult patients because it can lead to syncope, falls
and injury, or hypoperfusion of vital organ systems; there-
fore, it should be prevented. Hypotension can be categorized
as acute, chronic, or orthostatic. Chronic implies the blood
pressure is consistently low despite the patient’s position.
Orthostatic describes a reduction in blood pressure when the
patient stands up. Hypotension can also be the result of auto-
nomic failure.
Hypotension risk is additive when several antihyperten-
sives are prescribed. Other risk factors include alcohol use,
dehydration and hot weather, hot tubs, bath or shower use,
and prolonged sitting or lying down. Several other agents
can induce hypotension unrelated to antihypertension
mechanisms.
Intravenous amiodarone, a common antiarrhythmic, is sus-
pended in polysorbate-80 and benzyl alcohol. Polysorbate-80
has potent vasodilatory and negative inotropic effects. Ben-
zyl alcohol also causes hypotension. It is recommended to
administer an amiodarone 150-mg bolus over 10 minutes to
prevent hypotension. The infusion can be slowed further if
hypotension occurs.
Tricyclic antidepressants have activity at unintended
receptors, causing hypotension. Hypotension is common with
imipramine but is also reported with other antidepressants
PSAP 2022 Book 1 • Cardiology
such as trazodone. Lowering the dose or discontinuing the
medication should be considered in symptomatic patients.
Tricyclic antidepressant overdose can cause profound hypo-
tension requiring medical intervention, including intravenous
fluid boluses and use of vasopressors. Lowering of antihyper-
tensives may also be required to allow the patient to tolerate
the hypotension associated with antidepressant therapy.
Antiparkinsonian agents work by increasing the amount
of circulating dopamine. Hypotension can occur through
vasodilation by dopamine receptors in the mesenteric and
renal circulation, shift of norepinephrine from receptor sites,
decreased sympathetic outflow, and inhibition of renin and
aldosterone secretion. Several agents exist in this class,
including bromocriptine, carbidopa/levodopa, entacapone,
pergolide, pramipexole, rasagiline, ropinirole, selegiline, and
tolcapone. No specific therapies for hypotension are asso-
ciated with antiparkinsonian medications. Nonpharmaco-
logic strategies that may be beneficial include increasing
fluid and salt intake, tilting the head of bed during nighttime
sleep, using compression stockings or abdominal bandages,
and performing physical movements such as leg crossing
or squatting (Sánchez-Ferro 2013). If these do not produce
the desired effect, pharmacologic agents can be used. Flud-
rocortisone, pyridostigmine, midodrine, and droxidopa are
all used to improve hypotension associated with antipar-
kinsonian therapy. Fludrocortisone works by expanding vol-
ume through renal sodium reabsorption. Pyridostigmine
inhibits cholinesterase, improving transmission of acetyl-
choline signaling. Midodrine is an α1-agonist that increases
systemic vascular resistance. Finally, droxidopa is a syn-
thetic norepinephrine precursor that can used in the setting
of severe orthostasis from autonomic disorders. Of impor-
tance, although these medications can improve orthostatic
hypotension, they can worsen supine hypertension. Fre-
quent monitoring is recommended to avoid overcorrection
of hypotension.
Endothelin (ET) receptor antagonists are used to treat pul-
monary arterial hypertension. Inhibition of ET-1 causes vaso-
dilation in smooth muscle at receptor targets ETA and ETB.
Available agents include nonselective bosentan and maci-
tentan and the selective ETA inhibitor ambrisentan. Because
of vasodilation, hypotension can result. The risk appears to
be low but can be synergistic if other antihypertensives are
added.
Myocardial Ischemia
Several mechanisms for medication-induced myocardial
ischemia exist. Myocardial ischemia results from an oxy-
gen supply and demand mismatch. Commonly, ischemia
can occur from the development of atherosclerotic disease,
though coronary vasospasm or drug withdrawal can also
lead to infarction. Ischemia can occur acutely, which may
be directly attributable to a drug. Acute coronary syndromes
48 Drug-Induced Cardiovascular Disease
that are associated with longer-term therapy are more chal- protective against MI (Llibre 2016). On the basis of current
lenging to prove a direct correlation with; however, some ther- evidence, it is reasonable to avoid use of abacavir in patients
apies have been noted to increase the risk of atherosclerotic at risk of CVD. Although some regimens are unavoidable
coronary artery disease and its associated morbidity. because of resistance patterns, other combination therapies
should be considered in treatment-naive at-risk patients.
HIV Medications
Antiretroviral therapy for HIV infection has prolonged the Nonsteroidal Anti-inflammatory Drugs
lives of many with HIV infection. Several medications have
Nonsteroidal anti-inflammatory drugs are widely available
been linked to an increased risk of CVD, mainly limited to old-
and commonly prescribed for pain management. Neverthe-
er-generation medications from the protease inhibitor and
less, they have been associated with an increased risk of
nucleoside reverse transcriptase inhibitor classes. An analy-
CV events. This risk has garnered attention in recent years
sis of Veterans Affairs registry data showed that patients with
because of the removal of two selective COX-2 inhibitors from
HIV-positive infection had a 48% increased risk of MI (Freiberg
the U.S. market, rofecoxib and valdecoxib. Overall, major vas-
2013). Both HIV and antiretroviral therapy can contribute to
cular events are more frequently seen with the use of NSAIDs
CVD. Human immunodeficiency virus infection itself alters
compared to placebo, regardless of COX selectivity. Cardio-
immune function, causes chronic inflammation, and predis-
vascular risk seems to be lower for nonselective NSAIDs
poses patients to dyslipidemia and hypercoagulable states.
like naproxen and ibuprofen but is still higher than seen in
Antiretroviral therapy has several long-term adverse effects,
non-users. Additionally, available COX-2 selective agents
including insulin resistance, dyslipidemia, and lipodystrophy
such as celecoxib demonstrate increased rates of vascular
(Overton 2014). Protease inhibitors cause increases in serum
events compared to nonselective agents. The AHA issued a
cholesterol and triglycerides. Increases in cholesterol of
recommendation in 2014 stating that analgesic agents with
30%–40% and triglycerides of 200%–300% can occur within
lower risk (e.g., acetaminophen, tramadol) should be used
the first week of therapy. In addition, after 2 years of therapy,
first line in the treatment of musculoskeletal pain symptoms
more than 50% of patients taking protease inhibitors will have
in patients with known CVD or risk factors for CVD. Naproxen
hypercholesterolemia or hypertriglyceridemia (Penzak 2002).
is preferred if the other agents are ineffective, according to
Abacavir, a nucleoside reverse transcriptase inhibitor, can
a meta-analysis of randomized controlled trials showing no
cause CVD. Recent exposure to abacavir was associated
increase in risk (Patrono 2014).
with increased rates of acute MI. Several other cohort stud-
ies failed to replicate this finding. Two more recent studies Heart Failure
have added more data to the debate. The first, NA-ACCORD,
Heart failure is estimated to affect 6.2 million Americans.
showed that treatment-naive patients initiated on abacavir-
Heart failure is the primary diagnosis for hospital discharge
containing regimens had an increased risk of acute MI. The
for 1 million and secondary diagnosis for 2 million hospital-
second study of a Swiss cohort found that recent exposure
izations per year (Hollenberg 2019). Patients with HF are pre-
to abacavir in the past 6 months was associated with an
scribed an average of seven prescription drugs with complex
increased risk of acute MI; however, current abacavir use was
dosing regimens (Page 2016). Polypharmacy, usually defined

Table 8. Medications That May Cause or Exacerbate HF

Medication Cause HF Exacerbate HF Mechanism Onset

α1-Antagonists: X β1-Receptor stimulation Intermediate to delayed

Doxazosin

Amphotericin B X Unknown Unknown

Anesthetics: Immediate

Dexmedetomidine X α 2-Agonist

Etomidate X Suppression of adrenal

function

Ketamine X Negative inotrope

(continued)

PSAP 2022 Book 1 • Cardiology 49 Drug-Induced Cardiovascular Disease

 Table 8. Medications That May Cause or Exacerbate HF  (continued)

Propofol X Negative inotrope,

vasodilation

Anthracyclines: X X Reduced contractility, many Immediate to delayed

Doxorubicin potential mechanisms
Epirubicin
Idarubicin

Antiarrhythmics: X Negative inotrope Immediate to intermediate

Disopyramide
Dronedarone
Flecainide
Lidocaine
Mexiletine
Propafenone

Antidiabetics: Immediate to delayed

Dipeptidyl peptidase-4 X Unknown

inhibitors:
Saxagliptin
Sitagliptin

Thiazolidinediones X Possible calcium channel

blockage

Calcium channel blockers: X Negative inotrope Immediate

Diltiazem
Nifedipine
Verapamil

Cilostazol X PDE-3 inhibitor, resulting in Unknown

arrhythmias

Clozapine X IgE-mediated Intermediate to delayed

hypersensitivity reaction,
calcium channel blockage

COX-2 inhibitors: X Sodium and water retention Immediate

Celecoxib

HER2 receptor inhibitor: X X Antibody-dependent Immediate to delayed

Trastuzumab cytotoxicity

Parkinson disease agents: X Excess serotonin activity Intermediate to delayed

Pramipexole leading to valvular damage
Ropinirole

Tricyclic antidepressants X Negative inotrope, Intermediate to delayed

proarrhythmic

VEGF inhibitors: X Unknown Unknown

Bevacizumab
Sunitinib
Sorafenib
Ponatinib

HER2 = human epidermal growth factor; IgE = immunoglobulin E.

Information from: Page RL II, O’Bryant CL, Cheng D, et al. Drugs that may cause or exacerbate heart failure: a scientific statement
from the American Heart Association [published correction appears in Circulation 2016;134:e261]. Circulation 2016;134:e32-e69;
Hamarneh YN, Tsuyuki RT. Heart failure. In: Tisdale JE, Miller DA, eds. Drug-Induced Diseases: Prevention, Detection and
Management. American Society of Health-System Pharmacists 2018:501-21.

PSAP 2022 Book 1 • Cardiology 50 Drug-Induced Cardiovascular Disease


Practice Points
• Patients with cancer, especially those with breast cancer,
face an elevated risk of cardiomyopathy in their lifetime
secondary to first-line therapy with anthracyclines and/or
HER2 inhibitors. Screening for and management of CV risk
factors can help mitigate overall risk.
• Both bradyarrhythmias and tachyarrhythmias can be in-
duced by the overprescribing of multiple cardiac medica-
tions. It is important to recognize which medications will
exacerbate existing arrhythmias and which can unmask
electrophysiologic issues within the heart.
• Ventricular arrhythmias such as TdP can occur in the
setting of a congenital prolonged QTc disease or as an
additive effect from multiple medications. Pharmacists
can help patient care teams with alternatives that are less
prolonging or provide information on the risk associated
with certain classes of medications.
• The cause of medication-induced hypertension is related to
several mechanisms, including volume retention, sympa-
thetic activation, and direct vasoconstriction. Pharmacists
can help identify the offending medications and provide
reasonable alternatives if they exist.
• Antiretroviral therapy and NSAIDs can increase a patient’s
risk of CVD. Combined with risk modification, knowing
the risk of the individual agent can help prevent untoward
ischemic heart disease.
as five or more medications daily, places patients at risk of
more adverse drug reactions and drug-drug interactions
(Masnoon 2017). Medications known to cause or exacerbate
HF are too numerous for individual discussion in this chap-
ter. Table 8 summarizes the agents, and the beginning of the
chapter provides suggestions for additional reading.
CONCLUSION
Drug-induced CVD can present a challenge for both the gen-
eral patient population and patients with cancer. Anticipating
potential adverse events can provide the opportunity to opti-
mize therapy through screening. Understanding the mecha-
nism that causes cardiac diseases and the treatment for it
is vital to providing comprehensive care. Pharmacists are
uniquely positioned to provide drug information to the patient
care team. Identification of drug-induced diseases, therapeu-
tic treatment, prevention strategies, and patient counseling
are all essential services in the care of our patients.
REFERENCES
Aghel N, Delgado DH, Lipton JH. Cardiovascular toxicities
of BCR-ABL tyrosine kinase inhibitors in chronic myeloid
leukemia: preventive strategies and cardiovascular
surveillance. Vasc Health Risk Manag. 2017;13:293-303.
Alexandre J, Cautela J, Ederhy S, et al. Cardiovascular Toxicity
Related to Cancer Treatment: A Pragmatic Approach to the
American and European Cardio-Oncology Guidelines.
J Am Heart Assoc. 2020;9:e018403.
PSAP 2022 Book 1 • Cardiology
Armenian SH, Lacchetti C, Barac A et al. Prevention and
monitoring of cardiac dysfunction in survivors of adult
cancers: American Society of Clinical Oncology Clinical
Practice Guideline. J Clin Oncol 2016 35:893-911.
Barac A, Murtagth G, Carver JR et al. Cardiovascular health
of patients with cancer and cancer survivors:
a roadmap to the next level. J Am Coll Cardio 2015 Jun 30;
65:2739–46.
Blanter JB, Frishman WH. The preventative role of angioten-
sin converting enzyme inhibitors/ angiotensin-II receptor
blockers and beta-adrenergic blockers in anthracycline-
and trastuzumab-inducted cardiotoxicity. Cardiology in
Review 2019;12:256-9.
Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of
Immune-Related Adverse Events in Patients Treated With
Immune Checkpoint Inhibitor Therapy: American Society
of Clinical Oncology Clinical Practice Guideline. J Clin
Oncol. 2018;36(17):1714-1768.
Cardinale D, Colombo A, Sandri M et al. Prevention of high-
dose chemotherapy-induced cardiotoxicity in high-risk
patients by angiotensin-converting enzyme inhibition.
Circulation 2006;114:2474-81.
Cardinale D, Iacopo F, Cipolla CM. Cardiotoxicity of anthracy-
clines. Front Cardiovasc Med 2020; 7: 26.
Centers for Disease Control. Facts about Hypertension. 2020
Sept.
Chen MH, Kerkelä R, Force T. Mechanisms of cardiac dys-
function associated with tyrosine kinase inhibitor cancer
therapeutics. Circulation. 2008 Jul 1;118:84-95.
Claus LW, Saseen JJ. Hypertension. In: In: Tisdale JE, Miller
DA, eds. Drug-induced diseases: prevention, detection
and management. Bethesda MD: American Society of
Health-System Pharmacists 2018: 617-30.
Copeland-Halperin RS, Liu JE, Yu AF. Cardiotoxicity of
HER2-targeted therapies. Curr Opin Cardiol 2019 Jul; 34:
451-8.
D’Souza M, Carlson N, Fosbøl E, et al. CHA2DS2-VASc score
and risk of thromboembolism and bleeding in patients
with atrial fibrillation and recent cancer. Eur J Prev Cardiol.
2018;25(6):651-658.
Domercant J, Polin N, Jahangir E. Cardio-oncology: a focused
review of anthracycline-, human epidermal growth factor
receptor 2 inhibitor-, and radiation-induced cardiotoxicity
and management. Ochsner J. 2016 Fall;15:250-6.
Florescu M, Cinteza M, Vinereanu D. Chemotherapy-induced
cardiotoxicity. Maedica (Bucur) 2013 Mar; 8: 59-67.
Francomano D, Lenzi A, Aversa A. Effects of five-year treat-
ment with testosterone undecanoate on metabolic and
hormonal parameters in ageing men with metabolic
syndrome. Int J Endocrinol. 2014;2014:527470.
Ganatra S, Sharma A, Shah S, et al. Ibrutinib-Associated Atrial
Fibrillation. JACC Clin Electrophysiol. 2018;4(12):1491-1500
51 Drug-Induced Cardiovascular Disease
Georgakopoulos P, Kyriakidis M, Perpinia A, et al. The role
of metoprolol and enalapril in the prevention of doxorubi-
cin-induced cardiotoxicity in lymphoma patients. Anti Can
Res 2019;39:5703-7.
Hollenberg SM, Warner Stevenson L, Ahmad T, et al. 2019
ACC Expert Consensus Decision Pathway on Risk Assess-
ment, Management, and Clinical Trajectory of Patients
Hospitalized With Heart Failure: A Report of the American
College of Cardiology Solution Set Oversight Committee
[published correction appears in J Am Coll Cardiol. 2020
Jan 7;75(1):132]. J Am Coll Cardiol. 2019;74:1966-2011.
Hu YF, Liu CJ, Chang PM, et al. Incident thromboembolism
and heart failure associated with new-onset atrial fibrilla-
tion in cancer patients. Int J Cardiol. 2013;165(2):355-357.
Imbruvica (ibrutinib). Package insert. Janssen Biotech Inc.
July 2019.
Jerusalem G, Lancellotti P, Kim SB. HER2+ breast cancer
treatment and cardiotoxicity: monitoring and manage-
ment. Breast Cancer Res Treat. 2019;177(2):237-250.
Koutsoukis A, Ntalianis A, Repasos E, et al. Cardio-oncology:
A Focus on Cardiotoxicity. Eur Cardiol. 2018;13:64-69.
Lee M, Chung WB, Lee JE, et al. Candesartan and carvedilol for
primary prevention of subclinical cardiotoxicity in breast
cancer patients without a cardiovascular risk treated with
doxorubicin. Cancer Med. 2021;10(12):3964-3973.
Leong DP, Caron F, Hillis C, et al. The risk of atrial fibrillation
with ibrutinib use: a systematic review and meta-analysis.
Blood 2016 Jul 7;128:138-40.
Lin H, Liang G, Wu Y, Chen L. Protective Effects of ACEI/ARB
on Left Ventricular Function in Anthracycline-Induced
Chronic Cardiotoxicity: A Meta-Analysis of Randomized
Controlled Trials. Cardiology. 2021;146(4):469-480.
Llibre JM, Hill A. Abacavir and cardiovascular disease: A
critical look at the data. Antiviral Res. 2016 Aug;132:116-21.
Lovell AR, Ernst ME. Drug-Induced Hypertension: Focus
on Mechanisms and Management. Curr Hypertens Rep.
2017;19(5):39.
Masnoon N, Shakib S, Kalisch-Ellett L, Caughey GE. What is
polypharmacy? A systematic review of definitions. BMC
Geriatr. 2017;17(1):230. Published 2017 Oct 10.
Mesas AE, Leon-Muñoz LM, Rodriguez-Artalejo F, et al. The
effect of coffee on blood pressure and cardiovascular dis-
ease in hypertensive individuals: a systematic review and
meta-analysis. Am J Clin Nutr. 2011 Oct;94:1113-26.
Michel L, Rassaf T, Totzeck M. Cardiotoxicity from
immune checkpoint inhibitors. Int J Cardiol Heart Vasc.
2019;25:100420. Published 2019 Sep 7.
More L, Patell, R, Asnani, A. Ibrutinib-Associated Cardiotoxic-
ity. American College of Cardiology. 2020 Jan 21.
PSAP 2022 Book 1 • Cardiology
National Comprehensive Cancer Network: NCCN Clinical
Practice Guideline in Oncology. Survivorship Version 1.
Fort Washington, PA, Nation Comprehensive Cancer
Network. 2021.
Octavia Y, Tocchetti CG, Gabrielson KL et al. Doxorubi-
cin-induced cardiomyopathy: from molecular mecha-
nisms to therapeutic strategies. J Mol Cell Cardiol 2012
June;52:1213-25.
Overton ET. Metabolic complications of HIV infection and its
therapies. Top Antivir Med. 2014;22:651-4.
Page RL 2nd, O’Bryant CL, Cheng D, et al. Drugs That May
Cause or Exacerbate Heart Failure: A Scientific Statement
From the American Heart Association [published correc-
tion appears in Circulation. 2016 Sep 20;134(12):e261].
Circulation. 2016;134:e32-e69.
Patrono C, Baigent C. Nonsteroidal anti-inflammatory drugs
and the heart. Circulation. 2014 Feb 25;129(8):907-16.
Penzak SR, Chuck SK. Management of protease inhibitor-­
associated hyperlipidemia. Am J Cardiovasc Drugs. 2002;
2:91-106.
Sánchez-Ferro A, Benito-León J, Gómez-Esteban JC. The
management of orthostatic hypotension in Parkinson’s
disease. Front Neurol. 2013;4:64. Published 2013 Jun 10.
Słowik A, Jagielski P, Potocki P, et al. Anthracycline-induced
cardiotoxicity prevention with angiotensin-converting
enzyme inhibitor ramipril in women with low-risk breast
cancer: results of a prospective randomized study. Kardiol
Pol. 2020;78(2):131-137.
Swain SM, Ewer MS, Cortés J, et al. Cardiac tolerability of
pertuzumab plus trastuzumab plus docetaxel in patients
with HER2-positive metastatic breast cancer in CLEOP-
ATRA: a randomized, double-blind, placebo-controlled
phase III study. Oncologist. 2013;18:257-64.
Vetter VL, Elia J, Erickson C, et al.; American Heart Asso-
ciation Council on Cardiovascular Disease in the Young
Congenital Cardiac Defects Committee; American Heart
Association Council on Cardiovascular Nursing. Cardio-
vascular monitoring of children and adolescents with
heart disease receiving medications for attention deficit/
hyperactivity disorder [corrected]: a scientific statement
from the American Heart Association Council on Cardio-
vascular Disease in the Young Congenital Cardiac Defects
Committee and the Council on Cardiovascular Nursing.
Circulation. 2008 May 6;117:2407-23.
Yeh ETH, Bickford CL. Cardiovascular complications of
cancer therapy. J Am Coll Cardiol 2009:53:2231-47.
52 Drug-Induced Cardiovascular Disease
Self-Assessment Questions
Questions 16 and 17 pertain to the following case.
J.E. is a 55-year-old woman diagnosed with breast cancer.
She will soon undergo chemotherapy with doxorubicin. Her
anticipated cumulative dose will be 300 mg/m2. Her medical
history includes hypertension, for which she takes hydrochlo-
rothiazide 25 mg daily.
16. Which one of the following is best to recommend to
decrease J.E.’s risk of cardiotoxicity?
A. Use standard formulation of doxorubicin.
B. Change antihypertensive to lisinopril 10 mg daily.
C. Change antihypertensive to metoprolol tartrate
25 mg twice daily.
D. Administer dexrazoxane before doxorubicin infusion.
17. Four months after completing the doxorubicin infusions,
J.E. has shortness of breath and is evaluated by a car-
diologist for new-onset heart failure (HF). Her new left
ventricular ejection fraction (LVEF) is 35%. Given her new
diagnosis of HF with reduced EF, which one of the follow-
ing is best to recommend for J.E.?
A. Discontinue hydrochlorothiazide and initiate
guideline-directed medical therapy.
B. Continue hydrochlorothiazide.
C. Change hydrochlorothiazide to furosemide.
D. Refer her to a cardio-oncologist for further
evaluation and initiate guideline-directed medical
therapy.
18. A 76-year-old man will be initiated on ponatinib for chronic
myeloid leukemia. Which one of the following is best to
recommend for this patient before initiating therapy?
A. Cardio-oncologic evaluation and ankle-brachial
index with lower extremity Doppler
B. Cardio-oncologic evaluation with echocardiography
C. Serum troponin
D. Nuclear stress test
19. A 54-year-old woman was recently diagnosed with met-
astatic pancreatic neuroendocrine tumors, and the team
is discussing treatments with her. She has a history of
hypertension and takes amlodipine 5 mg daily at home.
Her vital signs today include heart rate 69 beats/minute
and blood pressure 127/79 mm Hg. The patient and the
team want to initiate sunitinib. Which one of the follow-
ing is best to recommend for this patient?
A. Her blood pressure is at goal; no change is
necessary. She can return to the clinic for a blood
pressure check 4 weeks after initiation of therapy.
B. Her blood pressure is at goal; she should start
home blood pressure monitoring for the duration of
sunitinib therapy.
PSAP 2022 Book 1 • Cardiology
C. Her blood pressure is not at goal; amlodipine should
be increased to 10 mg daily and her blood pressure
rechecked in 2 weeks.
D. Her blood pressure is not at goal; amlodipine should
be changed to lisinopril because this will prevent
progression to HF.
20. A 29-year-old man (weight 90 kg) with metastatic mela-
noma presents to the ED with chest pain, shortness of
breath, and lower extremity swelling. His home drugs
include ipilimumab 270 mg intravenously every 3 weeks.
His last dose was over 2 weeks ago. The consulting car-
diology team diagnoses clinically suspected myocardi-
tis and admits him for observation and management of
edema. Which one of the following is best to recommend
regarding this patient’s anticancer treatment?
A. Permanently discontinue ipilimumab therapy.
B. Reinitiate ipilimumab therapy as inpatient because
his next dose is due soon.
C. Hold next ipilimumab dose and reinitiate after
hospital discharge, after symptoms resolve.
D. Initiate corticosteroid taper and resume ipilimumab
after completion.
21. A 78-year-old man presents to the ED with syncope. On
presentation, his heart rate is 45 beats/minute. His home
drugs include amiodarone 200 mg daily, rivaroxaban
20 mg daily, metoprolol succinate 50 mg daily, and levothy-
roxine 88 mcg daily. The attending physician asks which
medication most likely caused his symptomatic bradycar-
dia. Which one of the following is the best response?
A. Amiodarone and metoprolol can cause bradycardia.
B. Metoprolol is likely the sole cause of bradycardia.
C. Levothyroxine has been associated with
bradycardia.
D. Rivaroxaban could be contributing to a hemorrhage-
associated bradycardia.
22. A 65-year-old man underwent an elective total knee
replacement. His medical history includes hyperten-
sion, depression, and benign prostatic hyperplasia. His
home drugs include lisinopril 10 mg daily, doxazosin
4 mg daily, sertraline 100 mg daily, and metoprolol 50 mg
twice daily. On the morning of surgery, he forgot to take
his home drugs. His blood pressure after the operation is
195/94 mm Hg. Which one of the following is most likely
contributing to this patient’s hypertension?
A. Lisinopril
B. Doxazosin
C. Sertraline
D. Metoprolol
53 Drug-Induced Cardiovascular Disease
23. During rounds with your patient care team, the attending
physician is discussing drugs that have been removed
from the market because of safety concerns. The sub-
ject of rofecoxib is mentioned. Which one of the follow-
ing best evaluates the current evidence with respect to
cardiovascular disease (CVD) and NSAID use?
A. Rofecoxib was removed from the market because of
increased risk of bleeding.
B. Risk of ischemic heart disease is lowest with
selective COX-2 inhibitors like celecoxib.
C. Selective COX-2 inhibitors are the only NSAIDs that
cause hypertension.
D. Naproxen is associated with increased blood
pressure.
24. An 87-year-old woman (weight 50 kg) is admitted to
the hospital after experiencing altered mental status at
home. On arrival at the ED, she is dehydrated with dry
mucous membranes and an SCr of 4.5 mg/dL (base-
line 1.2 mg/dL) and a potassium of 4.1 mEq/L. She has
a medical history of atrial fibrillation on digoxin 125 mcg
daily and rivaroxaban 15 mg with dinner. The patient’s
blood pressure is 100/76 mm Hg, heart rate is 76 beats/
minute, and ECG is normal. A routine digoxin concentra-
tion is 2.2 ng/mL. The patient has no concerns for visual
disturbances. Which one of the following is best to rec-
ommend for this patient?
A. Administer 10 vials of digoxin immune Fab.
B. Administer 1 vial of digoxin immune Fab and
recheck digoxin concentration in 12 hours.
C. Hold digoxin until SCr normalizes and closely
monitor K.
D. Continue digoxin and obtain a serum potassium
concentration every 4–6 hours.
25. A 61-year-old man has a medical history that includes
HF (EF 30%), atrial fibrillation, and depression. His home
drugs include furosemide 60 mg twice daily, lisinopril 10
mg daily, metoprolol succinate 100 mg daily, and apix-
aban 5 mg twice daily. His atrial fibrillation symptoms
continue to worsen despite optimization of β-blocker
therapy. Which one of the following is best to recom-
mend for this patient?
A. Add dofetilide.
B. Change to metoprolol tartrate.
C. Add diltiazem.
D. Add flecainide.
26. A 65-year-old man presents to urgent care with fever, dys-
pnea, and a productive cough. Chest radiography reveals
ground-glass opacities and new left lower lobe infiltrates.
His WBC is elevated at 16.1 × 103 cells/mm3. An ECG reveals
normal sinus rhythm with a QTc of 465 milliseconds.
PSAP 2022 Book 1 • Cardiology
He is diagnosed with COVID-19 pneumonia, and the
physician would also like to treat him for community-
acquired pneumonia. His medical history includes
severe mitral regurgitation, depression, and hyperten-
sion. At home, he takes escitalopram 20 mg daily, furo-
semide 80 mg daily, and valsartan 160 mg daily. The
physician writes a prescription for azithromycin 500 mg
daily today, then 250 mg daily and cefpodoxime 200 mg
twice daily. As you review the medication orders for the
outpatient clinic, which one of the following is best to
recommend for this patient?
A. Continue azithromycin; discontinue escitalopram
while on antibiotics.
B. Continue azithromycin and cefpodoxime; monitor
QTc daily while on antibiotics.
C. Discontinue azithromycin and cefpodoxime; initiate
levofloxacin 750 mg daily.
D. Discontinue azithromycin; initiate doxycycline
100 mg twice daily.
27. You are rounding with an internal medicine team and
reviewing home drugs for a man who was admitted with
new-onset HF. The patient’s home drugs include nifed-
ipine extended release 90 mg daily, metformin 500 mg
twice daily, lisinopril 20 mg daily, and clozapine 100 mg
daily. The team wants to know which of his home drugs
may be contributing to his HF. Which one of the follow-
ing is best to share with the care team regarding this
patient’s medications?
A. Nifedipine can cause HF because it causes edema.
B. Metformin exacerbates HF because it causes lactic
acid production in cardiac tissue.
C. Lisinopril exacerbates HF because it decreases the
glomerular filtration rate and causes edema.
D. Clozapine can cause HF through IgE-mediated
hypersensitivity reactions.
28. A 40-year-old woman has a medical history that includes
depression and atrial fibrillation with a recent community-
acquired pneumonia. She is seen in the ED after experi-
encing a syncopal episode while performing household
chores. The patient’s ECG reveals polymorphic ventric-
ular tachycardia (VT) indicative of torsades de pointes
(TdP). Her home drugs include fluoxetine 20 mg daily,
alprazolam 0.5 mg twice daily as needed, dofetilide 500
mcg twice daily, and clarithromycin 500 mg daily twice
daily initiated 4 days ago. The cardiology team reviews
her medication profile; discontinues fluoxetine, clarithro-
mycin, and dofetilide; and corrects her hypokalemia. The
patient has a recurrence of TdP while in the ED but is
hemodynamically stable. Later that evening, after being
transferred to the ICU, she begins to experience nausea
and vomiting. In the setting of prolonged QTc, which one
54 Drug-Induced Cardiovascular Disease
 of the following is the best antiemetic to recommend for A. Add amlodipine 10 mg daily.
this patient? B. Add hydrochlorothiazide 25 mg daily.
C. Discontinue tacrolimus.
A. Droperidol
D. Change tacrolimus to cyclosporine 150 mg twice
B. Ondansetron
daily.
C. Chlorpromazine
D. Promethazine 30. A 55-year-old man (weight 80 kg) presents to your primary
care clinic for a routine diabetes follow-up. His medical his-
29. A 62-year-old woman presents for an outpatient visit
tory includes HF with reduced EF and type 2 diabetes. His
with her cardiologist. Her medical history includes a kid-
home drugs include metformin 1000 mg twice daily, enal-
ney transplant 4 months ago, unstable angina, diabetes,
april 10 mg daily, carvedilol 12.5 mg twice daily, and furo-
and hypertension. Her home drugs include tacrolimus
semide 60 mg twice daily. The patient’s vital signs today
4 mg twice daily (concentrations within normal range),
in the clinic are blood pressure 123/67 mm Hg and heart
prednisone 5 mg daily, mycophenolate mofetil 1000 mg
rate 73 beats/minute. Fasting laboratory tests at this visit
twice daily, metformin 1000 mg twice daily, aspirin 81 mg
include glucose 175 mg/dL, A1C 8.3%, SCr 1.2 mg/dL, and
daily, rosuvastatin 20 mg daily, losartan 50 mg daily, and
K 4.2 mEq/mL. Given his level of glucose control, which
atenolol 50 mg daily. The patient reports doing well other
one of the following is best to recommend for this patient?
than having high blood pressure readings when check-
ing her blood pressure at home. Her primary care phy- A. Pioglitazone 15 mg oral daily
sician recently doubled the doses of both atenolol and B. Saxagliptin 5 mg oral daily
losartan. Her physical examination is notable for blood C. Dapagliflozin 10 mg oral daily
pressure 168/96 mm Hg and heart rate 62 beats/minute. D. Insulin glargine 10 units subcutaneously
After confirming your plan with the transplant nephrolo-
gist, which one of the following is best to recommend for
this patient?

PSAP 2022 Book 1 • Cardiology 55 Drug-Induced Cardiovascular Disease

Learner Chapter Evaluation: Drug-Induced Cardiovascular Disease
As you take the posttest for this chapter, also evaluate the
material’s quality and usefulness, as well as the achievement
of learning objectives. Rate each item using this 5-point scale:
• Strongly agree
• Agree
• Neutral
• Disagree
• Strongly disagree
16. The content of the chapter met my educational needs.
17. The content of the chapter satisfied my expectations.
18. The author presented the chapter content effectively.
19. The content of the chapter was relevant to my practice
and presented at the appropriate depth and scope.
20. The content of the chapter was objective and balanced.
21. The content of the chapter is free of bias, promotion, and
advertisement of commercial products.
22. The content of the chapter was useful to me.
23. The teaching and learning methods used in the chapter
were effective.
24. The active learning methods used in the chapter were
effective.
PSAP 2022 Book 1 • Cardiology
25. The learning assessment activities used in the chapter
were effective.
26. The chapter was effective overall.
27. The activity met the stated learning objectives.
28. If any objectives were not met, please list them here.
OTHER COMMENTS
29. Please provide any specific comments related to any
perceptions of bias, promotion, or advertisement of
commercial products.
30. Please expand on any of your above responses, and/or
provide any additional comments regarding this chapter:
Questions 31–33 apply to the entire learning module.
31. How long did it take you to read the instructional materi-
als in this module?
32. How long did it take you to read and answer the assess-
ment questions in this module?
33. Please provide any additional comments you may have
regarding this module:
56 Drug-Induced Cardiovascular Disease
Cardiology II
Cardiology II Panel
Series Editors:
Cynthia A. Sanoski, Pharm.D., FCCP, BCPS
Department Chair
Associate Professor of Pharmacy Practice
Thomas Jefferson University
Philadelphia, Pennsylvania
Daniel M. Witt, Pharm.D., FCCP, BCPS
Professor and Chair
Department of Pharmacotherapy
Assistant Dean of Clinical Affairs
University of Utah College of Pharmacy
Salt Lake City, Utah
Faculty Panel Chair:
Craig J. Beavers, Pharm.D., FCCP, FACC, FAHA, BCCP,
BCPS-AQ Cardiology, CACP
Director of Cardiovascular Services
Baptist Health Paducah
Cardiovascular Clinical Pharmacist
Department of Pharmacy Services
UK Healthcare
Assistant Adjunct Professor
Department of Pharmacy Practice and Science
University of Kentucky College of Pharmacy
Paducah, Kentucky
Peripheral Arterial Disease
Author
Anastasia L. Armbruster, Pharm.D., FACC, BCPS, BCCP
Associate Professor
Department of Pharmacy Practice
St. Louis College of Pharmacy at UHSP
St. Louis, Missouri
Reviewers
Toby Trujillo, Pharm.D., FCCP, FAHA, BCPS
Associate Professor
Department of Clinical Pharmacy
University of Colorado Skaggs School of Pharmacy
Aurora, Colorado
Brenda L. Pahl, Pharm.D., BCPS
Assistant Dean of Student Affairs and Admissions
Assistant Professor of Pharmacy Practice
Cedarville University School of Pharmacy
Cedarville, Ohio
Antithrombotic Therapy in Cardiac
Interventions
Authors
Stephanie Dwyer Kaluzna, Pharm.D., BCCP
Clinical Assistant Professor
Department of Pharmacy Practice
University of Illinois Chicago College of Pharmacy
Cardiovascular Clinical Pharmacist
University of Illinois Hospital and Health Sciences System
Chicago, Illinois
Jaclynne Gowen, Pharm.D., BCCP
Clinical Ambulatory Pharmacist
Department of Cardiology
Wentworth-Douglass Hospital
Dover, New Hampshire
Reviewers
A. Josh Roberts, Pharm.D., BCCP,
BCPS-AQ Cardiology, AACC
Pharmacist Specialist - Cardiology
PGY2 Cardiology Pharmacy Residency Program Director
UC Davis Medical Center
Sacramento, California
Associate Professor of Pharmacy (WOS)
UC San Francisco School of Pharmacy
San Francisco, California
Bethany A. Ford, Pharm.D., BCPS
Assistant Professor
Department of Clinical and Administrative Sciences
Notre Dame of Maryland University School of Pharmacy
Baltimore, Maryland
Christine S. Ji, Pharm.D., BCPS, BCCP
Clinical Pharmacy Specialist Cardiology
Department of Pharmacy
Massachusetts General Hospital
Boston, Massachusetts
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Consultancies: Anastasia Armbruster (ACC/AHA Joint Committee Clinical Practice Guidelines); Jessica Bente (ACCP); Allison
Burnett: Consultancies (Anticoagulation Forum; National Certification Board for Anticoagulation Providers; Global Strategies);
Jessie L. Dunne (Pulmonary Hypertension Association); Nancy M. Nix (Pharmacosmos); Daniel M. Riche (Novo Nordisk; Merck;
AstraZeneca); Ralph J. Riello III (AstraZeneca; Johnson & Johnson); Sara Vazquez (Anticoagulation Forum);

Stock Ownership:

Royalties: Allison Burnett (Wolters-Kluwer); Daniel M. Riche (McGraw-Hill); Honoraria (Merck); Sara Vazquez (UpToDate)

Grants: Anastasia Armbruster (ACCP); Jessica Bente (New Jersey Society of Health-System Pharmacists); Gregory Castelli
(American Board of Family Medicine); Kevin Cowart (University of South Florida Taneja College of Pharmacy); Ralph J. Riello
III (AstraZeneca)

Honoraria: Anastasia Armbruster (AstraZeneca); John Bucheit (Association of Diabetes Care & Education Specialists); Nancy M.
Nix (Coherus; Pfizer; AstraZeneca); Ralph J. Riello III (Alexion; AstraZeneca; Janssen)

Other:

Nothing to disclose: Katherine Aymond, Eugene N. Bush, Nicholas W. Carris, Stephanie Dwyer Kaluzna, Lindsey Federle, Beth-
any A. Ford, Stormi E. Gale, Jaclynne R. Gowen, Glenn Herrington, Christine Ji, Amy L. Lehnert, Nilam R. Naik, Brenda Pahl, Joel
J. Peterson, A. Joshua Roberts, Kelly M. Rudd, Ashley Schenk, Susan M. Smith, Elisabeth M. Wang, Toby C. Trujillo, Barbara Wig-
gins, Leslie Wooten, Eman El Sayed Younis

ROLE OF BPS: The Board of Pharmacy Specialties (BPS) is an autonomous division of the American Pharmacists Association
(APhA). To maintain its strict, independent standards for certification, BPS does NOT endorse or provide review information,
preparatory courses, or study guides for Board Certification Examinations. The Board, through its specialty councils, is respon-
sible for specialty examination content, administration, scoring, and all other aspects of its certification programs. BPS is totally
separate and distinct from ACCP. PSAP has been approved by BPS for use in BCPS recertification. Information about the BPS
recertification process is available online.

Questions regarding BPS specialty recertification should be directed to:

Board of Pharmacy Specialties

2215 Constitution Avenue NW
Washington, DC 20037
(202) 429-7591
Continuing Pharmacy Education
and Recertification Instructions
Continuing Pharmacy Education (CPE) Credit: The American College of Clinical Pharmacy is accredited by the
Accreditation Council for Pharmacy Education (ACPE) as a provider of CPE.

PSAP Target Audience: The target audience for PSAP 2022 Book 1 (Cardiology) is pharmacotherapy specialists and advanced
level clinical pharmacists encountering diverse cardiovascular patient populations.

Available CPE credits: Purchasers who successfully complete all posttests for PSAP 2022 Book 1 (Cardiology) can earn 21.5 contact
hours of CPE credit. The universal activity numbers are as follows: Cardiology I – 0217-0000-22-002-H01-P, 5.0 contact hours;
Cardiology II – 0217-0000-22-003-H01-P, 6.0 contact hours; Cardiology III – 0217-0000-22-004-H01-P, 5.0 contact hours; and
Cardiology IV – 0217-0000-22-005-H01-P, 5.5 contact hours. You may complete one or all available modules for credit. Tests may
not be submitted more than one time.

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Peripheral Arterial Disease
By Anastasia L. Armbruster, Pharm.D., FACC, BCPS, BCCP

Reviewed by Toby Trujillo, Pharm.D., FCCP, FAHA, BCPS; and Brenda L. Pahl, Pharm.D., BCPS

LEARNING OBJECTIVES

1. Assess patients for risk of peripheral arterial disease (PAD) and determine eligibility for cardiovascular risk reduction
strategies.
2. Assess the role of antithrombotic therapy after revascularization for the management of PAD.
3. Evaluate the role of emerging therapies in the management of PAD.
4. Develop a treatment plan for patients with a diagnosis of PAD.
5. Design a treatment plan for patients who present with critical or acute limb ischemia.

ABBREVIATIONS IN THIS CHAPTER
ABI Ankle-brachial index
ACC American College of Cardiology
ACEI Angiotensin-converting enzyme
inhibitor
ADA American Diabetes Association
AHA American Heart Association
ALI Acute limb ischemia
ARB Angiotensin-receptor blockers
ASCVD Atherosclerotic cardiovascular
disease
CAD Coronary artery disease
CDT Catheter-directed thrombolysis
CLI Critical limb ischemia
CV Cardiovascular
DAPT Dual antiplatelet therapy
DM Diabetes mellitus
ESC European Society of Cardiology
IC Intermittent claudication
MACE Major adverse cardiovascular
events
MALE Major adverse limb events
MI Myocardial infarction
PAD Peripheral arterial disease
SBP Systolic blood pressure
SGLT2 Sodium-glucose co-transporter-2
Table of other common abbreviations.
INTRODUCTION
Peripheral arterial disease (PAD) is a manifestation of systemic ath-
erosclerosis and is part of a disease spectrum that includes coro-
nary artery disease (CAD) and cerebrovascular disease. A variety of
terms have been used to describe this condition, including peripheral
vascular disease, peripheral artery disease, and lower extremity arterial
disease. Atherosclerosis can develop in arterial beds throughout the
body. This chapter focuses on management of lower extremity PAD.
Narrowing of vessels decreases blood flow, and occlusion can occur
secondary to plaque rupture and/or thrombosis of narrowed ves-
sels. The most common sites are the femoral and popliteal arteries
(Gerhard-Herman 2017). This anatomy is outlined in Figure 1. As
plaque builds and arteries are narrowed, an oxygen supply/demand
mismatch occurs and results in ischemia and extremity pain, known
as intermittent claudication (IC). This condition can be described as
fatigue and cramping or pain in the lower extremities elicited by walk-
ing and relieved by rest, typically within 10 minutes. More serious
complications may occur with the progression of PAD, including acute
limb ischemia (ALI), which is defined as an acute (less than 2 weeks)
hypoperfusion of the limb. Patients may report pain, pulselessness
in the affected limb, or cold extremities. Critical limb ischemia (CLI) is
characterized by chronic symptoms (more than 2 weeks), including
pain at rest, nonhealing ulcers, or gangrene (Gerhard-Herman 2017)
(see Figure 1).
Paucity of Data
Peripheral arterial disease remains grossly under recognized and
underdiagnosed, with much of the data regarding treatment deci-
sions derived from secondary outcomes or sub-analyses of larger
cardiovascular (CV) trials that focus to a greater degree on athero-
sclerotic cardiovascular disease (ASCVD) in other vascular beds.

PSAP 2022 Book 1 • Cardiology 63 Peripheral Arterial Disease

 Figure 1. Major arteries serving the lower limb are shown in anterior and posterior views.
Reprinted with permission from Lumen. Anatomy and Physiology II. Module 4: The Cardiovascular System: Blood Vessels and
Circulation.
BASELINE KNOWLEDGE STATEMENTS
Readers of this chapter are presumed to be familiar
with the following:
• General knowledge of the pathophysiology that
leads to development of atherosclerotic cardiovas-
cular disease
• Current guideline recommendations for the man-
agement of hypertension, hyperlipidemia, and type
2 diabetes mellitus
• Drug knowledge of antithrombotic therapy used to
reduce the risk of cardiovascular events
Table of common laboratory reference values
ADDITIONAL READINGS
The following free resources have additional back-
ground information on this topic:
• AHA PAD Go-To-Guide for Healthcare Professionals
• Tobacco Cessation for Patients with Cardiovascu-
lar Disease
PSAP 2022 Book 1 • Cardiology
This focus has left large knowledge gaps regarding the patho-
physiology and treatment of PAD. Major society guidelines
have conflicting information regarding screening recommen-
dations and use of pharmacotherapy. Moreover, the most
recent advances in medications have not been incorporated
into a major cardiovascular guideline. This lack of clarity has
likely impacted patient care.
Updated American Heart Association (AHA)/American Col-
lege of Cardiology (ACC) clinical practice guidelines are esti-
mated to be released in the second quarter of 2022. A study
examining prescribing patterns within the U.S. Department of
Veterans Affairs demonstrated that, compared with patients
who have CAD, patients with PAD alone were less likely to
receive guideline-directed medical therapy, including statin
therapy, antiplatelet therapy, and achievement of A1C less
than 7% (Hira 2016). Similarly, the PARTNERS trial demon-
strated an overall low awareness of PAD diagnosis among
primary care physicians, as well as low use of guideline-
directed medical therapy (Hirsch 2001). Risk factor recogni-
tion and management is crucial in preventing the progression
of PAD and the need for amputation. While large gaps exist in
patient care, pharmacists have an opportunity to participate
in appropriate screening, risk reduction measures, and treat-
ment of patients with PAD. Engagement in research focusing
64 Peripheral Arterial Disease
on the management of PAD as well as educational efforts
within the health care community to improve overall treat-
ment of this patient population are also needed.
Epidemiology and Risk Factors
Peripheral arterial disease is a marker for systemic athero-
sclerotic disease; these patients are likely to have disease
in other vascular beds—coronary, carotid, renal arteries, and
the abdominal aorta. The incidence of PAD is estimated to be
10%–15% and increases with age (more than 20% in patients
older than 80 years), affecting 8–10 million Americans
(Shu 2018). Box 1 summarizes characteristics of patients
at increased risk of PAD. These risk factors have varying
degrees of impact on disease progression. Diabetic patients
have 2–4 times the risk of developing PAD, CAD, and ischemic
stroke. Regarding racial disparities, the likelihood of PAD is
50% higher in African American patients compared with
white patients (Shu 2018). Cigarette smoking has a stronger
association with development of PAD compared with CAD
and stroke (symptomatic PAD: HR 4.13; CAD: HR 2.1; stroke:
HR 1.8) (Ding 2019). The association of PAD with smoking
is not only the most significant compared with other CV dis-
eases, but PAD is also correlated with quantity of cigarettes
smoked—both with number of cigarettes smoked per day and
number of years smoked (Ding 2019). Patients should receive
aggressive risk factor management to reduce the risk of CV
events and improve functional status (see Box 1).
Health Care Disparities
Although overall diagnosis and management of PAD must be
improved at a national level, significant health care disparities
exist, particularly with respect to management of advanced
stages of the disease. After adjusting for patient-related
factors, African American, Native American, and Hispanic
patients are more likely to undergo major amputation as a
management strategy for CLI. Socioeconomic factors such as
lower income and non-private insurance are also associated
Box 1. Patients at Increased Risk of PAD
• Age < 50 yr, with DM and 1 additional risk factor for
atherosclerosis
• Age ≥ 50– 64 yr, with risk factors for atherosclerosis (DM,
smoking, hyperlipidemia, hypertension) or family history
of PAD
• Age ≥ 65 yr
• Individuals with known atherosclerosis in another vascular
bed (e.g., coronary, carotid)
DM = diabetes mellitus; PAD = peripheral arterial disease.
Information from: Gerhard-Herman MD, Gornik HL, Barrett C,
et al. 2016 AHA/ACC guideline on the management of patients
with lower extremity peripheral artery disease: a report of the
American College of Cardiology/American Heart Association
Task Force on Clinical Practice Guidelines. J Am Coll Cardiol
2017;69:e71-126.
PSAP 2022 Book 1 • Cardiology
with major amputation. Patients who receive a diagnostic
angiogram are significantly less likely to undergo amputa-
tion. However, African American patients and those with lower
incomes were less likely to undergo diagnostic angiograms
during index hospitalizations. Access to specialized care also
plays a crucial role in avoiding amputation because patients
are more likely to receive alternate management strategies
at centers with specially trained physicians available and
higher patient volume (Henry 2011). Efforts should be made
to ensure patients have equal access to adequate PAD screen-
ing and work-up before considering major amputation.
DIAGNOSIS
Appropriate screening of patients for PAD is crucial because
an estimated 50% of patients are asymptomatic or at least
report no symptoms without intentional screening (Shu
2018). Screening of high-risk patients is recommended by the
2016 AHA/ACC guidelines. Early identification is important
to reduce the development of complications and advanced
disease, combined with crucial risk reduction strategies. For
patients considered to have a high risk of PAD, see Box 1.
History and Physical Examination
Initial assessment for PAD can be performed in any clinical
setting. A detailed clinical history and basic physical exam-
ination are the first steps in establishing a diagnosis; however,
diagnostic tests are required for confirmation. Although most
clinicians associate IC with PAD, only 10% of patients report
this classic symptom at the time of diagnosis, with up to 40%
not reporting any leg pain (McDermott 2001). Therefore, the
presence of symptoms alone is inadequate to identify every-
one who will benefit from risk-reducing interventions, high-
lighting the important role of screening. Similar to CAD, not
all patients present with classic symptoms; atypical symp-
toms exist for lower extremity ischemia as well. These symp-
toms may include other exertional symptoms or perceived
walking impairment. Patients should be asked about all
non-joint related limb pain to fully evaluate for potential PAD
symptoms. It is important to remember symptoms and their
intensity may vary among patients and do not necessarily
correlate with degree of disease. The Edinburgh Claudication
Questionnaire is recommended by the 2018 European Society
of Cardiology (ESC) guideline as a symptom screening tool to
use with patients and has been validated in several studies
(Leng 1992). Both the Fontaine and Rutherford classification
systems can be used to categorize a patient’s description of
symptoms (Aboyans 2018; Gerhard-Herman 2017).
Physical examination is also crucial when screening for
PAD. High-risk patients should undergo palpation of lower
extremity pulses, auscultation for femoral bruits, and visual
inspection of the legs and feet. Pulses can be described in
the following manner: absent (0), diminished (1), normal (2),
or bounding (3). An absent or diminished posterior tibial
65 Peripheral Arterial Disease
 Table 1. Resting ABI Interpretation in Symptomatic Patients
Resting ABI Interpretation
≤0.90 Abnormal
0.91–0.99 Borderline
1.00–1.40 Normal
>1.40 Noncompressible
ABI = ankle-brachial index; TBI = toe-brachial index; PAD = peripheral arterial disease.
Information from: Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management of patients with
lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association Task Force
on Clinical Practice Guidelines. J Am Coll Cardiol 2017;69:e71-126.
pulse, compared with dorsalis pedis pulse, is most consis-
tent with PAD. Several abnormal physical findings increase
the likelihood of a confirmatory PAD diagnosis, whereas a
normal examination absent of bruits decreases the likelihood
of PAD. Other potential physical findings include limb hair
loss, shiny skin, or muscle atrophy. Physical findings such as
cool extremities or non-healing ulcers are more consistent
with advanced disease, including CLI or ALI (Aboyans 2018;
Gerhard-Herman 2017).
Diagnostic Testing
Resting Ankle-Brachial Index
Ankle-brachial index (ABI) should be the first diagnostic test
after a thorough history and clinical examination. An ABI less
than 0.9 is both sensitive and specific for diagnosis. Sensi-
tivity can be decreased by diabetes mellitus (DM) and end-
stage chronic kidney disease (Aboyans 2012). A resting ABI is
performed with the patient in the supine position for at least
10 minutes while brachial blood pressure is checked in both
arms. The highest systolic blood pressure (SBP) should be
used to perform the ABI calculation for each leg. Pressures
should then be obtained using a continuous-wave Doppler
device on the dorsalis pedis and posterior tibial arteries of
the legs. The ABI is the ratio of the highest pressure in each
leg and the obtained SBP. Table 1 outlines appropriate inter-
pretation and follow-up testing of ABI results in symptom-
atic patients. Up to 30% of symptomatic patients with normal
resting ABI studies may have an abnormal ABI after exercise
(Stein 2006). Exercise ABI testing is also indicated in patients
with borderline results. Of note, ABI can be falsely elevated in
patients with advanced diseased related to severely calcified,
noncompressible arteries.
Exercise ABI
A treadmill test can be performed for functional assessment
and in symptomatic patients with normal resting ABIs. No
specific treadmill protocol is recommended over another.
The ESC guidelines recommend a speed of 3 km/hour at 10%
PSAP 2022 Book 1 • Cardiology
Recommendation
Diagnostic for PAD
Exercise ABI necessary to establish diagnosis of PAD
Exercise ABI necessary to establish diagnosis of PAD
Perform TBI; ≤0.7 is diagnostic of PAD
slope; then the test is stopped when the patient can walk
no further because of pain. A post-exercise ABI decrease of
more than 20% is diagnostic for PAD (Aboyans 2018). Alter-
native tests are available if a treadmill is unavailable. The
6-minute walk test has previously been correlated with the
hemodynamic severity of PAD (Montgomery 1998). The pedal
plantarflexion ABI test has also been suggested as an alter-
native to treadmill testing (Gerhard-Herman 2017).
Diagnostic Imaging
Additional testing, including diagnostic imaging, is reserved
for patients undergoing revascularization. These tests
may include duplex ultrasonography, CT angiography, or
MRI angiography. Selection of specific diagnostic testing
should consider patient-specific factors, including risk of
contrast-induced nephropathy. It is important to note that
diagnostic angiography should not be performed in asymp-
tomatic patients because of a lack of benefit and risk of harm
(Gerhard-Herman 2017).
PHARMACOTHERAPY IN PATIENTS
WITH PAD
The mainstay of treatment in patients with PAD is addressing
modifiable risk factors with the goals of reducing CV risk and
disease progression, including major amputation. There is a
lack of high-quality, randomized controlled trials evaluating
pharmacotherapy specifically in patients with PAD. Currently,
the strongest recommendations exist for antiplatelet and sta-
tin therapies, as discussed in following text. Table 2 outlines
the pharmacotherapy recommendations from both the 2016
AHA/ACC and 2018 ESC guidelines.
Hypertension
Current AHA/ACC guidelines recommend that patients
receive antihypertensive therapy to reduce the risk of myo-
cardial infarction (MI), stroke, heart failure, and CV death.
Although a specific blood pressure goal is not provided, cli-
nicians should follow the current guidelines for treating
66 Peripheral Arterial Disease
 Table 2. ACC/AHA and ESC Recommendations for Medical Management of PAD

Recommendations ACC/AHA ESC

COR, LOE Class, LOE

Antiplatelet Therapy

Antiplatelet monotherapy (either aspirin 75–325 mg/day or clopidogrel 75 mg/day) to IA IA

reduce myocardial infarction, stroke and vascular death in symptomatic patients

Clopidogrel may be preferred to aspirin in patients who require antiplatelet therapy — IIb, B

Antiplatelet monotherapy is reasonable to reduce the risk of MACE in asymptomatic IIa, C-EO III, A
patients with ABI ≤ 0.90

Efficacy of dual antiplatelet therapy with aspirin and clopidogrel to reduce the risk of IIb, B-R —
MACE in symptomatic patients is not well established

Overall clinical benefit of adding vorapaxar to aspirin or clopidogrel in symptomatic IIb, B-R —
patients is uncertain

DAPT may be reasonable to reduce the risk of limb-related events in symptomatic IIb, C-LD IIb, B/C
patients after lower limb revascularization

Anticoagulation

Vitamin K antagonists should not be used to reduce the risk of CV ischemic events in III: Harm, A —
patients

Statin Therapy

Treatment with a statin medication is recommended for all patients I, A I, A

Reduction of LDL cholesterol to < 70 mg/dL or decrease by >50% is recommended if — I, C

baseline values are 70–135 mg/dL

Antihypertensive Therapy

Angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers can be IIa, A IIa, B

effective to reduce the risk of CV ischemic events in hypertensive patients

Smoking Cessation

Smoking cessation is recommended in all patients I, A I, B

Patients who smoke cigarettes should be helped to develop a plan for quitting that I, A —
includes pharmacotherapy (i.e., varenicline, bupropion, and/or nicotine replacement
therapy) and/or referral to a smoking cessation program

Glycemic Control

In diabetic patients, glycemic control is recommended and should be coordinated I, C-EO I, C

between health care team members

Symptomatic Treatment of Claudication

Cilostazol is an effective therapy to improve symptoms and increase walking distance I, A —

in patients with claudication

Pentoxifylline is not effective for treatment of claudication III: No benefit, —

B-R

ABI = ankle-brachial index; ACC = American College of Cardiology; AHA = American Heart Association; C = consensus; COR = class of
recommendation; CV = cardiovascular; DAPT = dual antiplatelet therapy; EO = expert opinion; ESC = European Society of Cardiology;
LD = limited data; LOE = level of evidence; MACE = major adverse cardiac event; PAD = peripheral artery disease; R = randomized.
Information from: Aboyans V, Ricco J, Bartelink M, et al. 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial
diseases, in collaboration with the European Society for Vascular Surgery. Eur Heart J 2018;39:763-816; Gerhard-Herman MD,
Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease:
a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll
Cardiol 2017;69:e71-126.

PSAP 2022 Book 1 • Cardiology 67 Peripheral Arterial Disease

hypertension (Gerhard-Herman 2017). Therefore, patients
with PAD should target a blood pressure of 130/80 mm Hg or
less, consistent with the 2017 ACC/AHA guideline for manag-
ing blood pressure (Whelton 2018). A J-shaped relationship
has been noted among patients with PAD regarding SBP and
occurrence of CV events in a post hoc analysis of the INVEST
trial. The composite outcome of all-cause death, non-fatal
MI or stroke occurred least often with an average treated
SBP of 135–145 mm Hg. For patients who achieving SBP of
110 mm Hg or less, the occurrence of the primary outcome
increased compared with patients without PAD (HR 1.69 vs.
0.99; p=0.04) (Bavry 2010).
The use of angiotensin-converting enzyme inhibitors
(ACEIs) or angiotensin-receptor blockers (ARBs) is reason-
able in patients with PAD (class of recommendation IIa, A)
(Gerhard-Herman 2017). A subgroup analysis of the HOPE
trial evaluated patients who were normotensive randomized
to ramipril or placebo and followed for 4.5 years. Patients
with an ABI of 0.90 of less were enrolled, with or without
symptoms. In the subgroup of 4051 patients with PAD, rami-
pril reduced the risk of MI, stroke, or vascular death by 25%
(Ostergren 2004). Similar results were noted in the ONTARGET
trial, which compared telmisartan versus ramipril, thus sup-
porting the use of ARBs as an alternative agent (ONTARGET
Investigators 2008). The ESC guidelines also list calcium
channel blockers as preferred agents based on their poten-
tial for peripheral arterial dilation. In addition, some data sug-
gest β-blockers with vasodilation properties may also offer
benefit related to increased walking distance. Nebivolol
demonstrated a 31% increase in walking distance in patients
with claudication and hypertension. Based on the additional
nitric-oxide releasing properties, nebivolol may have benefit
in PAD compared with other β-blockers (Espinola-Klein 2011,
Maffei 2009). Other than ACEIs/ARBs, no CV outcome data
are available to guide the selection of antihypertensive ther-
apy. Patients with PAD often have other comorbid disease
states, which should be considered when selecting antihy-
pertensive pharmacotherapy.
Dyslipidemia
Statin therapy is the cornerstone of lipid management in
patients with PAD. Data from the REACH registry demon-
strated a reduction in adverse limb outcomes, including wors-
ening claudication, new episode of CLI, new percutaneous/
surgical revascularization, or amputation, in statin users ver-
sus non-users [22.0% vs. 26.2%; HR 0.82; 95% CI, 0.72–0.92).
A statistically significant reduction in the composite of CV
death, MI, and stroke was also noted (Kumbhani 2014). The
2018 AHA/ACC guideline on the management of blood choles-
terol includes PAD as part of clinical ASCVD, which provides
additional guidance on lipid management. Patients should
receive a high-intensity statin to achieve a 50% or greater
reduction in LDL cholesterol, and they may be considered
for addition of ezetimibe if LDL cholesterol remains greater
PSAP 2022 Book 1 • Cardiology
Box 2. High-Risk Conditions for
Developing Peripheral Arterial Disease
• Age ≥ 65 yr
• Chronic kidney disease (estimated glomerular filtration rate
15–59 mL/min/1.73 m2)
• Current smoking
• Diabetes mellitus
• Heterozygous familial hypercholesterolemia
• History of congestive heart failure
• History of coronary artery bypass graft surgery or percuta-
neous coronary intervention other than for management of
a major atherosclerotic cardiovascular disease event
• Hypertension
• Persistently elevated LDL cholesterol (≥100 mg/dL) despite
maximally tolerated statin therapy and ezetimibe
Information from: Grundy SM, Stone NJ, Bailey AL, et al. 2018
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ ADA/AGS/ APhA/ASPC/
NLA/PCNA guideline on the management of blood cholesterol:
a report of the American College of Cardiology/American Heart
Association Task Force on Clinical Practice Guidelines. J Am
Coll Cardiol 2019;73:e285-350.
than 70 mg/dL. For the highest risk patients, addition of a
proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibi-
tor should be considered. Highest risk patients include those
with symptomatic PAD (i.e., ABI less than 0.85 with history
of claudication, or previous revascularization or amputation)
and one other ASCVD event or several high-risk conditions,
as defined in the guidelines (Grundy 2019). High-risk con-
ditions are outlined in Box 2. These recommendations are
based on both the IMPROVE-IT trial and a sub-analysis of the
FOURIER trial among patients with a history of MI, stroke, or
PAD. These study results showed that evolocumab reduced
the risk of major adverse limb events (MALE), including ALI,
major amputation, and urgent revascularization (HR 0.58; 95%
CI, 0.38–0.88) (Bonaca 2018; Cannon 2015). Data exists for
the PCSK9 inhibitor, alirocumab as well, from a pre-specified
sub-analysis of the ODYSSEY OUTCOMES trial. Authors
noted the absolute risk reduction increased in patients who
had additional types of cerebrovascular disease, demonstrat-
ing that patients with PAD had an added benefit with PCSK9
inhibitors, although patients with PAD were a small percent-
age of the trial population (Jukema 2019). It is important to
follow guideline recommendations to reach a target of 70
mg/dL or less in patients with known PAD, this may require
the addition of ezetimibe and/or a PCSK9 inhibitor. The 2018
AHA/ACC guideline on the management of blood cholesterol
should also be followed for patients at high-risk of develop-
ing PAD, similar to any patient at risk of ASCVD (Grundy 2019)
(see Box 2).
Diabetes Mellitus
The presence of DM increases the risk of adverse PAD out-
comes, including progression to CLI, amputation, and mor-
tality. Diabetes is especially important to address because
68 Peripheral Arterial Disease
nontraumatic lower extremity amputation increased by 50%
in patients with DM between 2009 and 2015 (Virani 2020;
Gerhard-Herman 2017). Similar to other pharmacotherapy,
specific data are limited regarding which anti-hyperglycemic
agents have benefit in patients with PAD. Current American
Diabetes Association (ADA) standards recommend priori-
tizing agents associated with reduction in CV death. These
agents include either a glucagon-like peptide-1 (GLP-1) recep-
tor agonist (i.e., liraglutide, semaglutide, dulaglutide) or a
sodium-glucose co-transporter-2 (SGLT2) inhibitor (i.e., cana-
gliflozin, dapagliflozin empagliflozin). Both should be consid-
ered regardless of A1C target. Figure 9.1 in the ADA standards
outlines current treatment recommendations (ADA 2021a).
Previously, a boxed warning was issued for canagliflozin
related to an increased risk of amputation. This warning was
primarily based on the CANVAS trial results, in which the risk
of amputations was increased in patients receiving canagli-
flozin versus placebo (6.3 vs. 3.4 per 1000 patient-years; HR
1.97; 95% CI, 1.41–2.75) (Neal 2017). Since that time, addi-
tional benefits have been demonstrated and lower rates of
amputation with canagliflozin have been reported. The risk
of amputation has also not been statistically significant in
other landmark SGLT-2 inhibitor trials. For these reasons, the
FDA removed the boxed warning regarding an increased risk
of amputations. A subgroup analysis of EMP-REG OUTCOME,
a landmark trial for empagliflozin, demonstrated consistent
CV benefit in patients with DM and PAD without an increased
risk of amputation (5.5% vs. 6.3%; HR 0.84; 95% CI, 0.54–1.32)
(Verma 2018). One meta-analysis compared the association
of amputation in patients with PAD between SGLT-2 inhib-
itors and dipeptidyl peptidase-4 inhibitors (DPP4Is). Over-
all lower rates of heart failure and adverse lower limb events
were reported for patients with PAD receiving SGLT-2 inhib-
itors, compared with patients receiving DPP4Is (Lee 2020).
This evidence mitigates previous concerns related to ampu-
tations in patients receiving SGLT-2 inhibitors (Lee 2020).
Because PAD is under the ASCVD umbrella, the ADA stan-
dards of care are an excellent resource regarding DM man-
agement and appropriate agent selection. Like hypertension,
it is always important to consider patient-specific factors and
comorbid conditions when selecting glucose-lowering ther-
apy (ADA 2021a).
Smoking Cessation
Smoking is one of the most important modifiable risk fac-
tors to prevent progression of PAD. The risks of MI, death
and amputation are substantially higher in patients with
PAD who continue to smoke compared with those who stop
(Armstrong 2014). The AHA/ACC guidelines currently recom-
mend counselling on smoking cessation at every office visit
(Gerhard-Herman 2017). A recent study using data from the
Atherosclerosis Risk in Communities (ARIC) database eval-
uated the association between smoking cessation and inci-
dence of the three major atherosclerotic diseases—CAD,
PSAP 2022 Book 1 • Cardiology
stroke, and PAD. A stronger association with smoking dura-
tion and intensity (patient-reported pack-years) was consis-
tently observed with PAD compared with stroke and CAD.
Current smoking of 1 pack or more per day had the high-
est association with PAD (HR 5.36; 95% CI, 4.16–6.91) com-
pared with CAD (HR 2.38; 95% CI, 2.08–2.73) and stroke (HR
1.88; 95% CI, 1.57–2.26). Smoking cessation was associated
with the greatest risk reduction for PAD among the three ath-
erosclerotic diseases (Ding 2019). This finding dramatically
highlights the need for smoking cessation for both patients
at risk of PAD and those with a diagnosis of PAD to prevent
disease progression. This point was clearly demonstrated
with 5-year outcomes in an observational cohort study of
739 patients with advanced PAD who underwent angiog-
raphy for CLI or claudication. Patients who successfully
quit smoking had a decreased rate of all-cause mortality
(14% vs. 31%; HR 0.33; 95% CI, 0.13–0.80) and improved
amputation-free survival (81% vs. 60%; adjusted HR 0.40;
95% CI, 0.19–0.83) compared with patients who continued to
smoke (Armstrong 2014). Smoking cessation is difficult to
achieve, and patients often require several attempts to quit.
Clinicians may lack comfort in prescribing pharmacotherapy
in patients with cerebrovascular disease, which is specifi-
cally addressed in the 2018 ACC Expert Consensus Decision
Pathway on Tobacco Cessation Treatment (Barua 2018). Cur-
rent AHA/ACC guidelines provide a class of recommendation
I level of evidence A recommendation for current smokers to
receive assistance in developing a plan to quit that includes
pharmacotherapy with varenicline, bupropion, and/or nico-
tine replacement therapy (Gerhard-Herman 2017).
Antiplatelet Therapy
Antiplatelet agents are the cornerstone of therapy in patients
with PAD to prevent limb events, MI, stroke, and CV death. Lit-
erature is limited regarding an optimal antiplatelet strategy,
including agents and duration, and is derived from subgroup
analyses of trials to evaluate primarily CAD. Current AHA/ACC
guidelines recommend monotherapy with aspirin (75–325
mg/day) or clopidogrel (75 mg/day) to reduce the risk of MI,
stroke, and vascular death in patients with symptomatic PAD
(Gerhard-Herman 2017).
Aspirin
The strongest data in support of aspirin monotherapy to
reduce major adverse cardiovascular events (MACE) are from
a meta-analysis from the Antithrombotic Trialists’ Collabora-
tion (ATC). A 23% reduction in the odds of MACE was observed
in 9214 patients with PAD across 42 trials (p=0.004) (ATC
2002). Aspirin has clear benefit in patients with symptomatic
PAD, whereas the benefits of use are less clear in patients
who remain asymptomatic. In a randomized controlled trial of
patients followed for 8.2 years who were screened, had an ABI
less than 0.95, and were without symptoms, no statistically
significant difference was evident for patients who received
69 Peripheral Arterial Disease
aspirin (13.7 events per 1000 person-years vs. 13.3; HR 1.03;
95% CI, 0.84–1.27) (Fowkes 2010). Although available data do
not support the efficacy of aspirin in patients with asymptom-
atic PAD, it is important to consider the increased risk of other
CV events, especially when disease is present in another vas-
cular bed.
Single Antiplatelet Therapy with P2Y12
Inhibitors
Both clopidogrel and ticagrelor have been studied as single
antiplatelet agents for treatment of symptomatic PAD. The
CAPRIE trial assessed 19,185 patients and compared aspirin
325 mg/day with clopidogrel 75 mg/day in those with ath-
erosclerotic vascular disease, which included a subgroup of
patients with symptomatic PAD. Patients were followed for
1.9 years with a primary outcome of reduction in MACE. The
PAD subgroup analysis of 6452 patients showed that clopi-
dogrel was associated with fewer ischemic events than aspi-
rin (3.71% vs. 4.86%; HR 0.76; 95% CI, 0.64–0.91) (CAPRIE
Steering Committee 1996). Overall differences in bleeding
rates between groups were not statistically significant; how-
ever, GI bleeding was more common in patients treated with
aspirin compared with clopidogrel (2.66% vs. 1.99%, p<0.05)
(CAPRIE Steering Committee 1996). Based on these data,
ESC guidelines prefer clopidogrel over aspirin in patients
with PAD.
A large randomized controlled trial in patients with symp-
tomatic PAD compared monotherapy with ticagrelor 90 mg
twice daily to clopidogrel 75 mg/day. The EUCLID trial included
13,885 patients with symptomatic PAD, defined as an ABI less
than 0.80 or prior revascularization of the lower limbs, with a
primary efficacy end point of MACE within 30 months. Tica-
grelor was not superior to clopidogrel at reducing the inci-
dence of MACE (10.8% vs. 10.6%; HR 1.02; 95% CI, 0.92–1.13).
No difference in major bleeding was noted (1.6%vs. 1.6%; HR
1.10; 95% CI, 0.84–1.43) (Hiatt 2017). Patients also discontin-
ued ticagrelor more often due to dyspnea and minor bleed-
ing. Ticagrelor could present limitations related to cost and
adverse effects, primarily dyspnea, however; this drug could
be considered in patients with concomitant acute coronary
syndrome and PAD.
Dual Antiplatelet Therapy
Dual aspirin and clopidogrel therapy versus aspirin alone was
studied in the CHARISMA trial, which included patients with
established CV disease (including symptomatic PAD) or sev-
eral atherothrombotic risk factors. There was no difference
in MACE observed in the general trial population. However, in
a post hoc analysis of those with polyvascular disease (CAD
plus PAD) there was an increased risk of MACE and acute
limb events. A reduction in MI and ischemic hospitalization
was observed, with an increased in minor bleeding in those
patients receiving DAPT (Cacoub 2009). The PEGASUS-TIMI
54 trial demonstrated a reduction in CV death, MI, or stroke
PSAP 2022 Book 1 • Cardiology
with ticagrelor 60 mg twice daily combined with aspirin 81
mg/day in stable patients with history of MI. Patients in this
trial could also be randomized to ticagrelor 90 mg twice daily.
A sub-analysis evaluating patients in the placebo arm (aspirin
only) with confirmed PAD at enrollment (5%) had more than a
2-fold increase in MACE versus patients without PAD (19.3%
vs. 8.4%; unadjusted HR 2.46; 95% CI, 1.92–3.15). An increase
in bleeding was observed compared with aspirin alone.
Patients with PAD and a history of MI appeared to derive
even more benefit from dual antiplatelet therapy (DAPT) than
patients with only CAD (Bonaca 2016). Currently, AHA/ACC
guidelines highlight that the effectiveness of DAPT in symp-
tomatic patients is not well established (class IIb recommen-
dation) (Gerhard-Herman 2017).
Vorapaxar
Vorapaxar is a novel antagonist of protease-activated
receptor-1, the primary platelet receptor for thrombin. This
drug received FDA approval in 2014 for the reduction of
thrombotic CV events in patients with history of MI or PAD
in combination with aspirin and/or clopidogrel. The TRA 2oP-
TIMI 50 trial was a randomized, double-blind, placebo-control
trial that enrolled 26,449 patients with a history of MI, stroke,
or symptomatic PAD. Of those enrolled, 5845 patients had
known PAD at the start of the trial, including those with
polyvascular disease (Morrow 2012). In this sub-analysis,
vorapaxar did not reduce the rates of MACE compared with
placebo in patients with PAD (11.9% vs. 11.3%; HR 0.94; 95%
CI, 0.78–1.14). In addition, rates of GUSTO (Global Use of
Strategies to Open Occluded Coronary Arteries) moderate or
severe bleeding were increased (7.4% vs. 4.5%; HR 1.62; 95%
CI, 1.21–2.18), regardless of concomitant antiplatelet therapy
(Bonaca 2013). It is important to note vorapaxar is contrain-
dicated in patients with history of stroke, transient ischemic
attack, or intracerebral hemorrhage. Based on the available
literature, current AHA/ACC guidelines describe the overall
clinical benefit of vorapaxar to be uncertain in patients with
symptomatic PAD (Gerhard-Herman 2017).
Oral Anticoagulation
In addition to antiplatelet therapy, a growing body of litera-
ture is addressing the use of oral anticoagulants in patients
with PAD. Historically, anticoagulation has not been recom-
mended to reduce the risk of CV events in this patient pop-
ulation. In the WAVE trial, warfarin was combined with an
antiplatelet agent, primarily aspirin, in patients with PAD.
Combination therapy with warfarin was not more effective
and was associated with an increase in life-threatening bleed-
ing compared with antiplatelet therapy alone (Anand 2007).
Edoxaban, a direct factor Xa inhibitor, has been inves-
tigated in patients with recent endovascular treatment
for PAD management. The ePAD study was a randomized,
open-label trial that evaluated the combination of edoxaban
60 mg/day plus aspirin 100 mg/day or a clopidogrel 300-mg
70 Peripheral Arterial Disease
loading dose, followed by edoxaban 75 mg/day plus aspi-
rin 100 mg/day for 3 months after femoropopliteal interven-
tion. The study assessed 203 patients who were followed for
6 months. For the primary efficacy end point of restenosis,
no difference was found between the two groups (30.9% vs.
34.7%; RR 0.89; 95% CI, 0.59–1.34; p=0.643), and no differ-
ence in International Society on Thrombosis and Hemosta-
sis (ISTH) or Thrombolysis in Myocardial Infarction bleeding
score was found. Although this study did not find a differ-
ence, it was likely underpowered and concern was cited for
higher risk of restenosis because of comorbid conditions in
the edoxaban group (Moll 2018). It is important to note within
6 months there was a 30% risk of restenosis in both groups,
which highlights the difficulty of managing this patient
population.
Rivaroxaban, a direct factor Xa inhibitor, has been inves-
tigated in patients with PAD in two large randomized clinical
trials. The COMPASS study was a randomized, double-blind,
placebo-control trial in stable CV disease, including patients
with both CAD and PAD, which enrolled almost 27,000
patients. Patients received rivaroxaban 2.5 mg twice daily
(defined as low-dose) plus aspirin 100 mg, rivaroxaban 5
mg twice daily, or aspirin 100 mg/day. The trial was stopped
early because of significant reduction in the primary end
point in the treatment group (4.1% vs. 5.4%; HR 0.76; 95% CI,
0.66–0.86); however, more major bleeding events occurred
in patients in the rivaroxaban plus aspirin group (3.1% vs.
1.9% HR 1.70; 95% CI, 1.40–2.05). No difference was noted in
fatal or intracranial bleeding, and most of the excess bleed-
ing was attributed to the GI tract (Eikelboom 2017). The PAD
subgroup analysis included 6391 patients who could have
history of revascularization, symptoms of PAD with objec-
tive confirmatory testing, or presence of CAD with ABI less
than 0.90. Use of rivaroxaban 2.5 mg twice daily plus aspi-
rin 100 mg/day was associated with a reduction in MACE,
as well as incidence of MALE compared with aspirin alone
in this population. Similar to the primary analysis, rivarox-
aban plus aspirin resulted in an increase in major bleeding
compared with aspirin alone (Anand 2018). Of note, the most
recent ADA guidelines state that combination therapy with
aspirin and low-dose rivaroxaban should be considered in
patients with stable CAD and/or PAD with a low bleeding risk
(ADA 2021b).
Most recently, the VOYAGER PAD trial evaluated 6564
patients with PAD undergoing revascularization, comparing
rivaroxaban 2.5 mg twice daily plus aspirin 100 mg/day to aspi-
rin 100 mg/day alone. Clopidogrel was allowed at the discre-
tion of investigator for up to 6 months. Of those randomized,
50.6% received clopidogrel for a median of 29 days. Patients
were randomized based on revascularization approach (sur-
gical, 35%; endovascular, 66%) and planned use of clopidogrel
(50% in each arm). The combination of rivaroxaban and aspi-
rin was associated with a reduction in a composite of MALE
and MACE (17.3% vs. 19.9%; HR 0.85; 95% CI, 0.76–0.96), with
PSAP 2022 Book 1 • Cardiology
no increase in Thrombolysis in Myocardial Infarction major
bleeding. A significant increase in ISTH major bleeding was
observed in the rivaroxaban plus aspirin group (5.94% vs.
4.06%; HR 1.42; 95% CI, 1.10–1.84), but no increase in intra-
cranial hemorrhage or fatal bleeding was noted (Bonaca
2020). Concomitant clopidogrel was explored in more detail
in a subgroup analysis. Rivaroxaban demonstrated a consis-
tent reduction in the primary outcome regardless of clopido-
grel use (HR 0.85; 95% CI, 0.71–1.01 with clopidogrel vs. HR
0.86; 95% CI, 0.73–1.01 without clopidogrel). Rivaroxaban was
associated with more ISTH major bleeding within 365 days
(HR 3.20; 95% CI, 1.44–7.13), compared with shorter durations
of clopidogrel. Based on this analysis, it should be noted that
triple therapy should be used with caution and limited to 30
days (Hiatt 2020). Based on these landmark trials, rivarox-
aban is now indicated in combination with aspirin to reduce
the risk of major thrombotic vascular events in patients with
PAD, specifically including those who have recently under-
gone a revascularization procedure.
For patients with favorable bleeding risk and symptom-
atic PAD or with recent revascularization, it is reasonable to
replace aspirin alone with low-dose rivaroxaban and aspirin. It
is also important to consider a patient’s ability to afford rivar-
oxaban; clopidogrel is generic and in many clinical scenar-
ios may provide a comparable alternative. Patients receiving
hemodialysis were excluded from both trials, and no dosing
recommendations currently exist for this population. At this
time, rivaroxaban is the only oral anticoagulant with compel-
ling data in this patient population. The AGRIPPA trial will
investigate the efficacy and safety of apixaban 2.5 mg twice
daily plus aspirin compared with clopidogrel plus aspirin
in patients with CLI undergoing endovascular intervention
(clinicaltrials.gov/NCT04229264).
SYMPTOMATIC MANAGEMENT
Cilostazol
Cilostazol, a phosphodiesterase 3 inhibitor, provides poten-
tial benefit to patients with PAD through reversible inhi-
bition of platelet aggregation and vasodilation. Current
AHA/ACC guidelines note that cilostazol is an effective ther-
apy to improve symptoms and increase walking distance in
patients with IC (Gerhard-Herman 2017). A 2014 Cochrane
review evaluating cilostazol included 15 randomized con-
trolled trials with 3718 patients. Cilostazol doses ranged from
50–150 mg twice daily and were compared with both pent-
oxifylline and placebo. The pooled results demonstrated
improved initial claudication distance and absolute claudi-
cation distance with cilostazol. Few studies reported MI and
stroke, precluding any conclusions regarding the impact of
cilostazol on these outcomes. Some adverse effects occurred
more often with cilostazol, including headache, diarrhea, diz-
ziness, and palpitations (Bedenis 2014). In an update to the
previous Cochrane review, in which a pooled analysis was
71 Peripheral Arterial Disease
not performed because of differences in measures used
and reporting, limited data indicated no difference between
cilostazol and pentoxifylline (Brown 2021). Cilostazol is con-
traindicated in patients with heart failure at any stage because
of an observed decrease in survival for patients with stage
III and IV heart failure. Although cilostazol is recommended
by the 2016 AHA/ACC guidelines, 2017 ESC guidelines do not
make a formal recommendation and call into question clinical
usefulness of the medication (Aboyans 2018; Gerhard-Her-
man 2017).
Pentoxifylline
Pentoxifylline, a blood viscosity reducer, is approved
for the symptomatic management of IC. A randomized,
double-blind, placebo-controlled trial compared cilostazol
100 mg twice daily to pentoxifylline 400 mg three times daily
or placebo. The primary outcome, maximal walking distance,
was assessed every 4 weeks for 24 weeks. Mean maximal
walking distance for those receiving cilostazol increased by
54% compared to pentoxifylline and placebo. Improvement
in the pentoxifylline group was similar to placebo (Dawson
2000). Current AHA/ACC guidelines do not recommend the
use of pentoxifylline due to lack of benefit (Gerhard-Herman
2017).
Structured Exercise
Structured exercise is recommended for all symptomatic
patients with PAD to improve quality of life and symptoms.
General principles of structured exercise include walking until
significant IC pain occurs, then briefly resting until the pain
subsides. Data consistently support the benefits of struc-
tured exercise therapy in patients with symptomatic PAD. Pro-
grams can exist in hospital or outpatient facilities, as well as
within a structured community or home-based exercise pro-
gram. The sessions are typically, 30–45 minutes, three times
per week, for 12 weeks (Gerhard-Herman 2017).
CRITICAL LIMB ISCHEMIA
In patients with PAD, CLI contributes substantially to mor-
bidity and mortality. Adverse effects include pain, decreased
quality of life, immobility, and, ultimately, amputation and
death. An analogous term, chronic limb-threatening ischemia,
encompasses the full spectrum of complications that arise
from this condition, including impaired wound healing, neu-
ropathy, gangrene, and limb pain. All of these complications
contribute to the high morbidity and mortality rate associ-
ated with this advanced stage of disease. Long-term prog-
nosis once a diagnosis of CLI has been established is very
poor and associated with a fatality rate higher than many can-
cers. Within 4 years of CLI diagnosis, mortality exceeds 50%;
regardless of the revascularization approach, major amputa-
tion rates range from 6%–10% (Mustapha 2019).
PSAP 2022 Book 1 • Cardiology
Patients with CLI present with chronic (more than 2 weeks)
symptoms, such as pain at rest or ulceration. Revasculariza-
tion is a priority to improve arterial blood flow. Selection of
revascularization strategy depends on patient-specific fac-
tors and the expertise of available providers. Patients should
receive imaging before a decision regarding revascularization
strategy. A key factor in decision-making for patients with
CLI is the lesion characteristics—location, length, and cal-
cification. An observational study of Medicare beneficiaries
reported 4-year mortality rate from 49.3%–54.7% and major
amputation rates from 7.8%–10.8%. Although these findings
were statistically significant because of the large sample
size, the authors questioned the clinical significance because
of the observational study design. All treatment groups (per-
cutaneous angioplasty, stent placement, atherectomy, or
surgical bypass) were numerically similar, with very high mor-
tality rates regardless of revascularization approach (Musta-
pha 2019).
Endovascular Revascularization
Use of endovascular therapy for CLI management contin-
ues to increase. From 2003 to 2011, the use of endovascu-
lar procedures significantly increased (5.1%–11.0%) and was
associated with lower rates of in-hospital mortality, major
amputation, and decreased length of stay (Agarwal 2016).
Current approaches for endovascular procedures include
balloon angioplasty, stents (covered and drug-eluting), and
atherectomy. In general, endovascular revascularization is
indicated when lifestyle-limiting claudication arises and sig-
nificant lesions are found on angiography (Gerhard-Herman
2017).
Despite high rates of restenosis, only minimal low-
level data exist regarding optimal antiplatelet therapy
post-intervention, which is a stark contrast from percutane-
ous coronary interventions from which much of the data are
extrapolated. Dual antiplatelet therapy is recommended for
at least 1 month by the 2017 ESC guidelines (class IIa, level
C) in patients who do not otherwise have an indication for
oral anticoagulation (Aboyans 2018). These guidelines were
published before the results of the VOYAGER PAD trial, which
demonstrated benefit with low-dose rivaroxaban after revas-
cularization (Bonaca 2020).
Surgical Revascularization
Surgical intervention should not be performed solely to pre-
vent progression of disease. Primarily, surgery should be
considered when a patient has progressed to CLI to pre-
vent amputation. In patients who have undergone surgi-
cal bypass grafting, aspirin monotherapy improves graft
patency. For patients receiving a prosthetic graft, DAPT is
effective compared with aspirin alone (Aboyans 2018; Ger-
hard-Herman 2017). With the recently published VOGAYER
PAD data, low-dose rivaroxaban plus aspirin should be con-
sidered for patients undergoing surgical or endovascular
72 Peripheral Arterial Disease
 Asymptomatic Symptomatic Revascularization

Aspirin, or
Consider
clopidogrelb, Surgery Endovascular
aspirina
or ticagrelorc

Or

Low-dose Low-dose
DAPT for
rivaroxaband + rivaroxaband +
1–6 months
aspirine aspirine

Or/followed by

Low-dose
rivaroxaband +
aspirine,f

Figure 2. Approach to antithrombotic therapy in patients with PAD.

a
Recommended by the American Heart Association/American College of Cardiology guidelines.
b
Clopidogrel is preferred by European Society of Cardiology guidelines for single antiplatelet therapy.
c
Benefit with ticagrelor established in patients with history of percutaneous coronary stents.
d
Low-dose rivaroxaban is 2.5 mg twice daily.
e
Consider in patients with low bleeding risk.
f
Based on VOYAGER-PAD, limit overlap of 30-days of DAPT plus low-dose rivaroxaban.
DAPT = dual antiplatelet therapy; PAD = peripheral arterial disease.
Information from: Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management of patients with
lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association Task
Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;69:e71-126; Aboyans V, Ricco J, Bartelink M, et al. 2017 ESC
guidelines on the diagnosis and treatment of peripheral arterial diseases. Eur Heart J 2018;39:763-816; Bonaca MP, Bauersachs
RM, Anand SS, et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med 2020;382:1994-2004;
Hussain MA, Al-Omran M, Creager MA, et al. Antithrombotic therapy for peripheral artery disease: recent advances. J Am Coll
Cardiol 2018;71:2450-67.

revascularization (Bonaca 2020). Figure 2 provides a pro-
posed treatment algorithm for patients with PAD.
ACUTE LIMB ISCHEMIA
Acute limb ischemia is a medical emergency and should
be recognized and treated rapidly. Commonly also referred
to as cold leg, patients require rapid intervention to restore
arterial blood flow. Lower extremity symptoms may include
pain, loss of function or paresthesias, and coolness in the
affected extremity The acute nature is primarily caused by
a rapid decrease in blood flow resulting from thrombosis or
embolization. The source of embolization is primarily the
heart, aorta, or larger arteries and may be associated with
atrial fibrillation or left ventricular mural thrombosis after MI.
Shared decision-making should be incorporated when possi-
ble. Options for management include catheter-direct throm-
bolysis and endovascular or surgical thrombectomy. Limbs
may not be salvageable upon presentation, and major ampu-
tation may be necessary in cases of irreversible tissue loss.
Urgent angiography, either by computed tomography or inva-
sively, is indicated when patients present with loss of sensa-
tion, paralysis, or lack of Doppler-detected blood flow (Fluck
2020; Gerhard-Herman 2017). Staging of ALI to make clinical
decisions can be done using the Rutherford classification
(Table 3).
Anticoagulation

PSAP 2022 Book 1 • Cardiology 73 Peripheral Arterial Disease

 Patient Care Scenario
A 72-year-old woman presents for follow-up after place-
ment of a stent to the iliac artery 5 weeks ago. Today she
reports that her symptoms have improved. She is able to
walk her dog around the block and complete her grocery
shopping without stopping. Her history includes type 2
DM, hypertension, and dyslipidemia. She recently quit
smoking. Relevant vital signs and laboratory values today
are blood pressure 138/82 mm Hg, LDL cholesterol 115
mg/dL, and A1C 8.0%. Her current medications include
metformin 1000 mg twice daily, amlodipine 10 mg/day,
pravastatin 80 mg/day at bedtime, aspirin 81 mg/day, and
clopidogrel 75 mg/day. What recommendations should be
made to optimize her medical regimen?
This patient presents with PAD with recent revascu-
larization. Her symptoms have improved; however, her
modifiable risk factors should continue to be addressed
to reduce her risk of MACE and acute limb events. She
should be encouraged to maintain her smoking cessation.
This patient should be receiving a high-intensity sta-
tin (atorvastatin 40–80 mg/day or rosuvastatin 20–40
mg/day). Her LDL cholesterol should be rechecked in 12
weeks, as recommended by the 2018 AHA/ACC guideline
on management of blood cholesterol. To improve her A1C
control and further reduce her risk of CV events, adding
a SGLT-2 inhibitor or a GLP-1 receptor agonist should be
considered. This patient is also not achieving her blood
pressure goal of less than 130/80 mm Hg. She should be
receiving an ACEI or ARB to reduce her risk of future CV
events. Based on the results of the VOYAGER PAD trial,
this patient would benefit from the addition of rivaroxaban
2.5 mg twice daily. Because it has been longer than 30
days from her surgical intervention, little data are avail-
able to support continuing clopidogrel as part of DAPT at
this time. However, the addition of low-dose rivaroxaban,
in combination with aspirin, will reduce her risk of future
MACE and MALE.

1. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral
artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
J Am Coll Cardiol 2017;69:e71-126.
2. Aboyans V, Ricco J, Bartelink M, et al. 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collabora-
tion with the European Society for Vascular Surgery. Eur Heart J 2018;39:763-816.
3. Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med
2020;382:1994-2004.

Table 3. Rutherford Classification of Acute Limb Ischemia

Muscle Arterial Venous

Class Description Sensory Loss Weakness Doppler Doppler

I Viable Not immediately threatened None None Audible Audible

IIa Marginally Salvageable with prompt None or minimal None Absent Audible
threatened treatment (toes only)

IIb Immediately Salvageable with immediate More than toes; Mild to Absent Audible
threatened revascularization rest pain moderate

III Irreversible Major tissue loss, inevitable Profound Profound Absent Absent
nerve damage

Information from: Rutherford RB, Baker JD, Ernst C, et al. Recommended standards for reports dealing with lower extremity ischemia:
revised version. J Vasc Surg 1997;26:517–38.

Systemic anticoagulation should be initiated as soon as the
diagnosis of ALI is suspected. The most common agent for
management is intravenous unfractionated heparin using a
weight-based protocol (bolus 60–80 units/kg, followed by
12–18 units/kg/hour, titrated to goal activated partial throm-
boplastin time). Enoxaparin is not ideal because of the poten-
tial acute need for surgery or invasive procedures requiring
rapid anticoagulant reversal. The goal of anticoagulation is
to prevent further thrombus propagation and to inhibit distal
thrombosis caused by decreased arterial flow. Although spe-
cific literature is lacking, it is reasonable to use alternative
agents (bivalirudin or argatroban) in a patient with history of
heparin-induced thrombocytopenia (Patel 2013).

PSAP 2022 Book 1 • Cardiology 74 Peripheral Arterial Disease

 Table 4. Catheter-Directed Thrombolysis Dosing for
Acute Limb Ischemia
Thrombolytic Dose
Alteplase 0.12–2 mg/hr; maximum, 40 mg total
Reteplase 0.25 to 1.0 U/h; maximum, 20 U in 24 hr
Tenecteplase Bolus infusion of 1–5 mg, followed by
0.125–0.5 mg/hr
Information from: Patel NH, Krishnamurthy VN, Kim S, et al.
Quality improvement guidelines for percutaneous manage-
ment of acute lower-extremity ischemia. J Vasc Interv
Radiol 2013;24:3-15; Ebben HP, Jongkind V, Wisselink W, et
al. Catheter directed thrombolysis protocols for peripheral
arterial occlusions: a systematic review. Eur J Vasc Endo-
vasc Surg 2019;57:667-75.
Catheter-Directed Strategies
Catheter-directed thrombolysis (CDT) in the management of
ALI has been associated with lower morbidity, decreased hos-
pital length of stay, and less patient discomfort. It is currently
recommended when symptoms have been present for less
than 14 days. Current AHA/ACC guidelines state CDT is effec-
tive for patients with a salvageable limb (Gerhard-Herman
2017). There is no consensus regarding which fibrinolytic
agent or dosing regimen is optimal. Two general approaches
are commonly used, although each has an associated
risk: low-dose, long-duration thrombolytic infusions are
associated with risk of hemorrhage and high-dose, and
short-duration infusions may increase risk of distal embo-
lization. Most institutions design dosing regimens with
short-durations (between 18–22 hours) and attempt to min-
imize overall drug exposure. Suggested dosing is outlined in
Table 4 (Patel 2013).
A recent systematic review included 9877 patients who
received CDT in the lower extremities. The mean treatment
duration was 21.4 hours (95% CI, 21.0–21.8), with 82% of pro-
tocols reporting bolus dosing. Overall angiographic patency
was achieved in 75% (95% CI, 74.6–75.1) of patients. No ampu-
tation was performed for 91% (95% CI, 90.3 - 90.7) of patients.
Bleeding complications occurred in 18% (95% CI, 17.8–18.3),
which remains the primary concern regarding this approach
(Ebben 2019). The Society of Interventional Radiology main-
tains quality improvement guidelines that include absolute
and relative contraindications to thrombolytics. Authors note
this list was reached by consensus, rather than literature eval-
uation. The suggested contraindications (Box 3) should be
considered and discussed with patients as part of a shared
decision-making process (Patel 2013).
Patients who undergo CDT benefit from subsequent sur-
gical or endovascular revascularization to decrease need for
PSAP 2022 Book 1 • Cardiology
Box 3. Contraindications to Catheter-
Directed Thrombolysis
Absolute contraindications
• Absolute contraindication to anticoagulation
• Active clinically significant bleeding
• Intracranial hemorrhage
• Presence/development of compartment syndrome
Relative contraindications
• Bacterial endocarditis
• Bleeding diathesis
• Cardiopulmonary resuscitation within past 10 days
• Diabetic hemorrhagic retinopathy
• Disseminated intravascular coagulation
• Established cerebrovascular event (including transient
ischemic attacks) within past 2 mo
• Life expectancy < 1 yr
• Intracranial tumor, vascular malformation, aneurysm, or
seizure disorder
• Major surgery, or major trauma within past 10 days
• Neurosurgery (intracranial, spinal), or intracranial trauma
within past 3 mo
• Pregnancy and immediate postpartum status
• Recent eye surgery within past 3 mo
• Recent internal hemorrhage, puncture of noncompressible
vessel or organ biopsy
• Recent major GI bleeding within past 10 days
• Serious allergic or other reaction to thrombolytic agent,
anticoagulant, or contrast media (not controlled by steroid/
antihistamine pretreatment)
• Severe liver dysfunction, particularly in cases with
coagulopathy
• Severe thrombocytopenia
• Uncontrolled hypertension (SBP >180 mm Hg or diastolic
blood pressure >110 mm Hg)
Information from: Patel NH, Krishnamurthy VN, Kim S, et al.
Quality improvement guidelines for percutaneous manage-
ment of acute lower-extremity ischemia. J Vasc Interv Radiol
2013;24:3-15.
future amputation (Fluck 2020). Hybrid CDT can also be used
in combination with aspiration or mechanical thrombectomy
to facilitate restoration of blood flow (see Table 4). Pharmaco-
therapy after CDT is dependent on the underlying lesion. If no
endovascular or surgical intervention is necessary, patients
should receive anticoagulation (Patel 2013).
CONCLUSION
Peripheral arterial disease continues to be underdiagnosed
and undertreated despite the high morbidity and mortality
associated with this disease. Major gaps in data related to
appropriate treatment exist. However, advances have been
made with the COMPASS and VOYAGER PAD trials. Patients
presenting with ALI require emergency management to
75 Peripheral Arterial Disease

Practice Points
• Clinically, PAD is considered ASCVD, and mitigation of CV
risk factors is important to reduction of disease progres-
sion and ischemic events.
• Early detection by appropriate screening and aggressive
risk reduction strategies are crucial to prevent disease
progression and mortality.
• Treatment is primarily focused on patients with symptom-
atic PAD with limited data on screening patients who are
truly asymptomatic.
• Smoking cessation should be offered at every office visit
for current smokers.
• Aspirin, clopidogrel, statins, evolocumab, rivaroxaban and
ACEI/ARBs all reduce the risk of MACE in patients with
symptomatic PAD.
• Rivaroxaban reduced the risk of MACE and MALE after
revascularization, regardless of short-term clopidogrel use.
• Patients with ALI have a very high morbidity and mortality,
and this condition should be managed as an emergency,
including intravenous anticoagulation.
• The use of CDT can offer an alternative to surgery in
patients with ALI; however, this approach carries a risk of
bleeding, and dosing strategies lack standardization.
increase likelihood of limb salvage. Pharmacists are well
positioned to advocate for patients with PAD, to address mod-
ifiable risk factors, and to initiate pharmacotherapy to lower
CV risk.
REFERENCES
Aboyans V, Criqui MH, Abraham P, et al. Measurement and
interpretation of the ankle-brachial index: a scientific
statement from the American Heart Association. Circula-
tion 2012;126:2890-909.
Aboyans V, Ricco J, Bartelink M, et al. 2017 ESC guidelines
on the diagnosis and treatment of peripheral arterial dis-
eases, in collaboration with the European Society for Vas-
cular Surgery (ESVS). Eur Heart J 2018;39:763-816.
Agarwal S, Sud K, Shishehbor MH. Nationwide trends of
hospital admission and outcomes among critical limb
ischemia patients: from 2003–2011. J Am Coll Cardiol
2016;67:1901-13.
American Diabetes Association. 9. Pharmacologic
approaches to glycemic treatment: standards of medical
care in diabetes—2021. Diabetes Care 2021a;44:S111-24.
American Diabetes Association. 10. Cardiovascular disease
and risk management: standards of medical care in diabe-
tes—2021. Diabetes Care 2021b;44:S125-50.
Anand S, Yusuf S, Xie C, et al; Warfarin Antiplatelet Vascular
Evaluation (WAVE) Trial Investigators. Oral anticoagulant
and antiplatelet therapy and peripheral arterial disease. N
Engl J Med 2007;357:217-27.
Anand SS, Bosch J, Eikelboom JW, et al. Rivaroxaban with or
without aspirin in patients with stable peripheral or carotid
PSAP 2022 Book 1 • Cardiology
artery disease: an international, randomised, double-blind,
placebo-controlled trial. Lancet 2018;391:219-29.
Antithrombotic Trialists’ Collaboration. Collaborative
meta-analysis of randomised trials of antiplatelet therapy
for prevention of death, myocardial infarction, and stroke
in high risk patients. BMJ. 2002 Jan 12;324(7329):71-86.
Armstrong EJ, Wu J, Singh GD, et al. Smoking ces-
sation is associated with decreased mortality and
improved amputation-free survival among patients with
symptomatic peripheral artery disease. J Vasc Surg
2014;60:1565-71.
Bavry AA, Anderson RD, Gong Y, et al. Outcomes among
hypertensive patients with concomitant peripheral
and coronary artery disease: findings from the Interna-
tional Verapamil-SR/Trandolapril Study. Hypertension
2010;55:48-53.
Barua RS, Rigotti NA, Benowitz NL, et al. 2018 ACC expert
consensus decision pathway on tobacco cessation treat-
ment: a report of the American College of Cardiology Task
Force on Clinical Expert Consensus Documents. J Am Coll
Cardiol 2018;72:3332-65.
Bedenis R, Stewart M, Cleanthis M, et al. Cilostazol for
intermittent claudication. Cochrane Database Syst Rev
2014:CD003748.
Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in
peripheral artery disease after revascularization. N Engl J
Med 2020;382:1994–2004.
Bonaca MP, Bhatt DL, Storey RF, et al. Ticagrelor for pre-
vention of ischemic events after myocardial infarction in
patients with peripheral artery disease. J Am Coll Cardiol
2016;67:2719-28.
Bonaca MP, Nault P, Giugliano RP, et al. Low-density lipo-
protein cholesterol lowering with evolocumab and out-
comes in patients with peripheral artery disease: insights
from the FOURIER trial (further cardiovascular outcomes
research with PCSK9 inhibition in subjects with elevated
risk). Circulation 2018;137:338-50.
Bonaca MP, Scirica BM, Creager MA, et al. Vorapaxar in
patients with peripheral artery disease: results from
TRA2{degrees}P-TIMI 50. Circulation 2013;127:1522-9.
Brown T, Forster RB, Cleanthis M, et al. Cilostazol for inter-
mittent claudication. Cochrane Database Syst Rev
2021:CD003748.
Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added
to statin therapy after acute coronary syndromes. N Engl J
Med 2015;372:2387-97.
CAPRIE Steering Committee. A randomised, blinded, trial of
clopidogrel versus aspirin in patients at risk of ischaemic
events (CAPRIE). CAPRIE Steering Committee. Lancet
1996;348:1329-39.
Cacoub PP, Bhatt DL, Steg PG, at al. CHARISMA Investiga-
tors. Patients with peripheral arterial disease in the CHA-
RISMA trial. Eur Heart J. 2009;2:192-201.
76 Peripheral Arterial Disease
Dawson DL, Cutler BS, Hiatt WR, et al. A comparison of
cilostazol and pentoxifylline for treating intermittent clau-
dication. Am J Med 2000;109:523-30.
Ding N, Sang Y, Chen J, et al. Cigarette smoking, smoking
cessation, and long-term risk of 3 major atherosclerotic
diseases. J Am Coll Cardiol 2019;74:498-507.
Ebben HP, Jongkind V, Wisselink W, et al. Catheter directed
thrombolysis protocols for peripheral arterial occlu-
sions: a systematic review. Eur J Vasc Endovasc Surg
2019;57:667-75.
Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with
or without aspirin in stable cardiovascular disease. N Engl
J Med 2017;377:1319-30.
Espinola-Klein C, Weisser G, Jagodzinski A, et al. β-Blockers
in patients with intermittent claudication and arterial
hypertension: results from the nebivolol or metopr-
olol in arterial occlusive disease trial. Hypertension
2011;58:148-54.
Fluck F, Augustin AM, Bley T, et al. Current treatment options
in acute limb ischemia. Rofo 2020;192:319-26.
Fowkes FG, Price JF, Stewart MC, et al. Aspirin for prevention
of cardiovascular events in a general population screened
for a low ankle brachial index: a randomized controlled
trial. JAMA 2010;303:841-8.
Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/
ACC guideline on the management of patients with lower
extremity peripheral artery disease: a report of the Amer-
ican College of Cardiology/American Heart Association
Task Force on Clinical Practice Guidelines. J Am Coll Car-
diol 2017;21;69:e71-126.
Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/
AACVPR/AAPA/ABC/ACPM/ ADA/AGS/ APhA/ASPC/NLA/
PCNA guideline on the management of blood cholesterol:
a report of the American College of Cardiology/American
Heart Association Task Force on Clinical Practice Guide-
lines. J Am Coll Cardiol 2019;73:e285-350.
Henry AJ, Hevelone ND, Belkin M, Nguyen LL. Socioeco-
nomic and hospital-related predictors of amputation for
critical limb ischemia. J Vasc Surg 2011;53:330-9.e.1.
Hiatt WR, Bonaca MP, Patel MR, et al. Rivaroxaban and aspi-
rin in peripheral artery disease lower extremity revascular-
ization: impact of concomitant clopidogrel on efficacy and
safety. Circulation 2020;142:2219-30.
Hiatt WR, Fowkes FG, Heizer G, et al. Ticagrelor versus clopi-
dogrel in symptomatic peripheral artery disease. N Engl J
Med 2017;376:32-40.
Hira RS, Cowart JB, Akeroyd JM, et al. Risk factor optimiza-
tion and guideline-directed medical therapy in US Veter-
ans with peripheral arterial and ischemic cerebrovascular
disease compared to Veterans with coronary heart dis-
ease. Am J Cardiol 2016;118:1144-9.
PSAP 2022 Book 1 • Cardiology
Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral
arterial disease detection, awareness, and treatment in
primary care. JAMA 2001;286:1317-24.
Jukema JW, Szarek M, Zijlstra LE, et al. Alirocumab in
patients with polyvascular disease and recent acute coro-
nary syndrome: ODYSSEY OUTCOMES trial. J Am Coll Car-
diol 2019;74:1167-76.
Kumbhani DJ, Steg PG, Cannon CP, et al. Statin therapy and
long-term adverse limb outcomes in patients with periph-
eral artery disease: insights from the REACH registry. Eur
Heart J 2014;35:2864-72.
Lee HF, Chen SW, Liu JR, et al. Major adverse cardiovascu-
lar and limb events in patients with diabetes and concomi-
tant peripheral artery disease treated with sodium glucose
cotransporter 2 inhibitor versus dipeptidyl peptidase-4
inhibitor. Cardiovasc Diabetol 2020;19:160.
Leng GC, Fowkes FG. The Edinburgh Claudication Question-
naire: an improved version of the WHO/Rose question-
naire for use in epidemiological surveys. J Clin Epidemiol
1992;45:1101-09.
Maffei A, Lembo G. Nitric oxide mechanisms of nebivolol.
Ther Adv Cardiovasc Dis 2009; 4:317-27.
McDermott MM, Kerwin DR, Liu K, et al. Prevalence and sig-
nificance of unrecognized lower extremity peripheral arte-
rial disease in general medicine practice. J Gen Intern
Med. 2001; 6:384-90.
Moll F, Baumgartner I, Jaff M, et al. Edoxaban plus aspirin
vs dual antiplatelet therapy in endovascular treatment
of patients with peripheral artery disease: results of the
ePAD trial. J Endovasc Ther 2018;25:158-68.
Montgomery PS, Gardner AW. The clinical utility of a six-min-
ute walk test in peripheral arterial occlusive disease
patients. J Am Geriatr Soc 1998;46:706-11.
Morrow DA, Braunwald E, Bonaca MP, et al. Vorapaxar in the
secondary prevention of atherothrombotic events. N Engl
J Med 2012;366:1404-13.
Mustapha JA, Katzen BT, Neville RF, et al. Propensity
score-adjusted comparison of long-term outcomes among
revascularization strategies for critical limb ischemia. Circ
Cardiovasc Interv 2019;12:e008097.
Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and car-
diovascular and renal events in type 2 diabetes. N Engl J
Med 2017;377:644-57.
ONTARGET Investigators, Yusuf S, Teo KK, et al. Telmisar-
tan, ramipril, or both in patients at high risk for vascular
events. N Engl J Med 2008;358:1547-59.
Ostergren J, Sleight P, Dagenais G, et al. Impact of ramipril in
patients with evidence of clinical or subclinical peripheral
arterial disease. Eur Heart J 2004;25:17-24.
Patel NH, Krishnamurthy VN, Kim S, et al. Quality improve-
ment guidelines for percutaneous management of
acute lower-extremity ischemia. J Vasc Interv Radiol
2013;24:3-15.
77 Peripheral Arterial Disease
Shu J, Santulli G. Update on peripheral artery disease: epi-
demiology and evidence-based facts. Atherosclerosis
2018;275:379-81.

Stein R, Hriljac I, Halperin JL, et al. Limitation of the resting

ankle-brachial index in symptomatic patients with periph-
eral arterial disease. Vasc Med 2006;11:29-33.

Verma S, Mazer CD, Al-Omran M, et al. Cardiovascular out-

comes and safety of empagliflozin in patients with type 2
diabetes mellitus and peripheral artery disease: a subanal-
ysis of EMPA-REG OUTCOME. Circulation 2018;137:405-7.

Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and

stroke statistics—2020 update: a report from the American
Heart Association. Circulation 2020;141:e139-596.

Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/

AAPA/ABC/ACPM/AGS/APhA/ASH/ ASPC/NMA/PCNA
guideline for the prevention, detection, evaluation, and
management of high blood pressure in adults: a report of
the American College of Cardiology/American Heart Asso-
ciation Task Force on Clinical Practice Guidelines. Hyper-
tension 2018;71:e13-115.

PSAP 2022 Book 1 • Cardiology 78 Peripheral Arterial Disease

Self-Assessment Questions
1. A 50-year-old African American man (weight 98 kg
[216 lb], height 70 inches) has a medical history that
includes type 2 diabetes mellitus (T2DM), hypertension,
and hyperlipidemia. He quit smoking 25 years ago and
currently drinks 1–2 beers per day. The patient reports
pain and cramping in his calves when walking his dog
around the block. The pain subsides when he rests on a
park bench. Physical examination reveals loss of leg hair
and shiny calves with diminished pulses. Ankle-brachial
index (ABI) are measured at 0.65 on the right leg and 0.72
on the left leg. Which one of the following is this patient’s
greatest risk factor for major amputation?
A. Obesity
B. Race
C. Hypertension
D. Age
2. A 61-year-old woman with a medical history of T2DM
(A1C 7.2%), hypertension, and hyperlipidemia presents
with complaints of lower extremity pain when walking
short distances. The pain resolves with rest. The patient
is a current 1 pack per day smoker. Testing reveals ABIs
of 0.80 in both legs with no visible skin ulcers or gan-
grene. Today’s vital signs include blood pressure 122/74
mm Hg and heart rate 78 beats/minute. Her home drugs
include amlodipine 10 mg/day, rosuvastatin 20 mg/day,
lisinopril 20 mg/day, metformin 1000 mg twice daily, and
semaglutide 1 mg subcutaneously weekly. Which one
of the following is best to recommend for this patient
to decrease her risk of a major adverse cardiovascular
event (MACE)?
A. Increase lisinopril to 40 mg/day.
B. Initiate aspirin 81 mg/day.
C. Initiate cilostazol 100 mg twice daily.
D. Initiate warfarin (INR goal 2–3).
3. A 71-year-old woman with established PAD (previous
ABIs 0.87 and 0.88) was initiated on atorvastatin
80 mg/day 4 months ago. Today she returns to the office
for follow-up. The patient has no history of previous
peripheral revascularization. Her LDL cholesterol today
is 82 mg/dL. Which one of the following is best to recom-
mend to optimize this patient’s medical regimen?
A. Maintain current therapy.
B. Add ezetimibe.
C. Change to rosuvastatin 40 mg/day.
D. Add evolocumab.
PSAP 2022 Book 1 • Cardiology
Questions 4–6 pertain to the following case.
A.Y., a 65-year-old woman with a medical history of T2DM
(A1C 8.1%), stable ischemic heart disease (SIHD), and hyper-
tension presents to the clinic with a chief complaint of wors-
ening leg cramping and fatigue that increases on her daily
walks and is relieved by rest. She notes that compared with
6 months ago, she can no longer walk as far as she used to,
especially in the past month. A.Y. has smoked 1 pack of ciga-
rettes per day for the past 40 years. Upon physical examina-
tion her legs are cool to the touch but pulses are palpable. Her
home drugs include metformin 1000 mg twice daily, lisinopril
20 mg/day, and aspirin 81 mg/day.
4. Based on her symptoms and physical examination, A.Y.
is referred for ABI evaluation. The patient’s systolic blood
pressure (SBP) measurements are recorded as the fol-
lowing: 136 mm Hg (brachial, right arm), 142 mm Hg (bra-
chial, left arm), 110 mm Hg (dorsalis pedis, right foot), 118
mm Hg (posterior tibial, right foot), 120 mm Hg (dorsa-
lis pedis, left foot), and 122 mm Hg (posterior tibial, left
foot). Given these measurements, which one of the fol-
lowing best evaluates A.Y.’s left and right ABIs?
A. 0.88 (left) and 0.77 (right)
B. 0.84 (left) and 0.86 (right)
C. 0.86 (left) and 0.83 (right)
D. 0.81 (left) and 0.81 (right)
5. To optimize her diabetes regimen by providing cardiovas-
cular (CV) risk reduction, which one of the following is
best to recommend for A.Y.?
A. Insulin
B. Empagliflozin
C. Glipizide
D. Exenatide
6. Which one of the following is best to recommend to
reduce A.Y.’s risk of CV death and acute limb events?
A. Clopidogrel
B. Cilostazol
C. Rivaroxaban
D. Amlodipine
Questions 7 and 8 pertain to the following case.
K.T., a 69-year-old man, is preparing for discharge from
the hospital after placement of a drug-eluting stent (DES)
to his femoral artery due to chronic limb ischemia with a
non-healing ulcer on his left foot. His medical history includes
coronary artery disease, hypertension, and hyperlipidemia.
79 Peripheral Arterial Disease
K.T. has smoked one pack per day for the past 45 years. His
drugs prior to the procedure included aspirin 81 mg/day, tel-
misartan 80 mg/day, rosuvastatin 20 mg/day, and amlodipine
10 mg/day.
7. Which one of the following is best to recommend to
decrease K.T.’s risk of acute limb events?
A. Low-dose rivaroxaban plus low-dose aspirin
B. Dual antiplatelet therapy (DAPT) for 30 days, then
aspirin 325 mg/day indefinitely
C. Low-dose aspirin monotherapy
D. Warfarin (INR goal 2–3)
8. A 59-year-old white man with a medical history that
includes ST-segment elevation myocardial infarction
12 months ago, PAD, hypertension, and hyperlipidemia
is seen today for his 1-year follow-up. His home drugs
include aspirin 81 mg/day, lisinopril 40 mg/day, ator-
vastatin 80 mg/day, metoprolol succinate 100 mg/day,
amlodipine 10 mg/day, and ticagrelor 90 mg twice daily.
Upon physical examination his blood pressure is 102/64
mm Hg and heart rate is 71 beats/minute. His home
blood pressure logs are consistent with the office mea-
surement. Which one of the following is best to recom-
mend to manage this patient’s blood pressure?
A. Increase metoprolol succinate to 150 mg/day.
B. Discontinue amlodipine.
C. Discontinue lisinopril.
D. Continue current therapy.
9. A 68-year-old man with previously documented PAD,
T2DM, and hypertension is seen in clinic for follow-up.
He has participated in a structured exercised program
with some improvement in his symptoms; however,
he still feels his quality of life is limited by symptoms.
His current drugs include aspirin 81 mg/day, atorvas-
tatin 40 mg/day, losartan 100 mg/day, and metformin
500 mg twice daily. Which one of the following is best
to recommend to address this patient’s symptoms of
claudication?
A. Cilostazol
B. Pentoxifylline
C. Clopidogrel
D. Ticagrelor
10. A 66-year-old woman with a medical history of PAD pres-
ents to her cardiologist for follow-up. Her current home
drugs include: aspirin 81 mg/day, cilostazol 100 mg
twice daily, lisinopril 10 mg/day, atorvastatin 80 mg/day,
and ezetimibe 10 mg/day. The patient reports improve-
ment in her symptoms since cilostazol was started 6
months ago. Pertinent objective data include blood pres-
sure 128/74 mm Hg, heart rate 88 beats/minute, and LDL
cholesterol 90 mg/dL; ECG shows normal sinus rhythm,
PSAP 2022 Book 1 • Cardiology
and ejection fraction (EF) is 52% (on ECHO). Which one of
the following is best to recommend to optimize manage-
ment of this patient’s PAD?
A. Initiate evolocumab 420 mg subcutaneously
monthly.
B. Discontinue cilostazol 100 mg twice daily.
C. Increase lisinopril to 20 mg/day.
D. Change aspirin to rivaroxaban 2.5 mg twice daily.
11. You are developing an institutional protocol for catheter-
directed thrombolysis for patients presenting with acute
limb ischemia. Alteplase is the thrombolytic on formu-
lary. Which one of the following dosing protocols best
balances the risks and benefits in this patient population?
A. 2 mg/hour for 48 hours
B. 1 mg/hour for 5 hours
C. 1 mg/hour for 18 hours
D. 0.5 mg/hour for 10 hours
12. A 68-year-old man with medical history of T2DM, hyper-
tension, coronary artery disease, and heart failure with
reduced EF presents to the ED with worsening leg pain.
Upon examination, his foot is cool to the touch and a
large non-healing ulcer is noted. Dopplers are absent.
The patient undergoes femoropopliteal bypass surgery.
Which one of the following antithrombotic regimens is
best to recommend to reduce this patient’s risk of recur-
rence of CV death and future limb events?
A. Low-dose rivaroxaban plus low-dose aspirin
B. DAPT for 30 days, then aspirin 81 mg/day
indefinitely
C. Low-dose aspirin monotherapy
D. Warfarin (INR goal 2–3)
Questions 13–15 pertain to the following case.
R.A., a 73-year-old man (weight 98 kg [216 lb], CrCl 58 mL/min)
with a medical history of T2DM, hypertension, and hyperlipid-
emia presents to the ED with 2 days of worsening leg pain.
This morning his leg became increasingly painful at rest and
he has lost sensation in his toes. R.A.’s arterial Dopplers are
absent, but venous Dopplers are audible. He reports no mus-
cle weakness at this time.
13. Given his current symptoms, which one of the follow-
ing anticoagulation strategies is best to recommend for
R.A.?
A. Intravenous heparin
B. Enoxaparin 100 mg subcutaneously every 12 hours
C. Warfarin (INR 2–3)
D. Rivaroxaban 2.5 mg twice daily
80 Peripheral Arterial Disease
14. Based on R.A.’s presentation and additional imaging, he
is scheduled to undergo catheter-directed thrombolysis.
Balancing dosing regimens and principles, which one of
the following thrombolytic regimens is best to recom-
mend for R.A.?
A. Tenecteplase 2 mg bolus, followed 0.25 mg/hour
infusion for 18 hours
B. Alteplase 2 mg/hour infusion for 36 hours
C. Tenecteplase 0.125 mg/hour infusion for 36 hours
D. Reteplase 1 U/hour infusion for 24 hours
PSAP 2022 Book 1 • Cardiology
15. After catheter-directed thrombolysis, R.A. undergoes
peripheral angiography and receives a DES to superficial
femoral artery. In addition to aspirin 81 mg/day, which
one of the following antithrombotic regimens is best to
recommend for 30 days after R.A.’s procedure?
A. Warfarin (INR 2-3)
B. Ticagrelor 60 mg twice daily
C. Clopidogrel 75 mg/day
D. Apixaban 2.5 mg twice daily
81 Peripheral Arterial Disease
Learner Chapter Evaluation: Peripheral Arterial Disease

As you take the posttest for this chapter, also evaluate the 8. The teaching and learning methods used in the chapter
material’s quality and usefulness, as well as the achievement were effective.
of learning objectives. Rate each item using this 5-point scale: 9. The active learning methods used in the chapter were
effective.
• Strongly agree
10. The learning assessment activities used in the chapter
• Agree
were effective.
• Neutral
• Disagree 11. The chapter was effective overall.
• Strongly disagree 12. The activity met the stated learning objectives.
13. If any objectives were not met, please list them here.
1. The content of the chapter met my educational needs.
2. The content of the chapter satisfied my expectations.
3. The author presented the chapter content effectively.
OTHER COMMENTS
4. The content of the chapter was relevant to my practice 14. Please provide any specific comments related to any
and presented at the appropriate depth and scope. perceptions of bias, promotion, or advertisement of
commercial products.
5. The content of the chapter was objective and balanced.
15. Please expand on any of your above responses, and/or
6. The content of the chapter is free of bias, promotion, and
provide any additional comments regarding this chapter:
advertisement of commercial products.
7. The content of the chapter was useful to me.

PSAP 2022 Book 1 • Cardiology 82 Peripheral Arterial Disease

Antithrombotic Therapy in Cardiac
Interventions
By Stephanie Dwyer Kaluzna, Pharm.D., BCCP; and Jaclynne Gowen, Pharm.D., BCCP

Reviewed by A. Josh Roberts, Pharm.D., BCCP, BCPS-AQ Cardiology, AACC: Bethany A. Ford, Pharm.D., BCPS; and Christine S. Ji, Pharm.D.,
BCCP, BCPS

LEARNING OBJECTIVES

1. Apply the advances made in percutaneous coronary intervention and complications with coronary stenting to determine
appropriate antithrombotic regimens.
2. Analyze recent literature surrounding the use of chemoreceptor P2Y12 inhibitors and oral anticoagulants in patients with
coronary artery disease and acute coronary syndromes.
3. Design a treatment plan for a patient with an indication for chronic anticoagulation who is undergoing percutaneous
coronary intervention.
4. Distinguish between the various antithrombotic treatment regimens indicated for patients undergoing transcatheter
valvular interventions.

ABBREVIATIONS IN THIS CHAPTER
ACS Acute coronary syndrome
AS Aortic stenosis
CABG Coronary artery bypass graft
CAD Coronary artery disease
DAPT Dual antiplatelet therapy
DAT Dual antithrombotic therapy
DES Drug-eluting stent
DOAC Direct oral anticoagulant
ESC European Society of Cardiology
ISR In-stent restenosis
NSTE-ACS Non-ST-elevation acute coronary
syndrome
OAC Oral anticoagulation
PCI Percutaneous coronary
intervention
SAPT Single antiplatelet therapy
SIHD Stable ischemic heart disease
ST Stent thrombosis
STEMI ST-segment-elevation myocardial
infarction
TAT Triple antithrombotic therapy
TAVI Transcatheter aortic valvular
implantation
VKA Vitamin K antagonist
Table of other common abbreviations.
PERCUTANEOUS CORONARY
INTERVENTION
Overview of Procedure and Indications
Coronary artery disease (CAD) is a pathological process charac-
terized by atherosclerotic plaque accumulation in the epicardial
arteries. It is categorized as either obstructive or nonobstructive
depending on the degree of blockade within the coronary arteries.
The disease state can have lengthy, stable periods, but it can become
unstable at any time. An unstable presentation is most often caused
by an acute, atherothrombotic event caused by plaque rupture or ero-
sion. Depending on the nature of the CAD process, various clinical
presentations may emerge as either an acute coronary syndrome
(ACS) or stable CAD, also known as stable ischemic heart disease
(SIHD). Invasive interventions such as percutaneous coronary inter-
vention (PCI) may be conducted to treat acute symptoms and prevent
disease progression (Knuuti 2020). When a patient undergoes PCI, a
coronary stent is typically placed at the lesion site to restore blood
flow and prevent further myocardial ischemia.
After PCI, dual antiplatelet therapy (DAPT) is standard to prevent
coronary thrombotic complications (Levine 2016). The term DAPT
refers to a combination of aspirin—usually less than 100 mg daily—
and a P2Y12 inhibitor. In the United States, three common oral P2Y12
inhibitors are FDA approved for use after PCI: clopidogrel, ticagre-
lor, and prasugrel. Recently, intravenous P2Y12 inhibitor cangrelor
became approved for use during PCI. Ticagrelor and prasugrel are
often referred to as novel P2Y12 inhibitors because they came to mar-
ket after clopidogrel and DAPT had become established post-PCI.
Both prasugrel and ticagrelor offer reductions in thrombotic events

PSAP 2022 Book 1 • Cardiology 83 Antithrombotic Therapy in Cardiac Interventions

based on increased platelet inhibition, but the reductions
come with an increased risk of bleeding (Levine 2016; Wal-
lentin 2009; Wiviott 2007). It is important to note that factors
BASELINE KNOWLEDGE STATEMENTS
Readers of this chapter are presumed to be familiar
with the following:
• General knowledge of the pathophysiology that
leads to acute coronary syndromes and valvular
heart disease
• General knowledge of coronary angiography, per-
cutaneous coronary intervention, transcatheter
aortic valve implantation, and MitraClip insertion
• General pharmacologic knowledge of P2Y 12
inhibi-
tors and oral anticoagulants used in the treatment
of coronary disease, atrial fibrillation, and valvular
heart disease
Table of common laboratory reference values
ADDITIONAL READINGS
The following free resources have additional back-
ground information on this topic:
• Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA
guideline focused update on duration of dual anti-
platelet therapy in patients with coronary artery
disease. J American Coll Cardiol 2016;68:1082-115.
• Angiolillo DJ, Bhatt DL, Cannon CP, et al. Antithrom-
botic therapy in patients with atrial fibrillation
treated with oral anticoagulation undergoing percu-
taneous coronary intervention: a north american
perspective: 2021 update. Circulation.
2021;143:583-96.
• ten Berg J, Sibbing D, Rocca B, et al. Management
of antithrombotic therapy in patients undergoing
transcatheter aortic valve implantation: a consen-
sus document of the ESC working group on throm-
bosis and the european association of
percutaneous cardiovascular interventions
(EAPCI), in collaboration with the ESC council on
valvular heart disease. European Heart Journal.
2021;42:2265-9.
• Cahill TJ, Chen M, Hayashida K, et al. Transcatheter
aortic valve implantation: current status and future
perspectives. European Heart Journal
2018;39:2625-34.
• Hensey M, Brown RA, Lal S, et al. Transcatheter
mitral valve replacement. JACC: Cardiovascular
Interventions. 2021;14:489-500.
• Patrono C, Morais J, Baigent C, et al. Antiplatelet
agents for the treatment and prevention of coro-
nary atherothrombosis. Journal of the American
College of Cardiology 2017;70:1760-76.
PSAP 2022 Book 1 • Cardiology
that influence P2Y12 inhibitor selection include indication for
PCI (i.e., SIHD versus ACS), adverse-effect profiles, cost,
drug interactions, and patient-specific ischemic and bleed-
ing risk factors. Table 1 summarizes the pertinent pharma-
cokinetic and pharmacodynamic properties of the P2Y12
inhibitors.
Evolution of Stent Types
Coronary stents have evolved significantly since their intro-
duction in the mid-1980s, and new features that refine their
design, structure, and material continue to emerge. Patient
factors such as bleeding risk, thrombotic risk, lesion charac-
teristics, and presenting symptoms (SIHD vs. ACS) are con-
sidered when the type of stent is getting selected because
recommendations for antiplatelet therapies and length of
therapy vary depending on stent type (Iqbal 2013).
Bare-metal stents (BMSs) have historically used stainless
steel or cobalt-chromium. Most recently, platinum-chromium
alloy metals produce thinner struts without compromising
strength or conformability. An incidence of in-stent rest-
enosis (ISR) of 20%–30% has been reported with a BMS,
which is associated with significant morbidity and mortal-
ity. Drug-eluting stents (DESs) were developed to specifically
correct ISR complications encountered with BMSs; they con-
tain antiproliferative drugs that reduce the development of
ISR. Second-generation DESs contain everolimus or zotar-
olimus and proved superiority in efficacy and safety com-
pared with first-generation stents containing paclitaxel or
sirolimus (Iqbal 2013). The antiproliferative drugs are incor-
porated within a polymer and coated on the surface of the
stent; then they are released slowly over several weeks after
stent deployment.
The evolution of DESs reduced the rate of ISR, but
increased rates of stent thrombosis (ST) resulted. In par-
ticular, late ST secondary to compromised polymer durabil-
ity remains of concern, and therefore, novel bioresorbable
stents were developed that are made up of metallic alloy or
polymer—with or without antiproliferative drugs. The ratio-
nale for a bioresorbable stent is to provide a scaffold, similar
to a stent, for a specific period of time after PCI, with grad-
ual resorption over time. After resorption, the vessel wall may
regain normal function without the presence of foreign mate-
rials, thus reducing the risk of ST and the requirement for
long-term DAPT (Iqbal 2013).
Complications with Stents
Two complications associated with coronary stent placement
are ST and ISR. Stent thrombosis is usually an acute process
involving a thrombotic occlusion of a coronary stent. The
complication has been significantly reduced by implemen-
tation of DAPT with aspirin plus a P2Y12 inhibitor after stent
placement (Neumann 1996). In contrast, ISR is a gradual nar-
rowing of the stent lumen that is caused by neointimal prolif-
eration and has been improved with the development of DES.
84 Antithrombotic Therapy in Cardiac Interventions
 Table 1. Pharmacokinetic and Pharmacodynamic Factors of P2Y12 Inhibitors

PK/PD Cangrelor (IV) Clopidogrel (PO) Prasugrel (PO) Ticagrelor (PO)

Dosing Load: 30 mcg/kg Load: 300–600 mg Load: 60 mg Load: 180 mg

Maintenance: Maintenance: 75 mg Maintenance: 10 mg Maintenance: 90 mg
4 mcg/kg/min daily daily (5 mg if weight twice daily
less than 60 kg)a

Pertinent pharmaco- Dephosphorylation to Prodrug Prodrug Hepatic via CYP3A4/5

kinetics inactive metabolite Esterase-mediated Rapid hydrolysis, to active metabolite
hydrolysis and CYP450-mediated
CYP450-mediated oxidation (CYP3A4
oxidation (CYP2C19) and CYP2B6)

Receptor blockade Reversible Irreversible Irreversible Reversible

Onset of action 2 minutes 2–6 hours ~30 minutes 30 minutes to 2 hours

Peak within 4 hours

Duration of Platelet function 5–10 days 7–10 days 3–5 days

antiplatelet effects normalizes within 1 hour
of discontinuation

a
Even though the FDA approved prasugrel for 5 mg daily in patients with body weights of less than 60 kg, the approval is based primar-
ily on pharmacokinetic data (Erlinge 2012). There are limited clinical efficacy and safety data with this dosing recommendation.
Information from: Brilakis ES, Patel VG, Banerjee S. Medical management after coronary stent implantation: a review. JAMA
2013;310:189-98; Baron TH, Kamath PS, McBane RD. Current concepts: management of antithrombotic therapy in patients
undergoing invasive procedures. N Engl J Med 2013;368:2113-24; Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind
assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary
artery disease: the ONSET/OFFSET study. Circulation 2009;120:2577-85.

Stent Thrombosis Thankfully, the introduction of DESs has drastically reduced

Stent thrombosis could occur at any time after coronary stent
placement and is strongly associated with mortality and myo-
cardial infarction (Guerra 2014). The timing of ST is catego-
rized as early (within 30 days), which is further divided into
acute (within 24 hours) and subacute (days 2–30); late (from
31 days to 1 year); and very late (beyond 1 year) (Valgimigli
2018). Factors leading to early ST include stent underexpan-
sion, incomplete stent contact to the vessel wall, and edge
dissection; neoatherosclerosis plays a large role in very late
ST (Adriaenssens 2014). It is suggested that after DES place-
ment, late and very late ST are caused by vascular damage
and impaired reendothelialization.
In-Stent Restenosis
The most common cause of ISR after stent implantation is
the occurrence of severe neointimal proliferation—a phe-
nomenon involving tunica intima hyperplasia of the coro-
nary artery that ultimately results in thickening of the arterial
wall and, thus, reduced lumen space (Dangas 2010). Patients
with ISR typically present with recurrent angina, electro-
cardiogram changes related to ischemia, or abnormal inva-
sive functional diagnostic tests (i.e., fractional flow reserve,
intravascular ultrasound). It is important to note that DAPT
does not influence the development of ISR (Neumann 1996).
ISR (Stefanini 2013), which occurred up to three times more
often with BMS compared with new-generation DESs within
12 months (Taniwaki 2014).
USE OF P2Y12 INHIBITORS IN
PERCUTANEOUS CORONARY
INTERVENTION
The P2Y12 inhibitors exert their antiplatelet effects by inhi-
bition of platelet ADP receptors. The inhibition prevents acti-
vation of the GP IIb/IIIa receptor complex and subsequent
platelet activation and aggregation. Table 2 summarizes
some of the landmark trials comparing ticagrelor, prasu-
grel, and intravenous cangrelor with clopidogrel in the set-
ting of ACS. Guideline recommendations have echoed those
results, preferring ticagrelor and prasugrel over clopidogrel in
the treatment of patients with ACS (Collet 2021; Amsterdam
2014). Cangrelor can be a therapeutic option for patients who
have not been given a P2Y12 inhibitor before coronary angio-
gram and PCI (Collet 2021).
Most recently, the ISAR-REACT 5 trial sought to answer
the long-standing question of prasugrel versus ticagrelor—
particularly in non-ST-elevation acute coronary syndrome
(NSTE-ACS) (Schüpke 2019). This open-label, superiority trial

PSAP 2022 Book 1 • Cardiology 85 Antithrombotic Therapy in Cardiac Interventions

 Table 2. Efficacy and Safety Comparison of P2Y12 Inhibitors

Trial (year) Patient population Intervention Outcomes Conclusion

TRITON-TIMI 38 Patients with Prasugrel 60-mg Primary Prasugrel demonstrated

(2007) moderate- to high- loading dose; then • Death from CV causes, a greater rate of life-
(prasugrel vs. risk ACS with 10 mg daily for nonfatal MI, or nonfatal threatening bleeding but
clopidogrel) scheduled PCI 6–15 months stroke: 9.9% vs. 12.1% was associated with lower
Vs. (p<0.001) rates of ischemic events
Clopidogrel 300- compared with clopidogrel
mg loading dose; Secondary
then 75 mg daily for • Major bleeding: 2.4% vs.
6–15 months 1.8% (p=0.03)
• Stent thrombosis: 1.1% vs.
2.4% (p<0.001)

PLATO (2009) Patients admitted Ticagrelor 180-mg Primary Ticagrelor was associated
(ticagrelor vs. with ACS, with loading dose followed • Composite of death from with lesser rates of
clopidogrel) or without by 90 mg twice daily vascular causes, MI, or ischemic events but was
ST-segment Vs. stroke at 12 months: 9.8% associated with more non-
elevation Clopidogrel 300– vs. 11.7% (p=0.001) procedure-related bleeding
600-mg loading dose
followed by 75 mg Secondary
daily • MI: 5.8% vs. 6.9%
(p=0.005)
• Death from vascular
causes: 4.0% vs. 5.1%
(p=0.001)
• Stroke: 1.5% vs. 1.3%
(p=0.22)
• Death from any cause:
4.5% vs. 5.9% (p=0.001)
• Major bleeding: 11.6% vs.
11.2% (p=0.43)
• Non-CABG-related major
bleeding: 4.5% vs. 3.8%
(p=0.03)

CHAMPION Patients with stable Cangrelor 30-mcg/kg Primary (cangrelor vs. Compared with clopidogrel,
PHOENIX or unstable CAD bolus followed by clopidogrel, respectively) cangrelor reduced early
(2016) undergoing PCI 4-mcg/kg/min bolus • Composite (death, ischemic events after PCI,
(cangrelor vs. for the duration of the MI, ischemia-driven including stent thrombosis
clopidogrel) PCI plus placebo pill revascularization, or stent
vs. clopidogrel 300– thrombosis at 48 hours):
600-mg loading dose 4.7% vs. 5.9% (p=0.005)
plus placebo bolus
or infusion Secondary
• Composite primary
outcome at 30 days:
6.0% vs. 7.0% (p=0.03)
• Stent thrombosis at
48 hours: 0.8% vs. 1.4%
(p=0.01)
• MI at 48 hours: 3.8% vs.
4.7% (p=0.02)
• Severe bleeding at
48 hours: 0.16% vs. 0.11%
(p=0.44)

(continued)

PSAP 2022 Book 1 • Cardiology 86 Antithrombotic Therapy in Cardiac Interventions

 Table 2. Efficacy and Safety Comparison of P2Y12 Inhibitors  (continued)

Trial (year) Patient population Intervention Outcomes Conclusion

ISAR-REACT 5 Patients presenting Ticagrelor (180-mg Primary Adverse outcomes were

(2019) with ACS and loading dose followed • Composite (death, MI, lower in patients who
(ticagrelor vs. planned—or by 90 mg twice daily) stroke) at 1 year: 9.3% vs. received prasugrel
prasugrel) uncertain— Vs. 6.9% (p=0.006) compared with ticagrelor
invasive evaluation Prasugrel (60 mg- without a difference in
loading dose followed Secondary major bleeding
by 10 mg daily and • Bleeding (BARC 3–5):
adjusted to 5 mg daily 5.4% vs. 4.8% (p=0.48) This trial not only compared
per package insert) two antiplatelet drugs,
but also compared two
treatment strategies
(upstream vs. downstream
administration)

ACS = acute coronary syndrome; BARC = Bleeding Academic Research Consortium; CABG = coronary artery bypass grafting; CAD =
coronary artery disease; CV = cardiovascular; MI = myocardial infarction; PCI = percutaneous coronary intervention.
Information from: Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary
syndromes. N Engl J Med 2007;357:2001-15; Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with
acute coronary syndromes. N Engl J Med 2009;361:1045-57; Schüpke S, Neumann F-J, Menichelli M, et al. Ticagrelor or prasugrel in
patients with acute coronary syndromes. N Engl J Med 2019;381:1524-34; Abtan J, Steg PG, Stone GW, et al. Efficacy and safety of
cangrelor in preventing periprocedural complications in patients with stable angina and acute coronary syndromes undergoing
percutaneous coronary intervention: the CHAMPION PHOENIX trial. JACC Cardiovasc Interv 2016;9:1905-13.

randomized more than 4000 patients to receive either tica-
grelor or prasugrel. In the ticagrelor arm, a loading dose was
administered as soon as possible after randomization. For
those randomized to prasugrel, the loading dose was delayed
in patients with NSTE-ACS undergoing PCI, which was per-
formed in a majority (84.1%) of patients, 58.9% of whom had
NSTE-ACS. The primary endpoint was a composite of death,
myocardial infarction (MI), and stroke and occurred in 6.3%
of patients randomized to prasugrel compared with 9.3% of
patients randomized to ticagrelor (HR 1.36; 95% CI, 1.09–
1.70; p=0.006). This was driven primarily by a reduction in MI
(3.7% taking prasugrel vs. 4.8% taking ticagrelor; HR 1.63; 95%
CI, 1.18–2.25). Surprisingly, there were no significant differ-
ences in rates of major bleeding between prasugrel and tica-
grelor, but that could have been attributed to certain design
limitations such as telephone follow-up for most patients,
differences in pretreatment, lack of formal assessment of
medication adherence, and the exclusion of more patients in
the safety analysis in the prasugrel arm than the ticagrelor
arm. But regardless of those limitations, this trial resulted in
the ESC’s inclusion of a class IIb guideline recommendation
favoring prasugrel over ticagrelor in the treatment of patients
with NSTE-ACS going for PCI (Collet 2021). Ultimately, the
selection of a P2Y12 inhibitor should consider several charac-
teristics, including clinical presentation (e.g., ACS vs. SIHD),
ischemic and bleeding risk factors, and cost. Further stud-
ies are warranted to confirm the results demonstrated by
ISAR-REACT 5.
Upstream vs. Downstream Administration
In the setting of NSTE-ACS, the optimal timing of oral P2Y12
inhibitor administration remains elusive. Administration of
an oral P2Y12 inhibitor before coronary angiography when
the coronary anatomy is unknown—also called pretreat-
ment or upstream strategy, detailed in Figure 1—may, theo-
retically, reduce the risk of ischemia while patients wait to
undergo coronary angiography (Tarantini 2020). In addition,
the achievement of sufficient platelet inhibition at the time
of PCI may reduce the risk of periprocedural thrombotic com-
plications caused by vascular damage and impaired reendo-
thelialization of the coronary arteries. However, an upstream
strategy may also increase the risk of periprocedural bleeding
during PCI or coronary artery bypass graft (CABG) and there-
fore increase hospital length of stay and cost.
Table 3 lists current guideline recommendations for the
use of P2Y12 inhibitors with regard to timing of PCI. In the set-
ting of SIHD, the recommendation is to administer a loading
dose of a P2Y12 inhibitor before PCI once coronary anatomy
is known (e.g., coronary angiogram is performed) and once
the decision has been made to perform an intervention (Neu-
mann 2019). In the setting of ST-segment-elevation myocar-
dial infarction (STEMI), P2Y12 administration should occur
as soon as possible—or at least at the time of PCI (Neumann
2019). In NSTE-ACS, upstream administration (or pretreat-
ment) may be considered for clopidogrel and ticagrelor, but
guidelines recommend against upstream administration of
prasugrel based on results of the ACCOAST trial detailed later.

PSAP 2022 Book 1 • Cardiology 87 Antithrombotic Therapy in Cardiac Interventions

 Upstream Strategy P2Y12 Inhibitor Loading Dose Coronary Angiography PCI

NSTE-ACS
PCI P2Y12 Inhibitor
Downstream Strategy Coronary Angiography +/– P2Y12 Inhibitor at start of (if not given at time of PCI)
PCI

Figure 1. Upstream vs. downstream P2Y12 administration relative to timing of PCI in NSTE-ACS.
ACS = acute coronary syndrome; NSTE = non-ST elevation; PCI = percutaneous coronary intervention.

Table 3. Clinical Guideline Recommendations Regarding Timing of P2Y12 Administration

Recommendations

2013 ACC/AHA STEMI guidelines A P2Y12 inhibitor loading dose should be given as early as possible or at time of PCI
(class Ib)
2014 AHA/ACC NSTE-ACS guidelines A P2Y12 inhibitor loading dose should be given before PCI with stenting (class Ia)
2018 ESC/EACTS myocardial SIHD
interventional guidelines Pretreatment with clopidogrel is recommended in patients undergoing elective PCI
once the coronary anatomy is known and a decision has been made to proceed with
PCI (class Ia)

NSTE-ACS
• Ticagrelor may be administered before PCI, and clopidogrel may be used if ticagrelor
is not available (class IIa)
• Administration of prasugrel in patients with unknown coronary anatomy is not
recommended (class III)

STEMI
Prasugrel or ticagrelor (clopidogrel if prasugrel or ticagrelor is either not available or
contraindicated) is recommended before or at least at the time of PCI (class Ia)
2020 ESC ACS without STEMI NSTE-ACS
guidelines • Pretreatment may be considered in patients who are not planning to undergo an
early invasive strategy (i.e., coronary angiography within 24–72 hours) and who do
not have high bleeding risk (class IIb)
• Not recommended to administer routine pretreatment P2Y12 when coronary anatomy
is not known and an early invasive management is planned (class III)

ACC = American College of Cardiology; ACS = acute coronary syndrome; AHA = American Heart Association; CAD = coronary artery
disease; ESC = European Society of Cardiology; NSTE-ACS = non-ST-elevation acute coronary syndrome; PCI = percutaneous coronary
intervention; SIHD = stable ischemic heart disease; STEMI = ST-segment-elevation myocardial infarction.
Information from: Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 ACC/AHA guideline for the management of patients with
non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines. Circulation 2014;130:e344-e426; O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline
for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines. Circulation 2013;127;e362-425; Neumann F-J, Sousa-Uva M, Ahlsson A, et al.
2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87-165. Collet J-P, Thiele H, Barbato E, et al. 2020
ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation.
Eur Heart J 2021;42:1289-367.

Literature Review Evaluating Timing angiography (upstream) compared with known coronary angi-
of P2Y12 Administration ography status—if PCI was indicated (downstream). Patients
ACCOAST in the upstream arm received a prasugrel 30-mg loading
The ACCOAST trial evaluated the effect of prasugrel adminis- dose before coronary angiography, and patients in the down-
tration at the time of NSTE-ACS diagnosis and before coronary stream arm received placebo. After the decision to undergo

PSAP 2022 Book 1 • Cardiology 88 Antithrombotic Therapy in Cardiac Interventions

PCI, an additional 30 mg of prasugrel was administered to
the upstream group, and 60 mg to the downstream group. In
this study, the use of an upstream prasugrel loading strategy
did not prove to be more efficacious in reducing major isch-
emic events compared with the downstream strategy and
was associated with increased risk of major bleeding events
(Montalescot 2013). As a result of this trial, both the American
and European guidelines recommend against the upstream
administration of prasugrel in NSTE-ACS (Class III: HARM).
DUBIUS
The DUBIUS trial compared downstream versus upstream oral
P2Y12 inhibitor administration strategies in patients with NSTE-
ACS undergoing invasive treatment (i.e., coronary angiography
within 24–72 hours of presentation). Patients in the upstream
administration arm received a ticagrelor loading dose before
angiography, and those in the downstream administration arm
received no P2Y12 inhibitor before angiography. After angi-
ography, patients in the downstream arm were then random-
ized to receive a ticagrelor or prasugrel loading dose before
PCI. Upon interim analysis, the trial was stopped prematurely
because of futility. Neither the rate of the primary end point,
death due to vascular causes, nonfatal MI, nonfatal stroke, nor
Bleeding Academic Research Consortium (BARC) types 2, 3,
and 4 bleeding at 30 days differed between the downstream
and upstream groups, respectively (2.9% and 3.3%; ARR –0.46;
95% CI, –2.87 to 1.89). Given the minimal difference in out-
comes between the groups, it was deemed unlikely that one
strategy was preferred over the other (Tarantini 2020).
Practical Considerations
In the setting of NSTE-ACS, pretreatment with clopidogrel and
ticagrelor should be patient specific depending on ischemic
and bleeding risk factors. The GRACE score has been found
to be a possible tool for determining patients who may require
CABG and thus may benefit from deferring upstream admin-
istration, but it has not been fully validated in clinical trials
(Avci 2015). However, in patients who are ultimately deemed
unsuitable for CABG and who undergo PCI as the revascu-
larization strategy after coronary anatomy is known, admin-
istration of a P2Y12 inhibitor as soon as possible before PCI
is reasonable. Because of the harm noted in the ACCOAST
study, prasugrel should not be given routinely before angiog-
raphy. For patients with STEMI, it is reasonable to administer
P2Y12 inhibitors once diagnosis has been made (O’Gara 2013).
Interaction Between Opioids and P2Y12
Inhibitors
Morphine in Acute Coronary Syndromes
Morphine is often used for chest pain associated with ACS
(Amsterdam 2014, O’Gara 2013). Although morphine pro-
vides patients with symptomatic relief, the pharmacologic
interaction between opioids and a blunted effect of P2Y12
inhibitors has become of concern (Furtado 2020; Kubica
PSAP 2022 Book 1 • Cardiology
2016). Morphine can slow gastric emptying, thereby slow-
ing absorption of oral P2Y12 inhibitors, potentially diminish-
ing the desired rapid platelet inhibition, and thus increasing
the risk of ischemic events. Several trials have demonstrated
reduced antiplatelet effects, including delayed maximal P2Y12
inhibitor plasma concentrations, reduced overall P2Y12 inhibi-
tor exposure, and higher rates of ischemic events associated
with opioid administration (Table 4).
Fentanyl for Procedural Sedation in PCI
Similarly, fentanyl is routinely utilized for procedural seda-
tion in patients undergoing PCI. The PACIFY trial (see Table 4)
described the impact of fentanyl on ticagrelor plasma concen-
trations and its antiplatelet effect. The trial demonstrated a
reduction in ticagrelor plasma concentrations, higher platelet
reactivity tested by VerifyNow and platelet aggregometry, and
an increase in troponin-I levels postprocedure. VerifyNow is an
available point-of-care blood test that measures responsive-
ness to P2Y12 receptor blockade, measured by platelet reactive
units. A result below the threshold cutoff indicates an antiplate-
let effect; values above the cutoff indicate a lack of antiplate-
let effect. In addition to those findings, self-reported maximal
intraprocedural pain was low at a median of 1.5 on a 10-point
scale, further supporting the need to reconsider the routine use
of fentanyl in patients undergoing PCI (McEvoy 2018).
Practical Solutions and Considerations
Upon the results of these clinical trials (see Table 4), the Food
and Drug Administration updated the prescribing information
for clopidogrel, prasugrel, and ticagrelor in 2018 to include
a warning about the interaction with opioids and to recom-
mend consideration of a parenteral antiplatelet (cangrelor or
GP IIb/IIIa inhibitors) agent in patients with ACS who require
opioid coadministration (Furtado 2020). In clinical practice,
it is important to discourage the routine use of opioids in the
absence of refractory chest pain—particularly in close prox-
imity to oral P2Y12 inhibitor administration. There are cur-
rently no recommendations to routinely assess impaired
P2Y12 inhibitor plasma concentrations or heightened platelet
reactivity with various testing modalities in patients receiv-
ing opioids, but such a testing option may be considered
in selected cases (e.g., increased bleeding risk, increased
thrombotic risk, planned escalation or de-escalation of anti-
platelet therapy) (Sibbing 2019). It is interesting that meto-
clopramide administered concomitantly with morphine and
ticagrelor demonstrated improvements in antiplatelet activ-
ity (Saad 2020). There may be a role for prokinetic agents
such as metoclopramide in this setting, though more stud-
ies are needed to determine the effect on clinical outcomes.
DAPT Duration After PCI
Clinical Practice Guideline Recommendations
Recommendations from the most-recent ACC/AHA Guide-
lines for duration of DAPT after PCI are given in Table 5
89 Antithrombotic Therapy in Cardiac Interventions
 Table 4. Interaction Between Opioids and P2Y12 Inhibitors

Trial (year) Patient Population Intervention Outcomes Conclusion

IMPRESSION (2016) Patients with acute Morphine 5 mg IV Primary Morphine exerted

MI vs. placebo • Ticagrelor AUC(0–12h): 36% a negative impact
followed by decrease (p=0.003) on ticagrelor by
ticagrelor 180 mg lowering total
Secondary exposure to
• Ticagrelor AUC(0–6h): 55% decrease ticagrelor and its
(p=0.002) active metabolite
• Ticagrelor active metabolite by 36% and delaying
AUC(0–6h): 53% decrease (p=0.006) its maximal plasma
• Ticagrelor Tmax: 2-hour delay concentration by
(p=0.004) 2 hours
• Ticagrelor Cmax: 1156 ± 771 vs.
1683 ± 847 ng/mL (p=0.006)

PACIFY (2018) Patients Fentanyl vs. Primary (fentanyl vs. no fentanyl, Fentanyl
undergoing no fentanyl respectively) administration
elective coronary for procedural • Ticagrelor AUC(0–24h): 2107 vng lowers plasma
angiography and sedation ml–1 h vs. 3301 vng ml–1 h (p=0.05) concentrations of
receiving ticagrelor ticagrelor and delays
Secondary (fentanyl vs. no fentanyl, its antiplatelet
respectively) effects
• 2-hour mean ± SD P2Y12 reaction
unit value: 112 ± 95 vs. 78 ± 72
(p=0.09)
• ADP response by aggregometry:
39.3 ± 8.7% vs. 27.5 ± 14.4%
(p=0.04)
• P2Y12 reaction unit values at
4 hours: 55 vs. 50 (p=0.73)
• Mean self-reported maximal
intraprocedural pain (10-point
numeric scale): 1.5 vs. 2.3
(p=0.14)

ATLANTIC- Patients with Morphine Primary (morphine vs. no morphine, The use of morphine
Morphine (2019) STEMI undergoing Vs. respectively) was associated with
PCI in the No morphine + Coprimary endpoint: increased GP IIb/IIIa
ATLANTIC trial ticagrelor 180 mg • Absence of pre-PCI TIMI 3 flow in inhibitor use, less
followed by 90 mg culprit artery: OR 1.54 (1.19, 1.99) pre-PCI TIMI 3 flow,
twice daily (p=0.001) and more bleeding
• Absence of pre-PCI ≥70%
ST-segment elevation resolution:
OR 1.32 (0.98, 1.77) (p=0.07)

Clinical end points (morphine vs. no

morphine, respectively)
• Absence of pre-PCI TIMI 3 flow:
85.8% vs. 79.7% (p=0.001)
• TIMI major bleeding: 1.1% vs. 0.1%
(p=0.02)
• Bailout use of GP IIb/IIIa
inhibitors: 11.3% vs. 7.9% (p=0.01)

(continued)

PSAP 2022 Book 1 • Cardiology 90 Antithrombotic Therapy in Cardiac Interventions

 Table 4. Interaction Between Opioids and P2Y12 Inhibitors (continued)

Trial (year) Patient Population Intervention Outcomes Conclusion

EARLY ACS Patients treated Patients treated Outcomes The use of morphine
subanalysis (2020) with clopidogrel with clopidogrel • Composite of death, MI, recurrent in combination with
presenting with within 24 hours ischemia, or thrombotic bailout clopidogrel was
non-ST-segment of randomization at 96 hours (four-way end point): associated with
elevation ACS in Vs. adjusted OR 1.40 (95% CI, 1.04– higher rates
the EARLY ACS Patients not 1.87) (p=0.026) of ischemic events
trial treated with • Composite of death or MI at 30
clopidogrel days: adjusted OR 1.29 (95% CI,
(negative control) 0.98–1.70) (p=0.072)
Both groups
received
morphine
prerandomization

ACS = acute coronary syndrome; ADP = adenosine diphosphate; AUC = area under the curve; CI = confidence interval; IV = intrave-
nously; MACE = major adverse cardiovascular events; MI = myocardial infarction; OR = odds ratio; PCI = percutaneous coronary inter-
vention; SD = standard deviation; STEMI = ST-segment-elevation myocardial infarction; TIMI = thrombolysis in myocardial
infarction.
Information from: Kubica J, Adamski P, Ostrowska M, et al. Morphine delays and attenuates ticagrelor exposure and action in
patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial. Eur Heart J 2016;37:245-
52; McEvoy JW, Ibrahim K, Kickler TS, et al. Effect of intravenous fentanyl on ticagrelor absorption and platelet inhibition among
patients undergoing percutaneous coronary intervention: the PACIFY randomized clinical trial (platelet aggregation with ticagrelor
inhibition and fentanyl). Circulation 2018;137:307-9; Lapostolle F, Van’t Hof AW, Hamm CW, et al. Morphine and ticagrelor interaction
in primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: ATLANTIC-Morphine. Am J
Cardiovasc Drugs 2019;19:173-83; Montalescot G, van ’t Hof AW, Lapostolle F, et al. Prehospital ticagrelor in ST-segment elevation
myocardial infarction. N Engl J Med 2014;371:1016-27; Furtado RHM, Nicolau JC, Guo J, et al. Morphine and cardiovascular
outcomes among patients with non-ST-segment elevation acute coronary syndromes undergoing coronary angiography. J Am Coll
Cardiol 2020;75:289-300.

Table 5. ACC/AHA Guidelines for DAPT Duration After PCI

Recommendations High Bleed Risk Low Bleed Risk

SIHD BMS: 1 month DES: 3 months (Class IIb) BMS: >1 month if high thrombotic
DES: 6 months BMS: 1 month riska
Clopidogrel preferred DES: >6 months if high
(Class I) thrombotic risk (Class IIb)

ACS 12 months 6 months regardless of stent >12 months regardless of stent

Ticagrelor or prasugrel type (Class IIb) type
preferred (Class IIa) No preferred P2Y12 inhibitor
(Class IIb)

a
Advanced age, multiple previous myocardial infarctions, extensive coronary artery disease, diabetes mellitus, chronic kidney
disease
ACS = acute coronary syndrome; BMS = bare-metal stent; DES = drug-eluting stent; SIHD = stable ischemic heart disease.
Information from: Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet
therapy in patients with coronary artery disease. Circulation 2016;134:e123-55.

PSAP 2022 Book 1 • Cardiology 91 Antithrombotic Therapy in Cardiac Interventions

(Levine 2016). In general, after PCI with a DES, DAPT is
recommended for at least 6 and 12 months for SIHD and
ACS, respectively. Shorter durations can be considered for
patients at low ischemic risk and high bleeding risk, whereas
longer durations can be considered for those with high isch-
emic and low bleeding risks.
Shorter DAPT Durations
Since publication of the AHA/ACC DAPT guidelines, several
clinical trials have evaluated shorter durations of DAPT after
PCI with stent placement—in the settings of both SIHD and
ACS. Those trials are summarized in Table 6. Overall, the
regimens and durations of DAPT followed by P2Y12 inhibitor

Table 6. Literature Review: Evaluating Shorter DAPT Durations

Trial (year)a Patient Population Intervention Outcomes Conclusion

GLOBAL Patients DAPT for Primary Ticagrelor

LEADERS (2018) undergoing PCI 1 month All-cause mortality or nonfatal MI: monotherapy for
with DES followed by 1 month DAPT 3.8% vs. 12 months 23 months after
ACS 50% ticagrelor for DAPT 4.4% (p=0.073) 1 month of DAPT
CAD 50% 23 months failed to show
Vs. Secondary (1 month DAPT followed by superiority to
DAPT for ticagrelor vs. 12 months DAPT followed standard therapy
12 months by aspirin, respectively)
followed by • All-cause mortality: 2.8% vs. 3.2%
aspirin for (p=0.18)
12 months • MI: 1.0% vs. 1.3% (p=0.14)
• Grade 3 or 5 BARC bleeding: 2.0% vs.
2.1% (p=0.77)

TWILIGHT (2019) Patients Aspirin + Primary Shorter DAPT duration

undergoing PCI ticagrelor for BARC 2, 3, or 5 bleeding at 12 months: resulted in less
(DES) with ≥1 3 months and ticagrelor monotherapy 4.0% vs. bleeding
high-risk feature then ticagrelor ticagrelor + aspirin 7.1% (p=0.001)
of ischemia or monotherapy
bleeding Vs. Secondary
ACS 65% Ticagrelor + All-cause mortality, MI, stroke: 3.9% vs.
CAD 35% aspirin for 12 3.9% (p for noninferiority = 0.001)
months MI 2.7% vs. 2.7% (p=0.001);
stent thrombosis: 0.4% vs. 0.6%
(p>0.05);
ischemic stroke: 0.5% vs. 0.2% (p>0.05)

STOPDAPT-2 3000 Japanese 1 month of DAPT Primary With regard to adverse

(2019) patients (with either Death, MI, stent thrombosis, stroke, ischemic events,
undergoing PCI clopidogrel TIMI major/minor bleeding at 1 year: 1 month of DAPT was
with DES or prasugrel) 1 month DAPT 2.4% vs. 12 months superior to 12 months
ACS 62% followed by DAPT 3.7% (p for superiority = 0.04) of DAPT
CAD 38% clopidogrel
Mostly patients monotherapy Secondary (1 month vs. 12 months
with low to for up to 5 years DAPT, respectively)
intermediate Vs. • Death, MI, stent thrombosis,
ischemic risk 12 months of or stroke at 1 year: 2.0% vs. 2.5%
DAPT followed (p for noninferiority = 0.005)
by aspirin • TIMI major/minor bleeding at 1 year:
monotherapy 0.4% vs. 1.5% (p for superiority =
for 5 years 0.004)
• BARC 3 or 5 bleeding at 1 year: 0.5%
vs. 1.8% (p for superiority = 0.003)
• Definite or probable stent
thrombosis: 0.3% vs. 0.07% (p for
superiority = 0.21)

(continued)

PSAP 2022 Book 1 • Cardiology 92 Antithrombotic Therapy in Cardiac Interventions

 Table 6. Literature Review: Evaluating Shorter DAPT Durations  (continued)

Trial (year)a Patient Population Intervention Outcomes Conclusion

SMART CHOICE Patients Aspirin + P2Y12 Primary After 3 months

(2019) undergoing PCI for 3 months Major adverse cardiac and of DAPT, P2Y12
with DES followed cerebrovascular events (a composite of monotherapy was
by P2Y12 all-cause death, myocardial infarction, noninferior compared
monotherapy or stroke) at 12 months: monotherapy with prolonged DAPT
vs. DAPT for 2.9% vs. DAPT 2.5% (p=0.007 for
12 months noninferiority)

Secondary (monotherapy vs. DAPT,

respectively)
• All-cause death: 1.4% vs. 1.2%
(p=0.61)
• MI: 0.8% vs. 1.2% (p=0.28
• Stroke: 0.8% vs. 0.3% (p=0.14)
• BARC bleeding 2–5: 2.0% vs. 3.4%
(p=.02)

TICO (2020) Patients Ticagrelor Primary Ticagrelor

undergoing monotherapy Death, MI, stent thrombosis, stroke, monotherapy after
PCI following after 3 months target vessel revascularization or TIMI 3 months of DAPT
after ACS with a of DAPT major bleeding at 12 months: ticagrelor was superior to
biodegradable DES vs. monotherapy after 3 months of DAPT standard therapy at
Standard DAPT 3.9% vs. standard DAPT therapy 5.9% 12 months
therapy for (p=0.01)
12 months
Secondary
Major bleeding: ticagrelor monotherapy
after 3 months of DAPT 1.7% vs.
standard DAPT therapy 3.0% (p=0.02)
Stent thrombosis: ticagrelor
monotherapy after 3 months of DAPT
0.4% vs. standard DAPT therapy 0.3%
(p=0.53)

a
All studies excluded patients who required chronic oral anticoagulation.
ACS = acute coronary syndromes; BARC = Bleeding Academic Research Consortium; CAD = coronary artery disease; DAPT = dual
antiplatelet therapy; DES = drug-eluting stent; MI = myocardial infarction; PCI = percutaneous coronary intervention; TIMI =
thrombolysis in myocardial infarction.
Information from: Vranckx P, Valgimigli M, Jüni P, et al. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for
23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation
of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet 2018;392:940-9; Mehran R, Baber U, Sharma
SK, et al. Ticagrelor with or without aspirin in high-risk patients after PCI. N Engl J Med 2019;381:2032-42; Watanabe H, Domei T,
Morimoto T, et al. Effect of 1-month dual antiplatelet therapy followed by clopidogrel vs 12-month dual antiplatelet therapy on
cardiovascular and bleeding events in patients receiving PCI: the STOPDAPT-2 randomized clinical trial. JAMA 2019;321:2414; Hahn
J-Y, Song YB, Oh J-H, et al. Effect of P2Y12 inhibitor monotherapy vs dual antiplatelet therapy on cardiovascular events in patients
undergoing percutaneous coronary intervention: the SMART-CHOICE randomized clinical trial. JAMA 2019;321:2428; Kim B-K, Hong
S-J, Cho Y-H, et al. Effect of ticagrelor monotherapy vs ticagrelor with aspirin on major bleeding and cardiovascular events in
patients with acute coronary syndrome: the TICO randomized clinical trial. JAMA 2020;323:2407.

monotherapy varied widely from trial to trial. DAPT duration
ranged from 1 to 3 months post-PCI followed by P2Y12 inhibi-
tor monotherapy for up to 12–24 months. The regimens were
compared with standard of care, which consists of DAPT
for 6–12 months post-PCI followed by aspirin monotherapy.
In general, the findings from the studies demonstrated com-
parable ischemic efficacy while reducing bleeding events
with P2Y12 inhibitor monotherapy compared with DAPT.
Although shortened DAPT duration has not become incor-
porated into clinical practice guidelines as yet, it is reasonable

PSAP 2022 Book 1 • Cardiology 93 Antithrombotic Therapy in Cardiac Interventions

for clinicians to consider shortening DAPT duration—particu-
Box 1. Clinical Characteristics of
larly in patients with higher bleeding risks or histories of pre-
Patients Who May Benefit from
vious bleeding while on DAPT. However, in the application of
Extended-DAPT Duration
these regimens in clinical practice, it is imperative that stent
ACS presentation/previous ACS event
type be considered. Although some of this evidence is in the
Current cigarette use
setting of DES placement, some trials have used bioresorb- Diabetes mellitus
able stents. Therefore, appropriate application of these trials Heart failure (both reduced and preserved ejection
will have to be done with the type of stent in mind. fraction)
High CAD burden
Extended-DAPT Duration Increased procedure complexity
On the other hand, some evidence suggests that longer Left ventricular ejection fraction < 30%
Older-generation stent(s)
courses of DAPT—beyond 12 months—could be beneficial.
Peripheral arterial disease
Extended-DAPT duration can be considered after PCI for up Renal dysfunction
to 30 months. But even though that approach has demon- Stent diameter < 3 mm
strated reduced risk of myocardial infarction, it comes with Vein graft PCI
an increased risk of bleeding. Because of that, patients who
ACS = acute coronary syndrome; CAD = coronary artery dis-
may be most optimal for this strategy are somewhat difficult
ease; DAPT = dual antiplatelet therapy; PCI = percutaneous
to identify. Patients with the high-risk characteristics listed coronary intervention.
in Box 1 may potentially benefit from extended-DAPT dura- Information from: Howard CE, Nambi V, Jneid H, et al. Extended
tion. But it is important to note that the promising evidence of duration of dual-antiplatelet therapy after percutaneous cor-
onary intervention: how long is too long? J Am Heart Assoc
extended-DAPT therapy is derived from studies in which old- 2019;8:e012639.
er-generation stents were used (Howard 2019). Such stents
pose a higher risk of late in-stent thrombosis, and so, the ben-
efits of extended DAPT in the placement of newer stents are bleeding risk factors, which can be assessed by using the
unknown. Ultimately, the approach to DAPT duration after PCI DAPT score and PRECISE-DAPT score as described in Table 7
should be individualized based on a patient’s ischemic and and Table 8, respectively.

Table 7. DAPT Score

Points Interpretation

Age (years) Score ≥2:

75 –2 Favorable risk–benefit ratio for prolonged
65–74 –1 DAPT (>12 months)
<65 0

Cigarette smokinga +1

Diabetes mellitus +1

MI at presentation +1

Prior PCI or previous MI +1 Score <2:

Unfavorable benefit/risk ratio for prolonged
Paclitaxel-eluting stent +1
DAPT
Stent diameter <3 mm +1

LVEF <30% +2

Vein graft stent +2

a
Smoking within 1 year before index procedure.
DAPT = dual antiplatelet therapy; LVEF = left ventricular ejection fraction; MI = myocardial infarction; PCI = percutaneous coronary
intervention.
Information from: Yeh RW, Secemsky EA, Kereiakes DJ, et al. Development and validation of a prediction rule for benefit and harm of
dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA 2016;315:1735; Levine GN, Bittl JA, Brindis
RG, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease.
J Am Coll Cardiol 2016;68:1082-115.

PSAP 2022 Book 1 • Cardiology 94 Antithrombotic Therapy in Cardiac Interventions

 Table 8. PRECISE-DAPT Score
Points
Hemoglobin (g/dL) 0–15
Age (years) 0–19
White blood cells (10 units/mcL)
3
0–15
Creatinine clearance (mL/min) 0–25
Prior major bleeding 0–26
Total score 0–100
To calculate score, use the online calculator at http://precisedaptscore.com/predapt/index.html
Information from: Costa F, van Klaveren D, James S, et al. Derivation and validation of the predicting bleeding complications in patients
undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-
patient datasets from clinical trials. Lancet 2017;389:1025-34.
Switching Between Different P2Y12 Inhibitors
Switching Between Oral P2Y12 Inhibitors
For several reasons—including adverse effects, cost, and
other clinical scenarios—switching between oral P2Y12 inhib-
itors is common in clinical practice. There are two scenarios
in the switching of P2Y12 inhibitors: de-escalation and escala-
tion. De-escalation involves transitioning from a more-potent
P2Y12 inhibitor to a less-potent option (e.g., ticagrelor or pras-
ugrel to clopidogrel). Escalation involves transitioning from a
less-potent P2Y12 inhibitor to a more-potent option (e.g., clopi-
dogrel to ticagrelor or prasugrel). Switching from ticagrelor
to prasugrel or vice versa is simply referred to as a change
in therapy. Several considerations must be considered before
a switch in agents, including timing of the index event (i.e.,
date of stent placement), potential drug-drug interactions
when agents overlap, and potential loading-dose require-
ments. A drug-drug interaction is not expected to occur in
a switch of agents within the same class (e.g., clopidogrel
to prasugrel), but a drug-drug interaction is likely to occur
in a switch between classes (e.g., ticagrelor to clopidogrel).
Because of the fast offset (3–5 days) and reversible receptor-
binding properties of ticagrelor, de-escalation to clopidogrel
produces a gap in platelet inhibition upon ticagrelor discon-
tinuation, which could increase the risk of stent thrombosis.
Therefore, a loading dose of clopidogrel is generally recom-
mended regardless of date of stent placement. With prasu-
grel, there is still the potential for a lapse in platelet inhibition
in a de-escalation to clopidogrel, but that is because of pras-
ugrel’s irreversible platelet inhibition and longer offset. New
platelets must be produced for clopidogrel to exert its anti-
platelet properties, so a loading dose of clopidogrel is still
recommended within 30 days of the index event in this set-
ting. Experts have produced a consensus recommendation
PSAP 2022 Book 1 • Cardiology
Interpretation
Total score ≥ 25
High PRECISE-DAPT score
Shortened duration of DAPT (3–6 months)
should be considered
Total score < 25
Nonhigh PRECISE DAPT score
Longer durations of DAPT (12–24 months)
should be considered
based on the pharmacodynamic properties of the agents and
previously published literature (Figure 2).
SWAP-4 Study
The SWAP-4 study was a prospective, randomized, open-
label, single-center study to assess the timing, dosing, and
impact of the commonly occurring need to switch P2Y12
classes in clinical practice in a de-escalation from tica-
grelor to clopidogrel therapy. The study was conducted in
80 patients receiving maintenance doses of aspirin and clopi-
dogrel for at least 30 days. After a 7-day run- in period of tica-
grelor (180 mg loading dose followed by 90 mg twice daily),
patients were randomized to one of four groups and contin-
ued for 7–13 days, in addition to aspirin:
• Group A: Clopidogrel 600 mg administered 24 hours after
the last dose of ticagrelor
• Group B: Clopidogrel 600 mg administered 12 hours after
the last dose of ticagrelor
• Group C: Clopidogrel 75 mg daily administered 24 hours
after the last dose of ticagrelor
• Group D: Ticagrelor 90 mg twice daily
Pharmacodynamic assessments of platelet reactiv-
ity were performed at baseline with three platelet reactivity
tools—after the run-in phase, and at 2, 24, 48, and 72 hours as
well as 10 days post randomization. Genetic status of the CYP
2C19 enzyme was also tested in all patients at baseline. After
a switch from clopidogrel to ticagrelor (run-in phase), platelet
reactivity by using three pharmacodynamic assays was sig-
nificantly reduced compared with baseline levels (p<0.001).
Compared with all clopidogrel groups, group D had lower plate-
let reactivity at all time points. Platelet reactivity remained
significantly lower (p<0.001) in patients randomized to group
95 Antithrombotic Therapy in Cardiac Interventions
 Figure 2. Recommendations on switching between oral P2Y12 inhibitors in acute and late phases.
Information from: Angiolillo DJ, Rollini F, Storey RF, et al. International expert consensus on switching platelet P2Y12 receptor–
inhibiting therapies. Circulation 2017;136:1955-75.
D compared with group A, B, or C and was similar between
group A and group C (p=0.29). In group C, platelet reactiv-
ity increased compared with baseline as early as 24 hours,
reaching statistical significance at 48 and 72 hours and up
to 10 days. De-escalation from ticagrelor therapy to clopido-
grel therapy was shown to be associated with an increase in
platelet reactivity regardless of timing of ticagrelor discon-
tinuation and administration of a clopidogrel loading dose,
which was suggestive of a drug interaction that is consistent
with the known pharmacodynamic properties of each drug
described earlier. Therefore, consistent with previously pub-
lished recommendations, results suggest that repeating a
clopidogrel 600-mg loading dose may be required to facilitate
a less-abrupt increase in platelet reactivity after de-escala-
tion from ticagrelor and to achieve prompt, fully therapeutic
effects (Angiolillo 2017). However, barring any ticagrelor-re-
lated adverse effects or cost restrictions, a strategy of de-es-
calation cannot be routinely recommended and should be
avoided early after an acute coronary event—especially
PSAP 2022 Book 1 • Cardiology
in patients undergoing PCI. It is also of note that CYP2C19
genetic status did not appear to have any meaningful impact
on the study findings (Franchi 2018).
TROPICAL-ACS
With the use of potent P2Y12 inhibitors (ticagrelor, prasugrel),
the greatest benefits are seen early after PCI, when the risk
of recurrent thrombotic events is highest. However, a higher
risk of bleeding is maintained during the chronic treatment
phase. While maintaining prevention of thrombotic events in
the early phase, efforts have been made to reduce the risk of
bleeding in the chronic phase through de-escalation of P2Y12
inhibitor therapy. De-escalation is the process of switch-
ing from a potent P2Y12 inhibitor to a less-potent agent (e.g.,
clopidogrel) (Claassens 2020).
The TROPICAL-ACS trial investigated the safety and effi-
cacy of early de-escalation from prasugrel to clopidogrel
guided by platelet function testing. Patients who underwent
PCI after an ACS event (STEMI or NSTEMI) were randomized
96 Antithrombotic Therapy in Cardiac Interventions
 Table 9. Transition from Intravenous to Oral P2Y12 Inhibitor

TRANSITION TO

Clopidogrel Prasugrel Ticagrelor

Cangrelor 30 mcg/kg bolus
and 4 mcg/kg/min infusion
600-mg loading dose
administered immediately
after cangrelor
discontinuation
60-mg loading dose
administered immediately
after cangrelor discontinuation
A loading dose may also be
administered 30 minutes
before the infusion is stoppeda
180-mg loading dose
administered as soon as
possible during cangrelor
infusion or immediately after
cangrelor discontinuation

a
Cangrelor European Medicines Agency full prescribing information.
Information from: Angiolillo DJ, Rollini F, Storey RF, et al. International expert consensus on switching platelet P2Y12 receptor–
inhibiting therapies. Circulation 2017;136:1955-75.

to prasugrel for 2 weeks (control group) or prasugrel for
7 days followed by clopidogrel for 7 days (guided de-escala-
tion group). Platelet function testing was completed 2 weeks
after hospital discharge by using the Multiplate Analyzer, a
rapid whole-blood assay that detects platelet function. After
platelet function testing, the control group remained on pra-
sugrel for the remainder of the study (11.5 months). Low
responders, defined as having high platelet reactivity, were
transitioned back to prasugrel; and good responders, defined
as not having high platelet reactivity, continued with clopido-
grel for the remainder of the study. With regard to the primary
outcome of cardiovascular death, stroke, myocardial infarc-
tion, or BARC ≥2 bleeding, de-escalation of maintenance anti-
platelet therapy was noninferior to 12 months of prasugrel.
De-escalation of P2Y12 inhibitors guided by platelet function
testing is a viable option and may be considered for patients
at elevated risk of bleeding (e.g., anemia, need for DAPT plus
oral anticoagulant therapy, clinically significant bleeding on
current therapy, socioeconomic factors, adverse effects)
(Claassens 2020). Current guidelines do not endorse a spe-
cific platelet function test, and therefore, clinicians may be
limited to whatever test is available at their institutions (Sib-
bing 2017).
Switching Between Oral and Intravenous
P2Y12 Inhibitors
In a transition from an oral to an intravenous P2Y12 inhibitor,
there is no lapse in platelet reactivity given the continuous
inhibition achieved with intravenous therapy. Therefore, in
a transition from an oral agent to cangrelor, cangrelor 0.75
mcg/kg/min infusion should be initiated within 72 hours of
discontinuation of oral P2Y12 inhibitors (Angiolillo 2017). Cur-
rent recommendations suggest starting cangrelor within
3 or 4 days after discontinuation of prasugrel and within
2 or 3 days after discontinuation of clopidogrel and ticagre-
lor, and earlier initiation may be warranted depending on
patient factors such as how recently the stent was placed
and the coronary vessel stented. An alternative method that
ensures appropriate cangrelor initiation timing is to perform
platelet function testing, but the means for such testing
may not be readily available at all institutions. In contrast,
patients undergoing PCI who are receiving cangrelor will
require transition to an oral P2Y12 inhibitor after the proce-
dure, and depending on which P2Y12 inhibitor is chosen for
maintenance therapy, potential drug-drug interactions will
drive transition instructions. Summarized consensus rec-
ommendations for transitioning from intravenous to oral are
listed in Table 9 (Angiolillo 2017).
Stable Ischemic Heart Disease Management
Antiplatelet Therapy for Secondary Prevention
As part of the thrombotic response, platelet aggregation plays
a key role in plaque disruption, and therefore, antiplatelet
agents are used for lessening the occurrence of these events.
For secondary prevention of myocardial infarction and death,
the 2012 ACC/AHA guidelines for the management of SIHD
recommend treatment with aspirin 75–162 mg daily, contin-
ued indefinitely (class Ia). In patients with contraindication
to aspirin, clopidogrel is a reasonable alternative (class Ib).
For certain patients who are at high risk, treatment with DAPT
(aspirin 75–162 mg plus clopidogrel 75 mg daily) may be con-
sidered (class IIb) (Fihn 2012). Similarly, the European Soci-
ety of Cardiology (ESC) recommends antithrombotic therapy
with aspirin 75–100 mg daily in patients with previous myo-
cardial infarctions or revascularizations of chronic coronary
syndromes who are in sinus rhythm (class Ia), with an alterna-
tive option of clopidogrel 75 mg daily for patients with aspirin
intolerance (class Ib) (Knuuti 2020).
ASET Pilot Study
After recent studies evaluated shortened DAPT duration in
an effort to minimize bleeding risk while maintaining pro-
tection from ischemia, the ASET study assessed the use

PSAP 2022 Book 1 • Cardiology 97 Antithrombotic Therapy in Cardiac Interventions

of prasugrel monotherapy after placement of an everolim-
us-eluting stent in 201 low-risk patients with stable CAD. The
study was a single-arm, open-label trial with a stopping rule
based on occurrence of stent thrombosis that would result in
patient recruitment termination. At the time of study enroll-
ment, all patients were on standard DAPT therapy. At the
time of elective PCI for SIHD, aspirin was discontinued and
prasugrel was initiated and continued for 3 months. The pri-
mary ischemia end point was a composite of cardiac death,
spontaneous target vessel MI, or definite stent thrombosis.
The primary bleeding end point was BARC 3 and 5 bleeding
during 3 months of follow-up. Both the primary ischemic and
bleeding end points occurred in one patient, and no stent
thrombosis events occurred. Although the ASET study had
several limitations, including small sample size, it may pave
the way for future, larger studies to assess this alternative
antiplatelet therapy regimen after PCI in low-risk patients
with stable CAD—particularly those with high bleeding risk
(Kogame 2020).
Anticoagulation for Secondary Prevention
In addition to low-dose aspirin, anticoagulation can be con-
sidered for patients who are in sinus rhythm with moderate
to high ischemic risk and low bleeding risk (Knuuti 2020). And
therefore, to reduce the risk of MI, stroke, and cardiovascu-
lar death, the 2019 ESC SIHD and 2020 ESC NSTE-ACS guide-
lines recommend the addition of low-dose rivaroxaban 2.5 mg
twice daily to aspirin in patients who are more than 1 year
post-MI or who have multivessel CAD. For patients with high
ischemic risk, this is labeled as a Class IIa recommendation
and as a Class IIb recommendation for those with moderate
risk. Currently, the 2014 ACC/AHA guidelines for the manage-
ment of SIHD do not include anticoagulation as an option, but
those guidelines were published before publications of clin-
ical trials that evaluated anticoagulation for secondary pre-
vention (Collet 2021; Knuuti 2020).
COMPASS
The COMPASS trial was a double-blind study to assess the
effectiveness of low-dose rivaroxaban 5 mg twice daily alone,
rivaroxaban 2.5 mg twice daily plus aspirin, and aspirin alone
for secondary prevention in patients with stable atheroscle-
rotic vascular disease. The primary outcome—a composite
of cardiovascular death, stroke, or MI—occurred least in the
rivaroxaban 2.5 mg twice daily plus aspirin group, but more
major bleeding occurred. In a comparison of rivaroxaban plus
aspirin versus aspirin alone, the hazard ratio for the compos-
ite outcome was 0.76 (95% CI, 0.66–0.86; p<0.001). The haz-
ard ratio for rivaroxaban alone versus aspirin alone was 0.90
(95% CI, 0.79–1.03; p=0.12). Recurrent cardiovascular events
did not occur less often in the rivaroxaban 5 mg twice daily
group compared with aspirin alone, but more major bleeding
events occurred. The study was stopped early for superiority
of the rivaroxaban plus aspirin group after a mean follow-up
PSAP 2022 Book 1 • Cardiology
of 23 months (Eikelboom 2017). Based on results from that
study, anticoagulation may be considered for secondary pre-
vention in patients who have stable atherosclerotic vascular
disease with elevated ischemic risk, as adopted by the 2019
and 2020 ESC guidelines.
TRIPLE ANTITHROMBOTIC THERAPY
Introduction to Dual and Triple Antithrombotic
Therapy
About 30% of patients with atrial fibrillation (AF) also have
coronary artery disease, and AF has been reported in 3% –
12% of patients undergoing PCI (Saito 2019). It is important
to note that the antithrombotic strategies for AF and PCI are
different from each other and therefore—because of differ-
ences in thrombus physiologies—are not interchangeable
(You 2012). Oral anticoagulation (OAC) is the preferred anti-
thrombotic therapy for stroke prevention in atrial fibrillation,
whereas DAPT remains the standard of care for prevention of
major adverse cardiac events and stent thrombosis after PCI
(January 2019; Levine 2016).
Triple antithrombotic therapy (TAT) was previously rec-
ognized as theoretically necessary and empirically recom-
mended for patients with AF undergoing PCI (Saito 2019). The
combination of OAC and DAPT is associated, unsurprisingly,
with significant increases in major and minor bleeding. For
example, the risk of nonfatal bleeding with TAT is four times
higher than with vitamin K antagonist (VKA) monotherapy,
and the risk of intracranial hemorrhage is twice that with
DAPT (Saito 2019; Hansen 2010).
Dual antithrombotic therapy (DAT) refers to the combina-
tion of OAC plus a P2Y12 inhibitor, and it has emerged as a
way to reduce bleeding events in patients without increasing
the risk of thromboembolic complications. Because the omis-
sion of OAC increases the risk of cardioembolic stroke and
mortality in patients with AF and because the addition of a
P2Y12 inhibitor to aspirin reduces the risk of stent thrombosis
after PCI, it was thought that the omission of aspirin might
decrease bleeding without sacrificing efficacy against isch-
emic events (Dewilde 2013; Connolly 2006). Since the first
publication of trials that evaluated DAT versus TAT in 2013,
several published clinical trials have solidified DAT as the
preferred antithrombotic strategy in most patients with AF
undergoing PCI.
Clinical Practice Guideline Recommendations
The AHA, ACC, and ESC recently published updated state-
ments about TAT and DAT (Angiolillo 2021; Hindricks 2021;
Kumbhani 2021) (Figure 3). In general, all favor DAT in most
patients with AF undergoing PCI. For patients during the peri-
PCI period and during a hospitalization of up to 1 week, TAT is
recommended. At that time, the decision to continue with TAT
for up to 30 days depends on evaluation of a patient’s isch-
emic and bleeding risk. In patients with high ischemic risk
98 Antithrombotic Therapy in Cardiac Interventions
 AHA/ACC Strategy for High AHA/ACC Strategy for Low
AHA/ACC Default Strategy
Ischemic/Low Bleed Risk Ischemic/High Bleed Risk

TAT up to 1 week TAT up to 1 month TAT up to 1 week

Peri-PCI to
ESC: Recommended strategy for ESC: Recommended strategy for ESC: Can discontinue aspirin
1 week
most SIHD and ACS patients most SIHD and ACS patients earlier than 1 week

1 month

3 months DAT up to 6 months

DAT up to 12 months
ESC: Consider for medically
ACC in SIHD: P2Y12 inhibitor
DAT up to 12 months managed ACS ACC in SIHD:
for 6 months, then aspirin + OAC
Discontinue P2Y12 after
6 months for 6 months
3 months

12 months

> 12 months OAC Monotherapy OAC Monotherapy OAC Monotherapy

Figure 3. Approaches to antithrombotic therapy in patients with atrial fibrillation undergoing percutaneous coronary
intervention.
ACC = American College of Cardiology; ACS = acute coronary syndrome; AHA = American Heart Association; DAT = dual
antithrombotic therapy (OAC + single antiplatelet); DAPT = dual antiplatelet therapy; ESC = European Society of Cardiology; OAC =
oral anticoagulant; PCI = percutaneous coronary intervention; SIHD = stable ischemic heart disease; TAT = triple antithrombotic
therapy (OAC + DAPT).
Information from: Angiolillo DJ, Bhatt DL, Cannon CP, et al. Antithrombotic therapy in patients with atrial fibrillation treated with oral
anticoagulation undergoing percutaneous coronary intervention: a North American perspective: 2021 update. Circulation 2021;143:
583-96; Kumbhani DJ, Cannon CP, Beavers CJ, et al. 2020 ACC expert consensus decision pathway for anticoagulant and antiplatelet
therapy in patients with atrial fibrillation or venous thromboembolism undergoing percutaneous coronary intervention or with
atherosclerotic cardiovascular disease: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll
Cardiol 2021;77:629-58; Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and management of atrial
fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2021;42:373-498.

and low bleed risk, TAT can be considered for the first month,
followed by DAT for 6 (SIHD) to 12 (ACS) months. In patients
with high bleeding risk, TAT duration can be as short as the
hospital stay, followed by DAT for 6 months. After comple-
tion of DAT, OAC monotherapy is recommended for second-
ary prevention. Table 10 summarizes current clinical practice
recommendations.
For patients without contraindications (e.g., moderate to
severe mitral stenosis, mechanical prosthetic valve), direct
oral anticoagulants (DOACs) are preferred for TAT and DAT.
The recommendation comes from several clinical trials
demonstrating DOACs’ better safety profiles compared with
VKA’s, including in the setting of DAT. The P2Y12 inhibitor of
choice in this setting is clopidogrel. Compared with ticagre-
lor and prasugrel, clopidogrel has been associated with less
bleeding (Wallentin 2009, Wiviott 2007), and an overwhelm-
ing majority of patients in the clinical trials assessing TAT
received clopidogrel. Data surrounding the use of ticagrelor
and prasugrel in this setting are limited. Current guidelines
state that ticagrelor is an acceptable alternative, but only if
the patient is considered a high-thrombotic, low-bleed risk.
Prasugrel should be avoided in this setting.
Landmark Trials Assessing Dual vs. Triple
Antithrombotic Therapy
The concept of DAT versus TAT was first studied by the
WOEST trial, wherein warfarin plus clopidogrel was compared
with warfarin plus DAPT. DAT was associated with less bleed-
ing than TAT—without sacrificing efficacy. That paved the way
for further studies assessing DAT, and each of the DOACs has
had a clinical trial published in recent years. Table 11 summa-
rizes those studies and key findings. The results of all of the
studies consistently support the fact that DAT is associated
with less bleeding—seemingly without sacrificing ischemic
efficacy. In addition, the AUGUSTUS trial assessing apixaban
in DAT versus TAT established that the reduction in bleeding
in fact results because of the removal of aspirin, because the

PSAP 2022 Book 1 • Cardiology 99 Antithrombotic Therapy in Cardiac Interventions

 Table 10. Summarized Clinical Practice Guideline Recommendations for Dual and Triple Antithrombotic Therapy

2021 AHA Focused 2020 ACC Expert Consensus

Update: Antithrombotic
Therapy in Patients
with AF Treated with
Oral Anticoagulation
Undergoing PCI
Decision Pathway for
Anticoagulant and
Antiplatelet Therapy in
Patients with AF or VTE 2020 ESC Atrial Fibrillation
Undergoing PCI Guidelines

Oral anticoagulant DOAC DOAC DOAC

recommendation
If warfarin used, aim for
a reduced target INR of
2.0–2.5
• Rivaroxaban 15 mg daily
If warfarin used, reasonable to and dabigatran 110 mg
target INR of 2.0–2.5 twice daily if HAS-BLED
>3 while prescribed
concomitant P2Y12 inhibitor

If VKA used, target INR of

2–2.5 (IIa-B)

Antiplatelet Aspirin + P2Y12 during peri- SIHD: SIHD:

recommendation PCI period until discharge
and up to 1 week after
PCI; then stop aspirin and
continue P2Y12
P2Y12 inhibitor for 6 months;
then aspirin or clopidogrel
for 6 months. Continue OAC
indefinitely
ACS:
P2Y12 inhibitor for 12 months.
Continue OAC indefinitely
Aspirin + P2Y12 for 1 month;
then stop aspirin
Continue P2Y12 for 6–12
months of total therapy
Continue OAC indefinitely
ACS:
Aspirin + P2Y12 for 1 month;
then stop aspirin
Continue P2Y12 for 6–12
months of total therapy
Continue OAC indefinitely

Medically treated ACS:

P2Y12 for 6 months

P2Y12 of choice Clopidogrel Clopidogrel Clopidogrel

Ticagrelor acceptable in Ticagrelor acceptable in high
high ischemic risk ischemic risk

Increased thrombotic risk, Continue TAT for up to 1 Can consider TAT for up to 30 Can consider TAT for up to 1
acceptable bleeding risk month; then DAT for 6–12 days month
months; then OAC alone

Low thrombotic risk or high Discontinue P2Y12 inhibitor 6 Discontinue P2Y12 inhibitor Can consider discontinuing
bleeding risk months after PCI after 3 months for SIHD or aspirin earlier than 1 month—
after 6 months for ACS even ≤ 1 week

ACS = acute coronary syndrome, AF = atrial fibrillation; DAPT = dual antiplatelet therapy; DAT = dual antithrombotic therapy; INR =
international normalized ratio; OAC = oral anticoagulant; PCI = percutaneous coronary intervention; SIHD = stable ischemic heart dis-
ease; VKA = vitamin K antagonist; VTE = venous thromboembolism.
Information from: Angiolillo DJ, Bhatt DL, Cannon CP, et al. Antithrombotic therapy in patients with atrial fibrillation treated with oral
anticoagulation undergoing percutaneous coronary intervention: a North American perspective: 2021 update. Circulation
2021;143:583-96.
Kumbhani DJ, Cannon CP, Beavers CJ, et al. 2020 ACC expert consensus decision pathway for anticoagulant and antiplatelet
therapy in patients with atrial fibrillation or venous thromboembolism undergoing percutaneous coronary intervention or with
atherosclerotic cardiovascular disease: a report of the American College of Cardiology Solution Set Oversight Committee. J Am
Coll Cardiol 2021;77:629-58; Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and management of
atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J
2021;42:373-498.

PSAP 2022 Book 1 • Cardiology 100 Antithrombotic Therapy in Cardiac Interventions

 Table 11. Landmark Trials Assessing Dual vs. Triple Antithrombotic Therapy

Trial (year) Antithrombotic regimens Outcomes

WOEST (2013) Warfarin + clopidogrel Compared with triple therapy, dual therapy resulted
in fewer bleeding complications—and without an
Warfarin + DAPT
increase in the rate of thrombotic events

PIONEER AF-PCI (2016) Rivaroxaban 15 mg daily (or 10 mg daily if Compared with warfarin + DAPT, rivaroxaban-based
CrCl 30–50 mL/min) + P2Y12 inhibitor antithrombotic therapies resulted in less TIMI major
and minor bleeding
Rivaroxaban 2.5 mg twice daily + DAPT for 1,
6, or 12 months
The rate of cardiovascular death, myocardial
After completion of DAPT, patients received
infarction, or stroke did not differ between the
rivaroxaban 15 mg daily + aspirin
groups
Warfarin + DAPT for 1, 6, or 12 months
After completion of DAPT, patients received
warfarin + aspirin

RE-DUAL PCI (2017) Dabigatran 110 mg twice daily + P2Y12 Compared with triple therapy using warfarin as the
inhibitor anticoagulant, dual therapy with a dabigatran-
based antithrombotic regimen resulted in reduced
Dabigatran 150 mg twice daily + P2Y12
bleeding events
inhibitor

Warfarin + P2Y12 inhibitor + aspirin
Dual therapy with dabigatran 110 mg twice daily
resulted in lower rates of bleeding (15.4%) compared
with 150 mg twice daily (20.2%), though these
groups were not directly compared with one another
for noninferiority

The incidence of thromboembolic events, death, or

unplanned revascularization in the dual therapy
groups was noninferior to triple therapy

AUGUSTUS (2019) Apixaban 5 mg twice dailya + P2Y12 + aspirin
Apixaban 5 mg twice dailya + P2Y12
Warfarin + P2Y12 + aspirin
Warfarin + P2Y12
Dual therapy with an apixaban-based regimen
resulted in lower bleeding compared with a
warfarin-based dual therapy—with lower rates of
death or rehospitalization.
Triple therapy resulted in greater bleeding without a
difference in efficacy

ENTRUST-AF PCI (2019) Edoxaban 60 mg daily + clopidogrel Dual therapy with an edoxaban-based antithrombotic
regimen was noninferior to VKA-based triple therapy
Warfarin + clopidogrel + aspirin
with regard to clinically relevant nonmajor bleeding

The rates of cardiovascular death, myocardial

infarction, stroke, systemic embolism, or definite
stent thrombosis did not differ between the groups

a
Dose adjusted to 2.5 mg twice daily if patient met two of the following criteria, per package insert: weight <60 kg, age >80 years,
serum creatinine ≥1.5 mg/dL or greater
CrCl = creatinine clearance; DAPT = dual antiplatelet therapy; VKA = vitamin K antagonist.
Information from: Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral
anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet
2013;381:1107-15; Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N
Engl J Med 2016;375:2423-34; Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial
fibrillation. N Engl J Med 2017;377:1513-24; Lopes RD, Heizer G, Aronson R, et al. Antithrombotic therapy after acute coronary
syndrome or PCI in atrial fibrillation. N Engl J Med 2019;380:1509-24; Vranckx P, Valgimigli M, Eckardt L, et al. Edoxaban-based
versus vitamin K antagonist–based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation
(ENTRUST-AF PCI): a randomised, open-label, phase 3b trial. Lancet 2019;394:1335-43.

PSAP 2022 Book 1 • Cardiology 101 Antithrombotic Therapy in Cardiac Interventions

combination of apixaban plus P2Y12 was associated with less
bleeding than was apixaban plus DAPT.
Clinical Controversies with Triple
Antithrombotic Therapy
Even though the recommendation for DAT comes with sup-
port from strong clinical evidence, some outstanding ques-
tions and gray areas within the application of DAT still remain.
Ischemic vs. Bleeding Risk During the First
Month of Therapy
As stated previously, clinical guidelines recommend that TAT
be considered for up to 30 days in patients with high-throm-
botic-, low-bleeding-risk profiles. It is important to note that
all of the clinical trials assessing TAT versus DAT were pow-
ered to detect differences in safety outcomes, such as bleed-
ing events. None of the trials were prospectively designed to
compare ischemic efficacy, and some data suggest the pos-
sibility of increased risk of stent thrombosis and MI with DAT
compared with TAT (Gargiulo 2019). Ischemic risk tends to be
highest in the initial period after PCI, whereas bleeding risk
is more cumulative over time (Schömig 2009). Post hoc anal-
yses from the AUGUSTUS trial demonstrated that the inci-
dence of stent thrombosis was numerically higher in patients
treated with DAT and that 80% of those occurred during the
first 30 days after PCI (Lopes 2020).
The authors of the AUGUSTUS trial assessed at 30 days
the outcomes of patients randomized to aspirin or placebo
(Alexander 2020). The increase in severe bleeding with the
addition of aspirin equaled the reduction in severe ischemic
events during the first 30 days, but the increase in bleeding
persisted beyond 30 days—without any benefit in reducing
ischemic outcomes. Taking those results into consideration,
recommendations for up to 30 days of TAT in patients with
high thrombosis risk are reasonable. Risk factors for throm-
bosis and bleeding are given in Box 2. Overall, an individu-
alized approach to antithrombotic therapy during the first
month after PCI is essential. Beyond 30 days, DAT is likely the
appropriate treatment strategy for most patients.
Novel P2Y12 Inhibitor Use
Guidelines recommend that ticagrelor be used in patients
with high-ischemic-, low-bleeding-risk profiles. It is import-
ant to note that the data assessing this particular P2Y12
inhibitor in the setting of TAT are limited. In landmark trials
(see Table 11), ticagrelor was used in up to 12% of patients.
Ticagrelor has demonstrated superiority to clopidogrel in
reducing ischemic events in ACS, but its increased potency
raises concerns about increased bleeding (Wallentin 2009).
Indeed, in the setting of concomitant OAC use, ticagrelor has
demonstrated increased bleeding compared with clopido-
grel (Andreou 2018). Based on the existing evidence, it is rea-
sonable to consider ticagrelor in treating patients with high
PSAP 2022 Book 1 • Cardiology
Box 2. Thrombotic and Bleeding
Risk Factors
Thrombosis Risk Factors
Acute coronary syndrome presentation
Recurrent MI
Prior stent thrombosis on antiplatelet therapy
Complex PCI (three vessels treated, more than three
stents implanted, bifurcation with two stents implant-
ed, total stent length > 60 mm, surgical bypass graft
or CTO target lesion, atherectomy device use, LM PCI,
stenting last patent vessel)
Multivessel CAD
Concomitant peripheral arterial disease
Premature CAD (occurring at age <45 years) or
accelerated CAD (new lesion within 2 years)
Diabetes mellitus requiring therapy
CKD (eGFR <60 mL/min)
Bleeding Risk Factors
Hypertension
Abnormal renal or liver function
History of stroke or ICH
Bleeding history or bleeding diathesis (e.g., anemia with
Hgb <11 g/dL)
Labile INR (if on VKA)
Older >65 years old
Drugs (concomitant OAC and antiplatelet therapy,
NSAIDs)
Excessive alcohol consumption
CAD = coronary artery disease; CKD = chronic kidney disease;
CTO = chronic total occlusion; eGFR = glomerular filtration rate;
ICH = intracranial hemorrhage; INR = international normal-
ized ratio; LM = left main; MI = myocardial infarction; NSAID =
nonsteroidal anti-inflammatory drug; OAC = oral anticoagula-
tion; PCI = percutaneous coronary intervention; VKA = vitamin
K antagonist.
Information from: Angiolillo DJ, Bhatt DL, Cannon CP, et al.
Antithrombotic therapy in patients with atrial fibrillation
treated with oral anticoagulation undergoing percutaneous
coronary intervention: a North American perspective: 2021
update. Circulation 2021;143:583-96; Hindricks G, Potpara
T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and
management of atrial fibrillation developed in collaboration
with the European Association for Cardio-Thoracic Surgery
(EACTS). Eur Heart J 2021;42:373-498.
ischemic and low bleed risk, but more data are needed spe-
cific to patients requiring OAC.
The data for prasugrel use in patients receiving OAC are
sparse. When used in the setting of TAT, prasugrel has been
associated with a fourfold increase in bleeding (Sarafoff
2013). As a result, guidelines recommend avoiding prasugrel,
but more data are needed to evaluate prasugrel’s role in the
setting of DAT.
Secondary Prevention in Patients Requiring
Anticoagulation
Clinical Guideline Recommendations
102 Antithrombotic Therapy in Cardiac Interventions
 Table 12. Landmark Trials Assessing OAC Monotherapy for Secondary Prevention

Trial Antithrombotic Regimens Outcomes

AFIRE (2019) a
Rivaroxaban 15 mg daily (10 mg daily for CrCl Trial terminated early based on excessive
15–49 mL/min) mortality in rivaroxaban + antiplatelet arm
Vs. (1.9% vs. 3.4%, p<0.05)
Rivaroxaban 15 mg (10 mg daily for CrCl
15–49 mL/min) + antiplatelet Rivaroxaban alone was noninferior for ischemic
outcomes and associated with less major
bleeding

OAC-ALONE (2019)a OAC monotherapy Trial terminated early based on slow enrollment
Vs.
OAC + antiplatelet Noninferiority of OAC alone was not established
for primary ischemic end point—likely because
of inadequate power

Significantly higher rates of major bleeding were

noted with OAC + antiplatelet

a
Both studies were conducted in Japan, so dosing strategies differ from US FDA–approved dosing.
CrCl = creatinine clearance; OAC = oral anticoagulation.
Information from: Matsumura-Nakano Y, Shizuta S, Komasa A, et al. Open-label randomized trial comparing oral anticoagulation
with and without single antiplatelet therapy in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after
coronary stent implantation. Circulation 2019;139:604-16; Yasuda S, Kaikita K, Akao M, et al. Antithrombotic therapy for atrial
fibrillation with stable coronary disease. N Engl J Med 2019;381:1103-13.

The most recent guidelines from the AHA, ACC, and ESC all
recommend that patients with stable coronary artery disease
requiring no further intervention beyond 12 months receive
oral anticoagulation monotherapy for secondary disease pre-
vention (Angiolillo 2021; Hindricks 2021; Kumbhani 2021).
The statements cite the AFIRE and OAC-ALONE trials as evi-
dence to support OAC monotherapy (Table 12) (Matsumura-
Nakano 2019, Yasuda 2019). However, in patients with high
thrombotic risk and low bleeding risk (see Table 12), it may be
reasonable to consider aspirin in addition to OAC for second-
ary prevention (Kumbhani 2021).
ANTITHROMBOTIC THERAPY IN
TRANSCATHETER AORTIC VALVE
IMPLANTATION
Overview of Aortic Stenosis
Aortic stenosis (AS) is a progressive, chronic valvular dis-
ease characterized by a narrowing of the aortic valve open-
ing (Otto 2014). The spectrum of disease spans from mild
fibrocalcific changes in the leaflets to obstruction of left ven-
tricular outflow. Endothelial disruption with inflammation
and lipid infiltration initiates this disease, ultimately lead-
ing to tissue calcification and valve obstruction. The preva-
lence of AS increases with age, occurring in 0.2% of adults
50–59 years and in 9.8% of adults 80–89 years. An
overwhelming majority of patients develop AS secondary to
degeneration of the aortic valve, but rheumatic heart disease
and congenital bicuspid aortic valve are other etiologies of
AS, particularly in younger patients. Clinical risk factors for
AS mirror those of CAD, including older age, male sex, ele-
vated LDL, hypertension, smoking, diabetes, and metabolic
syndrome. Patients with histories of mediastinal irradiation,
renal failure, familial hypercholesterolemia, or disorders of
calcium metabolism are also at increased risk of developing
AS.
Aortic stenosis is associated with several cardiac struc-
tural changes, including left ventricular hypertrophy, dia-
stolic dysfunction, and decreased longitudinal shortening,
although the ejection fraction typically remains normal
(Otto 2014). If left untreated, the resulting obstruction of
left ventricular outflow leads to inadequate cardiac output,
decreased exercise capacity, heart failure, and death from
cardiovascular causes. The classic triad of AS symptoms
consist of angina, dyspnea, and syncope and are typically
not present until late in the disease. Once a patient devel-
ops severe, symptomatic AS, mortality is greater than 50%
at 2 years if the valve is not replaced. Aortic valve replace-
ment remains the gold standard of treatment because no
medical therapies have been proven to slow the progres-
sion of or reverse AS. Current guidelines make a Class I rec-
ommendation for aortic valve replacement in patients with
severe, symptomatic AS and in those without symptoms but

PSAP 2022 Book 1 • Cardiology 103 Antithrombotic Therapy in Cardiac Interventions

with ejection fractions of less than 50% or who are under-
going coronary artery bypass graft (Otto 2021). For several
years, surgical aortic valve replacement (SAVR) was the only
approach to aortic valve replacement.
Transcatheter-Aortic-Valve-Implantation
Indication and Procedure
Transcatheter aortic valve implantation (TAVI)—also known
as transcatheter aortic valve replacement, or TAVR—recently
emerged as a less-invasive alternative to SAVR for the treat-
ment of AS. Transcatheter aortic valve implantation is rec-
ommended in patients older than 65 years who have severe,
symptomatic AS, and shared decision making should deter-
mine whether TAVI or SAVR is the more appropriate AVR
approach (Otto 2021). It is important to note that for patients
with severe AS and prohibitive surgical risk, TAVI offers an
option for valve replacement because it has demonstrated
improved mortality compared with management by means
of balloon valvuloplasty or medical therapy (Leon 2010). The
TAVI procedure involves percutaneous insertion of a bio-
prosthetic valve through either balloon expansion or a self-
expanding valve—without removing the calcified native valve.
Published literature surrounding TAVI involves the transfemo-
ral approach, though transapical and transaortic approaches
have been described but may carry a higher risk of mortality.
Clinical Guideline Recommendations
for Antithrombotic Therapy After TAVI
Antithrombotic therapy after TAVI has been an evolving
clinical practice since its implementation. Initially, studies
designed to evaluate TAVI technology defaulted to DAPT. Rea-
sons that DAPT was the initial chosen antithrombotic strat-
egy include the assumption of blood flow conditions similar
to those with coronary stents, similar to the goal of prevent-
ing device-related thromboembolic events, and similar to the
need to protect the metallic valve frame during endotheliali-
zation (Guedeney 2019). However, recent literature has chal-
lenged that empiric recommendation because it has not been
studied robustly and does not apply to patients requiring
chronic OAC.
The 2020 AHA/ACC Valvular Heart Disease Guidelines
recommend low-dose aspirin 75–100 mg daily for patients
undergoing TAVI in the absence of other indications for OAC
(Class 2A, LOE B-R) (Otto 2021). They also suggest the addi-
tion of clopidogrel for 3–6 months in patients at low risk of
bleeding (Class 2B, LOE B-NR). It is important to note that
these guidelines do not specifically address antithrombotic
therapy in patients requiring chronic OAC, nor do they include
data from the POPular-TAVI trials—the largest randomized tri-
als assessing single antiplatelet therapy (SAPT) versus DAPT
and OAC with or without antiplatelet therapy. The ESC 2021

OAC Indication No OAC Indication

Pre-TAVI

OAC Single Antiplatelet

Unfractionated Unfractionated
heparin heparin

Goal ACT ≥250–300s Goal ACT ≥250–300s

TAVI

Coronary stent <3 Coronary stent <3

months ago months ago

Yes No Yes No
Post-TAVI

Dual Therapy
1– 6 Months

Aspirin + Clopidogrel
OAC + Clopidogrel or
Aspirin
VKA or NOAC Aspirin OR
Monotherapy Clopidogrel
Lifelong

VKA or NOAC Aspirin OR

Monotherapy Clopidogrel

Figure 4. European Society of Cardiology Recommendations for Antithrombotic treatment before and after TAVI.
ACT = activated clotting time; NOAC = novel oral anticoagulant; OAC = oral anticoagulant; TAVI = transaortic valvular intervention.
Information from: Ten Berg J, Sibbing D, Rocca B, et al. Management of antithrombotic therapy in patients undergoing transcatheter
aortic valve implantation: a consensus document of the ESC Working Group on Thrombosis and the European Association of
Percutaneous Cardiovascular Interventions (EAPCI), in collaboration with the ESC Council on Valvular Heart Disease. Eur Heart J
2021;42:2265-9.

PSAP 2022 Book 1 • Cardiology 104 Antithrombotic Therapy in Cardiac Interventions

Consensus Statement on antithrombotic therapy after TAVI The results of the aforementioned studies are cited by
is presented in Figure 4 and presents more-thorough recom- the ESC to support the recommendation of SAPT mono-
mendations depending on whether or not a patient requires therapy after TAVI in patients without indications for OAC
OAC (Ten Berg 2021). They favor SAPT and OAC monotherapy who have not undergone recent coronary stenting (Ten
in the absence of recent coronary stenting. With the results of Berg 2021). In patients with recent coronary stents before
the POPular-TAVI trials and the publication of the recent 2021 or after TAVI, DAPT is the preferred treatment strategy for
ESC consensus statement, it is likely that clinical practice in durations described previously in this chapter. Anticoagu-
the United States will shift towards utilizing SAPT and OAC lation should not be used after TAVI unless there is another
monotherapy for most patients after TAVI. indication, such as atrial fibrillation or recent venous
thromboembolism.
Antithrombotic Therapy Without an Indication
Antithrombotic Therapy with an Indication
for OAC: Literature Review
for OAC: Literature Review
The first clinical trial designed to prospectively evaluate SAPT
Antithrombotic therapy in patients with indications for OAC
versus DAPT after TAVI was the ARTE Trial (Rodés-Cabau
(i.e., atrial fibrillation, recent venous thromboembolism) has
2017). A total of 222 patients were randomized to receive
been prospectively evaluated in only one study: the POPu-
either low-dose aspirin alone or aspirin plus clopidogrel after
lar TAVI Cohort B (Nijenhuis 2020). In this arm of the POPu-
TAVI. The composite end point of death, MI, stroke, or tran-
lar TAVI trial, 326 patients requiring OAC were randomized to
sient ischemic attack or a major or life-threatening bleeding
receive either clopidogrel or placebo for 3 months in addition
tended to occur more often in the DAPT group (15.3% vs. 7.2%;
to OAC. The majority of patients (95%) in this study had atrial
p=0.065); and the lack of statistical significance may have
fibrillation as their indication for OAC. All bleeding and non-
been the result of the small sample size and early termination
procedural-related bleeding events were significantly reduced
because of slow enrollment. It is important that the rates of
in the OAC group compared with OAC plus clopidogrel (all
death, MI, stroke, and transient ischemic attack appeared to
bleeding: 21.7% vs. 34.6%; p=0.01; non-procedural-related
be similar between the groups, whereas major and life-threat-
bleeding: 21.7% vs. 34.0%; p=0.02), and most of the bleeding
ening bleeding occurred more often in the DAPT group (10.8%
events were minor and occurred during the first month of ther-
vs. 3.6%; p=0.038).
apy. Ischemic outcomes were similar between the two groups.
The superior safety of SAPT compared with DAPT after
The ESC guidelines do not give preference to DOAC or VKA
TAVI was confirmed by the POPular TAVI Cohort A (POPular-
after TAVI, and there are only limited comparative data in this
TAVI-A) trial in 2020 (Brouwer 2020), a study designed sim-
setting (Ten Berg 2021). In POPular TAVI-B, nearly 70% of the
ilarly to the ARTE trial: patients were randomized to receive
patients were receiving a VKA as their anticoagulant. Obser-
either low-dose aspirin or aspirin plus clopidogrel for 3 months
vational data show inconsistent results for DOACs in AF after
after TAVI. However, POPular-TAVI-A comprised nearly three
TAVI. A German registry of more than 900 patients demon-
times the number of patients as the ARTE trial did, with 331
strated higher ischemic events at 1 year with DOAC use, and
patients randomized to receive SAPT and 334 randomized to
a Danish registry showed similar rates between DOACs and
receive DAPT. All of the primary outcomes in the POPular-TA-
VKA (Butt 2021; Jochheim 2019). In clinical practice, DOACs
VI-A trial were bleedings (minor, major, and life-threatening)
continue to be used very often in patients with AF undergoing
and non-procedure-related bleedings at 12 months, both of
TAVI, and the risk of ischemic events in DOACs versus VKA
which occurred significantly less in the SAPT arm compared
warrants further study.
with DAPT. Ischemic outcomes—including death from cardio-
As a result of the randomized POPular-TAVI-B data, the
vascular causes, MI, and stroke—were similar between the
ESC recommends OAC monotherapy in patients with indica-
two groups.
tions for OAC who are undergoing TAVI (Ten Berg 2021). In
After TAVI, anticoagulation in patients without any other
patients who have also undergone recent coronary stenting,
indications for anticoagulation was evaluated in the GALILEO
a dual-therapy approach that uses OAC plus an antiplatelet
study (Dangas 2020) and the ATLANTIS trial (pending pub-
as described previously is recommended, followed by OAC
lication). GALILEO terminated early because safety was of
monotherapy for secondary prevention.
concern based on the fact that the rivaroxaban arm was asso-
ciated with a higher risk of death or thromboembolic compli-
ANTITHROMBOTIC THERAPY
cations as well as a higher risk of bleeding compared with
IN MITRACLIP
DAPT. As a result, both the AHA/ACC and ESC guidelines
strongly recommend against the use of rivaroxaban after Mitral Regurgitation Overview

TAVI in the absence of other indications for anticoagulation. Mitral regurgitation (MR) is a result of retrograde blood flow
ATLANTIS failed to show any benefit with apixaban compared from the left ventricle into the left atrium through the mitral
with antiplatelet therapy. valve. With a prevalence that increases with age, MR is the
most common type of moderate or severe valvular heart

PSAP 2022 Book 1 • Cardiology 105 Antithrombotic Therapy in Cardiac Interventions

 Patient Care Scenario
A 76-year-old woman presents to the ED after a witnessed
syncopal event. She reports walking around her house
trying to clean up before her daughter came over, when
her husband witnessed her fall. She reports briefly los-
ing consciousness but came to shortly thereafter. She
did not hit her head, and CT head was negative for any
intracranial bleed. Her medical history is significant for
atrial fibrillation, CAD status post-PCI with drug-eluting
stent about 2 months prior for ongoing angina, hyper-
tension, and chronic kidney disease. Home medications
are apixaban 5 mg twice daily, atorvastatin 80 mg daily,
ANSWER
This patient undergoing TAVI has two factors to consider:
the need for oral anticoagulation for atrial fibrillation and
the need for DAPT after coronary stenting. According to
statements from the American Heart Association, the
American College of Cardiology, and the European Society
of Cardiology, triple antithrombotic therapy with antico-
agulation plus DAPT should be avoided. A combination
of OAC and a P2Y12 inhibitor—in this case continuation
clopidogrel 75 mg daily, metoprolol 25 mg twice daily, and
losartan 25 mg daily. A transthoracic echocardiogram is
performed and identifies severe, critical aortic stenosis.
Because of the patient’s high surgical risk, the patient
is scheduled for transcatheter aortic valve implantation
for the next day. She undergoes successful TAVI and is
admitted to the cardiology step-down floor for obser-
vation postprocedure. What are the most appropriate
antithrombotic regimen and duration of therapy for this
patient after her TAVI?
of home apixaban and clopidogrel—is the most appropri-
ate antithrombotic regimen for this patient after her TAVI.
With regard to duration of therapy, because placement of
the drug-eluting stent was in the setting of stable isch-
emic heart disease, the recommended duration of therapy
is 6 months. After completion, it is recommended that the
patient continue with OAC monotherapy for secondary
prevention.

1. Angiolillo DJ, Bhatt DL, Cannon CP, et al. Antithrombotic therapy in patients with atrial fibrillation treated with oral anticoagulation
undergoing percutaneous coronary intervention: a North American perspective: 2021 update. Circulation 2021;143:583-96.
2. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collab-
oration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2021;42:373-498.
3. Kumbhani DJ, Cannon CP, Beavers CJ, et al. 2020 ACC expert consensus decision pathway for anticoagulant and antiplatelet therapy
in patients with atrial fibrillation or venous thromboembolism undergoing percutaneous coronary intervention or with atheroscle-
rotic cardiovascular disease: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol
2021;77:629-58.
4. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with
coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice
Guidelines. J Am Coll Cardiol 2016;68:1082-115.
5. Ten Berg J, Sibbing D, Rocca B, et al. Management of antithrombotic therapy in patients undergoing transcatheter aortic valve implan-
tation: a consensus document of the ESC Working Group on Thrombosis and the European Association of Percutaneous Cardiovascular
Interventions (EAPCI), in collaboration with the ESC Council on Valvular Heart Disease. Eur Heart J 2021;42:2265-9.

disease among US adults older than 55 years (Nkomo 2006).
Chronic MR may present as one of two types—either chronic
primary MR or chronic secondary MR—with each having fea-
tures related to valvular anatomy and hemodynamics, which
facilitate appropriate diagnostic staging and determination
of treatment options. Primary MR, also called degenerative
MR or organic MR, results from structural deformity or dam-
age to the leaflets, chordae, and/or papillary muscles that
causes the leaflets to close insufficiently during systole. Sec-
ondary MR, also called ischemic MR or functional MR, is not
the result of a structural abnormality of the valve itself but
is, rather, a result of left-ventricular-wall-motion abnormali-
ties or left-ventricular remodeling resulting in improper clo-
sure of the valve during the cardiac cycle (Nishimura 2014).
Over time, continued retrograde blood flow leads to volume
overload and causes ventricular dilatation, widening of the
mitral annulus, and diminished coaptation of leaflets, lead-
ing to further worsening of MR. Eventually, volume overload
becomes so severe that wall-stress-related afterload on the
left ventricle leads to dilatation and decreased contractil-
ity, resulting in a reduction of ejection fraction (Apostolidou
2017).
MitraClip Indication and Procedure
Transcatheter mitral valve repair (TMVr) with the MitraClip
device is indicated for the treatment of both chronic pri-
mary MR and chronic secondary MR and is currently the only
US FDA–approved device for TMVr. The MitraClip device is
inserted percutaneously and is less invasive compared with
conventional cardiac surgery for mitral valve repair. Access
to the mitral valve is gained through the femoral vein, where a
catheter is threaded into the left atrium by way of transseptal
access with the assistance of fluoroscopy and transesopha-
geal echocardiography. The MitraClip is inserted through the
catheter and deployed upon access to the mitral valve, pulling
the front and back leaflets of the mitral valve, clipping them
together, and thus enabling the valve to close appropriately
during the cardiac cycle (Feldman 2011).

PSAP 2022 Book 1 • Cardiology 106 Antithrombotic Therapy in Cardiac Interventions

 Transcatheter mitral valve repair has also been associated
with improved outcomes compared with surgical repair—
specifically, reductions in death and surgery for valve dys-
function (Feldman 2011)—and is a reasonable alternative to
surgical repair. It is currently recommended in patients with
chronic, severe secondary MR related to left ventricular sys-
tolic dysfunction who have persistent symptoms despite
guideline-directed medical therapy (GDMT) (Otto 2020). Com-
pared with GDMT alone, TMVr with Mitraclip offers improve-
ment in survival, hospitalizations, symptoms, and quality of
life (Stone 2018).
Antithrombotic Therapy After MitraClip
Among studies assessing the MitraClip device in TMVr, the
incidence of stroke or transient ischemic attack occurred in
up to 4.4% of patients (Nusca 2018; Stone 2018). However,
no evidence-based guidelines exist to guide choice or dura-
tion of antithrombotic regimens. Similarly, standard anti-
thrombotic therapy neither before nor during the procedure
has been established; nor has the role of antiplatelet agent
loading doses before device implantation. Patients who are
chronically treated with antiplatelet therapy typically con-
tinue without interruption periprocedurally (Guyatt 2012).
Patients on oral anticoagulation should be managed the
same as for other percutaneous interventions, which is, typ-
ically, a short period of anticoagulation interruption to pre-
vent bleeding.
The manufacturer of MitraClip does not provide recom-
mendations on the choice or duration of antithrombotic
therapy postprocedure. The series of EVEREST studies main-
tained a study protocol that consisted of a regimen of aspi-
rin 325 mg daily for 6–12 months in addition to clopidogrel
75 mg daily for 1 month (Whitlow 2012; Feldman 2011; Mauri
2010; Feldman 2005). The ACCESS-EU study used a regimen
of aspirin 100 mg daily for 3 months in addition to clopidogrel
75 mg daily for 4 weeks, and the COAPT trial used a clopido-
grel loading dose (≥300 mg) within 24 hours before procedure
(6–24 hours if possible) or immediately after the procedure
(Maisano 2013). Aspirin was used at the proceduralist’s dis-
cretion, with a recommended loading dose of aspirin 325 mg
before or immediately after the procedure—if used. Postproce-
dural antithrombotic therapy consisted of clopidogrel 75 mg
daily with or without aspirin 81 mg daily for 6 months or lon-
ger. If patients were previously taking chronic oral anticoag-
ulation (warfarin or DOAC), the anticoagulant was continued
without antiplatelet therapy (Stone 2018).
The 2020 ACC/AHA Guideline for the Management of
Patients with Valvular Heart Disease provides no input with
regard to antithrombotic management surrounding Mitra-
Clip placement, nor do the 2017 ESC Valvular Heart Disease
Guidelines. Therefore, it is reasonable that antiplatelet-na-
ive patients may initiate aspirin and clopidogrel immedi-
ately after the procedure given the study protocols in the
PSAP 2022 Book 1 • Cardiology
most-recent clinical trials (Feldman 2005). However, further
studies are required to assess the use of other antiplatelet
agents such as ticagrelor and prasugrel in this setting.
CONCLUSION
The pathophysiology by which thrombotic events occur
during and after cardiac interventions is complex, and the
optimization of antithrombotic therapy pre- and postcar-
diac intervention is an essential aspect of care. It is imper-
ative that thrombotic and bleeding risks be evaluated so as
to be able to select the best therapy and duration of chronic
treatment. Pharmacists can play a critical role in assisting
Practice Points
• Coronary stents have evolved significantly since their intro-
duction in the mid-1980s, and new features in their design,
structure, and material continue to expand.
• Stent thrombosis and in-stent restenosis continue to be
significant complications after coronary stent placement.
DAPT has helped significantly reduce the incidence of ST,
and the development of DES has reduced the incidence of
ISR.
• All patients who undergo PCI should be treated with DAPT
unless also receiving oral anticoagulant treatment. The
exact agent and duration of therapy depend on various
patient-specific factors.
• When it comes to a switch between different P2Y12
inhibitors, several factors must be considered, including
drug-drug interactions, timing of index event, and reloading
of oral P2Y12 inhibitors.
• TAT (OAC plus DAPT) can be considered for up to 30 days
after PCI, but a dual-therapy (OAC-plus-P2Y12 inhibitor)
approach is generally safer for most patients. Ultimately,
the approach to antithrombotic therapy in patients
requiring both OAC and DAPT should be individualized
based on an individual patient’s ischemic and bleeding risk.
• Clopidogrel remains the P2Y12 inhibitor of choice in the
setting of TAT, but ticagrelor can be considered in patients
with high ischemic risks who present with an acute
coronary syndrome. Prasugrel should generally be avoided
in patients requiring anticoagulation.
• The evidence surrounding antithrombotic therapy after
TAVI has grown in the past few years and favors SAPT
or OAC monotherapy, as stated in the ESC consensus
statement.
• Because of increased harm in this setting, anticoagulation
should not be used after TAVI unless there is another
indication, such as atrial fibrillation or venous
thromboembolism.
• No evidence-based guidelines have been currently
published for guidance after MitraClip implantation, and
the existing literature specifies a combination of aspirin
and clopidogrel. Exact dosing and duration may be left to
the discretion of the interventionalists.
• Clinical pharmacists have a vital role to play in ensur-
ing optimal antithrombotic therapy after PCI, TAVI, and
Mitraclip.
107 Antithrombotic Therapy in Cardiac Interventions
with the selection of, duration of, and transition between
P2Y12 inhibitors for coronary stenting in both SIHD and
ACS. For patients requiring both anticoagulation and treat-
ment with antiplatelet therapy, pharmacists can apply the
approach of DAT—anticoagulation plus P2Y12 inhibitor—to
reduce bleeding risk while maintaining ischemic efficacy.
The approach to antithrombotic therapy in TAVI continues
to evolve, but current literature and consensus statements
suggest that SAPT and OAC monotherapy are appropriate for
most patients. Last, with regard to MitraClip, further data are
needed to better define the optimal agents and duration, but
DAPT with aspirin and clopidogrel is reasonable. Ultimately,
pharmacists maintain an essential role in the selection of
antithrombotic therapies to mitigate bleeding and prevent
ischemic-related events.
REFERENCES
ACTIVE Writing Group of the ACTIVE Investigators, Connolly
S, Pogue J, et al. Clopidogrel plus aspirin versus oral anti-
coagulation for atrial fibrillation in the atrial fibrillation
clopidogrel trial with irbesartan for prevention of vascu-
lar events (active w): a randomised controlled trial. Lancet
2006;367:1903-12.
Adriaenssens T, Byrne R. Prevention of late stent thrombosis
by an interdisciplinary global European effort: PRESTIGE.
Eur Heart J 2014;35:2128-9.
Alexander JH, Wojdyla D, Vora AN, et al. Risk/benefit tradeoff
of antithrombotic therapy in patients with atrial fibrillation
early and late after an acute coronary syndrome or percu-
taneous coronary intervention: insights from AUGUSTUS.
Circulation 2020;141:1618-27.
Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 ACC/
AHA guideline for the management of patients with non–
ST-elevation acute coronary syndromes: a report of the
American College of Cardiology/American Heart Asso-
ciation Task Force on Practice Guidelines. Circulation
2014;130:e344-e426.
Andreou I, Briasoulis A, Pappas C, et al. Ticagrelor versus
clopidogrel as part of dual or triple antithrombotic ther-
apy: a systematic review and meta-analysis. Cardiovasc
Drugs Ther 2018;32:287-94.
Angiolillo DJ, Bhatt DL, Cannon CP, et al. Antithrombotic
therapy in patients with atrial fibrillation treated with oral
anticoagulation undergoing percutaneous coronary inter-
vention: a North American perspective: 2021 update.
Circulation 2021;143:583-96.
Angiolillo DJ, Rollini F, Storey RF, et al. International expert
consensus on switching platelet P2Y12receptor–inhibiting
therapies. Circulation 2017;136:1955-75.
Apostolidou E, Maslow AD, Poppas A. Primary mitral valve
regurgitation: update and review. Glob Cardiol Sci Pract
2017;2017:e201703.
Avci BK, Ikitimur B, Tok OO, et al. The role of GRACE score in
the prediction of high-risk coronary anatomy in patients
PSAP 2022 Book 1 • Cardiology
with non-ST elevation acute coronary syndrome. Kardiol
Pol 2015;73:592-7.
Brouwer J, Nijenhuis VJ, Delewi R, et al. Aspirin with or with-
out clopidogrel after transcatheter aortic-valve implanta-
tion. N Engl J Med 2020;383:1447-57.
Butt JH, De Backer O, Olesen JB, et al. Vitamin K antagonists
vs. direct oral anticoagulants after transcatheter aortic
valve implantation in atrial fibrillation. Eur Heart J Cardio-
vasc Pharmacother 2021;7:11-9.
Claassens DM, Sibbing D. De-escalation of antiplatelet treat-
ment in patients with myocardial infarction who under-
went percutaneous coronary intervention: a review of the
current literature. J Clin Med 2020;9:2983.
Collet J-P, Thiele H, Barbato E, et al. 2020 ESC guidelines for
the management of acute coronary syndromes in patients
presenting without persistent ST-segment elevation.
Eur Heart J 2021;42:1289-367.
Dangas GD, Claessen BE, Caixeta A, et al. In-stent reste-
nosis in the drug-eluting stent era. J Am Coll Cardiol
2010;56:1897-907.
Dangas GD, Tijssen JGP, Wöhrle J, et al. A controlled trial of
rivaroxaban after transcatheter aortic-valve replacement.
N Engl J Med 2020;382:120-9.
Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopido-
grel with or without aspirin in patients taking oral antico-
agulant therapy and undergoing percutaneous coronary
intervention: an open-label, randomised, controlled trial.
Lancet 2013;381:1107-15
Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with
or without aspirin in stable cardiovascular disease. N Engl
J Med 2017;377:1319-30.
Erlinge D, Ten Berg J, Foley D, et al. Reduction in platelet
reactivity with prasugrel 5 mg in low-body-weight patients
is noninferior to prasugrel 10 mg in higher-body-weight
patients: results from the FEATHER trial. J Am Coll Cardiol
2012;60:2032-40.
Feldman T, Foster E, Glower DD, et al. Percutaneous
repair or surgery for mitral regurgitation. N Engl J Med
2011;364:1395-1406.
Feldman T, Wasserman HS, Herrmann HC, et al. Percutane-
ous mitral valve repair using the edge-to-edge technique:
six-month results of the EVEREST phase I clinical trial.
Am Coll Cardiol 2005;46:2134-40.
Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/
AATS/PCNA/SCAI/STS guideline for the diagnosis and
management of patients with stable ischemic heart
disease. J Am Coll Cardiol 2012;60:e44-164.
Franchi F, Rollini F, Rivas Rios J, et al. Pharmacodynamic
effects of switching from ticagrelor to clopidogrel in
patients with coronary artery disease: results of the
swap-4 study. Circulation 2018;137:2450-62.
Furtado RHM, Nicolau JC, Guo J, et al. Morphine and cardio-
vascular outcomes among patients with non-ST-segment
108 Antithrombotic Therapy in Cardiac Interventions
 elevation acute coronary syndromes undergoing coronary
angiography. J Am Coll Cardiol 2020;75:289-300.
Gargiulo G, Goette A, Tijssen J, et al. Safety and efficacy
outcomes of double vs. triple antithrombotic therapy
in patients with atrial fibrillation following percutaneous
coronary intervention: a systematic review and
meta-analysis of non–vitamin K antagonist oral
anticoagulant-based randomized clinical trials. Eur Heart
J 2019;40:3757-67.
Guedeney P, Mehran R, Collet J-P, et al. Antithrombotic ther-
apy after transcatheter aortic valve replacement. Circ Car-
diovasc Interv 2019;12: e007411.
Guerra E, Ndrepepa G, Schulz S, et al. Impact of inhospital
stent thrombosis and cerebrovascular accidents on long-
term prognosis after percutaneous coronary intervention.
Am Heart J 2014;168:862-8.e1.
Guyatt GH, Akl EA, Crowther M, et al. Introduction to the
ninth edition: Antithrombotic Therapy and Prevention of
Thrombosis, 9th ed: American College of Chest Physi-
cians evidence-based clinical practice guidelines. Chest
2012;141(2 Suppl):48S-52S.
Hansen ML, Sørensen R, Clausen MT, et al. Risk of bleed-
ing with single, dual, or triple therapy with warfarin, aspi-
rin, and clopidogrel in patients with atrial fibrillation. Arch
Intern Med 2010;170:1433-41.
Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines
for the diagnosis and management of atrial fibrillation
developed in collaboration with the European Associa-
tion for Cardio-Thoracic Surgery (EACTS). Eur Heart J
2021;42:373-498.
Howard CE, Nambi V, Jneid H, et al. Extended duration of
dual-antiplatelet therapy after percutaneous coronary
intervention: how long is too long? J Am Heart Assoc
2019;8:e012639.
Iqbal J, Gunn J, Serruys PW. Coronary stents: historical
development, current status and future directions. Br Med
Bull 2013;106:193-211.
January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS
focused update of the 2014 AHA/ACC/HRS guideline for
the management of patients with atrial fibrillation: a report
of the american college of cardiology/american heart
association task force on clinical practice guidelines and
the heart rhythm society in collaboration with the society
of thoracic surgeons. Circulation 2019;140:e125-51.
Jochheim D, Barbanti M, Capretti G, et al. Oral anticoagu-
lant type and outcomes after transcatheter aortic valve
replacement. JACC Cardiovasc Interv 2019;12:1566-76.
Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for
the diagnosis and management of chronic coronary syn-
dromes. Eur Heart J 2020;41:407-77.
Kogame N, Guimarães PO, Modolo R, et al. Aspirin-free pra-
sugrel monotherapy following coronary artery stenting in
patients with stable cad. JACC: Cardiovascular Interven-
tions 2020;13:2251-62.
PSAP 2022 Book 1 • Cardiology
Kubica J, Adamski P, Ostrowska M, et al. Morphine delays
and attenuates ticagrelor exposure and action in patients
with myocardial infarction: the randomized, double-blind,
placebo-controlled IMPRESSION trial. Eur Heart J
2016;37:245-52.
Kumbhani DJ, Cannon CP, Beavers CJ, et al. 2020 ACC
expert consensus decision pathway for anticoagulant
and antiplatelet therapy in patients with atrial fibrillation
or venous thromboembolism undergoing percutaneous
coronary intervention or with atherosclerotic cardiovas-
cular disease: a report of the American College of Cardiol-
ogy Solution Set Oversight Committee. J Am Coll Cardiol
2021;77:629-58.
Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve
implantation for aortic stenosis in patients who cannot
undergo surgery. N Engl J Med 2010;363:1597-1607.
Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline
focused update on duration of dual antiplatelet therapy
in patients with coronary artery disease: a report of the
American College of Cardiology/American Heart Associa-
tion Task Force on Clinical Practice Guidelines. J Am Coll
Cardiol 2016;68:1082-115.
Lopes RD, Leonardi S, Wojdyla DM, et al. Stent thrombosis in
patients with atrial fibrillation undergoing coronary stent-
ing in the AUGUSTUS trial. Circulation 2020;141:781-3.
Maisano F, Franzen O, Baldus S, et al. Percutaneous mitral
valve interventions in the real world. J Am Coll Cardiol
2013;62:1052-61.
Matsumura-Nakano Y, Shizuta S, Komasa A, et al. Open-label
randomized trial comparing oral anticoagulation with and
without single antiplatelet therapy in patients with atrial
fibrillation and stable coronary artery disease beyond
1 year after coronary stent implantation. Circulation
2019;139:604-16.
Mauri L, Garg P, Massaro JM, et al. The EVEREST II trial:
design and rationale for a randomized study of the
evalve MitraClip system compared with mitral valve sur-
gery for mitral regurgitation. American Heart Journal
2010;160:23-9.
McEvoy JW, Ibrahim K, Kickler TS, et al. Effect of intrave-
nous fentanyl on ticagrelor absorption and platelet inhibi-
tion among patients undergoing percutaneous coronary
intervention: the PACIFY randomized clinical trial (platelet
aggregation with ticagrelor inhibition and fentanyl). Circu-
lation 2018;137:307-9.
Montalescot G, Bolognese L, Dudek D, et al. Pretreatment
with prasugrel in non–ST-segment elevation acute coro-
nary syndromes. N Engl J Med 2013;369:999-1010.
Neumann FJ, Gawaz M, Ott I, et al. Prospective evaluation
of hemostatic predictors of subacute stent thrombosis
after coronary Palmaz-Schatz stenting. J Am Coll Cardiol
1996;27:15-21.
Neumann F-J, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/
EACTS guidelines on myocardial revascularization. Eur
Heart J 2019;40:87-165.
109 Antithrombotic Therapy in Cardiac Interventions
Nijenhuis VJ, Brouwer J, Delewi R, et al. Anticoagulation with
or without clopidogrel after transcatheter aortic-valve
implantation. N Engl J Med 2020;382:1696-1707.
Nishimura RA, Otto CM, Bonow RO, et al. American College
of Cardiology/American Heart Association Task Force on
Practice Guidelines. 2014 AHA/ACC guideline for the man-
agement of patients with valvular heart disease: executive
summary: a report of the American College of Cardiology/
American Heart Association Task Force on Practice Guide-
lines. J Am Coll Cardiol 2014;63:2438-88.
Nkomo VT, Gardin JM, Skelton TN, et al. Burden of valvu-
lar heart diseases: a population-based study. Lancet
2006;368:1005-11.
Nusca A, Bressi E, Colaiori I, et al. Antiplatelet therapy in val-
vular and structural heart disease interventions. Cardio-
vasc Diagn Ther 2018;8:678-93.
Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA
guideline for the management of patients with valvular
heart disease: a report of the American College of Cardiol-
ogy/American Heart Association Joint Committee on Clini-
cal Practice Guidelines. J Am Coll Cardiol 2021;77:e25-197.
Otto CM, Prendergast B. Aortic-valve stenosis—from
patients at risk to severe valve obstruction. N Engl J Med
2014;371:744-56.
Rodés-Cabau J, Masson J-B, Welsh RC, et al. Aspirin versus
aspirin plus clopidogrel as antithrombotic treatment
following transcatheter aortic valve replacement with
a balloon-expandable valve: the ARTE (aspirin versus
aspirin + clopidogrel following transcatheter aortic valve
implantation) randomized clinical trial. JACC Cardiovasc
Interv 2017;10:1357-65.
Saad M, Meyer-Saraei R, de Waha-Thiele S, et al. Impact of
morphine treatment with and without metoclopramide
coadministration on ticagrelor-induced platelet inhibition
in acute myocardial infarction: the randomized MonAMI
trial. Circulation 2020;141:1354-6.
Saito Y, Kobayashi Y. Triple therapy: A review of antithrom-
botic treatment for patients with atrial fibrillation under-
going percutaneous coronary intervention. Journal of
Cardiology 2019;73:1-6.
Sarafoff N, Martischnig A, Wealer J, et al. Triple therapy with
aspirin, prasugrel, and vitamin K antagonists in patients
with drug-eluting stent implantation and an indication for
oral anticoagulation. J Am Coll Cardiol 2013;61:2060-6.
Schömig A, Sarafoff N, Seyfarth M. Triple antithrombotic
management after stent implantation: when and how?
Heart 2009;95:1280-5.
Schüpke S, Neumann F-J, Menichelli M, et al. Ticagrelor or
prasugrel in patients with acute coronary syndromes.
N Engl J Med 2019;381:1524-34.
Sibbing D, Aradi D, Alexopoulos D, et al. Updated expert con-
sensus statement on platelet function and genetic testing
for guiding P2Y12 receptor inhibitor treatment in percuta-
neous coronary intervention. JACC: Cardiovascular Inter-
ventions 2019;12:1521-37.
PSAP 2022 Book 1 • Cardiology
Sibbing D, Aradi D, Jacobshagen C, et al. Guided de-escala-
tion of antiplatelet treatment in patients with acute cor-
onary syndrome undergoing percutaneous coronary
intervention (TROPICAL-ACS): a randomised, open-label,
multicentre trial. Lancet 2017;390:1747-57.
Stefanini GG, Holmes DR. Drug-eluting coronary-artery
stents. N Engl J Med 2013;368:254-65.
Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter
mitral-valve repair in patients with heart failure. N Engl
J Med 2018;379:2307-18.
Taniwaki M, Stefanini GG, Silber S, et al. RESOLUTE All-Com-
ers Investigators. 4-year clinical outcomes and predic-
tors of repeat revascularization in patients treated with
new-generation drug-eluting stents: a report from the
RESOLUTE All-Comers trial (A Randomized Comparison
of a Zotarolimus-Eluting Stent with an Everolimus-Eluting
Stent for Percutaneous Coronary Intervention). J Am Coll
Cardiol 2014;63:1617-25.
Tarantini G, Mojoli M, Varbella F, et al. Timing of oral P2Y12
inhibitor administration in patients with non-ST-segment
elevation acute coronary syndrome. J Am Coll Cardiol
2020;76:2450-9.
Ten Berg J, Sibbing D, Rocca B, et al. Management of anti-
thrombotic therapy in patients undergoing transcathe-
ter aortic valve implantation: a consensus document of
the ESC Working Group on Thrombosis and the European
Association of Percutaneous Cardiovascular Interventions
(EAPCI), in collaboration with the ESC Council on Valvular
Heart Disease. Eur Heart J 2021;42:2265-9.
Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused
update on dual antiplatelet therapy in coronary artery dis-
ease developed in collaboration with EACTS. Eur Heart
J 2018;39:213-60.
Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus
clopidogrel in patients with acute coronary syndromes.
N Engl J Med 2009;361:1045-57.
Whitlow PL, Feldman T, Pedersen WR, et al. Acute and
12-month results with catheter-based mitral valve leaflet
repair. J Am Coll Cardiol 2012;59:130-9.
Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus
clopidogrel in patients with acute coronary syndromes.
N Engl J Med 2007;357:2001-15.
Yasuda S, Kaikita K, Akao M, et al. Antithrombotic therapy
for atrial fibrillation with stable coronary disease. N Engl
J Med 2019;381:1103-13.
Yeh RW, Secemsky EA, Kereiakes DJ, et al. Development and
validation of a prediction rule for benefit and harm of dual
antiplatelet therapy beyond 1 year after percutaneous cor-
onary intervention. JAMA 2016;315:1735.
You JJ, Singer DE, Howard PA, et al. Antithrombotic ther-
apy for atrial fibrillation: Antithrombotic Therapy and Pre-
vention of Thrombosis, 9th ed: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines.
Chest 2012;141:e531S-75S.
110 Antithrombotic Therapy in Cardiac Interventions
Self-Assessment Questions
Questions 16–18 pertain to the following case.
T.W. is a 58-year-old man with a history of heart failure with
preserved ejection fraction (HFpEF), hypertension, mitral
regurgitation (MR) and type 2 diabetes mellitus (T2DM). His
home drugs include losartan 100 mg daily, spironolactone
25 mg daily, metformin 500 mg twice daily and sitagliptin
50 mg daily. Yesterday T.W. presented to the ED with chest
pressure and ECG demonstrated ST-elevations (STE). He was
diagnosed with STE myocardial infarction (STEMI) and under-
went urgent percutaneous coronary intervention (PCI) and a
drug-eluting stent was placed in the right coronary artery. 
16. Which one of the following antithrombotic regimens is
best to recommend for T.W. after PCI for STEMI?
A. Aspirin 81 mg daily plus prasugrel 10 mg daily for
36 months
B. Aspirin 81 mg daily plus ticagrelor 90 mg BID for
6 months
C. Aspirin 81 mg daily plus ticagrelor 90 mg BID for
12 months
D. Aspirin 81 mg daily plus prasugrel 10 mg daily for
6 months
17. T.W. has been taking ticagrelor for 2 months. He calls the
cardiology clinic requesting an alternative medication as
ticagrelor is too expensive. The cardiologist asks you to
provide a recommendation on how to switch to clopido-
grel. Which one of the following is best to recommend to
safely switch T.W. from ticagrelor to clopidogrel?
A. Start clopidogrel 75 mg daily 24 hours after last
dose of ticagrelor.
B. Start with a loading dose of clopidogrel 600 mg
24 hours after last dose of ticagrelor, then continue
clopidogrel 75 mg daily thereafter.
C. Stop ticagrelor, allow a washout period of 3 days,
then start clopidogrel 75 mg daily.
D. Stop ticagrelor, allow a washout period of 3 days,
then give a loading dose of clopidogrel 600 mg and
continue clopidogrel 75 mg daily thereafter.
18. Two months later, T.W. is urgently seen in the cardiol-
ogy office for shortness of breath and intermittent pal-
pitations. Atrial fibrillation is noted on the ECG and oral
anticoagulation is initiated. Which one of the following
adjustments to T.W.’s antithrombotic regimen is best to
recommend?
A. Start warfarin (INR goal 2-3), continue aspirin 81 mg
daily and clopidogrel 75 mg daily.
B. Start warfarin (INR goal 2-3), discontinue aspirin,
continue clopidogrel 75 mg daily.
PSAP 2022 Book 1 • Cardiology
C. Start apixaban 5 mg twice daily, discontinue aspirin,
continue clopidogrel 75 mg daily.
D. Start apixaban 5 mg twice daily, discontinue aspirin
and clopidogrel.
19. A 68-year-old man with a history of severe aortic steno-
sis, atrial fibrillation, and hypertension is scheduled to
undergo a transcatheter aortic valve implantation (TAVI).
His home drugs include losartan 100 mg daily, rosuvas-
tatin 20 mg daily, metoprolol succinate 150 mg daily, and
warfarin (INR goal 2.0–3.0). According to the most recent
European Society of Cardiology guidelines, which one of
the following antithrombotic therapies is best to recom-
mend for this patient post-TAVI?
A. Warfarin (INR 2.0-3.0) indefinitely plus aspirin 81 mg
daily for 6 months
B. Warfarin (INR 2.0-3.0) indefinitely
C. Aspirin 81 mg daily and clopidogrel 75 mg daily for
6 months, then warfarin INR goal 2.0 - 3.0)
D. Rivaroxaban 10 mg daily and aspirin 81 mg daily
indefinitely
20. Which one of the following patients undergoing PCI is
most likely to benefit from extended-DAPT duration
beyond 12 months?
A. 60-year-old man with a history of stage III chronic
kidney disease and peripheral arterial disease
B. 48-year-old woman with hypertension
C. 50-year-old man, current smoker, with heart failure
with reduced ejection fraction and diabetes mellitus
D. 68-year-old man with a history of myocardial infarction
21. A patient with a history of diabetes, ischemic stroke, and
hypertension presents with STEMI and is taken urgently
to the catheterization laboratory. Because the patient
was not loaded with an oral P2Y12 inhibitor, the interven-
tionalist begins a cangrelor 30 mcg/kg bolus followed by
4 mcg/kg/min infusion at the time of PCI. After comple-
tion of cangrelor therapy, which one of the following is
best to recommend to transition this patient to an oral
P2Y12 inhibitor?
A. Start clopidogrel 75 mg daily at time of cangrelor
discontinuation.
B. Give a clopidogrel 600 mg loading dose immediately
before cangrelor discontinuation, then continue
clopidogrel 75 mg daily thereafter.
C. Give a prasugrel 60 mg loading dose 60 minutes
before cangrelor discontinuation, then continue
prasugrel 10 mg daily thereafter.
D. Give a ticagrelor 180 mg loading dose as soon as
possible before cangrelor discontinuation, then
continue ticagrelor 90 mg twice daily thereafter.
111 Antithrombotic Therapy in Cardiac Interventions
22. A 68-year-old man has a medical history of severe aortic
stenosis in the setting of a bicuspid aortic valve, hyper-
tension, and hyperlipidemia. He undergoes an elective
TAVI and is admitted to the cardiac stepdown unit for
observation after the procedure. According to the Euro-
pean Society of Cardiology consensus statement, which
one of the following is best to recommend as the anti-
thrombotic regimen for this patient after successful
TAVI?
A. Aspirin 81 mg daily
B. Aspirin 81 mg daily plus clopidogrel 75 mg daily
C. Warfarin with goal INR of 2-3
D. Rivaroxaban 10 mg daily plus aspirin 81 mg daily
23. A 75-year-old woman has a medical history of stable
coronary artery disease status post-PCI with place-
ment of a drug-eluting stent (DES) to left main and
proximal left anterior descending artery (2 months
ago), hypertension, T2DM, and GERD. The patient pres-
ents to the cardiology service after elective TAVI. Her
home drugs include aspirin 81 mg daily, atorvastatin
40 mg daily, carvedilol 6.25 mg BID, clopidogrel 75 mg
daily, lisinopril 10 mg daily, metformin 500 mg BID, and
pantoprazole 40 mg daily. Which one of the following is
best to recommend for this patient after her TAVI?
A. Aspirin 81 mg daily indefinitely, discontinue
clopidogrel
B. Aspirin 81 mg daily plus clopidogrel 75 mg daily for
4 months, followed by aspirin indefinitely
C. Rivaroxaban 10 mg daily plus clopidogrel 75 mg
daily, discontinue aspirin
D. Aspirin 81 mg daily plus clopidogrel daily for
10 months, followed by clopidogrel indefinitely
24. A patient with a history of recent venous thromboembo-
lism on apixaban is undergoing TAVI. Which one of the
following is best to recommend for this patient after
TAVI?
A. Apixaban 5 mg PO BID
B. Apixaban 5 mg PO BID plus aspirin 81 mg daily
C. Apixaban 5 mg PO BID plus clopidogrel 75 mg daily
D. Apixaban 5 mg PO BID plus ticagrelor 90 mg BID
25. A 76-year-old man with a history of heart failure with
reduced ejection fraction and hypertension is under-
going Mitraclip placement. After Mitraclip placement,
which one of the following is best to recommend for this
patient?
A. Aspirin 81 mg daily
B. Aspirin 81 mg daily plus clopidogrel 75 mg daily
C. Aspirin 81 mg daily plus ticagrelor 90 mg BID
D. Aspirin 81 mg daily plus prasugrel 10 mg daily
PSAP 2022 Book 1 • Cardiology
Questions 26 and 27 pertain to the following case.
W.B. is a 67-year-old man who underwent placement of a DES
to his left circumflex coronary artery 5 days ago. He is pre-
scribed aspirin and clopidogrel upon discharge. 
26. W.B. asks you why he is being prescribed clopidogrel
and aspirin. This dual antiplatelet therapy will most
likely reduce W.B.’s risk of which one of the following
complications?
A. In-stent restenosis
B. Early stent thrombosis
C. Very late stent thrombosis
D. Stroke
27. Three years later, W.B. is admitted for progressive
angina, and he undergoes a coronary angiogram. The
angiogram reveals significant in-stent restenosis (ISR),
and he undergoes orbital atherectomy with repeat stent-
ing to his left circumflex coronary artery. Which one of
the following is most likely associated with W.B.’s ISR?
A. Poor adherence with DAPT
B. Coronary artery hyperplasia
C. Stent underexpansion
D. Impaired re-endothelialization 
28. Emergency Medical Services responds to the local gro-
cery store to assist a patient who is diaphoretic with
crushing chest pain. Morphine 2 mg IV for chest pain is
administered in the ambulance on the way to the hos-
pital. Upon arrival, the patient is diagnosed with an
ST-elevation MI, given 180 mg of ticagrelor and is taken
to the catheterization lab for PCI 10 minutes later. Due to
the interaction between morphine and ticagrelor, which
one of the following laboratory abnormalities is mostly
likely to be seen after this patient’s PCI?
A. Reduced troponin-I, reduced platelet reactivity
B. Increased troponin-I, increased platelet reactivity
C. Increased platelet reactivity, increased lactate
D. Reduced platelet reactivity, increased lactate
29. A 49-year-old man presents to the ED and is diagnosed
with a non ST-elevation MI. He has no contributory med-
ical history, but his BP on presentation is 156/74 mm Hg
and A1C is found to be 6.8%. His PRECISE-DAPT score is
14. The team is planning to take him for coronary angiog-
raphy and PCI with stent placement. Which one of the fol-
lowing P2Y12 inhibitor administration strategies is best to
recommend for this patient?
A. Prasugrel 60 mg x 1 dose before coronary
angiography
B. Clopidogrel 600 mg x 1 dose 2 hours after PCI
C. Ticagrelor 180 mg x 1 dose before coronary
angiography
D. Clopidogrel 300 mg x 1 dose immediately after PCI
112 Antithrombotic Therapy in Cardiac Interventions
30. A 59-year-old man is admitted to the coronary care unit for
NSTE-ACS. His medical history includes atrial fibrillation,
familial hypercholesterolemia, coronary artery disease
status post-multiple PCIs to left circumflex artery (2017),
right coronary artery (2019), hypertension, chronic kidney
disease stage III, and T2DM. His home drugs include apix-
aban 5 mg BID, aspirin 81 mg daily, atorvastatin 80 mg
daily, evolocumab 420 mg SQ every 2 weeks, lisinopril 20
mg daily, metoprolol succinate 100 mg daily. The patient
undergoes PCI to his left main and proximal left anterior
descending artery and is started on DAPT. Which one of
the following antithrombotic therapy regimens is best to
recommend for this patient?
A. Apixaban 5 mg BID plus aspirin 81 mg daily plus
clopidogrel 75 mg daily for 30 days, then apixaban
5 mg BID and clopidogrel 75 mg daily for to
12 months
B. Apixaban 5 mg BID plus aspirin 81 mg daily plus
clopidogrel 75 mg daily for 12 months, then
apixaban monotherapy
C. Apixaban 5 mg BID plus clopidogrel 75 mg daily for
12 months
D. Apixaban 5 mg BID plus prasugrel 10 mg daily for
12 months

PSAP 2022 Book 1 • Cardiology 113 Antithrombotic Therapy in Cardiac Interventions

Learner Chapter Evaluation: Antithrombotic Therapy in Cardiac Interventions

As you take the posttest for this chapter, also evaluate the 25. The learning assessment activities used in the chapter
material’s quality and usefulness, as well as the achievement were effective.
of learning objectives. Rate each item using this 5-point scale: 26. The chapter was effective overall.

• Strongly agree 27. The activity met the stated learning objectives.
• Agree 28. If any objectives were not met, please list them here.
• Neutral
• Disagree OTHER COMMENTS
• Strongly disagree
29. Please provide any specific comments related to any
16. The content of the chapter met my educational needs. perceptions of bias, promotion, or advertisement of
commercial products.
17. The content of the chapter satisfied my expectations.
30. Please expand on any of your above responses, and/or
18. The author presented the chapter content effectively.
provide any additional comments regarding this chapter:
19. The content of the chapter was relevant to my practice
and presented at the appropriate depth and scope.
Questions 31–33 apply to the entire learning module.
20. The content of the chapter was objective and balanced.
31. How long did it take you to read the instructional materi-
21. The content of the chapter is free of bias, promotion, and
als in this module?
advertisement of commercial products.
32. How long did it take you to read and answer the assess-
22. The content of the chapter was useful to me.
ment questions in this module?
23. The teaching and learning methods used in the chapter
33. Please provide any additional comments you may have
were effective.
regarding this module:
24. The active learning methods used in the chapter were
effective.

PSAP 2022 Book 1 • Cardiology 114 Antithrombotic Therapy in Cardiac Interventions

Cardiology III
Cardiology III Panel
Series Editors:
Cynthia A. Sanoski, Pharm.D., FCCP, BCPS
Department Chair
Associate Professor of Pharmacy Practice
Thomas Jefferson University
Philadelphia, Pennsylvania
Daniel M. Witt, Pharm.D., FCCP, BCPS
Professor and Chair
Department of Pharmacotherapy
Assistant Dean of Clinical Affairs
University of Utah College of Pharmacy
Salt Lake City, Utah
Faculty Panel Chair:
Craig J. Beavers, Pharm.D., FCCP, FACC, FAHA,
BCCP, BCPS-AQ Cardiology, CACP
Director of Cardiovascular Services
Baptist Health Paducah
Cardiovascular Clinical Pharmacist
Department of Pharmacy Services
UK Healthcare
Assistant Adjunct Professor
Department of Pharmacy Practice and Science
University of Kentucky College of Pharmacy
Paducah, Kentucky
Management of Atrial Fibrillation
Author
Amy L. Lehnert, Pharm.D., BCPS, BCCP
Cardiology Clinical Pharmacy Specialist
Roper Hospital
Charleston, South Carolina
Reviewers
Ashley Schenk, Pharm.D., BCPS, BCCP
Cardiology Clinical Pharmacist
Department of Pharmacy
UK HealthCare
Assistant Adjunct Professor
Department of Pharmacy Practice and Science
University of Kentucky College of Pharmacy
Lexington, Kentucky
Joel Peterson, Pharm.D., BCPS
Clinical Pharmacist
PGY-1 Residency Program Director
Department of Pharmacy
Hennepin Healthcare
Minneapolis, Minnesota
Non-Statin Therapy for Dyslipidemia
Authors
Nicholas W. Carris, Pharm.D., BCPS
Associate Professor
Department of Pharmacotherapeutics and Clinical
Research
USF Health Taneja College of Pharmacy
Tampa, Florida
Kevin Cowart, Pharm.D., MPH, BCACP, CDCES
Assistant Professor
Department of Pharmacotherapeu-
tics and Clinical Research
USF Health Taneja College of Pharmacy
Tampa, Florida
Reviewers
John Bucheit, Pharm.D., BCACP, CDCES
Associate Professor
Department of Pharmacotherapy and Outcomes Science
VCU School of Pharmacy
Richmond, Virginia
Gregory Castelli, Pharm.D., BCPS, BC-ADM
Clinical Pharmacist
Director, PGY1 Residency
Department of Medical Education
UPMC St. Margaret
Adjunct Assistant Professor
Department of Pharmacy and Therapeutics
University of Pittsburgh
Pittsburgh, Pennsylvania
Eugene N. Bush, Ph.D., BCPS, BCCCP
Clinical Staff Pharmacist
Vista Medical Center East
Waukegan, Illinois
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Consultancies: Anastasia Armbruster (ACC/AHA Joint Committee Clinical Practice Guidelines); Jessica Bente (ACCP); Allison
Burnett: Consultancies (Anticoagulation Forum; National Certification Board for Anticoagulation Providers; Global Strategies);
Jessie L. Dunne (Pulmonary Hypertension Association); Nancy M. Nix (Pharmacosmos); Daniel M. Riche (Novo Nordisk; Merck;
AstraZeneca); Ralph J. Riello III (AstraZeneca; Johnson & Johnson); Sara Vazquez (Anticoagulation Forum);

Stock Ownership:

Royalties: Allison Burnett (Wolters-Kluwer); Daniel M. Riche (McGraw-Hill); Honoraria (Merck); Sara Vazquez (UpToDate)

Grants: Anastasia Armbruster (ACCP); Jessica Bente (New Jersey Society of Health-System Pharmacists); Gregory Castelli
(American Board of Family Medicine); Kevin Cowart (University of South Florida Taneja College of Pharmacy); Ralph J. Riello
III (AstraZeneca)

Honoraria: Anastasia Armbruster (AstraZeneca); John Bucheit (Association of Diabetes Care & Education Specialists); Nancy M.
Nix (Coherus; Pfizer; AstraZeneca); Ralph J. Riello III (Alexion; AstraZeneca; Janssen)

Other:

Nothing to disclose: Katherine Aymond, Eugene N. Bush, Nicholas W. Carris, Stephanie Dwyer Kaluzna, Lindsey Federle, Beth-
any A. Ford, Stormi E. Gale, Jaclynne R. Gowen, Glenn Herrington, Christine Ji, Amy L. Lehnert, Nilam R. Naik, Brenda Pahl, Joel
J. Peterson, A. Joshua Roberts, Kelly M. Rudd, Ashley Schenk, Susan M. Smith, Elisabeth M. Wang, Toby C. Trujillo, Barbara Wig-
gins, Leslie Wooten, Eman El Sayed Younis

ROLE OF BPS: The Board of Pharmacy Specialties (BPS) is an autonomous division of the American Pharmacists Association (APhA).
To maintain its strict, independent standards for certification, BPS does NOT endorse or provide review information, prepara-
tory courses, or study guides for Board Certification Examinations. The Board, through its specialty councils, is responsible for
specialty examination content, administration, scoring, and all other aspects of its certification programs. BPS is totally separate
and distinct from ACCP. PSAP has been approved by BPS for use in BCPS recertification. Information about the BPS recertification
process is available online.

Questions regarding BPS specialty recertification should be directed to:

Board of Pharmacy Specialties

2215 Constitution Avenue NW
Washington, DC 20037
(202) 429-7591
Continuing Pharmacy Education
and Recertification Instructions
Continuing Pharmacy Education (CPE) Credit: The American College of Clinical Pharmacy is accredited by the
Accreditation Council for Pharmacy Education (ACPE) as a provider of CPE.

PSAP Target Audience: The target audience for PSAP 2022 Book 1 (Cardiology) is pharmacotherapy specialists and advanced
level clinical pharmacists encountering diverse cardiovascular patient populations.

Available CPE credits: Purchasers who successfully complete all posttests for PSAP 2022 Book 1 (Cardiology) can earn 21.5 contact
hours of CPE credit. The universal activity numbers are as follows: Cardiology I – 0217-0000-22-002-H01-P, 5.0 contact hours;
Cardiology II – 0217-0000-22-003-H01-P, 6.0 contact hours; Cardiology III – 0217-0000-22-004-H01-P, 5.0 contact hours; and
Cardiology IV – 0217-0000-22-005-H01-P, 5.5 contact hours. You may complete one or all available modules for credit. Tests may
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Management of Atrial Fibrillation
By Amy L. Lehnert, Pharm.D., BCPS, BCCP

Reviewed by Ashley Schenk, Pharm.D., BCPS, BCCP; and Joel Peterson, Pharm.D., BCPS

LEARNING OBJECTIVES

1. Evaluate various types of atrial fibrillation (AF), clinical features, and risk factors according to current literature and
guideline recommendations.
2. Justify the place in therapy of oral anticoagulants in AF management.
3. Evaluate differences between rate- and rhythm-control strategies in AF management.
4. Assess nonpharmacologic therapies for stroke prevention and rhythm control in AF, together with clinical considerations
surrounding anticoagulation, complications, and contraindications to these therapies.
5. Develop an appropriate treatment plan for AF management in special patient populations.

ABBREVIATIONS IN THIS CHAPTER
AAD Antiarrhythmic drug
AC Anticoagulation
ACS Acute coronary syndrome
AF Atrial fibrillation
AV Atrioventricular
CAD Coronary artery disease
CV Cardiovascular
DCCV Direct current cardioversion
DOAC Direct oral anticoagulant
HF Heart failure
HFrEF Heart failure with reduced ejection
fraction
LA Left atrium
LAA Left atrial appendage
LMWH Low-molecular-weight heparin
LV Left ventricular
MI Myocardial infarction
OAC Oral anticoagulation
PV Pulmonary vein
TEE Transesophageal echocardiogram
TIA Transient ischemic attack
UFH Unfractionated heparin
Table of other common abbreviations.
INTRODUCTION
Atrial fibrillation (AF) is the most common cardiac arrhythmia in
adults worldwide. Complications from AF are associated with sub-
stantial morbidity and mortality and pose a significant burden on
patients, physicians, and health care systems (Hindricks 2021). The
best strategies for managing AF and preventing complications have
been debated for decades, and newer technologies have evolved to
add to the arsenal of detection and treatment modalities for this dis-
ease. This chapter discusses the current pharmacologic and non-
pharmacologic management strategies for AF and how they are
implemented in practice.
Background
Currently, AF affects around 43.6 million people worldwide and more
than 3 million Americans (Hindricks 2021; Chung 2020). As patient
life expectancy increases and AF detection methods improve, these
numbers are expected to double over the next 25 years (January
2014). The prevalence of AF increases with age, from 0.5% in indi-
viduals 50–59 years of age to greater than 33% in those older than
80 (Hindricks 2021). Complications of AF include frequent hospital-
izations, thromboembolic events, hemodynamic abnormalities, and
decreased patient quality of life. In the United States, patients with
AF are hospitalized twice as often as patients without AF and are 3
times more likely to have several hospital admissions. Stroke risk is
increased by 5-fold in patients with AF, with AF-related stroke typically
more severe than non–AF-related stroke. Finally, a 3-fold increased
risk of heart failure (HF) and 2-fold increased risk of both dementia
and mortality have been associated with AF (January 2014).

PSAP 2022 Book 1 • Cardiology 121 Management of Atrial Fibrillation

Clinical Features
Atrial fibrillation is caused by a lack of organized atrial depo-
larization, leading to chaotic and disorganized atrial activity.
Characteristic ECG findings include irregular R-R intervals,
an absence of distinct repeating P waves, and irregular
atrial activity. Clinical symptoms of AF vary, but 50%–87%
of patients are initially asymptomatic. Other symptoms may
BASELINE KNOWLEDGE STATEMENTS
Readers of this chapter are presumed to be familiar
with the following:
• General knowledge of the pathophysiology that
leads to atrial fibrillation (AF)
• Baseline familiarity with ECGs
• General drug knowledge of the various oral and
intravenous pharmacologic agents used to treat AF
• Familiarity with guideline-recommended risk
assessment modalities and a general understand-
ing of the clinical sequelae of AF, namely stroke
and systemic embolism
Table of common laboratory reference values
ADDITIONAL READINGS
The following free resources have additional back-
ground information on this topic:
• Hindricks G, Potpara T, Dagres N, et al. 2020 ESC
guidelines for the diagnosis and management of
atrial fibrillation developed in collaboration with the
European Association for Cardio-Thoracic Surgery
(EACTS). Eur Heart J 2021;42:373-498.
• January CT, Wann LS, Calkins H, et al. 2019 AHA/
ACC/HRS focused update of the 2014 AHA/ACC/
HRS guideline for the management of patients with
atrial fibrillation: a report of the American College
of Cardiology/American Heart Association Task
Force on Clinical Practice Guidelines and the Heart
Rhythm Society in Collaboration with the Society
of Thoracic Surgeons [published correction
appears in Circulation 2019;140:e285]. Circulation
2019;140:e125-e151.
• Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/
EHRA/ECAS/APHRS/SOLAECE expert consensus
statement on catheter and surgical ablation of
atrial fibrillation. Heart Rhythm 2017;14:e275-e444.
• January CT, Wann LS, Alpert JS, et al. 2014 AHA/
ACC/HRS guideline for the management of patients
with atrial fibrillation: a report of the American Col-
lege of Cardiology/American Heart Association
Task Force on Practice Guidelines and the Heart
Rhythm Society [published correction appears in J
Am Coll Cardiol 2014;64:2305-7]. J Am Coll Cardiol
2014;64:e1-e76.
PSAP 2022 Book 1 • Cardiology
include fatigue, palpitations, dyspnea, hypotension, syncope,
or HF, with fatigue being the most common. Hemodynamic
disturbances from AF may be caused by abnormal ventricu-
lar conduction rates (either too fast or too slow), loss of atrial
contraction (i.e., loss of atrial “kick”), inconsistent ventricu-
lar filling time, and increased adrenergic tone (January 2014).
DEFINITIONS
Table 1 summarizes the different types of AF that can be
described on the basis of presentation, duration, and sponta-
neous termination of episodes. Over time, AF episodes often
increase in duration and frequency and in patients experienc-
ing more than one type of AF – for example, with paroxys-
mal and persistent AF, the more common type should be used
for classification (January 2014). Implantable cardiac elec-
tronic devices (i.e., implantable loop recorders, pacemakers,
defibrillators) offer enhanced reporting capabilities of AF epi-
sode duration, rate, and frequency; this collection of informa-
tion is often called the “AF burden.”
Atrial fibrillation can also be described with respect to
the presence of certain types of valvular disease and valvu-
lar intervention. Differentiating between “valvular” and “non-
valvular” AF has been confusing for clinicians for many years
because of varying definitions between guidelines and clinical
trials. The 2019 American Heart Association/American College
of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) focused
update of the 2014 AHA/ACC/HRS guideline for the treatment
of patients with AF clarified this terminology (see Table 1). Sup-
port for this distinction in terminology stems from the direct
oral anticoagulant (DOAC) AF clinical trials, in which about 20%
of patients were enrolled with various valvular defects, includ-
ing mild mitral stenosis, mitral regurgitation, aortic stenosis,
aortic regurgitation, and tricuspid regurgitation, together with
some patients with valve repair, valvuloplasty, and biopros-
thetic valves. Meta-analyses suggest that among patients
with AF and these valvular disorders, DOACs better reduce
stroke and systemic embolism than warfarin, but bleeding risk
varies among the different DOACs (January 2019).
MECHANISMS
Structural and/or electrophysiologic cardiac abnormalities
can alter atrial tissue, promoting abnormal impulse forma-
tion and/or propagation, causing AF. These abnormalities may
be precipitated by a wide variety of pathophysiologic mecha-
nisms, many of which are incompletely or poorly understood.
Ultimately, AF reflects a final common phenotype for a complex
interplay of triggers, substrates, and physiologic processes,
often making it difficult for clinicians to manage (January
2014). Figure 1 summarizes potential AF mechanisms.
Pathophysiology
For AF to occur, an initiation trigger and maintenance sub-
strate are required. Many hypotheses have surrounded the
122 Management of Atrial Fibrillation
 Table 1. Classification of AF

Term Definition

Paroxysmal AF that terminates spontaneously or with intervention within 7 days of onset

Episodes may recur with variable frequency

Persistent Continuous AF that is sustained beyond 7 days, including episodes terminated by cardioversion (drugs or
electrical cardioversion) at or beyond 7 days

Longstanding Continuous AF beyond 12 mo when the patient and physician have decided to adopt a rhythm-control
persistent strategy

Permanent AF that is accepted by the patient and physician, and no further attempts to restore/maintain sinus rhythm
will be made. Acceptance of AF represents a therapeutic attitude on the part of the patient and clinician
rather than an inherent pathophysiologic attribute of AF, and the term should not be used in the context of
a rhythm-control strategy with AAD therapy or AF ablation. Acceptance of AF may change as symptoms,
efficacy of interventions, and patient/clinician preferences evolve; should a rhythm-control strategy be
adopted, AF will be reclassified as “longstanding persistent AF”

Nonvalvular AF AF in the absence of moderate to severe mitral stenosis or a mechanical heart valve. Nonvalvular AF does not
imply the absence of valvular heart disease

Valvular AF AF in the setting of moderate to severe mitral stenosis or a mechanical heart valve

Terminology That Should Be Abandoned

Lone AF A historical descriptor that has been variably applied to younger individuals without clinical or
echocardiographic evidence of cardiopulmonary disease, HTN, or diabetesa

Chronic AF Has variable definitions and should not be used to describe populations of patients with AF

a
Increasing knowledge about the pathophysiology of AF shows that in every patient, a cause is present. Hence, this term is potentially
confusing and should be abandoned.
AAD = antiarrhythmic drug; AF = atrial fibrillation; HTN = hypertension.
Information from: Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation
developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2021;42:373-498;
January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the
management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task
Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration with the Society of Thoracic Surgeons
[published correction appears in Circulation 2019;140:e285]. Circulation 2019;140:e125-e151; January CT, Wann LS, Alpert JS, et al.
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society [published correction
appears in J Am Coll Cardiol 2014;64:2305-7]. J Am Coll Cardiol 2014;64:e1-e76.

pathophysiology of both AF initiation and maintenance; how-
ever, for most patients, this relationship is likely multifactorial
and extremely complex (January 2014).
Atrial fibrillation is typically triggered by rapidly firing ecto-
pic focal discharges, which are abnormal electrical impulses
originating from atrial tissue. These impulses lead to disorga-
nized atrial electrical activity, with subsequent lack of cohe-
sive atrial depolarization and mechanical contraction. The
impulses most commonly originate from the left atrial (LA)
myocardial sleeves extending into the pulmonary veins (PVs),
making this area one of the primary targets in catheter ablation
procedures. Another potential trigger for AF is abnormal cal-
cium handling in which calcium “leaks” from the sarcoplasmic
reticulum during diastole, causing delayed afterdepolarizations
(January 2014). Proposed theories for AF maintenance include
reentrant wavelets caused by heterogeneous conduction and
refractoriness, several rapidly firing foci in response to cardiac
ganglionic plexi activity, and several rotors or spiral wave reen-
trant circuits. Several AF therapies have been developed on the
basis of these proposed mechanisms, namely surgical maze
and catheter ablation procedures (January 2014).
Risk Factors
Like many chronic conditions, AF is highly associated with
many common disease states, underscoring the importance
of lifestyle modifications as a key aspect of AF prevention
and treatment. Box 1 summarizes the many nonmodifiable
and modifiable risk factors that have been recognized in the
development of AF. Some of these conditions can lead to pro-
gressive increases in atrial enlargement, LA fibrosis, auto-
nomic dysfunction, and left ventricular (LV) hypertrophy,
further increasing susceptibility to AF (Ponamgi 2021).

PSAP 2022 Book 1 • Cardiology 123 Management of Atrial Fibrillation

 Inflammation

Oxidative Stress Atrial Electrical

Atrial Structural
Abnormalities:
Abnormalities:
↑ Heterogeneity
Fibrosis
↓ Conduction
Dilation
↓ AP duration/refractoriness
Ischemia
↑ Automaticity
Infiltration
Abnormal intracellular Ca++
Hypertrophy
handling

AF

Genetic RAAS activation

Variants:
Autonomic
Channelopathy nervous system
Cardiomyopathy activation

Extracardiac Risk
Factors:

HTN
Obesity
Sleep apnea
Hyperthyroidism
Alcohol/drugs

Figure 1. Mechanisms of atrial fibrillation.

AF = atrial fibrillation; AP = action potential; Ca++ = ionized calcium; HTN = hypertension; RAAS = renin-angiotensin-aldosterone system.
Information from: January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial
fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the
Heart Rhythm Society [published correction appears in J Am Coll Cardiol 2014;64:2305-7]. J Am Coll Cardiol 2014;64:e1-e76.

Box 1. Potential Modifiable and Nonmodifiable Risk Factors for AF

Nonreversible Risk Factors • Chronic kidney disease
• AF risk genotypes • Chronic obstructive pulmonary disease
• Family history of AF • Coronary artery disease
• Height • Diabetes
• Older age • Heart failure/cardiomyopathy
Reversible Risk Factors • Hypertension
• Acute illness/surgery • Hyperthyroidism
• Alcohol/drugs/smoking • Inflammatory diseases
• Cardiac surgery • Obesity
• Chronic endurance training • Sleep apnea
• Valvular heart disease
AF = atrial fibrillation.
Information from: Ponamgi SP, Siontis KC, Rushlow DR, et al. Screening and management of atrial fibrillation in primary care. BMJ
2021;373:n379.

PSAP 2022 Book 1 • Cardiology 124 Management of Atrial Fibrillation

DIAGNOSTIC CRITERIA
Because most AF is asymptomatic, it is ultimately diagnosed
by ECG, with episodes lasting at least 30 seconds indicative
of clinical AF (Hindricks 2021; January 2014). Physical exam-
ination findings may include an irregular pulse, irregular jugu-
lar venous pulsations, or variations in the first or fourth heart
sound. Initial diagnosis of AF involves characterizing pattern
type (i.e., paroxysmal, persistent, longstanding persistent,
permanent), identifying potential causes, defining associ-
ated comorbidities, and assessing stroke risk. In addition, an
echocardiogram should be performed to identify underlying
structural heart disease and assess cardiac function. Serum
electrolytes and CBC, together with thyroid, renal, and hepatic
function testing, should also be assessed (January 2014).
CLINICAL MANAGEMENT OF AF
Once diagnosed, ideal AF management should involve a coor-
dinated multidisciplinary team approach to deliver individu-
alized patient care. Goals of care should center on reducing
stroke risk, improving symptoms, and treating comorbidi-
ties while recognizing that patient treatment plans are sub-
ject to change over time with development of new symptoms,
disease progression, and introduction of new treatment
modalities. The 2020 European Society of Cardiology (ESC)
guidelines describe this approach with the “Atrial fibrillation
Better Care” (ABC) holistic pathway (“A” Anticoagulation/
Avoid stroke; “B” Better symptom management; “C” Cardio-
vascular and Comorbidity optimization) (Hindricks 2021). In
several studies, implementation of the ABC pathway has sig-
nificantly reduced the risk of all-cause death, the composite
outcome of stroke/major bleeding/cardiovascular (CV) death
and first hospitalization, CV event rates, and health-related
costs compared with usual care (Pastori 2019a, 2019b; Yoon
2019; Proietti 2018; Lip 2017).
Stroke Prevention
Stroke is one of the most devastating potential complica-
tions of AF, with the left atrial appendage (LAA) being one
of the most common sites of thrombus formation and sub-
sequent thromboembolization. Compared with patients in
normal sinus rhythm, the risk of stroke is increased by 5-fold
in nonvalvular AF and 20-fold in AF in the setting of mitral
stenosis. Atrial fibrillation–related stroke is also associated
with greater severity of disability, risk of recurrent stroke,
and mortality than non–AF-related stroke (January 2014;
Lin 1996).
Risk Assessment
Although oral anticoagulation (OAC) is one of the cornerstones
of therapy in successfully reducing the risk of AF-related
stroke, it is also associated with an increased risk of bleeding.
In addition, although AF increases stroke risk, this risk is not
homogeneous and may vary significantly between patients
depending on differences in risk factors and comorbidities.
PSAP 2022 Book 1 • Cardiology
Thus, risk assessment tools have been developed and vali-
dated to help stratify both thrombotic and bleeding risk.
The CHA 2DS2-VASc risk scoring system is recommended
by the current guidelines to estimate annual stroke risk
and guide decisions surrounding anticoagulant therapy
(Table 2). Although the CHA 2DS2-VASc performs only mod-
estly in predicting stroke in high-risk patients, it consistently
Table 2. CHA 2DS2-VASc Scoring System
Step 1. Identify qualifying criteria
Point Value Criteria
1 C – Congestive HF/LV dysfunction
1 H – HTNa
2 A 2 – Age ≥ 75
1 D – Diabetesb
2 S2 – Stroke/TIA/TEc
1 V – Vascular diseased
1 A – Age 65–74
1 Sc – Female sex
Step 2. Determine annual stroke risk
Point Total Adjusted Stroke Rate (% per year)
1 1.3
2 2.2
3 3.2
4 4.0
5 6.7
6 9.8
7 9.6
8 6.7
9 15.2
a
Resting blood pressure > 140/90 mm Hg on at least two occa-
sions or current antihypertensive pharmacologic treatment.
b
Fasting glucose > 125 mg/dL or treatment with oral
hypoglycemic agent and/or insulin.
c
Includes any history of cerebral ischemia.
d
Prior MI, PAD, or aortic plaque.
HF = heart failure; LV = left ventricle; MI = myocardial
infarction; PAD = peripheral arterial disease;
TE = thromboembolism; TIA = transient ischemic attack.
Information from: January CT, Wann LS, Alpert JS, et al.
2014 AHA/ACC/HRS guideline for the management of
patients with atrial fibrillation: a report of the American
College of Cardiology/American Heart Association Task
Force on Practice Guidelines and the Heart Rhythm
Society [published correction appears in J Am Coll Cardiol
2014;64:2305-7]. J Am Coll Cardiol 2014;64:e1-e76.
125 Management of Atrial Fibrillation
identifies and differentiates patients at low to moderate
risk, which significantly helps in determining which patients
should receive anticoagulant therapy. The CHA 2DS2-VASc
score component of female sex has elicited many ques-
tions from practicing clinicians and may be more easily
described as an age-dependent stroke risk modifier than
a risk factor (Hindricks 2021). For example, observational
data show that women with no other stroke risk factors
(CHA 2DS2-VASc score 1) have a low stroke risk, similar to men
with a CHA 2DS2-VASc score of 0 (Nielsen 2020). However, in
the presence of more than one non-sex stroke risk factor,
women with AF consistently have a higher stroke risk than
men (Marzona 2018). Thus, not considering the sex compo-
nent in the CHA 2DS2-VASc scoring tool would significantly
underestimate stroke risk in women with AF.
When initiating anticoagulant therapy for AF, the poten-
tial risk of bleeding should also be assessed. The HAS-BLED
score is recommended by the current guidelines to help iden-
tify patients who are at increased risk of bleeding and may
require closer monitoring (Table 3). The HAS-BLED score
Table 3. HAS-BLED Scoring System
Point
Value Criteria
1 H – HTN (uncontrolled, SBP > 160 mm Hg)
1a A – Abnormal renal and/or hepatic functionb
1 S – Stroke (ischemic or hemorrhagicc)
1 B – Bleeding history or predispositiond
1 L – Labile INRe (TTR < 60%)
1 E – Elderly (age > 65 or extreme frailty)
1a D – Drugsf or excessive alcohol consumption
Max possible score = 9
Bleeding risk: 0 (low); 1 or 2 (moderate); ≥ 3 (high)
a
One point for each.
b
Dialysis, transplantation, SCr > 2.26 mg/dL, cirrhosis,
bilirubin > 2 × upper limit of normal; AST/ALT/ALP > 3 ×
upper limit of normal.
c
Hemorrhagic stroke would also score 1 point under the “B”
criterion.
d
Previous major hemorrhage, anemia, or severe
thrombocytopenia.
e
Only relevant if patient is receiving warfarin.
f
Concomitant use of antiplatelet or NSAID.
SBP = systolic blood pressure; TTR = time in therapeutic
range.
Information from: Hindricks G, Potpara T, Dagres N, et al.
2020 ESC guidelines for the diagnosis and management of
atrial fibrillation developed in collaboration with the
European Association for Cardio-Thoracic Surgery
(EACTS). Eur Heart J 2021;42:373-498.
PSAP 2022 Book 1 • Cardiology
includes an assessment of both modifiable and nonmodifi-
able risk factors, with a score of 3 or greater indicating poten-
tially “high” bleeding risk. Several of the bleeding risk factors
included in the HAS-BLED scoring tool are also described
in the CHA 2DS2-VASc scoring tool as stroke risk factors. As
such, a high bleeding risk score should not necessarily lead
to withholding anticoagulation because these patients are
also likely to have a higher risk of stroke, and the net clini-
cal benefit with continued anticoagulation is greater. Rather,
a high bleeding risk score should prompt focus on correction
of modifiable bleeding risk factors and closer monitoring of
nonmodifiable risk factors. Of note, a history of falls is not
included in the HAS-BLED score because it is not an indepen-
dent predictor of bleeding in patients receiving anticoagula-
tion (Hindricks 2021; January 2014).
Anticoagulant Therapy
Oral anticoagulation therapy is the first-line treatment for
stroke prevention in AF and includes the DOACs apixaban,
rivaroxaban, edoxaban, and dabigatran, together with warfa-
rin. Anticoagulation therapy helps prevent strokes and sys-
temic emboli among patients in AF, largely by reducing the
formation of thrombi in the LA or LAA. However, because anti-
coagulation increases the risk of bleeding, its benefits must
be weighed against the risk of harm. Current guidelines rec-
ommend use of the CHA 2DS2-VASc score to assess stroke risk,
with anticoagulation initiation if CHA 2DS2-VASc is 1 or greater
in men or 2 or greater in women (IIb, C-LD). The recommen-
dation for anticoagulation strengthens to I-A if the CHA 2DS2-
VASc score is 2 or greater in men or 3 or greater in women.
Use of aspirin in low-risk patients is no longer recommended
in the current guidelines (January 2019, 2014). Because the
DOACs were at least noninferior and, in some cases, supe-
rior to warfarin in preventing stroke and systemic embolism
and were associated with lower rates of intracranial bleed-
ing in AF clinical trials, the current guidelines recommend a
DOAC over warfarin in eligible patients for stroke prevention
in AF. Patients who have moderate to severe mitral stenosis
or a mechanical heart valve should not receive a DOAC and
should instead receive warfarin. Appropriate end-organ func-
tion, relevant drug-drug and drug-diet interactions, patient
adherence, and accessibility should all be assessed when
initiating OAC treatment for AF, with reassessment at peri-
odic intervals throughout therapy. Table 4 summarizes guide-
line recommendations for risk-based antithrombotic therapy.
Table 5 summarizes oral anticoagulation used for stroke pre-
vention in AF.
Symptom Management
For newly diagnosed AF, in concert with stroke risk assess-
ment and choice of anticoagulant, a decision should be
made regarding whether a rate- or rhythm-control strategy
will be pursued. A rate-control strategy usually involves
the use  of pharmacologic agents that slow conduction
126 Management of Atrial Fibrillation
 Table 4. Summary of Recommendations for Risk-Based Antithrombotic Therapy

COR LOE Recommendation

I C AC therapy should be based on shared decision-making, discussion of risk of stroke and bleeding, and
patient’s values and preferences

I B AC therapy should be selected on the basis of thromboembolism risk

I B CHA 2DS2-VASc score is recommended to assess stroke risk (exception: patients with moderate to severe
mitral stenosis or a mechanical heart valve)

IIa B For patients with CHA 2DS2-VASc score of 0 in men or 1 in women, it is reasonable to omit AC therapy

IIb C-LD For patients with CHA 2DS2-VASc score of 1 in men or 2 in women, it is reasonable to consider AC therapy

I A For patients with CHA 2DS2-VASc score ≥ 2 in men or ≥ 3 in women, AC therapy is recommended. Options
include:
• Warfarin (LOE: A)
• Dabigatran (LOE: B)
• Rivaroxaban (LOE: B)
• Apixaban (LOE: B)
• Edoxaban (LOE: B-R)

I A DOACs are recommended over warfarin in DOAC-eligiblea patients with AF

I C DOACs are recommended in DOAC-eligiblea patients if unable to maintain therapeutic INR on warfarin

I B For patients with AF who have mechanical heart valves, warfarin is recommended. Target INR intensity
should be based on type and location of valvular prosthesis

I A With warfarin, determine INR at least weekly during initiation, and monthly when stable

I B-NR With DOACs, renal and hepatic function should be evaluated before initiation and at least annually

I C Need for and choice of AC therapy should be reevaluated periodically to reassess stroke and bleeding risks

I C For patients with atrial flutter, AC therapy is recommended according to the same risk profile as used for AF

IIb B-R For patients with CHA 2DS2-VASc score ≥ 2 in men or ≥ 3 in women and who have renal dysfunction (as
defined in the text that follows), treatment with reduced doses of DOACs can be considered:
• Apixaban (SCr ≥ 1.5 mg/dL)
• Dabigatran (CrCl 15–30 mL/min)
• Rivaroxaban (CrCl ≤ 50 mL/min)
• Edoxaban (CrCl 15–50 mL/min)

IIb B-NR For patients with CHA 2DS2-VASc score ≥ 2 in men or ≥ 3 in women and who have end-stage CKD (CrCl <
15 mL/min) or are receiving dialysis, it may be reasonable to prescribe warfarin (INR 2–3) or apixaban

III: No C-EO In patients with AF and end-stage CKD or receiving dialysis, neither dabigatran, rivaroxaban, nor edoxaban
benefit is recommended because of lack of evidence that benefit exceeds risk

III: Harm B-R Dabigatran should not be used in patients with AF and a mechanical heart valve

a
Exclusion criteria for DOAC: moderate to severe mitral stenosis or a mechanical heart valve.
AC = anticoagulation; CKD = chronic kidney disease; COR = classification of recommendation; DOAC = direct oral anticoagulant;
LOE = level of evidence.
Information from: January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline
for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association
Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration with the Society of Thoracic Surgeons
[published correction appears in Circulation 2019;140:e285]. Circulation 2019;140:e125-e151; January CT, Wann LS, Alpert JS, et al.
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society [published correction
appears in J Am Coll Cardiol 2014;64:2305-7]. J Am Coll Cardiol 2014;64:e1-e76.

PSAP 2022 Book 1 • Cardiology 127 Management of Atrial Fibrillation

 Table 5. Oral Anticoagulants Used in Stroke Prevention for AF

Characteristic Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban

MOA Vitamin K antagonist Direct thrombin Factor Xa inhibition Factor Xa inhibition Factor Xa
inhibitor inhibition
Standard 5 mg daily (avoid loading 150 mg BID 20 mg daily with 5 mg BID 60 mg daily
dosing in AF doses), adjust to evening meal
achieve INR 2–3
Renal Consider starting doses 75 mg BID 15 mg daily 2.5 mg BID 30 mg daily
impairment of ≤ 2.5 mg daily if: (CrCl 15–30 (CrCl 15–50 mL/ If at least two of three (CrCl 15–50 mL/
dosing for AF — Age ≥ 65 mL/min) min) criteria: min)a
— Weight ≤ 70 kg — Age ≥ 80
— Poor nutritional status — Weight ≤ 60 kg
— Significant hepatic — SCr ≥ 1.5 mg/dL
Hepatic disease No adjustment Child-Pugh class B: Child-Pugh class B: Child-Pugh class
impairment — bleeding risk Avoid or use with Avoid or use with B: Avoid or use
dosing for AF — Known warfarin caution caution with caution
sensitivity Child-Pugh class C: Child-Pugh class C: Child-Pugh class
— Decompensated HF Avoid use Avoid use C: Avoid use
Time to peak 5–7 days 1–3 hr 2–4 hr 1–2 hr 1–2 hr
Half-life (hr) ~40 8–15 7–11 12 10–14
Excretion Hepatic, primarily 80% renal 66% renal (one-half 25% renal, 75% fecal 50% renal; also
through CYP2C9 as inactive form) bile, feces
Eliminated or CYP2C9, CYP1A2, P-gp P-gp P-gp P-gp
metabolized by CYP3A4, CYP2C19 CYP3A4 CYP3A4
P-gp and/or Consider higher starting Avoid use Avoid use Avoid use Avoid use
strong CYP3A4 dose, monitor INR
INDUCERSb closely
P-gp N/A If CrCl < 50 mL/ N/A N/A 30 mg daily
INHIBITORSc min, avoid use
or reduce dose
Dual P-gp and Consider lower starting N/A — Avoid use — Decrease dose by 50% N/A
strong CYP3A4 dose, monitor INR — No dose change — Avoid use if already
INHIBITORSd closely needed with on 2.5 mg BID
concomitant — No dose change
clarithromycin needed with
concomitant
clarithromycin
Dual P-gp Monitor INR closely N/A If CrCl < 80 mL/min, Use with caution N/A
and moderate avoid use unless
CYP3A4 benefit justifies
INHIBITORSe potential risk
Reversal Vitamin K, PCC, or FFP Idarucizumab Andexanet alfa Andexanet alfa Andexanet alfag
strategy PCC f PCC f PCC f

a
Avoid use in patients with CrCl > 95 mL/min.
b
For example, barbiturates, carbamazepine, dexamethasone, phenytoin, rifampin, St. John’s wort.
c
For example, amiodarone, carvedilol, diltiazem, dronedarone, macrolides, oral itraconazole or ketoconazole, quinidine, verapamil.
d
For example, clarithromycin, oral itraconazole or ketoconazole, cobicistat, indinavir, ritonavir, saquinavir, telaprevir.
e
For example, cyclosporine, diltiazem, dronedarone, erythromycin, verapamil.
f
Non–FDA-approved indication for PCC, but is recommended by guidelines as an option for reversal when andexanet alfa is unavailable.
g
Non–FDA-approved indication for andexanet alfa, but is recommended by guidelines as an option for anticoagulation reversal.
BID = twice daily; FFP = fresh frozen plasma; MOA = mechanism of action; N/A = not applicable; PCC = prothrombin complex
concentrate; P-gp = P-glycoprotein.
Information from: Lexi-Drugs. Lexicomp. Wolters Kluwer Health.

PSAP 2022 Book 1 • Cardiology 128 Management of Atrial Fibrillation

across the  atrioventricular (AV) node, slowing the ventricu-
lar response. A rhythm-control strategy may use electrical or
pharmacologic cardioversion, percutaneous catheter abla-
tion, or surgical ablation.
Historically, the choice between rate and rhythm control
has largely been determined on the basis of patient-specific
factors. Despite several studies, differences in rates of seri-
ous morbidity or mortality have not been shown between the
two approaches at the time of current guideline publication
(Hindricks 2021; January 2019, 2014). In addition, although it
might seem intuitive that patients would feel better if main-
tained in normal sinus rhythm than in AF, this is not always
true. In some instances, however, rhythm control can be
considered a preferred strategy. Symptomatic patients or
those with presumed tachycardia-induced cardiomyopathy
should be considered for rhythm control in order to prevent
the irreversible structural and electrical remodeling that can
occur with longstanding persistent AF. For similar reasons, a
rhythm-control approach may also be preferable in younger
patients (younger than 65) because rate control alone is
likely to result in progression to longstanding persistent AF
(Ponamgi 2021). In asymptomatic patients with longstanding
persistent AF or in those for whom a rhythm-control strategy
has failed or who cannot tolerate a rhythm-control strategy, a
rate-control approach is reasonable.
Recently published, the EAST-AFNET 4 trial provides con-
temporary evidence in support of an early rhythm-control
strategy. The authors randomized 2789 patients with early
AF (defined as AF diagnosed within 12 months before enroll-
ment, with a median time since diagnosis of 36 days) and at
high risk of CV complications to either early rhythm control
with antiarrhythmic drugs (AADs) or ablation or usual care,
which limited rhythm control to patients unable to tolerate
rate control. The trial was terminated early for efficacy after
a median of 5.1 years of follow-up because patients in the
rhythm-control group had a significantly lower incidence of
the composite clinical end point, including CV death, stroke,
or hospital admission for HF or acute coronary syndrome
(ACS), than patients in the rate-control group (3.9 vs. 5.0
per 100 person-years; HR 0.79; 95% CI, 0.66–0.94; p=0.005)
(Kirchhof 2020).
Figure 2 outlines a general approach to the management
of new-onset AF. Unstable patients with signs of hemody-
namic instability, severe symptoms, or decompensated HF
should be emergently treated with electrical cardioversion,
followed by therapeutic anticoagulation for at least 4 weeks.
In stable patients, a strategy of rate or rhythm control should
be determined (see Figure 2).
Rate Control
Slowing the ventricular response to AF is important for
many reasons – namely, reducing symptoms and increas-
ing quality of life together with reducing the potential for
tachycardia-induced cardiomyopathies. Table 6 summarizes
PSAP 2022 Book 1 • Cardiology
guideline recommendations for ventricular rate control.
Intensity of initial rate-control therapy depends on the clin-
ical scenario, where intravenous medications are used ini-
tially for symptomatic patients with a rapid ventricular
response (e.g., greater than 120 beats/minute) and oral
medications can be used upfront for those with few to no
symptoms. Once initial rate control is achieved with an intra-
venous agent, patients can be changed to oral rate-control
therapy.
Choice of initial rate-control agent also depends on the
presence of patient comorbidities, as outlined in Figure 3,
and adverse effects. In general, β-blockers or non-dihydropy-
ridine calcium channel blockers are considered first-line ther-
apy for rate control, followed by amiodarone and digoxin as
second line. β-Blockers are the most commonly used agents,
largely because of better rate control; however, calcium chan-
nel blockers can provide reasonable rate control and better
improve AF-related symptoms than β-blockers (Hindricks
2021). Combination therapy of β-blockers and calcium chan-
nel blockers can be considered in patients for whom ade-
quate ventricular rate control cannot be achieved with a
single agent; however, both heart rate and blood pressure
should be monitored closely. Both β-blockers and calcium
channel blockers should be avoided in the setting of decom-
pensated HF and in hemodynamically unstable patients (Hin-
dricks 2021; January 2014).
Digoxin is considered a second-line agent for rate control
for several reasons. Digoxin has a slow onset of action (greater
than 1 hour with intravenous administration), and effects do
not peak until 6 hours after initial administration, making it
ineffective for acute rate control. In addition, digoxin is inef-
fective in patients with increased sympathetic tone, making it
ineffective in controlling ventricular rate during exercise (Hin-
dricks 2021; January 2014). Observational studies have also
associated long-term digoxin therapy with increased mortal-
ity in patients with AF; however, these findings may be sub-
ject to selection bias because digoxin has historically been
prescribed most commonly to patients with more severe
disease. Lower digoxin doses with serum concentrations of
0.9  ng/mL or less have been associated with a better prog-
nosis in patients with AF (Hindricks 2021). Recently, in the
RATE-AF trial, 160 patients with permanent AF and symp-
toms of HF were randomized to either digoxin or bisoprolol.
Although the primary end point of patient-reported quality
of life did not differ, digoxin showed significant improvement
in other secondary quality-of-life measures at 12 months,
greater reductions in New York Heart Association (NYHA)
class and N-terminal pro–brain natriuretic peptide, and fewer
adverse events than bisoprolol (Kotecha 2020). Of note, only
19% of patients had an LVEF less than 50% at baseline in the
RATE-AF trial. Although the clinical significance of this trial
has not yet been determined, it provides much-needed data in
the area of permanent AF treatment and assessed clinically
important outcomes.
129 Management of Atrial Fibrillation
 New-Onset AF

UNSTABLE STABLE

Emergency DCCV Rhythm Control Rate Control

Followed by ≥ 4 wk AC,
with long-term AC according
to stroke/bleeding risk
Duration < 48 hr Duration ≥ 48 hr or unknown β-Blocker
CCB
Digoxin
Amiodaronee
Initiate UFH, Delayed cardioversion: (see Figure 3)
LMWH, or DOACa • AC × 3 wk, then DCCV WITH
• AC ≥ 4 wk post DCCV
AC according
OR to stroke risk
Electrical Pharmacologic
cardioversion: Early cardioversion:
cardioversion
• Initiate UFH, LMWH, or
(DCCV)b Amiodarone DOAC
Dofetilide • TEE to r/o LA thrombus
Ibutilidec – If no LA thrombus → try
Flecainided cardioversion
Propafenoned – If LA thrombus →
continue AC ≥ 4 wk,
then repeat TEE

Long-term AC according to stroke/bleeding risk profile

Figure 2. Approach to management of new-onset atrial fibrillation.

a
Can consider no anticoagulation in patients with a CHA 2DS2-VASc score of 0 in men or 1 in women.
b
Patients should not be sedated for synchronized DCCV if they have eaten a meal within 12 hr because of the risk of aspiration.
c
Ibutilide can be administered to patients with left ventricular ejection fraction (LVEF) 30%–40% but should be avoided in patients
with LVEF < 30% because of the risk of ventricular proarrhythmia.
d
Avoid use of flecainide or propafenone in structural heart disease (coronary artery disease, LVEF < 40%).
e
When used for rate control, amiodarone may result in pharmacologic cardioversion; consider LA thrombus r/o, and ensure
therapeutic anticoagulation, if possible, before amiodarone initiation.
CCB = calcium channel blocker; DCCV = direct current cardioversion; DOAC = direct oral anticoagulant; HF = heart failure; LA = left
atrium; LMWH = low-molecular-weight heparin; r/o = rule out; TEE = transesophageal echocardiogram; UFH = unfractionated heparin.
Information from: January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline
for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association
Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration with the Society of Thoracic Surgeons
[published correction appears in Circulation 2019;140:e285]. Circulation 2019;140:e125-e151; January CT, Wann LS, Alpert JS, et al.
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society [published correction
appears in J Am Coll Cardiol 2014;64:2305-7]. J Am Coll Cardiol 2014;64:e1-e76.

Amiodarone is a last-line option when ventricular rate can-
not be controlled by other therapies or combination therapies,
or in critically ill patients with severely impaired LV systolic
function. Amiodarone has several potential toxicities and
drug interactions together with a high monitoring burden that
limit its use long term in a ventricular rate-control strategy.
In addition, although initial use may be intended for rate con-
trol, amiodarone may result in unintentional pharmacologic
cardioversion. Careful consideration should be given to eval-
uating the duration of AF, presence of LA thrombus, and use
of therapeutic anticoagulation when initiating amiodarone
therapy. Table 7 summarizes the dosing, monitoring, and

PSAP 2022 Book 1 • Cardiology 130 Management of Atrial Fibrillation

 Table 6. Summary of Recommendations for Ventricular Rate Control

COR LOE Recommendation

I B Control ventricular rate using a β-blocker or non-DHP CCB for paroxysmal, persistent, or permanent AF

I B IV β-blockers or non-DHP CCBs are recommended to slow ventricular rate in the acute setting in patients
without preexcitation. In hemodynamically unstable patients, electrical cardioversion is indicated

1 C For AF, assess HR control during exertion and adjust pharmacologic treatment as necessary

IIa B An HR control (resting HR < 80 beats/min) strategy is reasonable for symptomatic management of AF

IIa B IV amiodarone can be useful for rate control in critically ill patients without preexcitation

IIa B AV nodal ablation with permanent ventricular pacing is reasonable when pharmacologic therapy is
inadequate and rhythm control is not achievable

IIb B A lenient rate-control strategy (resting HR < 110 beats/min) may be reasonable when patients remain
asymptomatic and LV systolic function is preserved

IIb C Oral amiodarone may be useful for ventricular rate control when other measures are unsuccessful or
contraindicated

III: Harm C AV nodal ablation should not be performed without prior attempts to achieve rate control with medications

III: Harm C Non-DHP CCBs should not be used in decompensated HF

III: Harm B With preexcitation and AF, digoxin, non-DHP CCBs, or amiodarone should not be administered

III: Harm B Dronedarone should not be used to control ventricular rate with permanent AF

AF = atrial fibrillation; AV = atrioventricular; CCB = calcium channel blocker; DDI = drug-drug interaction; DHP = dihydropyridine; HF =
heart failure; HR = heart rate; IV = intravenous(ly).
Information from: January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial
fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the
Heart Rhythm Society [published correction appears in J Am Coll Cardiol 2014;64:2305-7]. J Am Coll Cardiol 2014;64:e1-e76.

clinical considerations of various pharmacologic ventricular
rate-control therapies.
Ultimately, as last line, a nonpharmacologic strategy of AV
nodal ablation can be considered in patients for whom prior
attempts with rate-control therapy have failed and in whom
rhythm control cannot be achieved. However, because AV
nodal ablation results in pacemaker dependency, patients
should be monitored closely for appropriate device follow-up
and maintenance.
Rhythm Control
A rhythm-control strategy tries to restore and maintain
normal sinus rhythm using a combination of treatment
approaches, including electrical cardioversion, AADs, cath-
eter ablation, or surgical ablation, together with adequate
rate control and anticoagulant therapy. Several consider-
ations favor pursuit of a rhythm-control strategy, but per-
sistent AF symptoms and the goal of improving quality of life
are the most common driving factors. Other situations that
may favor rhythm control include difficulty maintaining rate
control, tachycardia-mediated cardiomyopathy, first episode
of AF, AF precipitated by an acute illness, younger age, and
patient preference (Hindricks 2021; January 2014).
Electrical cardioversion is performed using direct current
energy in the form of an electrical shock, delivered through
electrodes placed on the patient’s chest. Energy delivery is
synchronized with the QRS complex to avoid delivery during
the ventricular refractory period (the ST segment), which
can potentiate ventricular arrhythmias. Sedation is typically
given for patient comfort; however, in an emergency, seda-
tion may not be possible. In unstable patients, electrical car-
dioversion is the preferred rhythm control because it is more
effective than pharmacologic cardioversion and results in
immediate restoration of sinus rhythm. In stable patients,
either electrical or pharmacologic cardioversion can be
considered. Although pharmacologic cardioversion is less
effective, it does not require the use of sedation. However,
pretreatment with AADs may improve the efficacy of electri-
cal cardioversion.
Management of anticoagulation around the time of cardio-
version is important to reduce thromboembolic risk. Longer
AF durations (48 hours or more) are more likely to result in the
formation of LA thrombi, which can migrate in response to

PSAP 2022 Book 1 • Cardiology 131 Management of Atrial Fibrillation

 Atrial Fibrillation

No other CV HTN or LV dysfunction

HFpEF COPD
disease or HF

β-Blocker β-Blocker β-Blocker

β-Blockera
Diltiazem Diltiazem Diltiazem
Digoxinb
Verapamil Verapamil Verapamil

Amiodaronec

Figure 3. Approach to selecting therapy for ventricular rate control. Drugs are listed alphabetically.
a
β-Blockers should be instituted after stabilization of patients with decompensated HF. Choice of β-blocker (e.g., cardioselective)
depends on the patient’s clinical condition.
b
Digoxin is not usually first-line therapy. It can be combined with a β-blocker and/or a non-DHP CCB when ventricular rate control is
insufficient and may be useful in patients with HF.
c
Partly because of concern over its adverse effect profile, use of amiodarone for chronic rate control of ventricular rate should be
reserved for patients who do not respond to or are intolerant of β-blockers or non-DHP CCBs.
CCB = calcium channel blocker; COPD = chronic obstructive pulmonary disease; CV = cardiovascular; DHP = dihydropyridine;
HFpEF = heart failure with preserved ejection fraction; LV = left ventricular.
Information from: January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial
fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the
Heart Rhythm Society [published correction appears in J Am Coll Cardiol 2014;64:2305-7]. J Am Coll Cardiol 2014;64:e1-e76.

cardioversion and restoration of organized atrial contraction.
De novo atrial thrombi may also form after electrical cardio-
version as a result of atrial stunning and depressed mechan-
ical function. Thus, confirmation of both the duration of AF
and the presence of LA thrombi is key in determining the most
appropriate cardioversion strategy.
Table 8 summarizes guideline recommendations for elec-
trical and pharmacologic cardioversion of AF together with
maintenance of sinus rhythm. In patients at low throm-
boembolic risk (CHA 2DS2-VASc of 0 in men or 1 in women),
administration of intravenous unfractionated heparin (UFH),
low-molecular-weight heparin (LMWH), a DOAC, or no antico-
agulation can be considered before cardioversion (electrical
or pharmacologic), without the need for post-cardioversion
anticoagulation. For patients in AF for less than 48 hours
and a CHA 2DS2-VASc of 2 or greater in men or 3 or greater
in women, anticoagulation with intravenous UFH, LMWH, or
a DOAC should be initiated as soon as possible before car-
dioversion, with significant consideration for achieving ther-
apeutic serum drug concentrations before the procedure. For
example, in the EMANATE trial, patients with new-onset AF
could undergo cardioversion no sooner than 2 hours after
receiving one loading dose of apixaban 10 mg or five consec-
utive doses of apixaban 5 mg twice daily (Ezekowitz 2018).
Similarly, in the X-VeRT trial, patients with new-onset AF were
administered the first dose of a rivaroxaban 20-mg/day reg-
imen at least 4 hours before cardioversion (Cappato 2014).
For patients in AF for 48 hours or more or if the duration
of AF is unknown, anticoagulation with either warfarin or a
DOAC should be administered for 3 weeks before cardiover-
sion, given the increased risk of thrombus development. Per-
forming a transesophageal echocardiogram (TEE) to exclude
the presence of LA thrombus is an alternative to 3 weeks of
anticoagulation before cardioversion; if no thrombus is seen,
cardioversion can be performed as long as therapeutic anti-
coagulation is achieved at the time of cardioversion. If a
thrombus is identified, cardioversion should be postponed,
with anticoagulation continued for at least 3 weeks before
retrying cardioversion. A TEE may be repeated to ensure
thrombus resolution before retrying cardioversion. For unsta-
ble patients in AF requiring emergency cardioversion, antico-
agulation should be initiated as soon as possible but should
not delay interventions to stabilize the patient. After either
electrical or pharmacologic cardioversion, anticoagulation
should be continued for at least 4 weeks unless contraindi-
cated, and decisions regarding long-term anticoagulation for
all patients with AF should be based on the thromboembolic

PSAP 2022 Book 1 • Cardiology 132 Management of Atrial Fibrillation

 Table 7. Drugs Used for Ventricular Rate Control of AF

Maintenance Dose
Drug Loading Dose (IV) (PO) Adverse Effects Notes

β-Blockersa

Metoprolol 2.5- to 5-mg IV bolus over 2 min, 25–100 mg BID AV block Use β1-selective
tartrate up to three doses Bradycardia blockers in asthma,
HF exacerbation COPD
Metoprolol N/A 50–400 mg daily
Hypotension
succinate CI in ADHF and
history of severe
Esmolol 500-mcg IV bolus over 1 min, N/A
bronchospasm
then 50–300 mcg/kg/min

Propranolol 1-mg IV bolus over 1 min; up to 10–30 mg TID or QID Inhibit lidocaine
three doses at 2-min intervals clearance

Non-DHP Calcium Channel Blockers

Diltiazem 0.25-mg/kg IV bolus over 2 min, 120–360 mg once daily AV block CI in HFrEF
then 5–15 mg/hr (ER) Bradycardia
Adjust doses in
HF exacerbation
Verapamil 0.075- to 0.15-mg/kg IV bolus 180–480 mg once hepatic and renal
Hypotension
over 2 min; then 0.005 daily (ER) impairment
Constipationb
mg/kg/min (rarely used)
DDIs

Others

Digoxin 0.25- to 0.5-mg IV bolus, repeat 0.125–0.25 mg once Anorexia Not dialyzable,
with doses of 0.25 mg every 6 hr daily N/A adjust doses in
up to a max of 1.5 mg over 24 hr Ventricular arrhythmias renal impairment

Amiodarone 300 mg IV over 1 hr, then 10–50 100–200 mg once daily AV block May exacerbate
mg/hr over 24 hr (0.5–1 mg/min) Bradycardia thyroid disease
Hypotension (IV)
DDIs
Hypo/hyperthyroidism
Hepatotoxicity
Pulmonary fibrosis
Photosensitivity
Blue-gray skin
discoloration
Corneal microdeposits

a
Not an all-inclusive list.
b
Specific to oral verapamil only.
ADHF = acute decompensated heart failure; AV = atrioventricular; CI = contraindicated; DDI = drug-drug interaction; ER = extended
release; HFrEF = heart failure with reduced ejection fraction; IV = intravenous(ly); PO = oral(ly); QID = four times daily; TID = three
times daily.
Information from: January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial
fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the
Heart Rhythm Society [published correction appears in J Am Coll Cardiol 2014;64:2305-7]. J Am Coll Cardiol 2014;64:e1-e76;
Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in
collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2021;42:373-498.

and bleeding risk profile using the CHA 2DS2-VASc and HAS-
BLED scores for risk assessment (January 2019, 2014).
Antiarrhythmic drugs can be used for pharmacologic car-
dioversion or as adjunctive therapy to increase the efficacy
of electrical cardioversion. Efficacy of pharmacologic car-
dioversion varies but is highest when initiated within 7 days
after onset of AF. Table 9 lists selected AADs used in phar-
macologic cardioversion of AF, and Table 10 outlines AADs
used to maintain sinus rhythm. Selection of AAD therapy is
largely driven by concerns regarding drug safety rather than
drug efficacy, and selection of AADs is largely based on type
of severity of associated comorbidities. Figure 4 outlines a

PSAP 2022 Book 1 • Cardiology 133 Management of Atrial Fibrillation

 Table 8. Summary of Recommendations for Electrical and Pharmacologic Cardioversion of AF and Atrial Flutter and
Maintenance of Sinus Rhythm

COR LOE Recommendation

Prevention of Thromboembolism

I B-R With AF or atrial flutter for ≥ 48 hr or unknown duration, anticoagulation with warfarin (INR 2–3) or a DOAC is
recommended for at least 3 wk before and 4 wk after cardioversion, regardless of the CHA 2DS2-VASc score
or the method (electrical or pharmacologic) used to restore sinus rhythm

I C With AF or atrial flutter > 48 hr or unknown duration requiring immediate cardioversion for hemodynamic
instability, anticoagulation should be initiated as soon as possible and continued for at least 4 wk unless CI

IIa B-NR With AF or atrial flutter < 48 hr and a CHA 2DS2-VASc score ≥ 2 in men and ≥ 3 in women, administration of
IV UFH, LMWH, or a DOAC is reasonable as soon as possible before cardioversion, followed by long-term
anticoagulation

I C-EO After cardioversion of AF of any duration, the decision about long-term anticoagulation should be based on
the thromboembolic and bleeding risk profile

IIa B With AF or atrial flutter ≥ 48 hr or unknown duration and no anticoagulation for the preceding 3 wk, it is
reasonable to perform TEE before cardioversion and then cardiovert if no LA thrombus is identified (including
in the LAA) if anticoagulation is achieved before TEE and maintained after cardioversion for at least 4 wk

IIb B-NR With AF or atrial flutter < 48 hr and a CHA 2DS2-VASc score of 0 in men or 1 in women, administration of IV
UFH, LMWH, a DOAC, or no anticoagulation can be considered before cardioversion, without the need for
post-cardioversion anticoagulation

Direct Current Cardioversion

I B Cardioversion is recommended for AF or atrial flutter to restore sinus rhythm. If successful, cardioversion
attempts can be repeated

I C Cardioversion is recommended for AF or atrial flutter with RVR that does not respond to pharmacologic
therapies

I C Cardioversion is recommended for AF or atrial flutter and preexcitation with hemodynamic instability

IIa C It is reasonable to repeat cardioversion in persistent AF when sinus rhythm can be maintained for a clinically
meaningful time between procedures

Pharmacologic Cardioversion

I A Flecainide, dofetilide, propafenone, and IV ibutilide are useful for cardioversion for AF or atrial flutter if
contraindications to the selected drug are absent

IIa A Amiodarone is reasonable for pharmacologic conversion of AF

IIa B Propafenone or flecainide (“pill-in-the-pocket”) to terminate AF out of hospital is reasonable once observed
to be safe in a monitored setting

III: Harm B Dofetilide should not be initiated out of hospital

Maintenance of Sinus Rhythm

I C Before initiating AAD therapy, treatment of precipitating or reversible causes of AF is recommended

I A The following AADs are recommended in patients with AF to maintain NSR: amiodarone, dofetilide,
dronedarone, flecainide, propafenone, and sotalol

I C Risks of the AAD, including proarrhythmia, should be considered before initiating therapy

I C Because of potential toxicities, amiodarone should only be used after consideration of risks and when other
agents have failed or are CI

IIa C A rhythm-control strategy with pharmacologic therapy can be useful in patients with AF for the treatment of
tachycardia-induced cardiomyopathy

(continued)

PSAP 2022 Book 1 • Cardiology 134 Management of Atrial Fibrillation

 Table 8. Summary of Recommendations for Electrical and Pharmacologic Cardioversion of AF and Atrial Flutter and
Maintenance of Sinus Rhythm  (continued)

COR LOE Recommendation

IIb C It may be reasonable to continue current AAD therapy in the setting of infrequent, well-tolerated recurrences
of AF when the drug has reduced the frequency of symptoms of AF

III: Harm B AADs for rhythm control should not be continued when AF becomes permanent, including dronedarone

III: Harm B Dronedarone should not be used for treatment of AF in patients with NYHA class III or IV HF or patients who
have had an episode of decompensated HF in the past 4 wk

AAD = antiarrhythmic drug; AF = atrial fibrillation; CI = contraindicated; DOAC = direct oral anticoagulant; HF = heart failure; LAA = left
atrial appendage; NSR = normal sinus rhythm; RVR = rapid ventricular response.
Information from: January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline
for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association
Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration with the Society of Thoracic Surgeons
[published correction appears in Circulation 2019;140:e285]. Circulation 2019;140:e125-e151 January CT, Wann LS, Alpert JS, et al.
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society [published correction
appears in J Am Coll Cardiol 2014;64:2305-7]. J Am Coll Cardiol 2014;64:e1-e76.

Table 9. Drugs Used for Pharmacologic Conversion of AF

Drug Loading Dose Maintenance Dose Adverse Effects Notes

Amiodarone 600–800 mg PO daily in 200 mg PO daily Phlebitis (IV) Administer through a large
divided doses to a total Hypotension peripheral vein or central
load of up to 10 ga Bradycardia vein to minimize phlebitis
AV block risk; avoid infusions > 24 hr
150 mg IV over 10 min, then
QTc interval
1 mg/min × 6 hr, then 0.5
TdP (rare)
mg/min × 18 hr or change
GI upset
to PO dosing

Dofetilide CrCl (mL/min): Initial dosing: Measure QTc 2–3 hr after
> 60: 500 mcg BID
40–60: 250 mcg BID
20–39: 125 mcg BID
< 20: Do not use
Do not initiate if baseline
QTc > 440 ms (or >
500 ms in presence of
ventricular conductional
abnormalities)
QTc interval Patients must be
first dose: If QTc increases TdP (3%–4%) hospitalized for at least
to > 15% above baseline or 3 days (≥ 5 doses) during
> 500 ms (> 550 ms with initiation of therapy
conduction abnormalities),
See Table 10 for relevant
reduce dose by 50%
DDIs
Monitor QTc 2–3 hr after
each subsequent in-hospital
dose 2-5. If QTc > 500 ms
(> 550 ms with conduction
abnormalities) at any time,
discontinue dofetilide

Ibutilide 1 mg IV over 10 min; may None QTc interval Consider pretreatment with
repeat × 1 if needed TdP IV magnesium to lower TdP
(if weight < 60 kg, use risk
0.01 mg/kg)
CI in prolonged QTc
(> 440 ms), severe LVH, or
EF < 30%

(continued)

PSAP 2022 Book 1 • Cardiology 135 Management of Atrial Fibrillation

 Table 9. Drugs Used for Pharmacologic Conversion of AF  (continued)

Drug Loading Dose Maintenance Dose Adverse Effects Notes

Flecainide 200–300 mg single PO dose None (for conversion to sinus Blurred vision CI in CAD and structural
(pill-in-the-pocket)b rhythm) Dizziness heart disease
HF exacerbation
QRS
Ventricular
arrhythmias
Atrial flutter with
1:1 AV conduction

Propafenone 450–600 mg single PO dose None (for conversion to sinus AV block CI in CAD and structural
(pill-in-the-pocket)b rhythm) Bradycardia heart disease
HF exacerbation
QRS
Ventricular
arrhythmias
Atrial flutter with
1:1 AV conduction

a
Many dosing schemes exist for amiodarone.
b
Recommended to administer together with a β-blocker or non-DHP CCB given ≥ 30 min before administering the AAD to prevent
RVR because of 1:1 AV conduction during atrial flutter.
AV = atrioventricular; CI = contraindicated; DDI = drug-drug interaction; LVH = left ventricular hypertrophy; ms = millisecond(s);
TdP = torsades de pointes.
Information from: January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial
fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the
Heart Rhythm Society [published correction appears in J Am Coll Cardiol 2014;64:2305-7]. J Am Coll Cardiol 2014;64:e1-e76; Tisdale
JE. Arrhythmias. In: Updates in Therapeutics®: Cardiology Pharmacy Preparatory Review Course. American College of Clinical
Pharmacy, 2018:447-524.

Table 10. Drugs Used to Maintain Sinus Rhythm in Patients with AF

Recommended
Drug Dose Adverse Effects Monitoring Major DDIs

Amiodarone Loading dose:
400–600 mg/day PO
in two or three divided
doses for 2–4 wka
Maintenance dose:
100–200 mg PO once
daily
AV block LFTs – baseline and Inhibits CYP1A2, CYP2C9,
Bradycardia every 6 mo CYP2D6, and CYP3A4:
Hepatotoxicity Increases warfarin
TFTs – baseline and
Hyperthyroidism and (some) statin
every 6 mo
Hypothyroidism concentrations
Pulmonary fibrosis PFTs – baseline, for Inhibits P-gp: Increases
Photosensitivity unexplained dyspnea digoxin concentrations
Blue-gray skin
SCr, electrolytes –
discoloration
baseline and as indicated
Corneal microdeposits
QTc interval Chest radiography –
TdP (rare) baseline and annually
GI upset
ECG – baseline and
annually

Ophthalmologic
examination – at
baseline and for any
symptoms

(continued)

PSAP 2022 Book 1 • Cardiology 136 Management of Atrial Fibrillation

 Table 10. Drugs Used to Maintain Sinus Rhythm in Patients with AF  (continued)
Recommended
Drug Dose Adverse Effects Monitoring Major DDIs

Dofetilide CrCl (mL/min): Dosing: QTc interval Continuous ECG Renal tubular secretion
> 60: 500 mcg PO BID TdP monitoring during first and concentrations
40–60: 250 mcg PO BID 3 days of dosing while increased by cimetidine,
20–39: 125 mcg PO BID hospitalized HCTZ, ketoconazole,
< 20: Do not use itraconazole, megestrol,
ECG every 3–6 mo
prochlorperazine,
SCr every 3–6 mo trimethoprim,
dolutegravir, Biktarvy,
and verapamil
(concomitant use CI)
Dronedarone 400 mg PO BID Bradycardia LFTs – baseline and Inhibits CYP3A: Increases
Diarrhea every 6 mo concentrations of (some)
Hepatotoxicity ECG every 3 mo statins, verapamil, and
Nausea SCr every 3–6 mo diltiazem
Pulmonary fibrosis
Inhibits CYP2D6:
Worsening HF
Increases concentrations
of β-blockers, other
CYP2D6 substrates
Inhibits P-gp: Increases
dabigatran and digoxin
concentrations
Sotalol CrCl (mL/min): Initial Bradycardia Continuous ECG None; however, sotalol
dosing: QTc interval monitoring during the may have an additive
> 60: 80 mg PO BID TdP first 3 days of dosing effect with other drugs
40–60: 80 mg PO daily while hospitalized that prolong the QT
< 40: Do not use interval or cause sinus
ECG every 3–6 mo
bradycardia or AV block
Maintenance dosing:
SCr every 3–6 mo
If 80-mg doses are
tolerated and QTc
remains < 500 ms after
3 days, patient can be
discharged. Alternatively,
dose can be increased
to 120 mg once or twice
daily as appropriate
during hospitalization
and patient followed for
3 days on this dose
Propafenone Immediate release: AV block ECG as needed, at least Inhibits P-gp: Increases
150–300 mg PO every 8 hr Bradycardia every 6 mo digoxin concentrations
HF exacerbation
Extended release: Inhibits CYP2C9:
QRS
225–425 mg PO every Increases warfarin
Ventricular arrhythmias
12 hr concentrations
Flecainide 50–200 mg PO every 12 hr Blurred vision ECG as needed, at least Inhibitors of CYP2D6
Dizziness every 6 mo may increase serum
HF exacerbation flecainide concentrations
QRS Amiodarone increases
Ventricular arrhythmias serum flecainide
concentrations

a
Many dosing schemes exist for amiodarone.
CI = contraindicated; HCTZ = hydrochlorothiazide; LFT = liver function test; PFT = pulmonary function test; TFT = thyroid function test.
Information from: January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial
fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the
Heart Rhythm Society [published correction appears in J Am Coll Cardiol 2014;64:2305-7]. J Am Coll Cardiol 2014;64:e1-e76; Tisdale
JE. Arrhythmias. In: Updates in Therapeutics®: Cardiology Pharmacy Preparatory Review Course. American College of Clinical
Pharmacy, 2018:447-524.

PSAP 2022 Book 1 • Cardiology 137 Management of Atrial Fibrillation

 No Structural Heart Disease Structural Heart Disease

CAD HF

Dofetilidec,d
Dronedarone
Flecainidec,e Catheter Dofetilidec,d Catheter Amiodarone
Propafenonee ablationb Dronedarone ablationb Dofetilidec,d
Sotalolc,d Sotalolc,d

Amiodarone Amiodarone

Figure 4. Approach to selecting therapy for maintenance of sinus rhythm in patients with paroxysmala and persistent
AF. Drugs are listed alphabetically.
a
Catheter ablation is only recommended as first-line therapy for patients with paroxysmal AF (class IIa recommendation).
b
Depending on patient preference when performed in experienced centers.
c
Not recommended with severe LVH (wall thickness > 1.5 cm).
d
Should be used with caution in patients at risk of torsades de pointes ventricular tachycardia.
e
Should be combined with AV nodal-blocking agents.
AV = atrioventricular; CAD = coronary artery disease; HF = heart failure.
Information from: January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial
fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the
Heart Rhythm Society [published correction appears in J Am Coll Cardiol 2014;64:2305-7]. J Am Coll Cardiol 2014;64:e1-e76.

general approach to choosing an AAD, given concomitant management of OSA are recommended to reduce AF incidence,
disease states and risk factors. Because the efficacy of AAD progression, recurrence, and symptoms (Hindricks 2021).
therapy is usually modest and AF recurrences are common
(and often asymptomatic), a rhythm-control strategy should CONTEMPORARY STRATEGIES
not result in cessation of background anticoagulation, rate FOR STROKE PREVENTION
control, or treatment of underlying comorbidities. Although anticoagulant therapy can significantly reduce the
risk of stroke in patients with AF, it does not eliminate risk.
Concomitant Disease and Risk Factor
Adverse effects, including bleeding, may also be a significant
Management
limitation of long-term anticoagulant use for many patients.
Appropriate management of concomitant disease states and
Of interest, most strokes in AF occur primarily as a result of
AF risk factors complements stroke prevention and reduces
thromboembolism originating from the LA, specifically within
AF burden and symptom severity (Hindricks 2021). In the
the LAA. Lack of organized atrial contraction in AF contrib-
recently published RACE 3 trial, targeted therapy for under-
utes to blood stasis, increasing the risk of clot formation. The
lying conditions improved sinus rhythm maintenance in
area of the LA with the lowest state of blood flow, and thus
patients with persistent AF and HF (Rienstra 2018).
the highest rate of thrombus, is the LAA. Given the limitations
Specific recommendations are made by both the ACC/AHA
of anticoagulation and that the LAA is the primary source of
and the ESC guidelines regarding optimizing key risk factors
thromboembolism in AF, mechanical isolation of the LAA has
and concomitant disease states. In patients with hypertension
been an evolving strategy with the goal of reducing the risk of
or obstructive sleep apnea (OSA), opportunistic screening for
thromboembolism. Closure of the LAA can be accomplished
AF is recommended. If AF is present in the setting of hyperten-
either percutaneously or surgically using a wide variety of
sion, optimal blood pressure control is important to reduce AF
devices and techniques.
recurrence, together with stroke risk and bleeding. In overweight
patients or those with obesity, weight loss is recommended to
Percutaneous LAA Occlusion or Exclusion
reduce AF symptom burden, severity, and cumulative AF dura-
Percutaneous LAA closure devices have mainly been devel-
tion. Finally, alcohol avoidance, physical activity, and optimal
oped as nonpharmacologic alternatives to anticoagulation for

PSAP 2022 Book 1 • Cardiology 138 Management of Atrial Fibrillation

stroke prevention in AF. Percutaneous LAA closure devices
may prevent stroke by occluding the LAA and preventing
thrombus formation. There are two general approaches to
percutaneous closure of the LAA. The first approach uses
devices that are inserted into the LA to occlude the LAA,
or act as a plug. These include the WATCHMAN Left Atrial
Appendage System (Boston Scientific) and the Amplatzer
Amulet device (St. Jude Medical). These devices are inserted
percutaneously through a catheter delivery system by fem-
oral venous access and are deployed into the LAA through
transseptal atrial puncture. During the procedure, echocardi-
ography and fluoroscopy are used to guide device placement
and positioning. The WATCHMAN device is anchored within
the LAA through a self-expanding nitinol cage with barbs that
attach to the endocardium, whereas the Amplatzer Amulet
consists of a nitinol mesh disc to seal the ostium of the LAA
and a nitinol mesh distal lobe with hooks to anchor the device
within the LAA (January 2014).
The second approach for percutaneous LAA closure is to
tie off the LAA using an epicardial snare. The LARIAT Loop
Applicator (SentreHEART) is a suture delivery device origi-
nally designed to close a variety of soft tissue surgical wounds
that has been adapted for use in AF. Unlike the WATCHMAN
and Amplatzer Amulet, the LARIAT is a non-implant device
that combines a percutaneous epicardial and endocardial
approach to ligate the LAA with a pre-tied polyester suture.
Placement of the LARIAT requires percutaneous placement
of a magnetic guide within the LAA to guide an epicardially
placed lasso (through subxiphoid access) to tie off the LAA.
Patients with unusual LAA anatomy or those who have had
prior cardiac surgery are not typically candidates for the
LARIAT procedure (January 2014).
Indications
Currently, in the United States, only the WATCHMAN device
is FDA approved for LAA closure and stroke prevention
in patients with AF. The Amplatzer Amulet device has CE
Mark approval in Europe for LAA closure but is not currently
approved in the United States for this indication. However,
the global, multicenter CATALYST trial is currently under
way to compare the effectiveness of the Amulet device with
DOACs as an alternative treatment in an expanded popula-
tion of patients with AF. The LARIAT device is FDA approved
for suture placement and knot tying in surgical applications
where soft tissues are being approximated; however, it is not
specifically approved for LAA closure.
Currently, both the U.S. and European guidelines state that
percutaneous LAA occlusion can be considered in patients
with AF at an increased risk of stroke who have contraindica-
tions to long-term anticoagulation (IIb, B-NR) (January 2019).
This recommendation primarily stems from data comparing
the WATCHMAN device with warfarin in patients with AF at
an increased risk of stroke in two randomized controlled
trials – the PROTECT AF and PREVAIL studies (Holmes 2014;
PSAP 2022 Book 1 • Cardiology
Reddy 2014). A meta-analysis of these two trials showed that
patients receiving the WATCHMAN device had significantly
fewer hemorrhagic strokes than those receiving warfarin, but
more ischemic strokes. However, when periprocedural events
were excluded, the difference in ischemic strokes between
groups was not significant (Holmes 2015). Therefore, for
patients who are poor candidates for long-term anticoagulant
therapy (i.e., bleeding, drug intolerance, or adherence issues),
the WATCHMAN device may provide an alternative method of
stroke prevention (January 2019).
Complications
Both device- and procedure-related complications may occur
with percutaneous LAA closure, which can range from mild
to life threatening. In general, complications involving LAA
closure can be classified as access related, device implant
related, or antithrombotic treatment related.
Access-related bleeding is typically the most common
adverse event within interventional cardiology and may
require transfusion or surgical intervention, depending on
severity. Access-related bleeding events may include groin
hematomas, femoral arterial pseudoaneurysms, and retro-
peritoneal bleeding. Moreover, in percutaneous LAA closure
procedures, large delivery sheaths are used, placing patients
at higher risk of access-related events.
Device implant–related complications vary widely with
device type and user technique. In the PROTECT AF trial,
overall device-related complications with WATCHMAN place-
ment were 8.7%, with a specific rate of pericardial effusion
of 4.5%, with 3.3% requiring pericardiocentesis or surgical
intervention (Reddy 2014). More recent data analyses from
the EWOLUTION registry describe a 4.1% rate of pericar-
dial effusion with only 1.4% requiring surgical management
and no associated deaths, likely because of increased user
experience and mastery of implant techniques (Boersma
2016). Other, less common procedural complications include
periprocedural stroke/transient ischemic attack (TIA), device
migration or dislodgement, and cardiac perforation with
possible cardiac tamponade.
Given the difference in implant approach with the LARIAT
device compared with occlusion devices, most complications
with LARIAT placement are related to subxiphoid access to
the epicardium and include possible cardiac perforation,
pericardial effusion or tamponade, and severe pericarditis.
Although initial single-center data with LARIAT placement
showed a high rate of procedural success and minimal com-
plications, subsequent multicenter results have not been as
favorable. In 2015, the FDA issued a safety communication
stating that cases of death and complications such as lacer-
ation or perforation of the heart or complete LAA detachment
associated with the use of LARIAT had been reported. These
concerns surrounding the procedural safety of the LARIAT
have largely limited its use in the United States in patients
with absolute contraindications to anticoagulation or those
139 Management of Atrial Fibrillation
with LAA anatomies unsuitable for endovascular closure with
occlusion devices.
Antithrombotic Management
The role of antithrombotic therapy after LAA occlusion is
unclear, with current strategies varying widely and based
solely on historical studies, device type, and expert opinion.
Given the results of the PROTECT AF and PREVAIL trials, the
WATCHMAN device was FDA approved for patients with non-
valvular AF in whom long-term anticoagulation is indicated,
but who have an appropriate rationale to seek a nonpharma-
cologic alternative to anticoagulation (Holmes 2014; Reddy
2014). The post-implant antithrombotic regimen within these
two trials consisted of warfarin plus aspirin (81–325 mg) for
45 days, followed by clopidogrel plus aspirin for 6 months, fol-
lowed by aspirin alone indefinitely. With this protocol, patients
being considered for WATCHMAN placement must be able to
tolerate warfarin for at least 6 weeks after device implantation
and must not have an LAA clot at the time of device placement.
Most WATCHMAN implant centers in the United States follow
an antithrombotic protocol similar to the PROTECT AF and
PREVAIL trials. However, in patients with absolute contraindi-
cations to anticoagulation, LAA closure with the WATCHMAN
device has been evaluated. In the ASAP study, a post-procedure
regimen of clopidogrel plus aspirin for 6 months (or for 1–3
months in patients at very high risk of bleeding) followed by
lifelong aspirin was evaluated. During a mean follow-up of 14.4
months, the primary efficacy outcome of all-cause stroke or
systemic embolism occurred at a rate of 2.3% per year and
ischemic stroke at a rate of 1.7% per year, which was lower
than predicted rates for matched cohorts taking either aspirin
(7.3%) or clopidogrel (5%) (Reddy 2013). In addition, data from
EWOLUTION registry noted that of the 1021 patients receiving
a WATCHMAN device, 62% were deemed unsuitable for antico-
agulation and only 27% were treated with anticoagulation as
part of a post-implant antithrombotic therapy course. The rest
of the patients were receiving either dual (59%) or single (7%)
antiplatelet therapy, or no antithrombotic therapy (6%). At the
1-year follow-up, the rate of ischemic stroke was 1.1%, showing
success even in patients with contraindications to anticoagu-
lation (Boersma 2017).
Although the U.S. guidelines do not comment on a recom-
mended antithrombotic strategy, the ESC guidelines offer a
table outlining suggested antithrombotic strategies for the
WATCHMAN and Amulet occlusion devices (Table 11).
Surgical LAA Occlusion or Exclusion
Surgical ligation or amputation is another, though more
invasive means to exclude the LAA and conceivably reduce
stroke risk. In most instances, surgical exclusion of the LAA
is performed in patients already undergoing cardiac sur-
gery and is not typically a stand-alone procedure. Surgical

Table 11. Antithrombotic Therapy After LAA Occlusiona

Device
(patient type) Aspirin Oral Anticoagulant Clopidogrel Comments

WATCHMAN (low 75–325 mg/day Initiate warfarin after Initiate 75 mg/ Some centers do not
bleeding risk) indefinitely procedure (INR day when OAC withhold OAC at time
2–3) until 45 days discontinued, continue of procedure (no data
or continue until until 6 mo after the to support/deny this
adequate LAA sealingb procedure approach)
is confirmed by TEE.
DOAC is a possible
alternative

WATCHMAN (high 75–325 mg/day None 75 mg/day for 1–6 Clopidogrel often
bleeding risk) indefinitely mo while ensuring administered for
adequate LAA sealingb shorter time in very
high-risk situations

ACP/Amulet 75–325 mg/day None 75 mg/day for 1–6 Clopidogrel may

indefinitely mo while ensuring replace long-term
adequate LAA sealingb aspirin if better
tolerated

a
Note: Load aspirin or clopidogrel before procedure, if untreated. Heparin with activated clotting time > 250 s before or immediately
after transseptal puncture for all patients, followed by LMWH when warfarin is needed.
b
Less than 5-mm leak.
ACP = Amplatzer Cardiac Plug; DOAC = direct oral anticoagulant; LAA = left atrial appendage; OAC = oral anticoagulant;
TEE = transesophageal echocardiography.

PSAP 2022 Book 1 • Cardiology 140 Management of Atrial Fibrillation

exclusion of the LAA is performed in several ways. Epicardial
surgical techniques to exclude the LAA include simple suture
ligation, oversewing the base without excision, excising the
LAA and oversewing the base, and surgical stapling and
excision. Endocardial surgical techniques include inversion
of the appendage and amputation and then oversewing
the base from the endocardial aspect (January 2014). The
FDA-approved AtriClip LAA Exclusion System is also an
option for mechanical surgical closure.
Indications
Current guidelines state that surgical occlusion of the LAA can
be considered in patients with AF undergoing cardiac surgery
as a component of an overall heart team approach to man-
aging AF (IIB, B-NR) (January 2019). However, the guidelines
suggest no specific means of surgical LAA closure, partly
because of the tremendous diversity among surgical tech-
niques, cardiac and atrial anatomies, and concomitant thera-
pies. As a result, studies of surgical LAA removal have long
yielded inconsistent results and highly variable rates of suc-
cessful LAA occlusion and stroke reduction (January 2014).
Despite this, surgical LAA exclusion is still commonly per-
formed as part of cardiac surgery in patients with AF. How-
ever, the LAAOS III trial published in 2021 offers additional
evidence in support of surgical LAA occlusion during cardiac
surgery. In this multicenter trial, 4770 patients with AF and a
CHA 2DS2-VASc score of at least 2 who were undergoing car-
diac surgery for another indication were randomized to receive
either LAA occlusion or no occlusion. Patients were followed
for a mean of 3.8 years. Trial results showed significantly lower
rates of stroke or systemic embolism in the LAA occlusion
group (114 patients [4.8%]) than in the no-occlusion group (168
patients [7.0%]) (HR 0.67; 95% CI, 0.53–0.85; p=0.001). Further-
more, the incidence of perioperative bleeding, HF, or death
did not differ between trial groups. In the LAAOS III trial, LAA
occlusion was primarily performed by amputation and closure
(“cut and sew”) in over 50% of patients (Whitlock 2021).
Complications
Procedure-related complications of surgical LAA exclusion
are uncommon. One recent large meta-analysis noted no sig-
nificant differences in postoperative complications or the
need for reoperation for bleeding between patients receiving
LAA exclusion and those not receiving LAA exclusion during
any cardiac surgery (Atti 2018). A bigger limitation to surgical
LAA exclusion is that closure may be incomplete, with echo-
cardiographic follow-up suggesting incomplete occlusion in
more than 50% of patients (Kanderian 2008). Incomplete sur-
gical LAA occlusion has strongly been associated with the
occurrence of thromboembolic events (January 2014).
Anticoagulation Management
It is unknown whether anticoagulation should be continued
after surgical exclusion of the LAA. The highly variable rates
PSAP 2022 Book 1 • Cardiology
of successful closure and the unknown impact of LAA occlu-
sion on further thromboembolic events seem to underscore
the need for continued anticoagulation after the procedure.
Of note, in the LAAOS III trial, most patients continued OAC
after the procedure, with a total of 75.3% (LAA occlusion
group) and 78.2% (no-occlusion group) of patients remain-
ing on OAC at the 3-year visit (Whitlock 2021). At a minimum,
echocardiography should be performed after the operation to
confirm LAA closure before decisions are made regarding the
need for long-term anticoagulation.
CONTEMPORARY STRATEGIES
FOR RHYTHM CONTROL
Both catheter and surgical ablation procedures offer an alter-
native to AAD therapy in the maintenance of sinus rhythm.
The role of catheter and surgical ablation technologies has
rapidly been evolving, expanding the scope of these proce-
dures across a wide variety of patients with AF.
Catheter Ablation
Atrial fibrillation catheter ablation is performed by an elec-
trophysiologist using either cryoballoon or irrigated radiof-
requency techniques. During AF ablation, a catheter is
inserted percutaneously into the LA through transseptal
puncture. Energy in the form of either heat (radiofrequency)
or extreme cold (cryoballoon) is delivered to the surround-
ing endocardial tissue to create linear lesions around the
antrum of the PVs; these lesions form scar tissue that can-
not conduct or propagate electrical impulses. In many
cases, electrical triggers for AF are located near and within
the PVs. As such, the goal of the ablation procedure is to
achieve complete electrical isolation of the PVs from the
LA, with subsequent maintenance of sinus rhythm. More
advanced ablation techniques have also been developed
that target additional or alternative sites (non-pulmonary
foci); however, these are typically reserved for ablation in
patients with persistent or longstanding persistent AF, and
the benefit of targeting these extrapulmonary sites is still
undetermined.
Indications
In general, AF catheter ablation is recommended as a
second-line therapy after failure or intolerance of class I or
class III AADs. Table 12 summarizes these recommendations,
which are based on the results of several randomized con-
trolled trials showing the superiority of AF catheter ablation
over AADs regarding freedom from recurrent arrhythmia or
improvement in symptoms, exercise capacity, and quality of
life after medication failure (Hindricks 2021).
Several factors play into whether to pursue AF catheter
ablation, including type of AF (paroxysmal vs. persistent vs.
longstanding persistent), degree of symptoms, presence of
structural heart disease, risk of complications, and patient
141 Management of Atrial Fibrillation
 Table 12. Summary of Recommendations for AF Catheter Ablation or Surgical Ablation to Maintain Sinus Rhythm

COR LOE Recommendation

Catheter AF Ablation

I A AF catheter ablation is useful in patients with symptomatic paroxysmal AF refractory to or intolerant of at

least one class I or III AAD when a rhythm-control strategy is desired

I C Before consideration of AF catheter ablation, assessment of the procedural risks and outcomes relevant to
the individual patient is recommended

IIa A AF catheter ablation is reasonable for some patients with symptomatic persistent AF refractory to or
intolerant of at least one class I or III AAD

IIa B In patients with recurrent symptomatic paroxysmal AF, catheter ablation is a reasonable initial rhythm-
control strategy before therapeutic trials of AAD therapy after weighing the risks and outcomes of drug and
ablation therapy

IIb B AF catheter ablation can be considered in patients with symptomatic longstanding (> 12 mo) persistent AF
refractory to or intolerant of at least one class I or III AAD when a rhythm-control strategy is desired

IIb B-R AF catheter ablation may be reasonable in selected patients with symptomatic AF and HFrEF to potentially
lower mortality rate and reduce hospitalization for HF

IIb C AF catheter ablation can be considered before initiation of a class I or III AAD in patients with symptomatic
persistent AF when a rhythm-control strategy is desired

III: Harm C AF catheter ablation should not be performed in patients who cannot be treated with anticoagulant therapy
during and after the procedure

III: Harm C AF catheter ablation to restore sinus rhythm should not be performed solely to obviate the need for
anticoagulation

Surgical AF Ablation

IIa C An AF surgical ablation procedure is reasonable for selected patients with AF undergoing cardiac surgery for
other indications

IIb B A stand-alone AF surgical ablation procedure may be reasonable for selected patients with highly
symptomatic AF not well managed with other approaches

AAD = antiarrhythmic drug; AF = atrial fibrillation; HFrEF = heart failure with reduced ejection fraction.
Information from: January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline
for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association
Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration with the Society of Thoracic Surgeons
[published correction appears in Circulation 2019;140:e285]. Circulation 2019;140:e125-e151; January CT, Wann LS, Alpert JS, et al.
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society [published correction
appears in J Am Coll Cardiol 2014;64:2305-7]. J Am Coll Cardiol 2014;64:e1-e76.

preference. Overall, the main clinical benefit of AF catheter
ablation is reduction in arrhythmia-related symptoms. In the
recent CABANA trial, symptom improvement was confirmed
with catheter ablation compared with AAD therapy; however,
an ablation strategy did not significantly reduce the primary
composite outcome of death, disabling stroke, serious bleed-
ing, or cardiac arrest compared with AAD therapy (Packer
2019). As such, until a randomized controlled trial shows an
improvement in clinical end points outside symptoms, AF
catheter ablation in the general AF population is typically
reserved for symptom relief and is not indicated in asymp-
tomatic patients.
In contrast, in patients with HFrEF and AF, randomized
controlled trials have shown significant reductions in all-
cause mortality and hospitalization with AF catheter abla-
tion. In the CASTLE-AF trial, 363 patients with HFrEF (EF less
than 35%) and symptomatic AF were randomized to either
catheter ablation or medical therapy (rate or rhythm control).
After a median follow-up of 37.8 months, the primary compos-
ite end point of death from any cause or hospitalization for
worsening HF was significantly lower in the catheter ablation
group (28.5%) than in the medical therapy group (44.6%) (Mar-
rouche 2018). Given these findings, new recommendations
were added to the 2019 AHA/ACC/HRS guidelines supporting

PSAP 2022 Book 1 • Cardiology 142 Management of Atrial Fibrillation

 Table 13. Procedure-Related Complications in Catheter Ablation of AF

Complication Complication
Severity Complication Type Rate (%) Treatment

Life threatening Periprocedural death < 0.1 N/A

Esophageal perforation/fistula < 0.5 CT or MRI of esophagus, avoiding endoscopy,

immediate surgical correction

Periprocedural thromboembolic event < 1.0 Consider lysis therapy

Cardiac tamponade ~1 Pericardiocentesis, emergency surgical drainage

Severe PV stenosis < 1.0 PV dilation/stent or no therapy

Persistent phrenic nerve palsy < 1.0 None, usually resolves spontaneously

Vascular access complications 2–4 Observation, compression, possible surgical

intervention

Moderate or minor Various: 1–2 MI: Standard therapy

• MI Pericarditis: NSAIDs, colchicine, steroids
• Pericarditis Radiation injury: Treat as burn injury
• Radiation injury

Complications Asymptomatic cerebral embolism 5–15 N/A

of unknown
significance

PV = pulmonary vein.
Information from: Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation
developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2021;42:373-498;
January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report
of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm
Society [published correction appears in J Am Coll Cardiol 2014;64:2305-7]. J Am Coll Cardiol 2014;64:e1-e76.

AF ablation in patients with HFrEF and symptomatic AF to
potentially reduce mortality and HF hospitalizations (January
2019).
Complications and Recurrence
Although AF catheter ablation is relatively safe when per-
formed in experienced centers, several important risks and
complications are associated with it, as summarized in
Table  13. Catheter ablation may be complicated by peripro-
cedural stroke, resulting from catheter manipulation and the
creation of lesions in the endocardial tissue (Basu-Ray 2021).
Around 1% of patients who receive AF ablation are at risk of
stroke, and post-ablation brain MRI reveals silent stroke in
14%–40% of patients (Mao 2020).
Alternatively, as a result of background anticoagulation,
use of large sheaths, and femoral access, bleeding compli-
cations can occur and be severe. Most complications occur
within the first 24 hours after the procedure; however, some
may appear 1–2 months later (Arbelo 2017, 2014, 2012).
Recurrences of AF after a catheter ablation are common
during the first 3 months and do not rule out long-term pro-
cedural success, though they can increase the risk of rehos-
pitalization. In early AF recurrences (i.e., within 3 months),
rather than using early repeat ablation, it is usually reason-
able to try an AAD for additional rhythm control or cardiover-
sion for persistent AF. Theoretically, aggressive treatment
of early AF recurrences helps prevent both structural and
electrical remodeling and improves long-term outcomes,
but studies are needed to clarify the optimal management
strategy. In later AF recurrences (i.e., after 3 months), recur-
rence is usually an indication of PV conduction recovery,
and repeat ablation or AAD initiation may be helpful (Janu-
ary 2014).
Anticoagulation Management
Anticoagulation plays an integral role in both the peri- and
postprocedural management of AF catheter ablation, so
much so that patients who cannot be treated with anticoag-
ulation during and after the procedure should not undergo
AF catheter ablation. Large areas of LA endothelium are left
damaged from the procedure and can incite thrombus forma-
tion, as can manipulation of vascular sheaths and catheters.
After the operation, stunning of atrial tissue may occur, last-
ing for weeks or even months and contributing to blood stasis
and thrombus formation.

PSAP 2022 Book 1 • Cardiology 143 Management of Atrial Fibrillation

 Table 14. Periprocedural Anticoagulation Strategies for AF Catheter Ablation

COR LOE Recommendation

Before Ablation

I A For patients undergoing AF catheter ablation who have been therapeutically anticoagulated with warfarin or
dabigatran, performance of the procedure without interruption of anticoagulation is recommended

I B-R For patients undergoing AF catheter ablation who have been therapeutically anticoagulated with rivaroxaban,
performance of the procedure without interruption of rivaroxaban is recommended

IIa B-NR For patients undergoing AF catheter ablation who have been therapeutically anticoagulated with a DOAC
other than dabigatran or rivaroxaban, performance of the procedure without interruption of anticoagulation is
reasonable

IIa B-NR For patients anticoagulated with a DOAC before AF catheter ablation, it is reasonable to hold one or two doses
of the DOAC before AF ablation with reinitiation after ablation

During Ablation

I B-NR UFH should be administered before or immediately after transseptal puncture during AF catheter ablation
procedures and adjusted to achieve and maintain an ACT of at least 300 s

IIa B-NR Administration of protamine after AF catheter ablation to reverse UFH is reasonable

After Ablation

I C-EO In patients who do not undergo therapeutic anticoagulation before AF catheter ablation and in whom warfarin
will be used for anticoagulation after ablation, LMWH or IV UFH should be used as a bridge for initiation of
systemic anticoagulation with warfarin after AF ablation

I C-EO Systemic anticoagulation with warfarin or a DOAC is recommended for at least 2 mo after AF catheter ablation

I C-EO Adherence to AF anticoagulation guidelines is recommended for patients who have undergone an AF ablation
procedure, regardless of the apparent success or failure of the procedure

I C-EO Decisions regarding continuation of systemic anticoagulation > 2 mo after ablation should be based on the
patient’s stroke risk and not on the perceived success or failure of the ablation procedure

IIa C-EO In patients who have not been receiving anticoagulation before AF catheter ablation or in whom
anticoagulation with a DOAC or warfarin has been interrupted before ablation, administration of a DOAC 3–5
hr after achievement of hemostasis is reasonable after ablation

ACT = activated clotting time; AF = atrial fibrillation; DOAC = direct oral anticoagulant; HFrEF = heart failure with reduced ejection frac-
tion; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin.
Information from: Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement
on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2017;14:e275-e444.

Because of the considerable risks of both bleeding
and thromboembolic complications of the ablation proce-
dure itself, there are challenges in determining the optimal
periprocedural anticoagulation strategy for patients. The lat-
est international guidelines include detailed recommenda-
tions for anticoagulation surrounding the ablation procedure
(before, during, and after ablation), as summarized in Table 14
(Calkins 2017).
Since publication of these guidelines, additional evidence
has been published in support of uninterrupted anticoagula-
tion with DOACs. Two large meta-analyses comparing patients
receiving uninterrupted anticoagulation with interrupted anti-
coagulation during AF catheter ablation noted no differences
in major or minor bleeding, pericardial tamponade, pericardial
effusion, or puncture complications; however, uninterrupted
anticoagulation resulted in significantly fewer silent strokes
than interrupted anticoagulation (Basu-Ray 2021; Mao 2020).
Post-procedure anticoagulation should be continued for at
least 2 months after ablation in all patients. Afterward, the
decision to continue OAC is largely based on stroke risk rather
than rhythm status (Hindricks 2021).
Surgical Ablation
Unlike catheter ablation procedures that create lesions on the
endocardial surface of the LA, surgical ablation techniques
use an epicardial approach. In most cases, surgical ablations

PSAP 2022 Book 1 • Cardiology 144 Management of Atrial Fibrillation

 Patient Care Scenario
H.J. is a 70-year-old woman who underwent AF catheter
ablation about 4 weeks ago. Her medical history includes
hypertension, hyperlipidemia, and osteoarthritis. Her
home drugs include rivaroxaban 20 mg daily, verapamil
extended-release 180 mg daily, amlodipine 10 mg
daily and atorvastatin 20 mg daily. An ECG and a TEE
performed during follow-up today in clinic reveal AF
(ventricular rate 75 beats/minute) with a QTc interval of
ANSWER
Early recurrences (within 3 months) of AF after catheter
ablation are common and are not usually indicative of pro-
cedural success (Answer D is incorrect); however, they can
increase risk of rehospitalization. In early recurrences,
guidelines recommend that is generally reasonable to
trial an AAD for additional rhythm control or cardioversion
410 milliseconds and an LVEF of > 55%. Which one of
the following interventions would be most reasonable
for H.J.?
A. Initiate dofetilide 500 mcg orally twice daily.
B. Initiate flecainide 100 mg orally twice daily.
C. Increase verapamil to 240 mg once daily.
D. Refer for repeat AF catheter ablation.
for persistent AF (Answer C is incorrect). Both flecainide
and dofetilide are AADs that may be considered for H.J;
however, dofetilide requires hospitalization for initiation
and is contraindicated with concomitant use of verapamil
(Answer A is incorrect, Answer B is correct).

1. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collab-
oration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2021;42(5):373-498.
2. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management
of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical
Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons [published correction appears
in Circulation. 2019 Aug 6;140(6):e285]. Circulation. 2019;140(2):e125-e151.

are performed by a cardiothoracic surgeon in patients who Complications

are undergoing cardiac surgery for another reason (e.g., cor-
onary bypass grafting, valve repair or replacement). The prin-
cipal goal for surgical AF ablation is the same as for catheter
AF ablation – to create tissue lesions that result in conduc-
tion block of micro- and macro-reentrant circuits and main-
tain normal sinus rhythm. This creates a “maze” of functional
myocardium within the atrium that allows for appropriate
propagation of atrial depolarization.
Surgical ablation techniques have evolved significantly over
the past 30 years. Today, the most common surgical ablation
procedure is known as the Cox maze IV and is considered the
gold standard of surgical ablation techniques. The Cox maze
IV consists of a specific pattern of linear scars made on the
epicardial surface using incision, radiofrequency, or cryoab-
lation. In many cases, the LAA is also surgically removed or
ligated during these procedures (January 2014).
Indications
Although AF surgical ablation has been shown to be effica-
cious in restoring and maintaining sinus rhythm, long-term
clinical outcomes such as quality of life, stroke, hospitaliza-
tion, and mortality have not been well established. The ACC/
AHA 2014 guidelines give a weak recommendation for consid-
eration of AF surgical ablation in patients with AF undergoing
cardiac surgery for other indications, or as a stand-alone pro-
cedure for selected highly symptomatic patients with AF for
whom other approaches have failed (i.e., AADs, direct current
cardioversion [DCCV], catheter ablation) (see Table 12) (Janu-
ary 2014).
Many complications are possible during surgical AF ablation
that largely depend on patient characteristics, procedure
approach (open sternotomy vs. minimally invasive thoracot-
omy), procedure type (lesion patterns), and concomitant car-
diac surgeries (valve replacement/repair or coronary bypass
grafting). Although the risk of periprocedural stroke also
exists with surgical AF ablation, risk is much lower than with
catheter ablation because of the lack of transseptal punc-
ture and endocardial catheter manipulation. The risk of PV
stenosis is also much lower with a surgical approach. On the
contrary, given the large extent of tissue damaged in the cre-
ation of epicardial lesions, surgical ablation is associated
with a higher incidence of atrial dysfunction and diminished
atrial contractility compared with catheter ablation (Buber
2011). In addition, the postoperative need for a permanent
pacemaker is higher with surgical ablation, especially with
bi-atrial lesion sets, though published results are highly vari-
able and incidence ranges from 6.8% to 21.5% (Hindricks
2021).
Anticoagulation Management
Few to no data are available regarding the optimal approach
for anticoagulation after AF surgical ablation. Despite the
absence of evidence, the 2017 international expert consen-
sus guidelines recommend that the decisions to provide
anticoagulation and the therapy duration be made on an
individual basis, with consideration for the patient’s stroke
risk and bleeding risk and whether the LAA was ligated.
Authors state that anticoagulation may be reasonable in

PSAP 2022 Book 1 • Cardiology 145 Management of Atrial Fibrillation

patients for several months after surgical ablation with low
bleeding risk. For patients in whom LAA closure or ligation
was performed at the time of surgical ablation, TEE-based
assessment of LAA closure should be performed when
anticoagulation discontinuation is being considered (Calk-
ins 2017).
Hybrid Surgical/Catheter Ablation
Over the past decade, a hybrid approach to surgical and cath-
eter AF ablation has been developed whereby a minimally
invasive epicardial surgical ablation performed by a cardio-
thoracic surgeon is combined with a percutaneous cathe-
ter ablation performed by an electrophysiologist. This hybrid
approach can be performed as a single intervention, where
both procedures are performed during the same hospitaliza-
tion, or sequentially, where surgical and catheter ablation pro-
cedures are separated by no more than 6 months. Although
evidence is lacking to support this practice, an LAA clip (Atri-
Clip) may be included in a hybrid AF ablation, and an AAD can
also be considered after ablation to increase potential treat-
ment success.
Indications and Complications
Hybrid AF procedures have been developed and refined over
the past several years but are not yet formally indicated by
the current AHA/ACC guidelines. The 2020 ESC AF guide-
lines and the 2017 international consensus guidelines offer
a weak recommendation in support of a hybrid AF ablation
in patients with symptomatic paroxysmal or persistent AF
refractory to AAD therapy for whom at least one attempt at
catheter AF ablation has failed or for those who have signif-
icant risk factors for AF recurrence (Hindricks 2021; Calkins
2017). Hybrid AF ablation procedures achieve significantly
higher rates of long-term freedom from AF than AF cathe-
ter ablation, though they are associated with more compli-
cations (13.8% vs. 5.9%) (van der Heijden 2019). Although
complications are decreasing with procedure refinement and
increased center experiences, they may involve phrenic nerve
palsy, pericardial effusion or tamponade, esophageal injury
or perforation, bleeding, or stroke/TIA.
Anticoagulation Management
Much like surgical AF ablation, there are few to no data to
recommend or refute anticoagulation after a hybrid AF

Table 15. Summary of Recommendations for Specific Patient Groups and AF

COR LOE Recommendation

Hypertrophic Cardiomyopathy

I B Anticoagulation is indicated in HCM with AF independent of the CHA 2DS2-VASc score

IIa C AADs can help prevent recurrent AF in HCM. Amiodarone or disopyramide combined with a β-blocker
or non-DHP CCB is reasonable

IIa B AF catheter ablation can be beneficial for HCM to facilitate a rhythm-control strategy when AADs fail
or are not tolerated

IIb C Sotalol, dofetilide, and dronedarone can be considered for a rhythm-control strategy in HCM

AF Complicating ACS

I B-R With ACS and AF with a CHA 2DS2-VASc score ≥ 2, anticoagulation is recommended unless CI

I C Urgent DCCV of new-onset AF in the setting of ACS is recommended for patients with hemodynamic
compromise, ongoing ischemia, or inadequate rate control

I C IV β-blockers are recommended to slow RVR with ACS and no HF, hemodynamic instability,
bronchospasm

IIa B-NR If triple therapy (anticoagulant, ASA, and P2Y12 inhibitor) is prescribed for patients with AF at
increased risk of stroke (CHA 2DS2-VASc score ≥ 2) who have undergone PCI with stenting for ACS, it
is reasonable to choose clopidogrel in preference to prasugrel

IIa B-R In patients with AF and CHA 2DS2-VASc score ≥ 2 who have undergone PCI with stenting for ACS,
double therapy with a P2Y12 inhibitor (clopidogrel or ticagrelor) and dose-adjusted warfarin is more
reasonable to reduce risk of bleeding than triple therapy

IIa B-R In patients with AF and CHA 2DS2-VASc score ≥ 2 who have undergone PCI with stenting for ACS,
double therapy with P2Y12 inhibitors (clopidogrel) and low-dose rivaroxaban 15 mg daily is more
reasonable to reduce risk of bleeding than triple therapya

(continued)

PSAP 2022 Book 1 • Cardiology 146 Management of Atrial Fibrillation

 Table 15. Summary of Recommendations for Specific Patient Groups and AF  (continued)

COR LOE Recommendation

IIa B-R In patients with AF and CHA 2DS2-VASc score ≥ 2 who have undergone PCI with stenting for ACS,
double therapy with P2Y12 inhibitors (clopidogrel) and dabigatran 150 mg BID is more reasonable to
reduce risk of bleeding than triple therapy

IIb B-R If triple therapy (anticoagulant, ASA, and P2Y12 inhibitor) is prescribed for patients with AF who are
at increased risk of stroke (CHA 2DS2-VASc score ≥ 2) and who have undergone PCI with stenting for
ACS, changing to double therapy (anticoagulant and P2Y12 inhibitor) at 4–6 wk can be considered

IIb C Amiodarone or digoxin can be considered to slow RVR with ACS and AF and severe LV dysfunction
and HF or hemodynamic instability

IIb C Non-DHP CCBs can be considered to slow RVR with ACS and AF only in the absence of significant HF
or hemodynamic instability

Hyperthyroidism

I C β-Blockers are recommended to control ventricular rate with AF complicating thyrotoxicosis unless CI

I C When β-blockers cannot be used, a non-DHP CCB is recommended to control ventricular rate

Pulmonary Diseases

I C A non-DHP CCB is recommended to control ventricular rate with AF and COPD

I C Cardioversion should be tried for patients with pulmonary disease who become hemodynamically
unstable with new-onset AF

WPW and Preexcitation Syndromes

I C Cardioversion is recommended for patients with AF, WPW syndrome, and RVR who are
hemodynamically compromised

I C IV procainamide or ibutilide to restore sinus rhythm or slow ventricular rate is recommended for
patients with preexcited AF and RVR who are not hemodynamically compromised

I C Catheter ablation of the accessory pathway is recommended in symptomatic patients with preexcited
AF, especially if the accessory pathway has a short refractory period

III: Harm B Use of IV amiodarone, adenosine, digoxin, or non-DHP CCBs in patients with WPW syndrome who
have preexcited AF is potentially harmful

Heart Failure

I B A β-blocker or non-DHP CCB is recommended for persistent or permanent AF in patients with HFpEF

I B In the absence of preexcitation, an IV β-blocker (or a non-DHP CCB with HFpEF) is recommended to
slow ventricular response to AF in the acute setting, with caution in patients with overt congestion,
hypotension, or HFrEF

I B In the absence of preexcitation, IV digoxin or amiodarone is recommended to control HR acutely

I C Assess HR during exercise and adjust pharmacologic treatment in symptomatic patients during
activity

I C Digoxin is effective to control resting HR with HFrEF

IIa B A combination of digoxin and a β-blocker (or a non-DHP CCB with HFpEF) is reasonable to control
resting and exercise HR with AF

IIa B It is reasonable to perform AV node ablation with ventricular pacing to control HR when
pharmacologic therapy is insufficient or not tolerated

IIa C IV amiodarone can be useful to control HR with AF when other measures are unsuccessful or CI

(continued)

PSAP 2022 Book 1 • Cardiology 147 Management of Atrial Fibrillation

 Table 15. Summary of Recommendations for Specific Patient Groups and AF  (continued)

COR LOE Recommendation

IIa B With AF and RVR causing or suspected of causing tachycardia-induced cardiomyopathy, it is

reasonable to use a rhythm-control strategy

IIa C In patients with chronic HF who remain symptomatic from AF despite a rate-control strategy, it is
reasonable to use a rhythm-control strategy

IIb C Amiodarone can be considered when resting and exercise HR cannot be controlled with a β-blocker
(or a non-DHP CCB with HFpEF) or digoxin, alone or in combination

IIb C AV node ablation can be considered when rate cannot be controlled and tachycardia-mediated
cardiomyopathy is suspected

III: Harm C AV node ablation should not be performed without a pharmacologic trial to control ventricular rate

III: Harm C For rate control, IV non-DHP CCBs, IV β-blockers, and dronedarone should not be administered with
decompensated HF

Postoperative Cardiac and Thoracic Surgery

I A A β-blocker is recommended to treat postoperative AF unless CI

I B A non-DHP CCB is recommended when a β-blocker is inadequate to achieve rate control with
postoperative AF

IIa A Preoperative amiodarone reduced AF with cardiac surgery and is reasonable as prophylactic therapy
for patients at high risk of postoperative AF

IIa B It is reasonable to restore sinus rhythm pharmacologically with ibutilide or DCCV with postoperative
AF

IIa B It is reasonable to administer an AAD to maintain sinus rhythm with recurrent or refractory
postoperative AF

IIa B It is reasonable to administer antithrombotic medications for postoperative AF

IIa C It is reasonable to manage new-onset postoperative AF with rate control and anticoagulation with
cardioversion if AF does not revert spontaneously to sinus rhythm during follow-up

IIb B Prophylactic sotalol can be considered for patients at risk of AF after cardiac surgery

IIb B Colchicine can be considered after the operation to reduce AF after cardiac surgery

a
Apixaban 5 mg BID can also be considered, given the results of AUGUSTUS trial (Lopes RD, Heizer G, Aronson R, et al. Antithrombotic
therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med 2019;380:1509-24) (published after 2019 AHA/ACC/
HRS guideline update).
ACS = acute coronary syndrome; ASA = aspirin; CI = contraindicated; DCCV = direct current cardioversion; HCM = hypertrophic
cardiomyopathy; HR = heart rate; PCI = percutaneous coronary intervention; WPW = Wolff-Parkinson-White.
Information from: January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial
fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the
Heart Rhythm Society [published correction appears in J Am Coll Cardiol 2014;64:2305-7]. J Am Coll Cardiol 2014;64:e1-e76;
January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the
management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task
Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration with the Society of Thoracic Surgeons
[published correction appears in Circulation 2019;140:e285]. Circulation 2019;140:e125-e151.

ablation, and decisions surrounding anticoagulation initia- AF MANAGEMENT IN SPECIAL

tion or withdrawal should be made on the basis of patient- POPULATIONS
and procedure-specific factors. Although great strides have been made in managing AF as
a whole, many specific patient subgroups warrant additional

PSAP 2022 Book 1 • Cardiology 148 Management of Atrial Fibrillation

 Practice Points
• AF is a CV pandemic and contributes to signifi-
cant patient morbidity and mortality. The patho-
physiology of AF is complex, and both pharma-
cologic and nonpharmacologic strategies for AF
treatment have evolved tremendously over the
past several years. Pharmacists should have a
sound understanding of AF as a disease state,
together with an understanding of the currently
available treatment modalities, in order to make
appropriate recommendations surrounding
pharmacotherapy that maximizes benefit while
minimizing harm.
• Stroke prevention is a cornerstone of therapy in
AF management, regardless of treatment strat-
egy, and is quantified by the CHA2DS2-VASc risk
assessment tool. In determining appropriate an-
ticoagulant therapy, pharmacists should assess
stroke and bleeding risk, patient comorbidities,
indications/contraindications, renal/hepatic func-
tion, potential for interacting medications, adher-
ence, and affordability at a minimum.
• Symptom management of AF may involve either
a rate- or rhythm-control strategy, depending on
patient-specific factors and shared decision-mak-
ing. Pharmacists should be knowledgeable about
which medications are appropriate for each
strategy as well as consider comorbidities, indi-
cations/contraindications, renal/hepatic function,
potential for interacting medications, adherence,
and affordability.
consideration when treating concomitant AF. Pharmacists
should be cognizant of these patient AF subgroups and aware
of potential caveats to consider regarding appropriate phar-
macotherapy and disease state management. These condi-
tions are summarized in Table 15 and discussed elsewhere in
this module in greater detail.
CONCLUSION
Much progress has been made in preventing, detecting,
and treating AF, with much more to come. In the aging pop-
ulation, the global burden of AF is increasing, and it has
become one of the most common disease states world-
wide. Pharmacists can play an integral role in patient edu-
cation and treatment surrounding AF, and an understanding
of contemporary nonpharmacologic AF management strat-
egies is essential for making appropriate pharmacotherapy
recommendations.
REFERENCES
Arbelo E, Brugada J, Blomstrom-Lundqvist C, et al. Contem-
porary management of patients undergoing atrial fibril-
lation ablation: in-hospital and 1-year follow-up findings
PSAP 2022 Book 1 • Cardiology
• Pharmacists should recognize that both stroke
risk and a patient’s preferred AF treatment strat-
egy often change and may evolve over time. In
addition, management of concomitant disease
states and stroke risk factors is an important part
of an AF treatment strategy.
• Contemporary nonpharmacologic strategies for
stroke prevention in AF include percutaneous
LAA occlusion or ligation, or surgical LAA exclu-
sion or ligation. Pharmacists should be aware of
these procedures, potential complications, and
how anticoagulant therapy may be used in these
patients.
• Contemporary nonpharmacologic strategies for
rhythm control in AF include catheter ablation,
surgical ablation, or a hybrid surgical/catheter
ablation. Pharmacists should be aware of these
procedures, potential complications, and how
AAD and anticoagulant therapy can be used in
these patients.
• Certain populations of patients with AF warrant
special consideration because concomitant
disease states (e.g., ACS, hyperthyroidism,
congestive heart failure) may dictate alternative
treatment strategies that differ from general
AF guideline recommendations. Pharmacists
should be familiar with these subgroups and
how AF pharmacotherapy decisions may be
affected as a result.
from the ESC-EHRA atrial fibrillation ablation long-term
registry. Eur Heart J 2017;38:1303-16.
Arbelo E, Brugada J, Hindricks G, et al. ESC-EURObserva-
tional Research Programme: the Atrial Fibrillation Abla-
tion Pilot Study, conducted by the European Heart Rhythm
Association. Europace 2012;14:1094-103.
Arbelo E, Brugada J, Hindricks G, et al. The atrial fibrillation
ablation pilot study: a European survey on methodology
and results of catheter ablation for atrial fibrillation con-
ducted by the European Heart Rhythm Association. Eur
Heart J 2014;35:1466-78.
Atti V, Anantha-Narayanan M, Turagam MK, et al. Surgical
left atrial appendage occlusion during cardiac surgery:
a systematic review and meta-analysis. World J Cardiol
2018;10:242-9.
Basu-Ray I, Khanra D, Kupó P, et al. Outcomes of uninter-
rupted vs interrupted periprocedural direct oral antico-
agulants in atrial fibrillation ablation: a meta-analysis.
J Arrhythm 2021;37:384-93.
Boersma LV, Ince H, Kische S, et al. Efficacy and safety of
left atrial appendage closure with WATCHMAN in patients
with or without contraindication to oral anticoagulation:
149 Management of Atrial Fibrillation
 1-year follow-up outcome data of the EWOLUTION trial.
Heart Rhythm 2017;14:1302-8.
Boersma LV, Schmidt B, Betts TR, et al. Implant success and
safety of left atrial appendage closure with the WATCH-
MAN device: peri-procedural outcomes from the EWOLU-
TION registry. Eur Heart J 2016;37:2465.
Buber J, Luria D, Sternik L, et al. Left atrial contractile func-
tion following a successful modified maze procedure
at surgery and the risk for subsequent thromboembolic
stroke. J Am Coll Cardiol 2011;58:1614-21.
Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/
ECAS/APHRS/SOLAECE expert consensus statement on
catheter and surgical ablation of atrial fibrillation. Heart
Rhythm 2017;14:e275-e444.
Cappato R, Ezekowitz MD, Klein AL, et al. Rivaroxaban vs.
vitamin K antagonists for cardioversion in atrial fibrilla-
tion. Eur Heart J 2014;35:3346-55.
Chung MK, Refaat M, Shen WK, et al. Atrial fibrillation:
JACC Council perspectives. J Am Coll Cardiol
2020;75:1689-713.
Ezekowitz MD, Pollack CV Jr, Halperin JL, et al. Apixaban
compared to heparin/vitamin K antagonist in patients
with atrial fibrillation scheduled for cardioversion: the
EMANATE trial. Eur Heart J 2018;39:2959-71.
Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines
for the diagnosis and management of atrial fibrillation
developed in collaboration with the European Associa-
tion for Cardio-Thoracic Surgery (EACTS). Eur Heart J
2021;42:373-498.
Holmes DR Jr, Doshi SK, Kar S, et al. Left atrial appendage
closure as an alternative to warfarin for stroke prevention
in atrial fibrillation: a patient-level meta-analysis. J Am
Coll Cardiol 2015;65:2614-23.
Holmes DR Jr, Kar S, Price MJ, et al. Prospective randomized
evaluation of the WATCHMAN Left Atrial Appendage Clo-
sure Device in patients with atrial fibrillation versus long-
term warfarin therapy: the PREVAIL trial. J Am Coll Cardiol
2014;64:1-12.
January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS
guideline for the management of patients with atrial fibril-
lation: a report of the American College of Cardiology/
American Heart Association Task Force on Practice Guide-
lines and the Heart Rhythm Society [published correction
appears in J Am Coll Cardiol 2014;64:2305-7]. J Am Coll
Cardiol 2014;64:e1-e76.
January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS
focused update of the 2014 AHA/ACC/HRS guideline for
the management of patients with atrial fibrillation: a report
of the American College of Cardiology/American Heart
Association Task Force on Clinical Practice Guidelines and
the Heart Rhythm Society in Collaboration with the Soci-
ety of Thoracic Surgeons [published correction appears in
Circulation 2019;140:e285]. Circulation 2019;140:e125-e151.
PSAP 2022 Book 1 • Cardiology
Kanderian AS, Gillinov AM, Pettersson GB, et al. Success
of surgical left atrial appendage closure: assessment by
transesophageal echocardiography. J Am Coll Cardiol
2008;52:924-9.
Kirchhof P, Camm AJ, Goette A, et al. Early rhythm-control
therapy in patients with atrial fibrillation. N Engl J Med
2020;383:1305.
Kotecha D, Bunting KV, Gill SK, et al. Effect of digoxin vs
bisoprolol for heart rate control in atrial fibrillation on
patient-reported quality of life: the RATE-AF randomized
clinical trial. JAMA 2020;324:2497-508.
Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial
fibrillation. The Framingham Study. Stroke 1996;27:1760-4.
Lip GYH. The ABC pathway: an integrated approach to
improve AF management. Nat Rev Cardiol 2017;14:627-8.
Løfgren B, Pareek M, Larsen JM. Uninterrupted dabigatran
versus warfarin for ablation in atrial fibrillation. N Engl J
Med 2017;377:494-5.
Mao YJ, Wang H, Huang PF. Peri-procedural novel oral
anticoagulants dosing strategy during atrial fibrillation
ablation: a meta-analysis. Pacing Clin Electrophysiol
2020;43:1104-14.
Marrouche NF, Brachmann J, Andresen D, et al. Catheter
ablation for atrial fibrillation with heart failure. N Engl J
Med 2018;378:417-27.
Marzona I, Proietti M, Farcomeni A, et al. Sex differences in
stroke and major adverse clinical events in patients with
atrial fibrillation: a systematic review and meta-analysis of
993,600 patients. Int J Cardiol 2018;269:182-91.
Nielsen PB, Overvad TF. Female sex as a risk modifier for
stroke risk in atrial fibrillation: using CHA2DS2-VASc
versus CHA2DS2-VA for stroke risk stratification in
atrial fibrillation: a note of caution. Thromb Haemost
2020;120:894-8.
Packer DL, Mark DB, Robb RA, et al. Effect of catheter abla-
tion vs antiarrhythmic drug therapy on mortality, stroke,
bleeding, and cardiac arrest among patients with atrial
fibrillation: the CABANA randomized clinical trial. JAMA
2019;321:1261-74.
Pastori D, Farcomeni A, Pignatelli P, et al. ABC (Atrial
fibrillation Better Care) pathway and healthcare costs
in atrial fibrillation: the ATHERO-AF study. Am J Med
2019a;132:856-61.
Pastori D, Pignatelli P, Menichelli D, et al. Integrated care
management of patients with atrial fibrillation and risk of
cardiovascular events: the ABC (Atrial fibrillation Better
Care) pathway in the ATHERO-AF study cohort. Mayo Clin
Proc 2019b;94:1261-7.
Ponamgi SP, Siontis KC, Rushlow DR, et al. Screening and
management of atrial fibrillation in primary care. BMJ
2021;373:n379.
Proietti M, Romiti GF, Olshansky B, et al. Improved outcomes
by integrated care of anticoagulated patients with atrial
150 Management of Atrial Fibrillation
 fibrillation using the simple ABC (Atrial fibrillation Better
Care) pathway. Am J Med 2018;131:1359-1366.e6.
Reddy VY, Möbius-Winkler S, Miller MA, et al. Left atrial
appendage closure with the WATCHMAN device in
patients with a contraindication for oral anticoagulation:
the ASAP study (ASA Plavix Feasibility Study with Watch-
man Left Atrial Appendage Closure Technology). J Am Coll
Cardiol 2013;61:2551.
Reddy VY, Sievert H, Halperin J, et al. Percutaneous left
atrial appendage closure vs warfarin for atrial fibrillation: a
randomized clinical trial. JAMA 2014;312:1988-98.
Rienstra M, Hobbelt AH, Alings M, et al. Targeted therapy
of underlying conditions improves sinus rhythm mainte-
nance in patients with persistent atrial fibrillation: results
of the RACE 3 trial. Eur Heart J 2018;39:2987-96.
PSAP 2022 Book 1 • Cardiology
van der Heijden CAJ, Vroomen M, Luermans JG, et al. Hybrid
versus catheter ablation in patients with persistent and
longstanding persistent atrial fibrillation: a system-
atic review and meta-analysis. Eur J Cardiothorac Surg
2019;56:433-43.
Whitlock RP, Belley-Cote EP, Paparella D, et al. Left atrial
appendage occlusion during cardiac surgery to prevent
stroke. N Engl J Med 2021;384:2081-91.
Yoon M, Yang PS, Jang E, et al. Improved population-based
clinical outcomes of patients with atrial fibrillation by
compliance with the Simple ABC (Atrial Fibrillation Better
Care) pathway for integrated care management: a nation-
wide cohort study. Thromb Haemost 2019;119:1695-703.
151 Management of Atrial Fibrillation
Self-Assessment Questions
Questions 1 and 2 pertain to the following case.
R.C. is a 72-year-old woman (weight 75 kg) who presents to
her cardiologist’s office with a 1-week history of fatigue, with
periodic dizziness and palpitations. Her medical history is
significant for hypertension, diabetes, and stage 3 chronic
kidney disease (estimated CrCl 35 mL/minute/1.73 m2). R.C.
takes lisinopril 20 mg daily, furosemide 40 mg daily, insu-
lin glargine 15 units subcutaneously once daily, and insulin
aspart 5 units subcutaneously three times daily with meals.
Her vital signs are stable, and a physical examination reveals
no signs of volume overload. An ECG reveals atrial fibrillation
(AF) (no evidence of preexcitation).
1. According to her CHA 2DS2-VASc score, which one of the
following best evaluates R.C.’s annual stroke risk?
A. 1.3%
B. 2.2%
C. 3.2%
D. 4.0%
2. After a conversation between R.C. and her physician, a
decision is made to pursue a rate-control strategy. Which
one of the following is best to recommend for R.C.?
A. Diltiazem 180 mg extended release orally once daily
B. Amiodarone 400 mg orally twice daily for 2 weeks,
then 200 mg once daily
C. Digoxin 125 mcg orally daily
D. Flecainide 50 mg orally twice daily
Questions 3 and 4 pertain to the following case.
M.E. is a 52-year-old woman (weight 68 kg) who presents to
the ED this afternoon after new-onset palpitations and light-
headedness that began 3 hours ago after lunch with her
neighbor. She says she has never had symptoms like this
before. Her medical history is relevant for hyperlipidemia,
for which she takes atorvastatin 20 mg daily. A 12-lead ECG
reveals AF with a QRS duration of 90 milliseconds and QTc
interval of 410 milliseconds. M.E.’s blood pressure is 102/71
mm Hg with heart rate 148 beats/minute. She is resting com-
fortably in her hospital bed, and her basic metabolic panel
and CBC are within normal limits.
3. Which one of the following is best to recommend for car-
dioversion for M.E.?
A. Perform a transesophageal echocardiogram (TEE)
and sedate for direct current cardioversion (DCCV).
B. Sedate for DCCV.
C. Initiate dronedarone 400 mg orally twice daily.
D. Initiate ibutilide 1 mg intravenously over 10 minutes.
PSAP 2022 Book 1 • Cardiology
4. Which one of the following is best to recommend for pre-
vention of thromboembolism for M.E.?
A. Apixaban 5 mg orally twice daily
B. Rivaroxaban 15 mg orally once daily with the
evening meal
C. Anticoagulation not indicated
D. Aspirin 81 mg orally once daily
Questions 5 and 6 pertain to the following case.
G.K. is a 82-year-old man (weight 58 kg) with a medical history
that includes mitral stenosis (moderate), hypertension, diabe-
tes, and coronary artery disease (CAD). He arrives at the ED
after 1 week of dizziness and palpitations. G.K. has had peri-
odic episodes of “passing out” over the past 24 hours, accord-
ing to his wife. In the ED, his blood pressure is 85/63 mm Hg
and heart rate is 155 beats/minute. After his vital signs are
obtained, G.K. begins to lose consciousness.
5. Which one of the following is best to recommend for
G.K.?
A. Administer amiodarone 150 mg intravenously
administered over 10 minutes, followed by a
continuous infusion at 1 mg/minute.
B. Administer diltiazem 0.25 mg/kg intravenously
administered over 2 minutes, followed by a
continuous infusion at 5–15 mg/hour.
C. Administer therapeutic-dose low-molecular-weight
(LMWH) and perform an immediate TEE to assess
for LA thrombus.
D. Provide immediate DCCV.
6. Which one of the following is best to recommend to
reduce G.K.’s stroke risk?
A. Warfarin titrated to an INR goal of 2.0–3.0
B. Apixaban 2.5 mg orally twice daily
C. Catheter ablation
D. WATCHMAN device placement
7. A 62-year-old man (weight 98 kg) has a medical his-
tory that includes hypertension, diabetes, a myocardial
infarction (MI) (2 years ago), and paroxysmal AF diag-
nosed 2 months ago. His left ventricular ejection fraction
(LVEF) is 50%. The patient takes losartan 100 mg daily,
metformin 1000 mg twice daily, aspirin 81 mg daily, ator-
vastatin 80 mg daily, metoprolol succinate 200 mg daily,
and warfarin 7.5 mg once daily (INR 2.7). In the clinic
today, his heart rate is 78 beats/minute, with blood pres-
sure 118/80 mm Hg and ECG reflective of rate-controlled
AF (QRS 110 milliseconds, QTc interval 420 milliseconds).
152 Management of Atrial Fibrillation
 Despite being rate controlled, the patient continues to
have significant episodes of fatigue, dizziness, and palpi-
tations several times per week and would like to try phar-
macologic cardioversion. Which one of the following is
best to recommend for this patient?
A. Administer flecainide 100 mg orally twice daily.
B. Administer dronedarone 400 mg orally twice daily.
C. Admit to hospital and initiate dofetilide 500 mcg
orally twice daily.
D. Administer amiodarone 400 mg orally twice daily for
2 weeks, then 200 mg once daily.
Questions 8 and 9 pertain to the following case.
S.N. is a 67-year-old man with hypertension, heart failure
with reduced ejection fraction (HFrEF) (LVEF 25%), chronic
obstructive pulmonary disease, and paroxysmal AF; he pres-
ents to the clinic for a follow-up. S.N. takes apixaban 5 mg
twice daily, metoprolol succinate 200 mg daily, lisinopril
40  mg daily, hydrochlorothiazide 25 mg daily, furosemide
40  mg daily, and ipratropium 2 puffs as needed four times
daily. S.N. still has AF-related symptoms several times per
week, and his vital signs in the clinic today include blood pres-
sure 128/78 mm Hg and heart rate 115 beats/minute with an
irregularly irregular pulse on auscultation.
8. Which one of the following is best to recommend for
S.N.?
A. Digoxin 250 mcg orally once daily
B. Diltiazem 240 mg extended release orally once daily
C. Dronedarone 400 mg orally twice daily
D. Flecainide 100 mg orally twice daily
9. Which one of the following is the optimal target heart
rate (in beats/minute) to recommend for S.N.?
A. Less than 60
B. Less than 80
C. Less than 100
D. Less than 110
10. A 57-year-old man is admitted to the hospital for dofeti-
lide initiation. His CrCl is 78 mL/minute, and his baseline
ECG reveals AF (ventricular rate 104 beats/minute) with
a QTc interval of 430 milliseconds. A repeat ECG checked
after the first dofetilide dose of 500 mcg reveals a QTc
interval of 505 milliseconds. Which one of the following
is best to recommend for this patient?
A. Continue dofetilide 500 mcg orally twice daily.
B. Decrease dofetilide dose to 250 mcg orally twice
daily.
C. Decrease dofetilide dose to 125 mcg orally twice
daily.
D. Discontinue dofetilide.
PSAP 2022 Book 1 • Cardiology
11. A 64-year-old woman is seen in the clinic today in prepa-
ration for her upcoming AF catheter ablation next week.
She takes dabigatran 150 mg orally twice daily. Which
one of the following is best to recommend to manage
this patient’s periprocedural anticoagulation?
A. Hold dabigatran 24 hours before AF catheter
ablation procedure, administer unfractionated
heparin (UFH) to target an activated clotting time
(ACT) of 300 seconds or more during the procedure,
then resume dabigatran 3–5 hours after the
procedure.
B. Change dabigatran to LMWH 12–24 hours before the
procedure and continue LMWH during procedure,
then resume dabigatran 3–5 hours after the
procedure.
C. Continue taking dabigatran uninterrupted, and
administer UFH to target an ACT of 300 seconds or
greater during the procedure.
D. Change dabigatran to warfarin now, and continue
warfarin uninterrupted surrounding ablation
procedure, together with UFH to target an ACT of
300 seconds or more during the procedure.
12. A 58-year-old woman with newly diagnosed paroxysmal
AF presents to the ED with symptoms of dizziness and
palpitations that began about 1 hour ago. The patient
has hypertension and obesity; she takes lisinopril
10  mg daily, apixaban 5 mg twice daily, and metoprolol
tartrate 25 mg twice daily. Reviewing records of patient
self-documentation, together with the results of a 7-day
Holter monitor, reveals that the patient is symptom-
atic and aware of when she goes into AF. An ECG today
reveals AF (ventricular response rate 93 beats/minute)
and a QTc of 390 milliseconds, and her vital signs include
blood pressure 148/84 mm Hg. In the ED, an oral dose
of flecainide 200 mg is administered, which success-
fully converts the patient to normal sinus rhythm. The
patient wants to try a “pill-in-the-pocket” approach with
flecainide as needed. Which one of the following is best
to recommend for this patient?
A. Discontinue metoprolol.
B. Increase lisinopril to 20 mg daily.
C. Initiate aspirin 81 mg daily.
D. Discontinue apixaban.
153 Management of Atrial Fibrillation
13. A 63-year-old man has a history of severe GI bleeding
on direct oral anticoagulants (DOACs) (both apixaban
and  rivaroxaban) and is now being considered for
WATCHMAN placement. He currently has normal renal
function and stable vital signs. In considering his
post-WATCHMAN placement antithrombotic regimen,
which one of the following is best to recommend for this
patient?
A. Aspirin 81 mg daily indefinitely plus dabigatran
150 mg orally twice daily for 45 days, followed by
clopidogrel 75 mg orally daily for 6 months
B. Aspirin 325 mg orally daily
C. Aspirin 81 mg daily indefinitely plus clopidogrel
75 mg orally daily for 3 months
D. Aspirin 81 mg daily indefinitely plus warfarin 5 mg
daily (target INR 2–3) for 45 days, followed by
clopidogrel 75 mg daily for 6 months
Questions 14 and 15 pertain to the following case.
L.D. is an 85-year-old woman whose medical history includes
hypertension, AF, diabetes, end-stage renal disease on hemo-
dialysis, aortic stenosis (moderate), and sick sinus syndrome
after permanent pacemaker placement 6 years ago. Her
home drugs include losartan 100 mg daily, warfarin 2.5 mg
PSAP 2022 Book 1 • Cardiology
daily (INR 2.3 today), bisoprolol 2.5 mg daily, dronedarone 400
mg twice daily, and insulin glargine 30 units daily plus aspart
sliding scale with meals. L.D. presents today for her routine
clinic follow-up with no major concerns. Her vital signs and
ECG reveal blood pressure 121/78 mm Hg and AF (ventricular
rate 100 beats/minute) with a QTc of 425 milliseconds. Infor-
mation downloaded from her permanent pacemaker shows
that L.D. has been in AF more than 99% of the time for the past
14 months. After discussion with her cardiologist, she does
not want to undergo any more procedures or try any further
antiarrhythmic drugs.
14. Which one of the following best classifies L.D.’s AF?
A. Valvular AF
B. Longstanding persistent AF
C. Persistent AF
D. Permanent AF
15. After this office visit, which one of the following is best to
recommend for L.D.?
A. Change warfarin to rivaroxaban 15 mg orally daily,
with the evening meal.
B. Increase bisoprolol to 5 mg orally daily.
C. Discontinue dronedarone.
D. Make no medication adjustments.
154 Management of Atrial Fibrillation
Learner Chapter Evaluation: Management of Atrial Fibrillation

As you take the posttest for this chapter, also evaluate the 8. The teaching and learning methods used in the chapter
material’s quality and usefulness, as well as the achievement were effective.
of learning objectives. Rate each item using this 5-point scale: 9. The active learning methods used in the chapter were
effective.
• Strongly agree
10. The learning assessment activities used in the chapter
• Agree
were effective.
• Neutral
• Disagree 11. The chapter was effective overall.
• Strongly disagree 12. The activity met the stated learning objectives.
13. If any objectives were not met, please list them here.
1. The content of the chapter met my educational needs.
2. The content of the chapter satisfied my expectations.
3. The author presented the chapter content effectively.
OTHER COMMENTS
14. Please provide any specific comments related to any
4. The content of the chapter was relevant to my practice
perceptions of bias, promotion, or advertisement of
and presented at the appropriate depth and scope.
commercial products.
5. The content of the chapter was objective and balanced.
15. Please expand on any of your above responses, and/or
6. The content of the chapter is free of bias, promotion, and provide any additional comments regarding this chapter:
advertisement of commercial products.
7. The content of the chapter was useful to me.

PSAP 2022 Book 1 • Cardiology 155 Management of Atrial Fibrillation

Non-Statin Therapy for Dyslipidemia
By Nicholas W. Carris, Pharm.D., BCPS; and Kevin Cowart, Pharm.D., MPH, BCACP, CDCES

Reviewed by John Bucheit, Pharm.D., BCACP, CDCES; Gregory Castelli, Pharm.D., BCPS, BC-ADM; and Eugene N. Bush, Ph.D.,
BCPS, BCCCP

LEARNING OBJECTIVES

1. Distinguish between the drug therapy recommendations of several of the latest and leading guidelines.
2. Justify recommendations for individualized non-statin therapy.
3. Evaluate the role and place in therapy of specific non-statin medications.
4. Develop a comprehensive plan to optimize non-statin therapy.

ABBREVIATIONS IN THIS CHAPTER
ASCVD Atherosclerotic cardiovascular
disease
BAS Bile acid sequestrants
DHA Docosahexaenoic acid
EPA Eicosapentaenoic acid
FH Familial hypercholesterolemia
O3FAs Omega-3 fatty acids
PCSK9 Proprotein convertase subtilisin/
kexin type 9
RCT Randomized controlled trial
Table of other common abbreviations.
INTRODUCTION
Atherosclerotic cardiovascular disease (ASCVD) is the most common
cause of death in the United States and worldwide. Atherosclerotic
cardiovascular disease is defined as acute coronary syndrome, myo-
cardial infarction, stable or unstable angina, coronary or other arte-
rial revascularization, stroke, transient ischemic attack, or peripheral
artery disease, including aortic aneurysm, all of atherosclerotic origin.
Dyslipidemia is one of several factors contributing to the develop-
ment and progression of cardiovascular disease. In the United States,
69.6 million adults have high low-density lipoprotein cholesterol (LDL
cholesterol) (≥ 130 mg/dL), 41.9 million adults have low high-density
lipoprotein cholesterol (HDL cholesterol) (< 40 mg/dL), and 22.2% of
adults have high triglycerides (≥ 150 mg/dL) (Virani 2021). Statins are
the primary drug class used for managing dyslipidemia because of
the robust evidence supporting their effectiveness in reducing car-
diovascular events, their low cost, and their convenient daily oral
administration (Grundy 2019). The robust effectiveness for statins in
reducing ASCVD risk is primarily related to their ability to lower LDL
cholesterol. Non-statins can assist in further decreasing LDL choles-
terol to address residual risk. Other non-statin agents are indicated
for patients with elevated triglycerides to reduce both ASCVD and
pancreatic risk.
Before considering non-statin therapy, clinicians must ensure that
statin therapy has been optimized, and, in the case of statin intol-
erance, that several statins have been attempted. Only after these
optimization considerations should non-statin therapy be consid-
ered. Moreover, in cases for which clinicians do consider non-statin
therapies to manage dyslipidemia, the primary goal is prevention
of cardiovascular morbidity and mortality whereas the second-
ary goal is prevention of pancreatitis. Therefore, non-statin ther-
apy is reserved for patients who meet one or more of the following
criteria: 1) insufficient response to statin therapy; 2) intolerance to
statin therapy; 3)  severe hypertriglyceridemia, and 4) indicated use

PSAP 2022 Book 1 • Cardiology 157 Non-Statin Therapy for Dyslipidemia

of icosapent ethyl to lower cardiovascular risk. In all cases
of management with non-statin therapy, agents with cardio-
vascular benefit established in randomized controlled trials
(RCTs) should be used preferentially.
POPULATIONS LIKELY TO BENEFIT
FROM NON-STATIN THERAPY
A pathway summarizing the assessments and non-statin
treatment options is presented in Figure 1.
Insufficient Response to Statin Therapy
Insufficient responses to statin therapy can be grouped
into three categories, although each are addressed simi-
larly by the addition of non-statin therapy. First, patients
may have a high baseline LDL cholesterol, such that even
with a 50% reduction from baseline in LDL cholesterol with a
high-intensity statin, LDL cholesterol remains above a desired
threshold. Patients with homozygous or heterozygous famil-
ial hypercholesterolemia (FH) are likely to need non-sta-
tin therapy in addition to an optimized statin to surpass
BASELINE KNOWLEDGE STATEMENTS
Readers of this chapter are presumed to be familiar
with the following:
• Fundamental knowledge of lipid-lowering medica-
tions, their lipid-lowering effects, their safety
profile, and guideline-directed use of older
lipid-lowering medications, such as fibrates
• General treatment strategies, cardiovascular risk
assessment, and cardiovascular risk groups estab-
lished in the 2018 ACC/AHA Blood Cholesterol
Guideline
• Pathophysiology of atherosclerotic cardiovascular
disease
Table of common laboratory reference values
ADDITIONAL READINGS
The following free resources have additional back-
ground information on this topic:
• 2018 AHA/ACC Guideline on the Management of
Blood Cholesterol.
• Cardiovascular Disease and Risk Management:
Standards of Medical Care in Diabetes—2021.
• 2013 AHA/ACC/TOS Guideline for the Management
of Overweight and Obesity in Adults.
• 2017 Focused Update of the 2016 ACC Expert Con-
sensus Decision Pathway on the Role of Non-Statin
Therapies for LDL-Cholesterol Lowering in the Man-
agement of Atherosclerotic Cardiovascular Disease
Risk.
PSAP 2022 Book 1 • Cardiology
their LDL cholesterol threshold. Second, not all patients will
achieve the expected LDL cholesterol reduction based on
statin regimen potency, even with good adherence to ther-
apy. Thus, patients with residually elevated LDL cholesterol
(e.g., ≥ 70 mg/dL in a patient with ASCVD) may have the opportu-
nity to further reduce their cardiovascular risk with additional
therapy. Although medication-directed versus LDL cholesterol-
directed approaches to care have been debated, a growing
body of literature supporting very low LDL cholesterol as ben-
eficial was recently summarized (Karagiannis 2021). Finally,
some patients may not be able to tolerate the statin intensity
indicated for their disease and thus are more likely to have
an LDL cholesterol that remains above the desired threshold.
Across recent guidelines (Table 1 and Table 2), the most
common goal LDL cholesterol concentrations can be classi-
fied into two groups as follows: 1) in the primary prevention of
ASCVD, an LDL cholesterol goal less than 100 mg/dL, and 2) in
the secondary prevention of ASCVD, an LDL cholesterol goal
less than 70 mg/dL. To interpret these goals, knowledge of
risk factors is needed and is most conveniently summarized
by factors include in the ASCVD Risk Estimator Plus and “risk
enhancing factors” listed and described in the 2018 AHA/ACC
Guideline on the Management of Blood Cholesterol.
However, LDL cholesterol goals may be better viewed as
“thresholds” that, if not achieved, warrant consideration of
the addition of non-statin therapy. This approach is in con-
trast to a typical “goal” because some patients may have rela-
tively low LDL cholesterol at baseline, yet initial statin therapy
is based on cardiovascular risk; therefore, initial therapy may
often be the same as for a patient with relatively higher base-
line LDL cholesterol. For example, a statin-naive patient
status post-myocardial infarction with a baseline LDL choles-
terol of 99 mg/dL may be able to achieve an LDL cholesterol
less than 70 mg/dL with a moderate-intensity statin; however,
based on the patient’s cardiovascular risk, a high-intensity
statin is indicated. The “goal” of LDL cholesterol of less
than 70 mg/dL only becomes relevant if the optimized statin
dose (in this case, a high-intensity statin) does not achieve
an LDL cholesterol of less than 70 mg/dL. The potential to
achieve a goal LDL cholesterol with a lower potency statin
than indicated based on cardiovascular risk, in either pri-
mary or secondary prevention, should not be a rationale to
underdose statin therapy. Similarly, the potential to achieve
an LDL cholesterol goal with an intentionally underdosed
statin plus non-statin therapy is not warranted. Conversely, in
a patient with ASCVD who is unable to tolerate high-intensity
statin therapy, it is reasonable to treat with the maximum
tolerated statin (e.g., moderate-intensity statin), then add
non-statin therapy to achieve the recommended LDL cho-
lesterol reduction. These thresholds and approaches closely
relate between the American Diabetes Association standards
of care and the multi-society blood cholesterol guidelines.
However, the American Association of Clinical Endocrinolo-
gists and American College of Endocrinology joint consensus
158 Non-Statin Therapy for Dyslipidemia
 A.

Assess ASCVD Risk, Baseline and Current Lipid

Panel, Current and Past Lipid Therapies, Current
Statin Intensity, and Indicated Statin Intensity

Is Patient on Indicated Statin Therapy or Yes

Maximally Tolerated Statin Therapy AND is their
LDL-C at Goal Based on ASCVD Risk?

No
Maximize Statin Therapy

Does the Patient Need a 25% Reduction in LDL-C Evaluate for

or More to Reach Their Goal? Residual
ASCVD
Prefer Prefer Risk
In In Reduction
No Primary Secondary Yes and
Prevention Prevention Triglyceride
And FH Targeted
Therapy
Consider Ezetimibe, Consider a PCSK9 (Box 3B)
Alternatively or Inhibitor, Alternatively
Subsequently a PCSK9 or Subsequently
Inhibitor Can be Used Ezetimibe Can be Used

If Not at Goal, Consider Bile Acid Sequestrant,

Bempedoic Acid, or Referral to Lipid Specialist

Figure 1. Pathways for implementing non-statin therapy: A,  LDL cholesterol lowering with non-statin therapy;
B, residual ASCVD risk reduction and triglyceride targeted therapy.
Information from: Bays HE, Braeckman RA, Ballantyne CM, et al. Icosapent ethyl, a pure EPA omega-3 fatty acid: effects on
lipoprotein particle concentration and size in patients with very high triglyceride levels (the MARINE study). J Clin Lipidol
2012;6:565-72; Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl
J Med 2019;380:11-22; Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APHA/ASPC/
NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart
Association Task Force on clinical practice guidelines. Circulation 2019;139:e1082-143; Handelsman Y, Jellinger PS, Guerin CK, et al.
Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the
management of dyslipidemia and prevention of cardiovascular disease algorithm—2020 executive summary. Endocr Pract
2020;26:1196-224; Harris WS, Ginsberg HN, Arunakul N, et al. Safety and efficacy of Omacor in severe hypertriglyceridemia. J
Cardiovasc Risk 1997;4:385-91; Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-
centered management of dyslipidemia: part 1—full report. J Clin Lipidol 2015a;9:129-69; Jacobson TA, Maki KC, Orringer CE, et al.
National Lipid Association recommendations for patient-centered management of dyslipidemia: part 2. J Clin Lipidol 2015b;9:S1-
122.e1.

(continued)

statement offers an even lower threshold (LDL cholesterol <
55 mg/dL) for patients at the highest cardiovascular risk.
After confirming that statin therapy has been optimized,
non-statin therapy can be considered. The next class of
agents with the most compelling evidence of cardiovascular
benefit are the proprotein convertase subtilisin/kexin type 9
(PCSK9) inhibitors evolocumab and alirocumab (Schwartz
2018; Sabatine 2017). Alternatively, ezetimibe is an option
with evidence of cardiovascular benefit, although it offers
less LDL cholesterol reduction compared with PCSK9 inhib-
itors (Handelsman 2020; Cannon 2015). For patients near
their LDL cholesterol threshold, ezetimibe may be preferred

PSAP 2022 Book 1 • Cardiology 159 Non-Statin Therapy for Dyslipidemia

 B.

Is the Patient Indicated for Icosapent Ethyl for ASCVD Risk Reduction? Atherosclerotic cardiovascular
disease, ASCVD
- Triglycerides 135–499 mg/dL, and
- Maximally tolerated statin, and Docosahexaenoic acid, DHA
- ASCVD or Diabetes plus at least 2 ASCVD risk factors Eicosapentaenoic acid (EPA)

No Yes Low density lipoprotein

cholesterol, LDL-C
Does the Patient have Start Icosapent Ethyl for Proprotein convertase
Serum Triglycerides ASCVD Risk Reduction subtilisin/kexin type 9, PCSK9
500 mg/dL or greater?

Yes No

Does the Patient have

Continue to Monitor Yes Implement Triglyceride Targeted Lifestyle
Response to Serum Triglycerides Intervention, Consider Fibrate Therapy
Therapy, Implement 500 mg/dL or greater? and Referral to Lipid Specialist
Lifestyle
Intervention No

Continue to Monitor Response to Therapy, Implement Lifestyle Intervention

Does the Patient have

Serum Triglycerides Yes Start Prescription Combination EPA/DHA Product and Implement
650 mg/dL or greater? Triglyceride Targeted Lifestyle Intervention
No

Start lcosapent Ethyl for Does the Patient have Yes
Triglyceride Reduction and Serum Triglycerides
Implement Triglyceride Targeted 500 mg/dL or greater?
Lifestyle Intervention
No
Consider Fibrate Therapy and
Referral to Lipid Specialist,
Continue to Monitor Response to
Therapy

Continue to Monitor
Response to Therapy

Figure 1. Pathways for implementing non-statin therapy: A,  LDL cholesterol lowering with non-statin therapy;
B, residual ASCVD risk reduction and triglyceride targeted therapy.
Information from: Bays HE, Braeckman RA, Ballantyne CM, et al. Icosapent ethyl, a pure EPA omega-3 fatty acid: effects on
lipoprotein particle concentration and size in patients with very high triglyceride levels (the MARINE study). J Clin Lipidol
2012;6:565-72; Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl
J Med 2019;380:11-22; Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APHA/ASPC/
NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart
Association Task Force on clinical practice guidelines. Circulation 2019;139:e1082-143; Handelsman Y, Jellinger PS, Guerin CK, et al.
Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the
management of dyslipidemia and prevention of cardiovascular disease algorithm—2020 executive summary. Endocr Pract
2020;26:1196-224; Harris WS, Ginsberg HN, Arunakul N, et al. Safety and efficacy of Omacor in severe hypertriglyceridemia. J
Cardiovasc Risk 1997;4:385-91; Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-
centered management of dyslipidemia: part 1—full report. J Clin Lipidol 2015a;9:129-69; Jacobson TA, Maki KC, Orringer CE, et al.
National Lipid Association recommendations for patient-centered management of dyslipidemia: part 2. J Clin Lipidol 2015b;9:S1-
122.e1.

over PCSK9 inhibitors because of its lower cost and the con-
venience of oral administration. Of note, patients treated with
PCSK9 inhibitors may achieve very low LDL cholesterol con-
centrations. Concentrations as low as 20 mg/dL are consid-
ered safe and beneficial, although with some potential risks
(Karagiannis 2021; Giugliano 2017b).
Statin Intolerance
A leading cause for statin intolerance is muscle symptoms,
primarily myalgia, which can reduce statin adherence and
worsen cardiovascular outcomes (Box 1). In practice, up to
30% of patients experiences challenges in tolerating statin
therapy; however, this difficulty may be attributed to many

PSAP 2022 Book 1 • Cardiology 160 Non-Statin Therapy for Dyslipidemia

 Table 1. Summary of Guideline Recommendations for Managing Blood LDL Cholesterol for the Primary Prevention of
Atherosclerotic Cardiovascular Disease

Guideline Primary Prevention of ASCVD

2021 ADA: With diabetes: With diabetes: With diabetes: Adults with diabetes; 10-year
Standards of Age 20–39 yr; ASCVD Age 40–75 yr; use At higher ASCVD risk; ASCVD risk 20% or higher;
Medical Care in risk factors; moderate-intensity High-intensity statin May be reasonable to add
Diabetes Statin therapy may be statin therapy is reasonable ezetimibe to maximally
reasonable tolerated statin therapy
to reduce LDL-C by 50% or
more

2020 AACE/ACE: No risk factors: < 2 risk factors and 2 or more risk factors Diabetes with at least 1
Management of LDL-C Goal is < 130 10-year risk < 10%; and 10-year risk risk factor OR CKD at least
Dyslipidemia and mg/dL LDL-C Goal is < 100 10-20% OR diabetes stage 3 with albuminuria OR
Prevention of mg/dL OR CKD; heterozygous FH OR ASCVD
Cardiovascular LDL-C Goal < 100 mg/dL risk > 20%:
Disease LDL-C Goal < 70 mg/dL

To reach goal: Moderate-Intensity Statin→ High-Intensity Statin→ add PCSK9i→ add ezetimibea

2018 AHA/ACC/ Without Diabetes or Without diabetes or With diabetes; without LDL-C of 190 mg/dL or more;
AACVPR/AAPA/ LDL-C of 190 mg/dL LDL-C of 190 mg/dL LDL-C of 190 mg/dL high-intensity statin; add
ABC/ACPM/ or greater; 10-year or greater; 10-year or greater; moderate- ezetimibe if LDL-C not
ADA/AGS/ ASCVD risk of 5% ASCVD risk of 20% or intensity statin; reduced 50% or if LDL-C
APhA/ASPC/ to < 20%; assess more; high-intensity Consider high-intensity remains > 100 mg/dL;
NLA/PCNA cardiovascular risk statin; if would benefit statin based on Triple therapy options:
Guideline on the factors not accounted from high-intensity ASCVD risk; if high- a) if LDL-C still not reduced
Management for in risk calculator; statin, but cannot risk, can consider 50% and TGs 300 mg/dL or
of Blood consider moderate- tolerate, can consider adding ezetimibe to less consider BAS
Cholesterol intensity statin adding ezetimibe achieve 50% reduction b) if heterozygous FH and
in LDL-C LDL-C 100 mg/dL or
greater, consider PCSK9i
Age 40–75 yr
c) if baseline LDL-C was
220 mg/dL or greater and
LDL-C remains 130 mg/dL
or greater consider PCSK9i

a
Ezetimibe may be preferred as second-line therapy because of low cost in patients needing 20% LDL cholesterol reduction or less.
ASCVD = atherosclerotic cardiovascular disease; BAS = bile acid sequestrant; CKD = chronic kidney sisease; FH = familial
hypercholesterolemia; LDL-C = LDL cholesterol; PCSK9i = proprotein convertase subtilisin/kexin type 9 inhibitor; TGs = triglycerides.
Information from: American Diabetes Association. Cardiovascular disease and risk management: standards of medical care in
diabetes-2021. Diabetes Care 2021;44(Suppl 1):S125-S150; Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/
ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College
of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation. 2019;139:e1082-e1143;
Handelsman Y, Jellinger PS, Guerin CK, et al. Consensus statement by the American Association of Clinical Endocrinologists and
American College of Endocrinology on the management of dyslipidemia and prevention of cardiovascular disease algorithm - 2020
executive summary. Endocr Pract 2020;26:1196-2.

(continued)
causes, including the nocebo effect, based on the observa-
tion that only about 10% of patients in RCTs report statin intol-
erance (Newman 2019). In brief, the nocebo effect entails the
patient expectation of myalgia that subsequently results in
the actual experience of myalgia. Two recent major publica-
tions suggest that many statin-treated patients who report
myalgia may be experiencing these muscle symptoms not
because of the effects of the statin, but instead because of
a “nocebo” effect (Herrett 2021; Wood 2020). The nocebo
effect may arise with statin therapy because of medication
counseling provided to the patient regarding potential muscle
effects, the patient’s exposure to negative media regarding
statins and muscle effects, or the patient’s discussion with
peers regarding statins and muscle effects.
Two trials recently tested the nocebo effect using a method
known as a series of “n-of-1” trials (Herrett 2021; Wood 2020).

PSAP 2022 Book 1 • Cardiology 161 Non-Statin Therapy for Dyslipidemia

 Table 2. Summary of Guideline Recommendations for Managing Blood LDL Cholesterol for the Secondary Prevention of
Atherosclerotic Cardiovascular Disease

Guideline Secondary Prevention of ASCVD

2021 ADA: Standards With diabetes; high-intensity With diabetes; if very high risk with ASCVD; if LDL-C is 70 or greater
of Medical Care in statin for all patients on maximally tolerated statin consider adding ezetimibe or
Diabetes PCSK9i; ezetimibe may be preferred because of lower cost

2020 AACE/ACE: Recent hospitalization for LDL-C goal is < 55 mg/dL in three cases
Management of acute coronary syndrome OR a. Progressive ASCVD;
Dyslipidemia and established clinical ASCVD; b. E
 stablished clinical ASCVD AND diabetes OR CKD stage 3 or
Prevention of LDL-C goal is < 70 mg/dL greater OR heterozygous FH;
Cardiovascular Disease c. P
 remature ASCVD age < 55 yr (men), age < 65 yr (women);

To reach goal: High-Intensity Statin→ add PCSK9i→ add ezetimibea,b

2018 AHA/ACC/AACVPR/ ASCVDc and age over 75 yr; ASCVD and age 75 yr and Very high risk ASCVD; high-
AAPA/ABC/ACPM/ADA/ start moderate-or high- less; high-intensity statin or intensity statin or maximum
AGS/APhA/ASPC/NLA/ intensity statin; continue maximum tolerated statin; tolerated statin; if LDL-C remains
PCNA Guideline on the high-intensity statin if LDL-C remains > 70 mg/dL > 70 mg/dL consider adding
Management of Blood consider adding ezetimibe ezetimibe; if LDL-C remains > 70
Cholesterol mg/dL consider added PCSK9i

a
Ezetimibe may be preferred as second-line therapy because of low cost in patients needing 20% LDL-C reduction or less
b
Consider colesevelam or bempedoic acid as alternative third-line agent to ezetimibe or PCSK9 inhibitor if needed
c
With atherosclerotic origin, includes the following conditions: acute coronary syndrome, myocardial infarction, stable or unstable
angina, coronary or other arterial revascularization, stroke, transient ischemic attack, peripheral artery disease, and aortic aneurysm.
ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; FH = familial hypercholesterolemia; LDL-C = LDL
cholesterol; PCSK9i = proprotein convertase subtilisin/kexin type 9 inhibitor.
Information from: American Diabetes Association. 10. Cardiovascular disease and risk management: standards of medical care in
diabetes-2021. Diabetes Care. 2021;44(Suppl 1):S125-S150; Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/
ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College
of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation 2019;139(25):e1082-e1143;
Handelsman Y, Jellinger PS, Guerin CK, et al. Consensus statement by the American Association of Clinical Endocrinologists and
American College of Endocrinology on the management of dyslipidemia and prevention of cardiovascular disease algorithm—2020
executive summary. Endocr Pract 2020;26:1196-224.

Box 1. Definitions of SAMSa

2002 ACC/AHA Advisory on Statins • Myopathy: Weakness
• Myopathy: Any muscle symptoms (SAMS) • Myositis: Inflammation
• Myalgia: SAMS CK = NL • Myonecrosis: CK 3 × ULN
• Myositis: SAMS CK > ULN ○ Mild: CK > 3, < 10 × ULN
• Rhabdomyolysis: CK > 10 × ULN ○ Moderate: CK > 10, < 50 × ULN
○ Severe: CK > 50 × ULN
2013 Canadian Work Group
○ Rhabdomyolysis: CK > ULN and SCr > 0.5 mg/dL baseline
• Myopathy: Any muscle symptoms (SAMS)
• Symptomatic myalgia: 2018 ACC/AHA Cholesterol Guidelines
○ Myalgia CK ≤ ULN • Myalgias: CK = NL
○ Myositis CK > ULN • Myositis/myopathy: CK > ULN with symptoms of concern or
○ Rhabdomyolysis CK > 10 × ULN objective weakness

2014 NLA Muscle Safety Task Force • Rhabdomyolysis: CK >10 × ULN + renal injury
• Myalgia: Aching, stiffness, cramps
a
Normal CK range is 38–174 units/L for men and 96–140 units/L for women.
ACC = American College of Cardiology; AHA = American Heart Association; SAMS = statin-associated muscle symptoms; NL = normal
limit; NLA = National Lipid Association; ULN = upper limit of normal.
Reprinted from: Beavers CJ, Kelly MS. Dyslipidemia. In: Murphy JE, Lee MW, eds. Pharmacotherapy Self-Assessment Program, 2019 Book
1. Cardiology. Lenexa, KS: American College of Clinical Pharmacy, 2019:31-54.

PSAP 2022 Book 1 • Cardiology 162 Non-Statin Therapy for Dyslipidemia

The trials included patients who had stopped or were consid-
ering stopping statin therapy because of adverse effects. In
these studies, patients received blinded treatment with ator-
vastatin 20 mg tablets and placebo, alternating through sev-
eral phases. One of the trials also included a no-treatment
phase. While rotating through randomized, blinded phases,
patients reported their muscle symptoms. In both trials, patient
reported muscle symptoms were similar during the placebo
and statin phase, suggesting that statin-related myalgia may
be the result of a nocebo effect. However, the trials were not
without weakness. Although power is greatly increased by the
multiple paired comparison, with each patient serving as their
own control for several comparisons, one trial included only
60 patients. The second trial was only able to analyze data for
151 of 200 intended patients; only 114 patients completed all
six treatment periods. Among the 114 patients, 17 had average
muscle symptoms at least one unit higher during statin ther-
apy versus placebo, suggesting that statins may be contrib-
uting to muscle symptoms for these patients (Herrett 2021).
Another weakness is that the studies used atorvastatin
20 mg/day. Because of the potential for the adverse effects
of a statin on muscles to be dose related and because the
reports of muscle pain overall were low in both trials, it is pos-
sible that the results may have differed with a higher ator-
vastatin dose. Despite these weaknesses, on unblinding and
counseling, 34 patients (57% of all patients) in one trial and 65
patients (68% of patients informed that statins were unlikely
to be contributing to their muscle symptoms) in the other trial
had restarted or planned to restart statin therapy. Therefore,
it is possible that if “n-of-1 packs” were made available, clini-
cians could use this approach to assess muscle symptoms
and counsel patients to increase statin use. After attempts
to optimize statin therapy, non-statin options are the same as
those for an insufficient statin response.
In context on these considerations, clinicians should
obtain a detailed history of muscle symptoms at baseline,
including current muscle symptoms and activities known to
provoke muscle symptoms, to avoid misattribution of myal-
gia to statin therapy. The baseline history should be paired
with detailed counseling on the risks and benefits of statin
therapy to prevent undue statin interruption or discontinua-
tion. Statins are more likely the cause of myalgia if the pain
is bilateral, involves proximal muscles, has an onset within
weeks or months of statin therapy, and improves on statin
discontinuation. Neither the potential for adverse effects
of statins nor the adverse effects associated with one sta-
tin should typically dissuade clinicians from pursuing sta-
tin therapy (Grundy 2019). Indeed, a trial of as many different
statins as a patient is willing to attempt is often reasonable
in response to non-severe adverse effects before concluding
that a patient has complete statin intolerance (Nissen 2016).
For the management of non-severe muscle symptoms, sev-
eral approaches have been attempted in addition to trials of
several different statins. However, current data largely do
PSAP 2022 Book 1 • Cardiology
not support their use, including vitamin D or coenzyme Q10
(Grundy 2019). In cases of severe muscle symptoms, cre-
atinine kinase values should be measured. Notably, statins
are associated with more severe muscle conditions, such as
myopathy, myositis, rhabdomyolysis, and statin-associated
autoimmune myopathy, all of which are possible, but rare,
with each requiring their own management (Newman 2019).
Non-Statin Recommendations
for Hypertriglyceridemia
Apart from cardiovascular risk reduction, non-statin thera-
pies can be selectively used in the management of very high
triglycerides (≥ 1000 mg/dL) to reduce the risk for pancre-
atitis (Jacobson 2015a). Serum triglyceride concentrations
of 1000 mg/dL or greater should be managed with prescrip-
tion omega-3-acid ethyl esters (O3FAs), icosapent ethyl, or
fibrates. For patients with serum triglyceride concentrations
500–999 mg/dL and an ASCVD risk of 7.5% or higher, statin
therapy is often sufficient for cardiovascular risk reduction,
although high-intensity statin therapy may be needed for
sufficient triglyceride reduction. Non-statin therapy may be
required for additional lowering of triglycerides to achieve
a concentration less than 500 mg/dL after attempting to
address the underlying cause(s) for a patient’s high tri-
glycerides, including therapeutic lifestyle changes. Patients
whose triglycerides remain high may have success with ico-
spent ethyl to lower triglycerides (as discussed in the follow-
ing section). Or, in the case of very high triglycerides, patients
may benefit more with respect to triglyceride reduction and
the decreased risk of pancreatitis from treatment with typi-
cal prescription O3FA products containing eicosapentaenoic
acid (EPA) and docosahexaenoic acid (DHA) because tri-
glycerides can be reduced by as much as 45% depending on
baseline triglyceride concentration (Harris 1997). Fibrates are
alternative agents that include fenofibrate, which can be used
with statins, and gemfibrozil, which should not be used with
statins. For patients with triglyceride concentrations less
than 500 mg/dL, cardiovascular risk reduction is the sole con-
cern, and statin therapy based on cardiovascular risk should
predominate. For patients with triglycerides concentrations
less than 500 mg/dL, therapeutic lifestyle changes are the
primary intervention to directly address high triglycerides.
Indication Directed Use of Icosapent Ethyl
The REDUCE-IT trial (discussed in detail in the Omega-3 Fatty
Acids section) demonstrated the cardiovascular benefit of
icosapent ethyl (Bhatt 2019). Based on these data, icosapent
ethyl has been incorporated into several society guidelines
for ASCVD risk reduction, although for specific patients who
match the REDUCE-IT trial inclusion and exclusion criteria
(American Diabetes Association 2021b; Handelsman 2020).
However, in considering the tandem goal of lowering tri-
glycerides to less than 500 mg/dL and to decrease both the
pancreatitis risk and ASCVD risk, several considerations are
163 Non-Statin Therapy for Dyslipidemia
 key. Notably, the multi-society blood cholesterol guideline
Box 2. Non-Statin Drugs with Evidence
was published before the finding that icosapent ethyl low-
Supporting ASCVD Risk Reductiona
ered the cardiovascular risk; therefore, for pharmacologic
• PCSK9 inhibitors management of triglycerides, the guideline focused on low-
• Ezetimibe ering triglycerides less than 500 mg/dL to reduce pancreati-
• Icosapent ethyl
• Bile acid sequestrants tis risk (Bhatt 2019; Grundy 2019). In addition, because of
• Gemfibrozil the potential for cardiovascular benefit, icosapent ethyl may
be preferred in some circumstances for triglyceride lower-
a
Listed in order of preference. ing, despite no reflection of this preference in the multi-soci-
ASCVD = atherosclerotic cardiovascular disease; PCSK9 =
proprotein convertase subtilisin/kexin type 9.
ety guideline. However, use of icosapent ethyl in populations

Table 3. Non-Statin Pharmacotherapy

Drug Class Dosing Impact on Lipids Considerations

PCSK9 Inhibitors

Alirocumab • Initial: 75 mg SQ every • Mean LDL-C • Adverse effects

2 wk; may increase to reduction up to 60% ○ Alirocumab: nasopharyngitis, injection site

150 mg every 2 wk • Mean TG reduction reactions, influenza

• Alternative initial dose is up to 17% ○ Evolocumab: nasopharyngitis, upper

300 mg SQ every 4 wk • Mean non-HDL-C respiratory tract infection, influenza, back

reduction up to 53% pain, and injection site reactions
Evolocumab • ASCVD or Heterozygous
• No clinically significant drug–drug
FH: 140 mg SQ every 2 wk
interactions
or 420 mg SQ once monthly
• Other considerations: cost/prior authorization
• Homozygous FH: 420 mg
burden, injectable therapy
SQ once monthly

Omega-3 Fatty Acids

Omega-3-ethyl 4 g/day • Mean TG reduction • Adverse effects

esters (Lovaza) up to 50% ○ Lovaza: burping, dyspepsia, fishy aftertaste

• Mean HDL-C ○ Vascepa: musculoskeletal pain, peripheral

increase up to 9% edema, constipation, gout

• May increase LDL-C • Drug interactions: antiplatelets (increased
bleeding risk)
• Other considerations: may increase atrial
Icosapent Ethyl 4 g/day • Mean TG reduction
fibrillation risk (Lovaza and Vascepa); use
(Vascepa) up to 27%
caution with fish/shellfish allergy
• May decrease HDL-C
and increase LDL-C

Cholesterol Absorption Inhibitor

Ezetimibe 10 mg/day with or without • Mean LDL-C • Adverse effects

food reduction up to 20% ○ Monotherapy: upper respiratory tract

monotherapy (25% infection, diarrhea, arthralgia, sinusitis,

when used with a pain in extremity
statin) ○ In combination with statin:

• Mean HDL-C nasopharyngitis, myalgia, upper respiratory

increase up to 4% tract infection, arthralgia, diarrhea
• Mean TG reduction • Drug–drug interactions: cyclosporine,
up to 10% fibrates, cholestyramine (separate by ≥ 2 hr
before or ≥ 4 hr after BAS dose)
• Other considerations: well tolerated, available
as generic; contraindicated in active liver
disease, and pregnancy/breastfeeding

(continued)

PSAP 2022 Book 1 • Cardiology 164 Non-Statin Therapy for Dyslipidemia

 Table 3. Non-Statin Pharmacotherapy  (continued)

Drug Class Dosing Impact on Lipids Considerations

ACL Inhibitor

Bempedoic acid 180 mg/day with or without • Mean LDL-C • Adverse effects: gout, tendon rupture, upper
food reduction up to 23% respiratory tract infection, abdominal/back
(monotherapy), pain, anemia
up to 48% (with • Drug–drug interactions: statins
ezetimibe), up to • Considerations: pregnancy and breastfeeding
27% (with PCSK9
inhibitor), and up to
24% (with statin)
• Mean non-HDL-C
reduction up to 12%

BAS

Cholestyramine 8–16 g/day divided into
2 doses
Colestipol 2–16 g/day given once or in
divided doses
Colesevelam • Tablets: 6 tablets daily or
3 tablets twice daily; take
tablets with a meal and
liquid
• Suspension: one 3.75-g
• Mean LDL-C • Adverse effects: constipation, dyspepsia,
reduction up to 30% abdominal pain, and nausea
• Mean HDL-C • Drug–drug interactions: phenytoin, warfarin,
increase up to 5% digoxin, levothyroxine, fat-soluble vitamins
• May increase TG (A, D, E, K)
• Drugs with potential interaction should be
taken ≥ 1 hr before or ≥ 4 hr after BAS to avoid
impeding their absorption
• Other considerations:
○ Inconvenient preparation: pill burden with

packet daily, or one tablets and oral suspension

1.875-g packet twice daily; ○ Colesevelam lowers A1C by about 0.5% and

mix powder with 4–8 oz has fewer GI adverse effects than other
of water, fruit juice, or soft BAS
drink; take with meal ○ Cholestyramine is contraindicated with

• Note: 3.75 g is equivalent compete biliary obstruction

to 6 tablets, and 1.875 g is ○ Colesevelam is contraindicated with bowel

equivalent to 3 tablets obstruction

Fibrates

Gemfibrozil 600 mg twice daily • Mean HDL-C • Adverse effects: mild GI, dyspepsia, myopathy
increase up to 15% • Drug–drug interactions
Fenofibrate 48–145 mg once daily
• Mean TG decrease ○ Warfarin, immunosuppressants, BAS

up to 50% ○ Gemfibrozil: avoid with lovastatin,

Fenofibric acid 35–105 mg once daily pravastatin, simvastatin; may be

acceptable with atorvastatin, rosuvastatin,
and pitavastatin if fibrate needed and
fenofibrate is not an option
• Other considerations: contraindicated
in breastfeeding, severe liver, renal and
gallbladder disease; may increase liver
transaminases

ACL = adenosine triphosphate-citrate lyase; ASCVD = atherosclerotic cardiovascular disease; BAS = bile acid sequestrants;
FH = familial hypercholesterolemia; HDL-C = high-density lipoprotein cholesterol; LDL-C = LDL cholesterol; PCSK9 = proprotein
convertase subtilisin/kexin type 9; SQ = subcutaneous; TG = triglycerides.
Information from: Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APHA/ASPC/NLA/
PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart
Association Task Force on clinical practice guidelines. Circulation 2019;139:e1082-143; manufacturers’ package inserts.

PSAP 2022 Book 1 • Cardiology 165 Non-Statin Therapy for Dyslipidemia

beyond the REDUCE-IT trial inclusion/exclusion criteria may
or may not experience the same cardiovascular benefit.
NON-STATIN AGENTS
FOR DYSLIPIDEMIA
In choosing non-statin agents for the treatment of dyslipid-
emia, evidence supporting the reduction of ASCVD risk is the
primary deciding factor (Box 2). In Figure 1 and Table 3, the evi-
dence is summarized to facilitate this decision-making pro-
cess in a patient-specific manner. In addition, older agents,
some options and some to be avoided, are addressed. As a
part of choosing non-statin medications to reduce ASCVD
risk, the benefit of some agents may be limited to patients
with specific dyslipidemia patterns. Finally, safety and drug
interactions must also be taken into account. For patients
with very high triglyceride concentrations, specific pharma-
cologic treatment to reduce the risk of pancreatitis should be
considered.
PCSK9 Inhibitors
The LDL receptors on hepatocytes are degraded by the enzyme
PCSK9, which is predominately produced in the liver. By
inhibiting the PCSK9 enzyme, more LDL receptors are avail-
able to remove plasma LDL cholesterol, as described in the
manufacturers’ package inserts. When combined with sta-
tin therapy, PCSK9 inhibitors provide up to an additional 60%
reduction in LDL cholesterol and can lower triglycerides by up
to 17%. Currently available PCSK9 inhibitors are alirocumab
and evolocumab, which are humanized monoclonal antibodies.
The ASCVD benefit of alirocumab was demonstrated in the
ODYSSEY OUTCOMES trial (Schwartz 2018). Patients with an
acute coronary syndrome in the previous 12 months with an
LDL cholesterol 70 mg/dL or greater, or a non-HDL cholesterol
100 mg/dL or greater, or apolipoprotein B 80 mg/dL or greater
were randomly assigned to receive alirocumab added to their
current maximally tolerated statin and ezetimibe therapy. The
composite primary end point was death from coronary heart
disease, nonfatal myocardial infarction, fatal or nonfatal isch-
emic stroke, or unstable angina requiring hospitalization. At
median follow-up of almost 3 years, alirocumab significantly
reduced the composite primary end point, with the greatest
absolute benefit among patients with a baseline LDL choles-
terol greater than 100 mg/dL.
The FOURIER trial evaluated the second PCSK9 inhib-
itor, evolocumab, in patients with clinical ASCVD plus addi-
tional risk factors and who had an LDL cholesterol 70
mg/dL or greater or non-HDL cholesterol 100 mg/dL or greater
on maximally tolerated statin therapy with or without ezeti-
mibe (Sabatine 2017). The median baseline LDL cholesterol
was 92 mg/dL with 70% of patients on a high-intensity statin,
and 30% of patients on a moderate-intensity statin (Sabatine
2017). The composite primary end point was cardiovascu-
lar death, myocardial infarction, stroke, hospitalization for
PSAP 2022 Book 1 • Cardiology
unstable angina, or coronary revascularization. Evolocumab
significantly reduced the risk of the composite primary end
point (absolute risk reduction [ARR] 1.5%; HR 0.85; 95% CI,
0.79–0.92) and reduced the composite of cardiovascular
death, myocardial infarction, or stroke (ARR 1.5%; HR 0.80;
95% CI, 0.73–0.88). Although adverse events did not differ by
subgroups stratified by minimum LDL cholesterol achieved,
concerns were raised over the low LDL cholesterol reached
in FOURIER and the impact on cognition. The median LDL
cholesterol attained in the evolocumab arm was 30 mg/dL;
however, the EBBINGHAUS study, which analyzed a sub-
group of patients from the FOURIER trial, found no significant
between-group difference in cognitive function over a median
of 19 months (Giugliano 2017a). Evolocumab has also been
shown to reduce the LDL cholesterol with a similar adverse
event profile to placebo in pediatric patients with FH.
The PCSK9 inhibitors, which are available as subcutane-
ous injections and administered every 2–4 weeks, are gener-
ally well tolerated. The most common adverse drug reactions
are injection site reactions, immunologic or allergic reac-
tions, and nasopharyngitis, according to the manufacturers’
package inserts. Injection site reaction event rates in the
FOURIER and ODYSSEY trials for treatment versus placebo
were 2.1% vs. 1.6% and 3.8% vs. 2.1%, respectively (Schwartz
2018; Sabatine 2017). Monoclonal antibodies are not elimi-
nated by the kidneys and can therefore be used in patients
with mild to moderate renal impairment, although they are
not well studied in patients with severe renal impairment,
according to the manufacturers’ package inserts. A major
limitation to using PCSK9 inhibitors is their high cost. The
cost-effectiveness of PCSK9 inhibitors for primary preven-
tion among patients with an LDL cholesterol greater than
190 mg/dL or in those with FH has not been evaluated exten-
sively. However, because the cost of PCSK9 inhibitors has
decreased since the publication of the 2018 American Heart
Association/American College of Cardiology guidelines,
cost-effectiveness is now acceptable in those with very
high-risk ASCVD (Fonarow 2019).
The current place in therapy for PCSK9 inhibitors is in addi-
tion to maximally tolerated LDL cholesterol lowering therapy
(e.g., maximally tolerated statin and ezetimibe) for patients
with heterozygous or homozygous FH or for patients with
clinical ASCVD who require additional LDL cholesterol lower-
ing (Grundy 2019). The use of PCSK9 inhibitors is also recom-
mended for patients with statin intolerance and high ASCVD
risk. No RCTs have evaluated the strategy of adding ezetimibe
before a PCSK9 inhibitor.
Omega-3 Fatty Acids
Very low-density lipoprotein cholesterol and triglyceride
synthesis are inhibited in the liver by O3FAs, which are pre-
dominately used for triglyceride lowering (manufacturer
package insert). The O3FAs are available by prescription,
such as omega-3-ethyl esters (Lovaza) or icosapent ethyl
166 Non-Statin Therapy for Dyslipidemia
 Patient Care Scenario
A 51-year-old African American woman is referred to your
pharmacotherapy clinic for review of her ASCVD risk. She
has mild myalgia associated with statin therapy after
failure of 4 alternative statins and her current statin at a
higher dose. Her current diagnoses are hypertension, type
2 diabetes, and obesity, and her medical history is sig-
nificant for preeclampsia. She has no family history of
premature ASCVD. She denies use of tobacco and reports
drinking 1 standard alcoholic beverage 2–3 times weekly.
She reports full adherence to the following medications:
amlodipine 5 mg/day, candesartan 16 mg/day, rosuvasta-
tin 5 mg/day, and metformin 2000 mg/day.
The patient eats a typical Western diet and is gener-
ally inactive physically in her job as a middle school vice
ANSWER
The patient’s 10-year ASCVD risk score is 12.4% and she
has type 2 diabetes. Therefore, she is indicated, at the
very least, for a moderate-intensity statin. According to
the 2018 American Heart Association/American College
of Cardiology blood cholesterol guidelines, rosuvastatin
5 mg/day is a moderate-intensity statin. According to the
same guidelines to determine statin therapy for a patient
with diabetes, further risk assessment is warranted to
assess the potential benefit of additional lipid-lowering
therapy. The patient has several risk factors for ASCVD,
including hypertension, obesity, and a history of pre-
eclampsia (a risk enhancing factor). Therefore, the patient
is candidate for high-intensity statin therapy. However,
1. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APHA/ASPC/NLA/PCNA guideline on the
management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on clinical
practice guidelines. Circulation 2019;139:e1082-143.
2. Handelsman Y, Jellinger PS, Guerin CK, et al. Consensus statement by the American Association of Clinical Endocrinologists and
American College of Endocrinology on the management of dyslipidemia and prevention of cardiovascular disease algorithm—2020
executive summary. Endocr Pract 2020;26:1196-224.
(Vascepa, EPA only) or over-the-counter and contain a combi-
nation of EPA and/or DHA. Depending on the dose and base-
line triglyceride concentration, O3FAs lower triglycerides by
10%–50%. The combination products of O3FA with EPA and
DHA (i.e., omega-3-ethyl esters) may lead to small increases
in LDL cholesterol, particularly if triglycerides are mark-
edly elevated (e.g., ≥ 500 mg/dL) (Feingold 2000), whereas
O3FA combination products with EPA only (i.e., icosapent
ethyl) have not been shown to increase LDL cholesterol. The
O3FA products sold as a food supplement do not have FDA
approval, and the amount of EPA and DHA varies; therefore,
these agents are not preferred.
Several trials of low-dose O3FA have failed to demonstrate
an ASCVD benefit. However, several trials, including MARINE,
ANCHOR, JELIS, and REDUCE-IT, used higher doses of EPA
and demonstrated an ASCVD benefit when used in combina-
tion with statin therapy (Bhatt 2019; Ballantyne 2012; Bays
2012;Yokoyama 2007). The JELIS trial was conducted in Jap-
anese patients with or without coronary artery disease. The
median baseline LDL cholesterol was 85 mg/dL and 90% of
PSAP 2022 Book 1 • Cardiology
principal. Today her blood pressure is 139/85 mm Hg,
heart rate is 78 bpm, and BMI is 33.2 kg/m2. Her most
recent fasting lipid panel is as follows: total cholesterol
160 mg/dL, HDL cholesterol 45 mg/dL, LDL cholesterol
85 mg/dL, and triglycerides 149 mg/dL. Based on the
American Association of Clinical Endocrinologists and
American College of Endocrinology recommendations,
which of the following is the best recommendation for this
patient’s lipid-lowering therapy?
A. No change to current therapy
B. Change rosuvastatin to 10 mg/day and continue current
therapy
C. Add ezetimibe to current therapy
D. Add PCSK9 inhibitor to current therapy
increasing the rosuvastatin dose is not the best option
because her previous management has failed with sev-
eral statins, including rosuvastatin at a dose higher than
5 mg/day. Still, a change is warranted. According to the
2020 American Association of Clinical Endocrinologists/
American College of Endocrinology guidelines her goal
LDL cholesterol is less than 70 mg/dL because of her
many risk factors. Adding ezetimibe will reach this goal
and is the best option because data supporting the use of
PCSK9 inhibitors for primary prevention without markedly
elevated LDL cholesterol are scant; therefore, the greater
expense and injectable route are not justified.
patients were using a low-intensity statin (pravastatin 10 mg
or simvastatin 5 mg) (Yokoyama 2007). The primary com-
posite end point was sudden cardiac death, fatal and nonfa-
tal myocardial infarction, and other nonfatal events. Over a
median follow up of 4.6 years, a 19% reduction (ARR 0.7%; HR
0.81; 95% CI, 0.69–0.95) in the primary composite end point
was observed with EPA 1.8 g/day plus background statin ther-
apy compared with statin monotherapy (Yokoyama 2007).
Among those with preexisting coronary artery disease, a 19%
reduction in major coronary events was observed, compared
with patients only using a statin (ARR 2%; HR 0.81; 95% CI,
0.66–1.00).
The REDUCE-IT trial, published in 2018, included patients
age 45 years and older with clinical ASCVD or patients age
50 years and older with diabetes and other risk factors (Bhatt
2019). Other inclusion criteria were triglyceride concentra-
tions of 135–499 mg/dL and LDL cholesterol concentration of
41–100 mg/dL with stable statin therapy (with or without eze-
timibe). The trial found a significant 25% RR reduction (ARR
167 Non-Statin Therapy for Dyslipidemia
4.8%, HR 0.75; 95% CI, 0.68–0.83) in the primary composite
cardiovascular outcome.
Compared with JELIS, the REDUCE-IT trial used a higher
dose of EPA (icosapent ethyl 4 g/day) in patients already
using background statin therapy as well as a placebo group
(Bhatt 2019). The primary composite end point of cardiovas-
cular death, nonfatal myocardial infarction, nonfatal stroke,
coronary revascularization, or unstable angina occurred in
17.2% of patients compared with 22% in the placebo group
(HR 0.75; 95% CI, 0.68–0.83). Of interest, the results demon-
strated that the cardiovascular benefit was not specifically
related to the triglyceride reduction. However, in light of
the overall cardiovascular benefit, icosapent ethyl is rec-
ommended by several society guidelines for ASCVD risk
reduction in patients matching the study population. Both
the JELIS and REDUCE-IT findings are in contrast to those
of the STRENGTH trial, which studied an EPA/DHA formu-
lation in 13,078 patients with controlled LDL cholesterol,
low HDL cholesterol, and high triglycerides (Nicholls 2020).
Despite EPA/DHA significantly lowering triglycerides and
high-sensitivity C-reactive protein, there was no difference
in the composite outcome of cardiovascular death, nonfa-
tal myocardial infarction, nonfatal stroke, coronary revascu-
larization, or unstable angina requiring hospitalization (EPA/
DHA group, 12.0% vs. corn oil group 12.2%; HR 0.99; 95% CI,
0.90–1.09).
The most common adverse effects of O3FAs are GI (e.g.,
abdominal pain, nausea, diarrhea) and a fishy aftertaste, per
package inserts. Bleeding risk can be increased in those who
are concomitantly taking anticoagulants or antiplatelets.
Serious bleeding events occurred more often in patients ran-
domized to icosapent ethyl versus placebo in the REDUCE-IT
trial (2.7% vs. 2.1%, p=0.06), as did hospitalizations for atrial
fibrillation (3.1% vs. 2.1%, p=0.004) (Bhatt 2019). Three addi-
tional RCTs suggest a dose-related risk of atrial fibrillation
with O3FA supplementation (Albert 2021; Kalstad 2021; Nich-
olls 2020). At a dose of 4 g/day (EPA/DHA), a statistically sig-
nificant increase in the risk of atrial fibrillation was observed
(Nicholls 2020), although an intermediate dose of 1.8 g/day
(EPA/DHA) led to a nonsignificant increase in atrial fibrilla-
tion risk (Kalstad 2021). Among the available RCTs, the only
one to evaluate incident atrial fibrillation as the primary out-
come was the VITAL Rhythm Study, which used O3FA at 840
mg/day (EPA/DHA), and found a nonsignificant increase in
the incidence of atrial fibrillation compared with placebo (HR
1.09; 95% CI, 0.96–1.24) (Albert 2021). The risk of atrial fibril-
lation should be weighed against the benefits of high-dose
O3FA, and, if used in combination, warrants close monitoring
and patient education.
Although published before REDUCE-IT, the 2018 American
Heart Association/American College of Cardiology blood cho-
lesterol clinical practice guideline recommends O3FA (2–4 g/
day) as an adjunct to lifestyle intervention (e.g., low fat diet,
avoidance of refined carbohydrates, and alcohol) in patients
PSAP 2022 Book 1 • Cardiology
with triglycerides 500 mg/dL or greater to prevent acute pan-
creatitis (Grundy 2019). Although effective for triglyceride
lowering, results from clinical trials examining the efficacy of
O3FA on cardiovascular risk reduction have been mixed. Sev-
eral clinical trials are ongoing to better understand the asso-
ciation between elevated triglycerides, residual ASCVD risk
and O3FA formulations.
Ezetimibe
Ezetimibe is a selective inhibitor of the Niemann-Pick C1-Like
1 protein, which is involved in the absorption of dietary and
biliary cholesterol at the brush border of the small intestine,
per the manufacturer package insert. Inhibition leads to a
decrease in the delivery of dietary cholesterol to the liver.
This decreased delivery causes a reduction of hepatic cho-
lesterol stores by reducing the production of very low-density
lipoprotein cholesterol, and subsequently LDL cholesterol.
The reduction in hepatic cholesterol also leads to an increase
in the expression of LDL receptors, which promotes LDL
cholesterol clearance. Ezetimibe lowers LDL cholesterol by
13%–20% and by up to 25% when used in combination with a
statin (Grundy 2019).
Evidence for ASCVD risk reduction with ezetimibe has
been mixed and difficult to determine. Simvastatin and eze-
timibe were compared with placebo in two RCTs—the SEAS
and SHARP trials (Baigent 2011; Rossebø 2008). In the SEAS
trial, simvastatin and ezetimibe failed to significantly reduce
the composite outcome of combined aortic-valve events and
ischemic events in patients with aortic stenosis (HR 0.96;
95% CI, 0.83–1.12) (Rossebø 2008). However, in the SHARP
trial, simvastatin plus ezetimibe reduced LDL cholesterol and
reduced the primary end point of first major ASCVD events
compared with placebo over a median follow up of 4.9 years
in patients with chronic kidney disease (Baigent 2011). Isolat-
ing the actual effect of ezetimibe in the SHARP trial was dif-
ficult because of the lack of a statin-only comparator group.
In a third trial, ENHANCE, ezetimibe plus simvastatin did
not show a decrease in carotid intima media thickness, a
surrogate marker of ASCVD risk, compared with simvastatin
monotherapy among patients with heterozygous FH (Kaste-
lein 2008). Finally, in 2015, the IMPROVE-IT trial was the first
to demonstrate a reduction in ASCVD risk with the addition of
ezetimibe to simvastatin in patients with recent acute coro-
nary syndromes (Cannon 2015). Combination therapy demon-
strated a statistically significant, but clinically modest,
reduction in events over 7-year follow-up, without safety con-
cerns (HR 0.93; 95% CI, 0.89–0.99) (Cannon 2015). Because
evidence for the use of ezetimibe plus simvastatin in patients
with stable clinical ASCVD is lacking, the Food and Drug
Administration has not approved ASCVD risk reduction as an
indication for ezetimibe; however, the clinical practice guide-
lines still support the use of ezetimibe use in patients with
ASCVD, on maximally tolerated statin therapy, and in need of
additional LDL cholesterol lowering (Grundy 2019).
168 Non-Statin Therapy for Dyslipidemia
 Patient Care Scenario
H.G., a 61-year-old African American man with a medi- Part 1
cal history of hypertension, dyslipidemia, prediabetes, Above which one of the following LDL cholesterol thresh-
transient ischemic attack (2 years ago), presents for the olds would it be best to recommend a non-statin therapy
outpatient management of dyslipidemia. His home drugs for H.G.?
include: lisinopril 20 mg/day, indapamide 2.5 mg/day, A. < 130 mg/dL
aspirin 81 mg/day, and atorvastatin 20 mg/day. H.G.’s
B. < 100 mg/dL
most recent lipid panel shows total cholesterol 170 mg/
C. < 70 mg/dL
dL, high-density lipoprotein cholesterol (HDL cholesterol)
41 mg/dL, low-density lipoprotein cholesterol (LDL cho- D. < 55 mg/dL
lesterol) 96 mg/dL, and triglycerides 165 mg/dL. His most
recent blood pressure is 129/79 mm Hg.
ANSWER
Less than 70 mg/dL is the best option for this patient (Answer B), would be reasonable for some patients with-
because he has ASCVD as noted by his previous tran- out ASCVD. Less than 55 mg/dL (Answer D), would be
sient ischemic attack (Answer C is correct). Less than reasonable for premature ASCVD, progressive ASCVD, or
130 mg/dL (Answer A), is not reasonable for someone with ASCVD with multiple or substantial other risk factors.
ASCVD or risk factors for ASCVD. Less than 100 mg/dL

1. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APHA/ASPC/NLA/PCNA guideline on the
management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on clinical
practice guidelines. Circulation 2019;139:e1082-143.
2. Handelsman Y, Jellinger PS, Guerin CK, et al. Consensus statement by the American Association of Clinical Endocrinologists and
American College of Endocrinology on the management of dyslipidemia and prevention of cardiovascular disease algorithm—2020
executive summary. Endocr Pract 2020;26:1196-224.
Part 2 A. Add ezetimibe.
H.G.’s care team determines that additional LDL choles- B. Add evolocumab.
terol lowering is desired. Which one of the following is C. Increase atorvastatin dose.
best to recommend to lower H.G.’s LDL cholesterol below D. Increase atorvastatin dose and add ezetimibe.
his threshold?
ANSWER
Because the patient is not taking a high-intensity statin, threshold. But there is no such history (Answer B is incor-
although is indicated for one based on the presence of rect). Therefore, optimizing this patient’s statin dose and
ASCVD (his prior transient ischemic attack), the best first adding ezetimibe is the best option (Answer D is cor-
option is to increase his atorvastatin dose; however, this rect). If the patient was taking an optimized statin dose,
alone will likely still leave him above his LDL cholesterol but needed more than 25% additional LDL cholesterol
threshold (Answer C is incorrect). If there was a confirmed reduction to reach goal, then a PCSK9 inhibitor could be
history of statin intolerance, including trials of multiple considered. Answer A and Answer B are incorrect because
other statins including atorvastatin at a higher dose, then they do not increase the atorvastatin dose. Answer C is
a PCSK9 inhibitor could be considered as ezetimibe alone not correct because it is unlikely to achieve the LDL cho-
would not likely lower LDL cholesterol below the desired lesterol threshold.

1. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APHA/ASPC/NLA/PCNA guideline on the
management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on clinical
practice guidelines. Circulation 2019;139:e1082-143.
2. Handelsman Y, Jellinger PS, Guerin CK, et al. Consensus statement by the American Association of Clinical Endocrinologists and
American College of Endocrinology on the management of dyslipidemia and prevention of cardiovascular disease algorithm—2020
executive summary. Endocr Pract 2020;26:1196-224.

Adverse effects are uncommon with use of ezetimibe. In
clinical trials, the incidence of adverse effects and discontinua-
tions rates have been similar to placebo (manufacturer’s pack-
age insert). Adverse effects occurred in clinical trials in 2% or
less of patients, including fatigue, abdominal pain/diarrhea,
upper respiratory tract infections, arthralgia, and back pain.
Although outcomes from using combination therapy with
ezetimibe on top of maximally tolerated statin therapy in
stable clinical ASCVD patients are not extensively studied,
ezetimibe can be the preferred initial non-statin therapy
because of its expected benefit on ASCVD outcomes, mod-
est LDL cholesterol lowering, tolerability, cost, and once-daily
dosing (Grundy 2019). It is therefore reasonable to consider
adding ezetimibe to maximally tolerated statin therapy in
patients with clinical ASCVD and an LDL cholesterol of 70
mg/dL or greater. Additional factors that place patients with
clinical ASCVD at very high risk and may favor adding ezeti-
mibe to a statin include history of several major ASCVD events

PSAP 2022 Book 1 • Cardiology 169 Non-Statin Therapy for Dyslipidemia

or one major ASCVD event and several high-risk comorbidi-
ties, such as diabetes, hypertension, chronic kidney disease,
current smoking, persistent LDL cholesterol elevation, and
history of heart failure (Grundy 2019). In addition, ezetimibe
therapy is reasonable in patients age 20–75 years with an
LDL cholesterol 190 mg/dL or greater who do not achieve at
least a 50% reduction in LDL cholesterol on maximally toler-
ated statin therapy and/or have an LDL cholesterol concen-
tration of 100 mg/dL or greater (Grundy 2019). Ezetimibe can
also be considered as the initial therapy in patients with true
statin intolerance.
Bempedoic Acid
Bempedoic acid inhibits adenosine triphosphate-citrate
lyase (ACL), which is an enzyme upstream of 3-hydroxy-
3-methyl-glutaryl-coenzyme A reductase in the cholesterol
biosynthesis pathway (manufacturer’s package insert).
Bempedoic acid is a prodrug that requires coenzyme A acti-
vation in the liver. Inhibition of ACL results in decreased cho-
lesterol synthesis in the liver, which lowers LDL cholesterol
through up-regulation of LDL receptors. Bempedoic acid also
decreases non-HDL cholesterol, apolipoprotein B, and total
cholesterol. As a prodrug, bempedoic acid is converted in
the liver, so no active metabolites are present in the skeletal
muscles, making it a promising alternative for patients with
statin-associated muscle symptoms. Bempedoic acid is also
available in combination with ezetimibe, which lowers LDL
cholesterol by 48% compared with 23% with bempedoic acid
monotherapy (Thompson 2016; Ballantyne 2013).
In a phase 3 trial (CLEAR Harmony), patients with clini-
cal ASCVD, heterozygous FH, or both were randomized to
bempedoic acid 180 mg/day or placebo for 52 weeks (Ray
2019). Patients included those stable on maximally tolerated
statins alone or in combination with other non-statin thera-
pies. About 8% of patients were on ezetimibe and 4% were
on a fibrate in addition to statin therapy. Results from CLEAR
Harmony demonstrated that bempedoic acid did not lead to
a higher incidence of adverse events versus placebo, but did
significantly lower LDL cholesterol by an additional 18% ver-
sus placebo. Across other phase 3 trials conducted in the
CLEAR program, observed LDL cholesterol reductions with
bempedoic acid have been between 14%–40% when added
to background lipid-lowering therapy. The greatest reduc-
tions in LDL cholesterol were shown when added to ezetimibe
(Thompson 2016).
The CLEAR Serenity trial assessed the efficacy and
safety of bempedoic acid 180 mg/day compared with pla-
cebo in statin-intolerant patients over 24 weeks (Laufs 2019).
About 8.4% of patients continued low-dose statin therapy. At
12 weeks, bempedoic acid demonstrated a 21.4% reduction in
LDL cholesterol versus placebo. The most common muscle-
related adverse events were myalgia and occurred in 4.7% of
patients using bempedoic acid versus 7.2% of patients in the
placebo group.
PSAP 2022 Book 1 • Cardiology
Bempedoic acid has been associated with hyperuricemia
and gout, particularly among patients with a history of gout.
Gout event rates in CLEAR Harmony were 1.2% versus 0.3%
(p=0.03) and in the Clear Wisdom trial were 2.1% versus 0.8%
(p value not reported) (Goldberg 2019; Ray 2019). Bempe-
doic acid has also been associated with an increased risk of
tendon rupture, particularly among patients age 60 years or
older, those taking a corticosteroid or fluoroquinolone, and in
those with renal failure or previous tendon disorders.
Although consistent reductions in LDL cholesterol have
been observed with bempedoic acid monotherapy or in com-
bination with background lipid-lowering therapy in phase
3 trials, the effect on cardiovascular morbidity and mor-
tality has yet to be determined. The CLEAR Outcomes trial
(NCT02993406, expected to be completed in 2022), is enroll-
ing patients at high risk for cardiovascular disease and who
have statin intolerance. The primary composite end point
includes time from randomization to the first occurrence
of nonfatal myocardial infarction, nonfatal stroke, coronary
revascularization, or cardiovascular death. Despite the lack of
data on ASCVD risk reduction, bempedoic acid was granted
FDA approval in 2020 as an adjunct to diet and maximally tol-
erated statin therapy for the treatment of adults with heterozy-
gous FH (e.g., primary prevention) or established ASCVD (e.g.,
secondary prevention) who require additional lowering of LDL
cholesterol. Although the place of bempedoic acid in therapy
has yet to fully be determined, it provides an additional thera-
peutic option for LDL cholesterol lowering in statin-intolerant
patients, those requiring additional LDL cholesterol reduction
despite maximally tolerated statin therapy, and those who are
unable to afford a PCSK9 inhibitor.
Bile Acid Sequestrants
Under normal physiologic conditions, most bile acids are
secreted into the small intestine from the liver and reabsorbed
through enterohepatic recirculation. Bile acid sequestrants
(BAS) (e.g., cholestyramine, colestipol, colesevelam) form a
non-absorbed resin/bile acid complex in the small intestine
that is subsequently excreted in the feces (manufacturers’
package inserts). As bile acids decrease, the hepatic enzyme,
cholesterol 7-α-hydroxylase, is up-regulated, increasing con-
version of cholesterol to bile acid in the liver, which decreases
intracellular cholesterol concentrations. In addition, as cho-
lesterol concentrations decrease, LDL receptor uptake is
increased allowing for additional LDL cholesterol clear-
ance. Depending on the dose, BAS reduce LDL cholesterol by
15%–30% when added to statin therapy (Grundy 2019).
Three RCTs have evaluated the efficacy of cholestyramine
for ASCVD risk reduction, although results have been incon-
clusive (Watts 1992; Brensike 1984; Lipid Research Clin-
ics 1984). Among these three trials, only one demonstrated
a modest reduction in ASCVD risk with BAS monother-
apy (Lipid Research Clinics 1984). The LRC-CPPT trial ran-
domly assigned 3806 men younger than 60 years without
170 Non-Statin Therapy for Dyslipidemia
cardiovascular disease but with a total cholesterol of at least
265 mg/dL to cholestyramine 24 g/day or placebo for a mean
of 7.4 years. The cholestyramine group experienced a 19%
reduction in risk in the primary end point of coronary heart
disease death and/or definite nonfatal myocardial infarction
(OR 0.81, 95% CI, 0.70–1.02; p=0.07) (Lipid Research Clinics
1984). To date, the effects of colesevelam and colestipol on
ASCVD risk reduction have not been determined because
no adequately powered trials have explored their impact on
reducing ASCVD risk.
Given the inconclusive findings across trials exploring
impact of BAS on ASCVD risk reduction, several secondary
analyses have been conducted. In a systematic review and
meta-analysis of RCTs of cholestyramine and colesevelam,
Mendelian randomized was used to estimate the effect of BAS
on reducing coronary artery disease risk (Ross 2015). Both
cholestyramine and colesevelam reduced LDL cholesterol and
were associated with a reduction in the risk of coronary artery
disease. In a second systematic review and meta-regression
analysis, the use of statin and non-statin therapies that act
by up-regulation of LDL cholesterol receptor expression to
reduce LDL cholesterol (e.g., BAS) were associated with simi-
lar RR reductions of major vascular events per change in LDL
cholesterol; the RR for major vascular events per 38.7-mg/dL
reduction in LDL cholesterol was 0.77 for statins and 0.75 for
non-statins working primarily through LDL receptor up-reg-
ulation (Silverman 2016). Although the use of BAS is effec-
tive at lowering LDL cholesterol, data supporting ASCVD risk
reduction with BAS remains limited.
No systemic absorption occurs with BAS; therefore, they
do not cause systemic adverse effects (Grundy 2019). The
most common adverse effects are GI, including constipa-
tion, bloating, flatulence (manufacturers’ package inserts).
Comparatively, colesevelam has the lowest GI adverse
effect profile in the class. Of note, BAS may raise triglyceride
levels and should be avoided if fasting hypertriglyceridemia
(> 300 mg/dL) is present (Grundy 2019). Limitations to using
BAS include pill burden (most formulations require admin-
istering several tablets dosed twice daily), and potential for
drug–drug interactions (e.g., digoxin, warfarin, and thyroid
hormone). Also, BAS may impair the absorption of fat-soluble
vitamins (e.g., A, D, E, K), and should be administered at least
1 hour before or at least 4 hours after other medications to
limit potential for drug–drug interactions (manufacturers’
package inserts). Potential for drug–drug interactions are
less with colesevelam compared with cholestyramine and
colestipol (Grundy 2019).
Patients who are age 20–75 years can be treated with a
BAS when baseline LDL cholesterol is 190 mg/dL or greater
and a 50% reduction in LDL cholesterol is not achieved with
maximally tolerated statin therapy and ezetimibe (Grundy
2019). In addition, BAS can serve as an alternative agent for
patients who are intolerant to ezetimibe requiring additional
LDL cholesterol lowering beyond maximally tolerated statin
PSAP 2022 Book 1 • Cardiology
therapy. Finally, BAS may be used in pregnant women at high
ASCVD risk, although monitoring for vitamin K deficiency may
be required (Goldberg 2011).
Fibrates
Fibrates, such as gemfibrozil, fenofibrate, and fenofibric acid,
are derivatives of fibric acid and act as ligands for the nuclear
hormone transcription factor peroxisome proliferator-activated
receptor α (PPAR-α) (manufacturers’ package inserts). The
PPARs regulate lipid metabolism that function clinically to
decrease triglyceride concentrations by 20%–50% through
increased expression of lipoprotein lipase and decreasing
apolipoprotein CII concentration. Fenofibrate is more effec-
tive than gemfibrozil in lowering triglyceride levels. Fibrates
also increase HDL cholesterol by increasing the expression of
apolipoprotein AI and apolipoprotein AII, and have also been
shown to be effective at reducing non-HDL cholesterol.
The Helsinki Heart Study (HHS) compared gemfibrozil 600
mg twice daily versus placebo for 5 years in middle-age men
without clinical ASCVD, and found a 34% reduction in the pri-
mary end point of coronary heart disease events (myocar-
dial infarction and cardiovascular death) (Frick 1987). In an
18-year follow up of the HHS, those who received gemfibrozil
had a 23% lower RR of coronary heart disease mortality com-
pared with those in the placebo group (Tenkanen 2006). Those
in the highest tertile of BMI and triglycerides experienced the
greatest benefit. However, in 2010, results from the ACCORD-
Lipid trial demonstrated that fenofibrate and simvastatin did
not reduce ASCVD risk in patients with type 2 diabetes com-
pared with simvastatin monotherapy (Ginsberg 2010). Simi-
lar results were observed in a 5-year follow-up study of the
ACCORD-Lipid trial (Elam 2017). However, in subgroup anal-
yses of patients in the ACCORD-Lipid trial with triglycerides
in the highest third (≥ 204 mg/dL) and HDL cholesterol in the
lowest third (≤ 34 mg/dL), lower cardiovascular event rates
were observed with the addition of fenofibrate to simvasta-
tin compared with simvastatin monotherapy (Ginsberg 2010).
The most common adverse effects of fibrates are mild
GI disturbances that lessen with time. Because fibrates
increase biliary cholesterol excretion, the risk of gallstone
formation is increased. Muscle-related toxicity (e.g., myopa-
thy and rhabdomyolysis) has been reported in patients taking
fibrate monotherapy, and this risk is increased when com-
bined with a statin (Wiggins 2016). However, muscle-related
toxicity occurs more often with gemfibrozil versus fenofi-
brate in combination with a statin (Amend 2011; Jones 2005).
The FDA-approved product labeling for simvastatin states
that gemfibrozil is contraindicated and recommends avoid-
ing use of gemfibrozil with all other available statins. How-
ever, on the basis of differences in pharmacokinetic profiles
of the statins, a 2016 scientific statement from the Amer-
ican Heart Association recommended that gemfibrozil be
avoided in combination with lovastatin, pravastatin and sim-
vastatin—and may be acceptable to use in combination with
171 Non-Statin Therapy for Dyslipidemia
atorvastatin, rosuvastatin, and pitavastatin if clinically indi-
cated, and if fenofibrate (or fenofibric acid) is not an option
(Wiggins 2016). Fibrates should not be used in patients with
severe hepatic or renal dysfunction and in patients with pre-
existing gallbladder disease or biliary cirrhosis (manufactur-
ers’ package inserts).
Fibrates are primarily used in the treatment of hypertri-
glyceridemia when triglycerides are greater than 500 mg/dL
to prevent acute pancreatitis in combination with a statin
(Grundy 2019). Evidence does not support the use of fibrates
for ASCVD risk reduction, especially when used in combina-
tion with statin therapy. Fibrates may provide ASCVD risk
benefit in certain patients (e.g., those with type 2 diabetes),
or in those with certain patterns of dyslipidemia (e.g., high
triglycerides and low HDL cholesterol), but evidence remains
uncertain (Sisson 2018). If used in combination with a statin,
fenofibrate is preferred to gemfibrozil because of the lower
risk of muscle related toxicity (Grundy 2019).
Niacin
Niacin primarily lowers triglycerides, raises HDL cholesterol,
and has mild LDL cholesterol lowering (Grundy 2019). On the
basis of unfavorable results from the AIM-HIGH and HPS2-
THRIVE trials (Landray 2014; Boden 2011), current evidence
does not support the routine use of niacin in light of its lack of
efficacy in reducing ASCVD risk, potential adverse effects and
harms, such as flushing, hyperglycemia, and hepatoxicity.
EMERGING NON-STATIN THERAPIES:
MEDICATIONS IN THE PIPELINE
Inclisiran
The package insert for inclisiran describes it as a small inter-
fering ribonucleic acid that inhibits PCSK9 synthesis in the
liver through directing catalytic breakdown of mRNA for
PCSK9. This action increases LDL cholesterol receptor recy-
cling, which increases LDL cholesterol uptake and lowers LDL
cholesterol. On average, inclisiran lowers LDL cholesterol by
50%–55% with twice yearly dosing. Patients in the ORION 9,
10 and 11 trials required additional LDL cholesterol reduction
despite taking a maximally tolerated statin dose with or with-
out ezetimibe (Raal 2020; Ray 2020). ORION 9 assessed the
efficacy of inclisiran in patients with heterozygous FH (Raal
2020). Inclisiran significantly reduced the mean percentage
change in LDL cholesterol by 48% compared with placebo.
Both ORION-10 and ORION-11 included patients with clini-
cal ASCVD and ASCVD risk equivalents, and demonstrated a
significant reduction in the mean percentage change in LDL
cholesterol by 52% and 50%, respectively (Ray 2020). Incli-
siran also significantly reduced the time-adjusted percent-
age change in LDL cholesterol from baseline by 54% and 49%
in ORION 10 and 11, respectively. The only adverse reactions
associated with inclisiran in clinical trials were injection site
reactions. The cardiovascular efficacy and safety trial of
PSAP 2022 Book 1 • Cardiology
inclisiran (ORION 4, NCT03705234) began enrolling subjects
in 2018, with results expected in 2025. Inclisiran was denied
FDA approval in 2020 because of facility inspection-related
conditions. However, inclisiran gained approval in the Euro-
pean Union in 2020 for adults as an adjunct to diet  in com-
bination with maximally tolerated statin therapy in patients
who cannot reach LDL cholesterol goals. Inclisiran is also
approved in the European Union for use alone or in combina-
tion for patients who are statin-intolerant.
Pemafibrate
Through selective activation of the peroxisome proliferator-
activated receptors, pemafibrate is an advancement com-
pared with older fibrates, which have less potent activity and
limited efficacy. Several trials have demonstrated greater
triglyceride reductions with pemafibrate compared with
fenofibrate, with less frequent adverse events (Arai 2018;
Ishibashi 2018). Ongoing clinical trials are evaluating pema-
fibrate to reduce residual cardiovascular risk in patients
using statins (Pradhan 2018) and in patients with fasting
hypertriglyceridemia and renal impairment (NCT03011450,
NCT03001817).
Volanesorsen
Volanesorsen is an antisense oligonucleotide inhibitor of
apolipoprotein C-III mRNA, leading to its degradation and
the reduction in its synthesis. Synthesized primarily in the
liver, apolipoprotein C-III is a component of triglyceride lipo-
proteins, thus playing a role in regulating plasma triglyceride
concentrations (Ooi 2008). Increased levels of apolipopro-
tein C-III have been associated with impaired lipolysis and
reductions in the clearance of triglyceride lipoprotein as well
as hepatic lipase activity (Ginsberg 1986). In addition, apo-
lipoprotein C-III has been independently associated with an
increased risk for cardiovascular disease (Mendivil 2011;
Sacks 2000).
In a meta-analysis of phase 2 and phase 3 clinical studies
of volanesorsen, significant reductions in very low-density
lipoprotein cholesterol, triglycerides, and apolipoprotein
C-III, and increases in HDL cholesterol and LDL cholesterol
have been observed (Fogacci 2020). Although a signifi-
cant increase in LDL cholesterol was observed, the baseline
LDL cholesterol was very low (about 28 mg/dL) and did not
increase to more than 70 mg/dL. However, volanesorsen was
rejected by the FDA in 2018 because of concerns related to
thrombocytopenia and subsequent bleeding, although it was
approved in 2019 in the European Union for familial chylomi-
cronemia syndrome.
Evinacumab
Evinacumab is an antagonist of angiopoietin-like protein 3,
which inhibits hydrolysis of triglycerides by lipoprotein lipase
(Arca 2020; Ruscica 2020). Evinacumab reduces triglycerides
172 Non-Statin Therapy for Dyslipidemia
by up 76% and LDL cholesterol by more than 50% with no dif-
ferences in adverse events compared with placebo (Arca
2020; Rosenson 2020; Gaudet 2017; Dewey 2017). According
to the manufacturer package insert, evinacumab-dgnb injec-
tion was approved in 2021 for homozygous familial hypercho-
lesterolemia treatment in patients age 12 years and older.
IMPLEMENTING NON-STATIN
THERAPY
Therapeutic Lifestyle Change
The primary non-statin therapy for dyslipidemia is therapeu-
tic lifestyle change, ostensibly an approach able to benefit
all patients. As with drug therapy, the principal rationale is
to decrease cardiovascular morbidity and mortality. As such,
all core tenants of a healthy lifestyle should be assessed
and addressed in a patient-specific manner, including the
following: 1) smoking cessation; 2) dietary modification to
reduce saturated fat intake; decrease intake of highly pro-
cessed, high sodium, and high sugar foods and beverages;
increase fruit and vegetable intake; and moderate calories to
lose weight or maintain a healthy weight; 3) decrease alco-
hol intake; 4) increase physical activity; and 5) adopt healthy
sleep habits (Jacobson 2015b; Kuehn 2019). Specific life-
style approaches can be used to lower triglycerides, either
with drug therapy when triglyceride concentration is at least
500  mg/dL or independently for triglyceride concentrations
of 150–499 mg/dL. When used together, the following life-
style approaches can lower triglycerides by 20%–50%: 1) lim-
iting drinks high in sugar (especially fructose); 2)  limiting
foods high in sugar, particularly those without fiber; 3)
avoiding or limiting alcohol consumption; 4) increasing
dietary fiber; 5) avoiding trans fats; 6) eating marine-derived
omega-3 polyunsaturated fatty acids; and 7) performing at
least moderate-intensity aerobic activity at least 5 days per
week (Jacobson 2015b; Miller 2011).
In implementing therapeutic lifestyle changes, the impor-
tance of a patient-specific approach cannot be overstated.
Cultural and socioeconomic factors play a significant role
in what types of food patients may eat and the preferences
for what types of physical activity the patients will engage
in based on physical limitations and work-life/neighbor-
hood factors (American Diabetes Association 2021a; Spen-
cer Bonilla 2016; Jensen 2014). A whole-patient approach
will also benefit patients because comorbidities (e.g., depres-
sion, clinical hypothyroidism) and personal factors (e.g., poor
work-life balance) can impede effective therapeutic lifestyle
change. Moreover, social factors, including family behav-
iors, can either enhance or diminish patients’ ability to imple-
ment therapeutic lifestyle changes (Wang 2014). Although
these factors can be emphasized over time to help patients
shift toward healthier habits, the strongest evidence sup-
ports—in willing patients—implementing these changes as a
high-intensity, comprehensive lifestyle intervention (Jensen
PSAP 2022 Book 1 • Cardiology
2014). The key component to making a lifestyle intervention
“high-intensity” is the frequency of patient contact, at least
14 visits over 6 months (individually or in groups, in person or
remote). At least monthly contact thereafter can help main-
tain changes (Jensen 2014). Some programs include even
more frequent patient contact, such as the National Diabetes
Prevention Program, which meets weekly for 6 months, then
monthly for 6 months (Ely 2017).
Non-Statin Medications
In choosing which non-statin medication to implement, the
strongest consideration must be given to the evidence of car-
diovascular benefit. However, this concern must be weighed
with cost to the patient, insurance restrictions, and medica-
tion administration. For ASCVD risk reduction related to LDL
cholesterol, published data on the PCSK9 inhibitor class pro-
vide the most robust evidence for this indication. Clinicians
Practice Points
• Optimize statin therapy before considering non-statin
medications.
• The nocebo effect contributes to a substantial proportion
of statin-related myalgia.
• Many patients who cannot tolerate one statin can tolerate
another statin instead.
• In patients unable to tolerate the statin intensity for which
they are indicated, the maximum tolerated statin should be
used.
• Risk reduction for ASCVD is the primary rationale for using
non-statin medications.
• The PCSK9 inhibitors have the strongest data support-
ing cardiovascular risk reduction, among non-statin
medications.
• In patients already optimized on statin therapy who are
near their LDL cholesterol goal, ezetimibe can be consid-
ered over PCSK9 inhibitors because of the lower cost and
oral administration of ezetimibe.
• Icosapent ethyl should be used to reduce the risk for
ASCVD in patients with the following criteria: 1) controlled
LDL cholesterol, 2) triglycerides 135–499 mg/dL, and
3) ASCVD or several cardiovascular risk factors.
• The finding of elevated triglycerides is only a specific
indication for non-statin therapy when the concentration is
500 mg/dL or greater.
• Serum triglycerides less than 1000 mg/dL can be treated
with high-intensity statin therapy as a first-line option,
with or without triglyceride-specific agents, to lower tri-
glycerides and reduce cardiovascular risk.
• Serum triglyceride concentration of 1000 mg/dL or greater
should be treated with prescription omega-3-acid ethyl
esters, icosapent ethyl, or fibrates.
• Therapeutic lifestyle changes to increase physical
activity and adopt a healthier eating pattern can benefit
all patients.
• To optimize patient success with therapeutic lifestyle
changes, clinicians should provide frequent (up to weekly
for 6 months) and robust support to patients.
173 Non-Statin Therapy for Dyslipidemia
and their staff must be prepared to address prior authoriza-
tion paperwork in a timely manner to avoid therapy abandon-
ment. In addition, patients must be properly counseled and
willing to administer a subcutaneous injection. Despite the
limitations to PCSK9 inhibitor access and use, their uptake
in practice has been markedly increasing (Sumarsono 2021).
Ezetimibe, although with lesser evidence of cardiovascu-
lar benefit, has the advantage of generic availability and oral
administration. Thus, ezetimibe has a substantial access and
ease of use advantage over PCSK9 inhibitors. Although pro-
viding LDL cholesterol reduction similar to that with ezeti-
mibe, the effect of bempedoic acid on ASCVD risk is unknown.
These points are accentuated given the advantages of eze-
timibe, in addition to ezetimibe’s exceptional tolerability.
Although less expensive and administered orally, the use of
BAS is limited by adverse effects and chelating drug interac-
tions. Icosapent ethyl essentially stands alone with respect to
medications for ASCVD risk reduction that is not associated
LDL cholesterol lowering. As such, guideline-directed use in
the proper patient populations should guide implementation.
Regarding treatments specifically for very high triglycerides,
several options are reasonable and have generic availability,
such as omega-3-acid ethyl esters, and fibrates.
CONCLUSION
The use of non-statin therapy is generally reserved for
patients already optimized (or thoroughly trialed) on statin
therapy. The primary goal of non-statin therapy is ASCVD
risk reduction, not normalization of the lipid profile or another
non-evidence–based surrogate outcome. As such, strong
preference should be given to selecting agents with RCT
evidence supporting cardiovascular benefit and using them
clinically aligned with the populations in which they were
studied. Medications to lower triglycerides specifically are
limited to patients with very high triglyceride concentrations.
Therapeutic lifestyle changes have the potential to benefit
all patients; however, clinicians must provide robust and fre-
quent support to optimize the chances of successfully imple-
menting and maintaining healthy behaviors.
REFERENCES
Albert CM, Cook NR, Pester J, et al. Effect of marine omega-3
fatty acid and vitamin D supplementation on incident
atrial fibrillation: a randomized clinical trial. JAMA
2021;325:1061-73.
Amend KL, Landon J, Thyagarajan V, et al. Incidence of hos-
pitalized rhabdomyolysis with statin and fibrate use in an
insured us population. Ann Pharmacother 2011;45:1230-9.
American Diabetes Association. 5. Facilitating behavior
change and well-being to improve health outcomes: stan-
dards of medical care in diabetes—2021. Diabetes Care
2021a;44:S53-72.
PSAP 2022 Book 1 • Cardiology
American Diabetes Association. 10. Cardiovascular disease
and risk management: standards of medical care in diabe-
tes—2021. Diabetes Care 2021b;44:S125-50.
Arai H, Yamashita S, Yokote K, et al. Efficacy and safety of
pemafibrate versus fenofibrate in patients with high tri-
glyceride and low HDL cholesterol levels: a multicenter,
placebo-controlled, double-blind, randomized trial. J Ath-
eroscler Thromb 2018;25:521-38.
Arca M, D’Erasmo L, Minicocci I. Familial combined hypolip-
idemia: angiopoietin-like protein-3 deficiency. Curr Opin
Lipidol 2020;31:41-8.
Baigent C, Landray MJ, Reith C, et al. The effects of lower-
ing LDL cholesterol with simvastatin plus ezetimibe in
patients with chronic kidney disease (Study of Heart and
Renal Protection): a randomised placebo-controlled trial.
Lancet 2011;377:2181-92.
Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and
safety of eicosapentaenoic acid ethyl ester (AMR101)
therapy in statin-treated patients with persistent high
triglycerides (from the ANCHOR study). Am J Cardiol
2012;110:984-92.
Ballantyne CM, Davidson MH, Macdougall DE, et al. Effi-
cacy and safety of a novel dual modulator of adenosine
triphosphate-citrate lyase and adenosine monophos-
phate-activated protein kinase in patients with hyper-
cholesterolemia: results of a multicenter, randomized,
double-blind, placebo-controlled, parallel-group trial. J Am
Coll Cardiol 2013;62:1154-62.
Bays HE, Braeckman RA, Ballantyne CM, et al. Icosapent
ethyl, a pure EPA omega-3 fatty acid: effects on lipopro-
tein particle concentration and size in patients with very
high triglyceride levels (the MARINE study). J Clin Lipidol
2012;6:565-72.
Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduc-
tion with icosapent ethyl for hypertriglyceridemia. N Engl
J Med 2019;380:11-22.
Boden WE, Probstfield JL, Anderson T, et al. Niacin in
patients with low HDL cholesterol levels receiving inten-
sive statin therapy. N Engl J Med 2011;365:2255-67.
Brensike JF, Levy RI, Kelsey SF, et al. Effects of therapy with
cholestyramine on progression of coronary arterioscle-
rosis: results of the NHLBI type II coronary intervention
study. Circulation 1984;69:313-24.
Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added
to statin therapy after acute coronary syndromes. N Engl J
Med 2015;372:2387-97.
Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharma-
cologic inactivation of ANGPTL3 and cardiovascular dis-
ease. N Engl J Med 2017;377:211-21.
Elam MB, Ginsberg HN, Lovato LC, et al. Association of feno-
fibrate therapy with long-term cardiovascular risk in sta-
tin-treated patients with type 2 diabetes. JAMA Cardiol
2017;2:370-80.
Ely EK, Gruss SM, Luman ET, et al. A national effort to pre-
vent type 2 diabetes: participant-level evaluation of CDC’s
174 Non-Statin Therapy for Dyslipidemia
 National Diabetes Prevention Program. Diabetes Care
2017;40:1331-41.
Feingold KR. Triglyceride lowering drugs. In: Feingold KR,
Anawalt B, Boyce A et al., eds. Endotext. South Dartmouth,
MA: MDText.com, 2000–2021.
Fogacci F, Norata GD, Toth PP, et al. Efficacy and safety of
volanesorsen (ISIS 304801): the evidence from phase 2
and 3 clinical trials. Curr Atheroscler Rep 2020;22:18.
Fonarow GC, van Hout B, Villa G, et al. Updated cost-effec-
tiveness analysis of evolocumab in patients with very
high-risk atherosclerotic cardiovascular disease. JAMA
Cardiol 2019;4:691-5.
Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: prima-
ry-prevention trial with gemfibrozil in middle-aged men
with dyslipidemia. Safety of treatment, changes in risk
factors, and incidence of coronary heart disease. N Engl J
Med 1987;317:1237-45.
Gaudet D, Gipe DA, Pordy R, et al. ANGPTL3 inhibition in
homozygous familial hypercholesterolemia. N Engl J Med
2017;377:296-7.
Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combina-
tion lipid therapy in type 2 diabetes mellitus. N Engl J Med
2010;362:1563-74.
Ginsberg HN, Le NA, Goldberg IJ, et al. Apolipoprotein B
metabolism in subjects with deficiency of apolipopro-
teins CIII and AI. Evidence that apolipoprotein CIII inhibits
catabolism of triglyceride-rich lipoproteins by lipoprotein
lipase in vivo. J Clin Invest 1986;78:1287-95.
Giugliano RP, Mach F, Zavitz K, et al. Cognitive func-
tion in a randomized trial of evolocumab. N Engl J Med
2017a;377:633-43.
Giugliano RP, Pedersen TR, Park JG, et al. Clinical efficacy
and safety of achieving very low LDL-cholesterol con-
centrations with the PCSK9 inhibitor evolocumab: a pre-
specified secondary analysis of the Fourier trial. Lancet
2017b;390:1962-71.
Goldberg AC, Hopkins PN, Toth PP, et al. Familial hypercho-
lesterolemia: screening, diagnosis and management of
pediatric and adult patients: clinical guidance from the
National Lipid Association Expert Panel on Familial Hyper-
cholesterolemia. J Clin Lipidol 2011;5:S1-8.
Goldberg AC, Leiter LA, Stroes ESG, et al. Effect of bempe-
doic acid vs placebo added to maximally tolerated statins
on low-density lipoprotein cholesterol in patients at high
risk for cardiovascular disease: the clear wisdom random-
ized clinical trial. JAMA 2019;322:1780-8.
Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/
AACVPR/AAPA/ABC/ACPM/ADA/AGS/APHA/ASPC/NLA/
PCNA guideline on the management of blood cholesterol:
a report of the American College of Cardiology/American
Heart Association Task Force on clinical practice guide-
lines. Circulation 2019;139:e1082-143.
Handelsman Y, Jellinger PS, Guerin CK, et al. Consensus
statement by the American Association of Clinical Endo-
crinologists and American College of Endocrinology on
PSAP 2022 Book 1 • Cardiology
the management of dyslipidemia and prevention of car-
diovascular disease algorithm—2020 executive summary.
Endocr Pract 2020;26:1196-224.
Harris WS, Ginsberg HN, Arunakul N, et al. Safety and effi-
cacy of Omacor in severe hypertriglyceridemia. J Cardio-
vasc Risk 1997;4:385-91.
Herrett E, Williamson E, Brack K, et al. Statin treatment and
muscle symptoms: series of randomised, placebo con-
trolled n-of-1 trials. BMJ 2021;372:n135.
Ishibashi S, Arai H, Yokote K, et al. Efficacy and safety
of pemafibrate (K77), a selective peroxisome prolifer-
ator-activated receptor α modulator, in patients with
dyslipidemia: results from a 24-week, randomized, dou-
ble blind, active-controlled, phase 3 trial. J Clin Lipidol
2018;12:173-84.
Jacobson TA, Ito MK, Maki KC, et al. National Lipid Asso-
ciation recommendations for patient-centered manage-
ment of dyslipidemia: part 1—full report. J Clin Lipidol
2015a;9:129-69.
Jacobson TA, Maki KC, Orringer CE, et al. National Lipid
Association recommendations for patient-centered man-
agement of dyslipidemia: part 2. J Clin Lipidol 2015b;9:S1-
122.e1.
Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/
TOS guideline for the management of overweight and
obesity in adults: a report of the American College of
Cardiology/American Heart Association task force on
practice guidelines and the obesity society. Circulation
2014;129:S102-38.
Jones PH , Davidson MH. Reporting rate of rhabdomyolysis
with fenofibrate + statin versus gemfibrozil + any statin.
Am J Cardiol 2005;95:120-2.
Kalstad AA, Myhre PL, Laake K, et al. Effects of n-3 fatty
acid supplements in elderly patients after myocardial
infarction: a randomized, controlled trial. Circulation
2021;143:528-39.
Karagiannis AD, Mehta A, Dhindsa DS, et al. How low is safe?
The frontier of very low (<30 mg/dl) LDL cholesterol. Eur
Heart J 2021;42:2154-69.
Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or
without ezetimibe in familial hypercholesterolemia. N Engl
J Med 2008;358:1431-43.
Kuehn BM. Sleep duration linked to cardiovascular disease.
Circulation 2019;139:2483-4.
Landray MJ, Haynes R, Hopewell JC, et al. Effects of extend-
ed-release niacin with laropiprant in high-risk patients. N
Engl J Med 2014;371:203-12.
Laufs U, Banach M, Mancini GBJ, et al. Efficacy and safety of
bempedoic acid in patients with hypercholesterolemia and
statin intolerance. J Am Heart Assoc 2019;8:e011662.
The Lipid Research Clinics coronary primary prevention trial
results. I. Reduction in incidence of coronary heart dis-
ease. JAMA 1984;251:351-64.
175 Non-Statin Therapy for Dyslipidemia
Mendivil CO, Rimm EB, Furtado J, et al. Low-density lipopro-
teins containing apolipoprotein c-iii and the risk of coro-
nary heart disease. Circulation 2011;124:2065-72.
Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and car-
diovascular disease: a scientific statement from the Amer-
ican Heart Association. Circulation 2011;123:2292-333.
Newman CB, Preiss D, Tobert JA, et al. Statin safety and
associated adverse events: a scientific statement from the
American Heart Association. Arterioscler Thromb Vasc
Biol 2019;39:e38-81.
Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-
dose omega-3 fatty acids vs corn oil on major adverse
cardiovascular events in patients at high cardiovascu-
lar risk: the Strength Randomized Clinical Trial. JAMA
2020;324:2268-80.
Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tol-
erability of evolocumab vs ezetimibe in patients with mus-
cle-related statin intolerance: the GAUSS-3 randomized
clinical trial. JAMA 2016;315:1580-90.
Ooi EM, Barrett PH, Chan DC, et al. Apolipoprotein C-III:
understanding an emerging cardiovascular risk factor. Clin
Sci (Lond) 2008;114:611-24.
Pradhan AD, Paynter NP, Everett BM, et al. Rationale and
design of the pemafibrate to reduce cardiovascular out-
comes by reducing triglycerides in patients with diabetes
(PROMINENT) study. Am Heart J 2018;206:80-93.
Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the treatment
of heterozygous familial hypercholesterolemia. N Engl J
Med 2020;382:1520-30.
Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of
bempedoic acid to reduce LDL cholesterol. N Engl J Med
2019;380:1022-32.
Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of
inclisiran in patients with elevated LDL cholesterol. N Engl
J Med 2020;382:1507-19.
Rosenson RS, Burgess LJ, Ebenbichler CF, et al. Evinacumab
in patients with refractory hypercholesterolemia. N Engl J
Med 2020;383:2307-19.
Ross S, D’Mello M, Anand SS, et al. Effect of bile acid
sequestrants on the risk of cardiovascular events: a men-
delian randomization analysis. Circ Cardiovasc Genet
2015;8:618-27.
Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid
lowering with simvastatin and ezetimibe in aortic stenosis.
N Engl J Med 2008;359:1343-56.
Ruscica M, Zimetti F, Adorni MP, et al. Pharmacological
aspects of ANGPTL3 AND ANGPTL4 inhibitors: new thera-
peutic approaches for the treatment of atherogenic dyslip-
idemia. Pharmacol Res 2020;153:104653.
Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and
clinical outcomes in patients with cardiovascular disease.
N Engl J Med 2017;376:1713-22.
Sacks FM, Alaupovic P, Moye LA, et al. VLDL, apolipoproteins
B, CIII, and E, and risk of recurrent coronary events in the
PSAP 2022 Book 1 • Cardiology
cholesterol and recurrent events (CARE) trial. Circulation
2000;102:1886-92.
Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and car-
diovascular outcomes after acute coronary syndrome.
N Engl J Med 2018;379:2097-107.
Silverman MG, Ference BA, Im K, et al. Association between
lowering LCL-C and cardiovascular risk reduction among
different therapeutic interventions: a systematic review
and meta-analysis. JAMA 2016;316:1289-97.
Sisson EM, Pamulapati L, Bucheit JD, et al. Evolving role
of non-statin therapy for the management of dyslipid-
emia and cardiovascular risk reduction: past, present, and
future. Pharmacotherapy 2018;38:164-71.
Spencer Bonilla G, Rodriguez-Gutierrez R , V MM. What we
don’t talk about when we talk about preventing type 2 dia-
betes—addressing socioeconomic disadvantage. JAMA
Intern Med 2016;176:1053-4.
Sumarsono A, Lalani HS, Vaduganathan M, et al. Trends in
utilization and cost of low-density lipoprotein cholester-
ol-lowering therapies among Medicare beneficiaries: an
analysis from the Medicare part D database. JAMA Cardiol
2021;6:92-6.
Tenkanen L, Mänttäri M, Kovanen PT, et al. Gemfibrozil in
the treatment of dyslipidemia: an 18-year mortality fol-
low-up of the Helsinki Heart Study. Arch Intern Med
2006;166:743-8.
Thompson PD, MacDougall DE, Newton RS, et al. Treat-
ment with etc-1002 alone and in combination with eze-
timibe lowers LDL cholesterol in hypercholesterolemic
patients with or without statin intolerance. J Clin Lipidol
2016;10:556-67.
Virani SS, Alonso A, Aparicio HJ, et al. Heart disease and
stroke statistics—2021 update: a report from the American
Heart Association Circulation 2021;143:e254-743.
Wang ML, Pbert L, Lemon SC. Influence of family, friend and
coworker social support and social undermining on weight
gain prevention among adults. Obesity (Silver Spring)
2014;22:1973-80.
Watts GF, Lewis B, Brunt JN, et al. Effects on coronary artery
disease of lipid-lowering diet, or diet plus cholestyramine,
in the St Thomas’ Atherosclerosis Regression Study
(STARS). Lancet 1992;339:563-9.
Wiggins BS, Saseen JJ, Page RL, 2nd, et al. Recommen-
dations for management of clinically significant drug–
drug interactions with statins and select agents used in
patients with cardiovascular disease: a scientific state-
ment from the American Heart Association. Circulation
2016;134:e468-e95.
Wood FA, Howard JP, Finegold JA, et al. N-of-1 trial of a sta-
tin, placebo, or no treatment to assess side effects. N Engl
J Med 2020;383:2182-4.
Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicos-
apentaenoic acid on major coronary events in hypercho-
lesterolaemic patients (JELIS): a randomised open-label,
blinded endpoint analysis. Lancet 2007;369:1090-8.
176 Non-Statin Therapy for Dyslipidemia
Self-Assessment Questions
16. A 61-year-old African American man with a medical his-
tory of hypertension, dyslipidemia, prediabetes, and
transient ischemic attack (2 years ago) presents for
the outpatient management of dyslipidemia. His home
drugs include: lisinopril 20 mg/day, indapamide 2.5
mg/day, aspirin 81 mg/day, and atorvastatin 20 mg/day.
The patient’s most recent lipid panel shows total choles-
terol 170 mg/dL, HDL cholesterol 41 mg/dL, LDL choles-
terol 96 mg/dL, and TG 165 mg/dL. His most recent blood
pressure is 129/79 mm Hg. Which one of the following is
best to recommend for treating this patient’s elevated tri-
glyceride concentration?
A. Icosapent ethyl
B. Prescription omega-3-acid ethyl esters (O3FAs)
C. Dietary supplement O3FAs
D. Lifestyle change
Questions 17–19 pertain to the following case
M.G. is a 54-year-old non-Hispanic white woman who pres-
ents to clinic to follow-up on her lipid panel. She was referred
to you for determination of initial therapy and associated
counseling. M.G.’s medical history includes: hypertension,
blood pressure today 130/78 mm Hg; and current cigarette
smoking 1 pack per day, 35 pack-year history. Results of a
lipid panel include: TC 220 mg/dL, HDL cholesterol 31 mg/dL,
TG 265 mg/dL, and LDL cholesterol 136 mg/dL. M.G.’s home
drugs include: losartan 50 mg twice daily, amlodipine 10
mg/day, and chlortalidone 25 mg/day. Her 10-year athero-
sclerotic cardiovascular disease (ASCVD) risk score is 12%.
17. M.G. has agreed to statin therapy. Which one of the fol-
lowing is best to recommend to avoid unnecessary statin
discontinuation in M.G.?
A. Obtain baseline serum creatinine kinase.
B. Obtain detailed history of muscle pain.
C. Start coenzyme Q10 supplementation.
D. Start vitamin D supplementation.
18. Three weeks after being initiated on atorvastatin 20 mg/
day, M.G. returns to clinic. She reports bilateral calf pain
and cramping that started 3 days prior; this abated after
her self-discontinuation of atorvastatin. Which one of
the following is best to recommend for M.G.?
A. Retrial atorvastatin 20 mg/day.
B. Change to rosuvastatin 10 mg/day.
C. Change to ezetimibe 10 mg/day.
D. Change to evolocumab 420 mg once monthly.
PSAP 2022 Book 1 • Cardiology
19. Three weeks later, M.G. returns to clinic complaining of
the same pain. She wants to know what else she can do
to lower her cardiovascular risk. Which one of the follow-
ing is best to recommend for lowering M.G.’s calculated
ASCVD risk score?
A. Moderate-intensity exercise 150 minutes per week
B. Good adherence to a Mediterranean diet
C. Successfully quitting smoking
D. Lower blood pressure to 129/78 mm Hg
Question 20–22 pertain to the following case.
T.C., a 63-year-old African American woman (weight 88.5 kg
[195 lb], height 64 inches), is a new patient referred to your
lipid assessment and management program. She has trialed
and did not tolerate simvastatin, atorvastatin, pravastatin, and
lovastatin because of myalgia. T.C.’s dyslipidemia is currently
being treated with rosuvastatin 5 mg/day after the dose was
reduced from 10 mg/day following leg aches. Her medical his-
tory includes type 2 diabetes (A1C 7.2%), myocardial infarction
(6 months prior, status post 3 drug-eluting stent placements),
hypertension (blood pressure today is 135/82 mm Hg),
chronic kidney disease stage 3 (urinary albumin/creatinine
ratio 45 mg/g), former smoker (quit 3 months ago following
myocardial infarction). T.C.’s home drugs include: clopidogrel
75 mg/day, aspirin 81 mg/day, rosuvastatin 5 mg/day, lisino-
pril 40 mg/day, indapamide 2.5 mg/day, metformin 1000 mg
twice daily, liraglutide 1.8 mg/day, and empagliflozin 25 mg/
day. Her lipid panel after 3 months of rosuvastatin 5 mg/day
is: TC 231 mg/dL, HDL cholesterol 43 mg/dL, TG 260 mg/dL,
and LDL cholesterol 136 mg/dL.
20. Which one of the following is the most likely cause of
T.C.’s statin-induced muscle pain?
A. Vitamin D deficiency
B. Co-enzyme Q10 deficiency
C. Genetic predisposition
D. Nocebo effect
21. Which one of the following LDL cholesterol thresholds is
recommended by at least one major guideline and offers
T.C. the greatest possible ASCVD risk reduction?
A. < 130 mg/dL
B. < 100 mg/dL
C. < 70 mg/dL
D. < 55 mg/dL
177 Non-Statin Therapy for Dyslipidemia
22. Which one of the following is best to recommend for
additional LDL cholesterol lowering for T.C.?
A. Increase rosuvastatin dose.
B. Add evolocumab.
C. Add ezetimibe.
D. Add bempedoic acid.
Questions 23 and 24 pertain to the following case
A primary care physician contacts you to reassess lipid
therapy in F.B., a 57-year-old white man (weight 110.5 kg
[243 lb], height 69 inches) with a history of hypertension
(125/72 mm Hg taking losartan 50 mg twice daily), type 2 dia-
betes (A1C 6.8%, taking metformin 1000 mg twice daily), and
dyslipidemia. F.B.’s baseline lipid panel reveals TC 239 mg/dL,
HDL cholesterol 32 mg/dL, LDL cholesterol 165 mg, and TG
210 mg/dL. His baseline 10-year ASCVD risk was 23.3% After
3 months of therapy with atorvastatin 80 mg, F.B.’s LDL cho-
lesterol is 84 mg/dL. Patient report, pill count, and refill his-
tory indicate adherence to atorvastatin therapy.
23. Which one of the following LDL cholesterol thresholds is
recommended by at least one major guideline and offers
F.B. the greatest possible ASCVD risk reduction?
A. < 130 mg/dL
B. < 100 mg/dL
C. < 70 mg/dL
D. < 55 mg/dL
24. F.B.’s physician requests your opinion on adding a med-
ication for additional LDL cholesterol lowering. Which
one of the following is best to recommend for F.B.?
A. Add ezetimibe.
B. Add alirocumab.
C. Add a bile acid sequestrant.
D. Maintain current regimen.
25. A 47-year-old African American man (weight 106.8 kg
[235 lb], height 72 inches) with no contributory med-
ical history is establishing care in your clinic. He is a
never smoker and his baseline fasting laboratory values
and vital signs are: blood pressure 118/75 mm Hg, TC
190 mg/dL, HDL cholesterol 39 mg/dL, reflex direct LDL
cholesterol 142 mg/dL, TG 710 mg/dL, and blood sugar
102 mg/dL. The physician asks you for a recommenda-
tion to manage the patient’s dyslipidemia. Which one of
the following is best to recommend for this patient?
A. Fenofibrate 130 mg/day
B. Prescription O3FA 4 g/day
C. Icosapent ethyl 2g twice daily
D. Atorvastatin 80 mg/day
PSAP 2022 Book 1 • Cardiology
Questions 26 and 27 pertain to the following case.
C.B., a 52-year-old white man (weight 109 kg [240 lb], height
70 inches, waist 41 inches), presents to your clinic for man-
agement of dyslipidemia. His medical history includes osteo-
arthritis of the right knee, generalized anxiety disorder, and
hypertension (blood pressure 132/78 mm Hg). C.B.’s home
drugs include acetaminophen 650 mg four times daily, escit-
alopram 20 mg/day, amlodipine 10 mg/day, and lisinopril
20 mg/day. He reports having trouble paying for brand name
medications because of the more expensive co-pay. C.B.’s
most recent lipid panel results include: TC 220 mg/dL, HDL
cholesterol 42 mg/dL, LDL cholesterol 145 mg/dL, and TG
165 mg/dL. His ASCVD 10-year risk is 7%.
26. According to the American Association of Clinical Endo-
crinologist and American College of Endocrinology,
which one of the following LDL cholesterol goals is best
to recommend for C.B.?
A. < 130 mg/dL
B. < 100 mg/dL
C. < 70 mg/dL
D. < 55 mg/dL
27. C.B. has heard so many negative things about statins
from his friends that he refuses to even trial one. Which
one of the following is best to recommend to help C.B.
lower his LDL cholesterol?
A. Lifestyle intervention
B. Evolocumab and lifestyle intervention
C. Ezetimibe and lifestyle intervention
D. Gemfibrozil and lifestyle intervention
Questions 28 and 29 pertain to the following case.
J.B. is a 59-year-old woman being discharged from the hospi-
tal after a myocardial infarction (status post two drug-eluting
stent placements). Her medical history includes a previous
myocardial infarction 2 years ago (status post drug-eluting
stent placement), type 2 diabetes (A1C 8.3%), hypertension
(blood pressure 134/82 mm Hg), rheumatoid arthritis, hypo-
thyroidism, and depression. J.B.’s home drugs include: aspi-
rin 81 mg/day, ticagrelor 90 mg twice daily, candesartan 32
mg/day, amlodipine 10 mg/day, indapamide 2.5 mg/day, top-
ical diclofenac gel four times/day, methotrexate 20 mg once
weekly, levothyroxine 100 mcg/day, escitalopram 10 mg/day,
liraglutide 1.8 mg/day, empagliflozin 25 mg/day, atorvastatin
80 mg/day, ezetimibe 10 mg/day. Results of her current lipid
panel include: TC 115 mg/dL, HDL cholesterol 39 mg/dL, LDL
cholesterol 68 mg/dL, and TG 41 mg/dL.
178 Non-Statin Therapy for Dyslipidemia
28. Which one of the following LDL cholesterol goals is best 30. A 59-year-old man has a medical history that includes
to recommend for J.B. to optimize her risk for another dyslipidemia, peripheral artery disease, and hyperten-
myocardial infarction? sion. The patient is statin intolerant and cannot afford
proprotein convertase subtilisin/kexin type 9 (PCSK9)
A. < 130 mg/dL
inhibitor therapy. His home drugs include lisinopril 20
B. < 100 mg/dL
mg/day, aspirin 81 mg/day, and ezetimibe 10 mg/day.
C. < 70 mg/dL
The patient’s current lipid profile is: TC cholesterol 210
D. < 55 mg/dL
mg/dL, HDL cholesterol 42 mg/dL, reflex direct LDL cho-
29. Which one of the following is best to recommend to opti- lesterol 155 mg/dL, and TG 550 mg/dL. A clinical trial of
mize J.B.’s lipids? which one of the following medications is most likely to
A. Bempedoic acid benefit this patient?
B. Evolocumab A. Evinacumab
C. Cholestyramine B. Volanesorsen
D. No additional pharmacotherapy C. Pemafibrate
D. Inclisiran

PSAP 2022 Book 1 • Cardiology 179 Non-Statin Therapy for Dyslipidemia

Learner Chapter Evaluation: Non-Statin Therapy for Dyslipidemia

As you take the posttest for this chapter, also evaluate the 25. The learning assessment activities used in the chapter
material’s quality and usefulness, as well as the achievement were effective.
of learning objectives. Rate each item using this 5-point scale: 26. The chapter was effective overall.

• Strongly agree 27. The activity met the stated learning objectives.
• Agree 28. If any objectives were not met, please list them here.
• Neutral
• Disagree OTHER COMMENTS
• Strongly disagree
29. Please provide any specific comments related to any
16. The content of the chapter met my educational needs. perceptions of bias, promotion, or advertisement of
commercial products.
17. The content of the chapter satisfied my expectations.
30. Please expand on any of your above responses, and/or
18. The author presented the chapter content effectively.
provide any additional comments regarding this chapter:
19. The content of the chapter was relevant to my practice
and presented at the appropriate depth and scope.
Questions 31–33 apply to the entire learning module.
20. The content of the chapter was objective and balanced.
31. How long did it take you to read the instructional materi-
21. The content of the chapter is free of bias, promotion, and
als in this module?
advertisement of commercial products.
32. How long did it take you to read and answer the assess-
22. The content of the chapter was useful to me.
ment questions in this module?
23. The teaching and learning methods used in the chapter
33. Please provide any additional comments you may have
were effective.
regarding this module:
24. The active learning methods used in the chapter were
effective.

PSAP 2022 Book 1 • Cardiology 180 Non-Statin Therapy for Dyslipidemia

Cardiology IV
Cardiology IV Panel
Series Editors:
Cynthia A. Sanoski, Pharm.D., FCCP, BCPS
Department Chair
Associate Professor of Pharmacy Practice
Thomas Jefferson University
Philadelphia, Pennsylvania
Daniel M. Witt, Pharm.D., FCCP, BCPS
Professor and Chair
Department of Pharmacotherapy
Assistant Dean of Clinical Affairs
University of Utah College of Pharmacy
Salt Lake City, Utah
Faculty Panel Chair:
Craig J. Beavers, Pharm.D., FCCP, FACC, FAHA, BCCP,
BCPS-AQ Cardiology, CACP
Director of Cardiovascular Services
Baptist Health Paducah
Cardiovascular Clinical Pharmacist
Department of Pharmacy Services
UK Healthcare
Assistant Adjunct Professor
Department of Pharmacy Practice and Science
University of Kentucky College of Pharmacy
Paducah, Kentucky
Interactive Case: Hyperlipidemia
Management for Special Populations
Authors
Glenn Herrington, Pharm.D., AACC, BCCP, BCPS, CDCES
Clinical Pharmacist Practitioner
Cape Fear Heart Associates
Novant Health New Hanover Regional Medical Center
Wilmington, North Carolina
Daniel M. Riche, Pharm.D., FCCP, CLS, ASH-CHC
Professor
Department of Pharmacy Practice
University of Mississippi School of Pharmacy
Jackson, Mississippi
Reviewers
Elisabeth M. Wang, Pharm.D., BCCP
Clinical Assistant Professor
Department of Pharmacy Practice and Translational
Research
University of Houston College of Pharmacy
Houston, Texas
Jessica A. Bente, Pharm.D., BCPS, BCGP
Geriatric Clinical Pharmacy Specialist
PGY-2 Geriatric Pharmacy Residency Program Director
Department of Pharmacy
Cooperman Barnabas Medical Center
Livingston, New Jersey
Eman Elsayed Younis, Pharm.D., BCPS-AQ Cardiology
Senior Clinical Pharmacist
Department of Pharmacy
Saudi German Hospital Madinah
Madinah, Saudi Arabia
Interactive Case: Anticoagulation in
Special Populations
Authors
Allison E. Burnett, Pharm.D., CACP
Antithrombosis Stewardship Pharmacist
Inpatient Pharmacy
University of New Mexico Hospital
Adjunct Associate Professor of Clinical Pharmacy
President, Anticoagulation Forum
University of New Mexico College of Pharmacy
Albuquerque, New Mexico
Kelly M. Rudd, Pharm.D., FCCP, BCPS, CACP
Clinical Associate Professor of Medicine
Department of Medical Education
Oklahoma State University Center for Health Sciences
College of Osteopathic Medicine
Tulsa, Oklahoma
Reviewers
Sara R. Vazquez, Pharm.D., BCPS, CACP
Clinical Pharmacist
Department of Pharmacy Services
University of Utah Health
Adjunct Associate Professor in Pharmacotherapy
University of Utah College of Pharmacy
Salt Lake City, Utah
Nancy Nix, Pharm.D., BCPS, BCOP
Oncology Clinical Coordinator
Corporate Pharmacy
Ballad Health
Johnson City, Tennessee
Interactive Case: Cardiovascular Reviewers

Diseases in Pregnancy Jessie Dunne, Pharm.D., BCPS, BCCP

Clinical Pharmacy Specialist – Advanced
Author
Heart Failure and Transplant
Lindsey Federle, Pharm.D., BCCP, BCPS Department of Pharmacy
Clinical Pharmacy Specialist, Cardiology Oregon Health and Science University
Inpatient Pharmacy Portland, Oregon
UC Health – University of Cincinnati Medical Center Leslie Wooten, Pharm.D., BCPS
Cincinnati, Ohio
Clinical Manager Internal Medicine
Department of Pharmacy
AdventHealth Orlando
Orlando, Florida
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Consultancies: Anastasia Armbruster (ACC/AHA Joint Committee Clinical Practice Guidelines); Jessica Bente (ACCP); Allison
Burnett: Consultancies (Anticoagulation Forum; National Certification Board for Anticoagulation Providers; Global Strategies);
Jessie L. Dunne (Pulmonary Hypertension Association); Nancy M. Nix (Pharmacosmos); Daniel M. Riche (Novo Nordisk; Merck;
AstraZeneca); Ralph J. Riello III (AstraZeneca; Johnson & Johnson); Sara Vazquez (Anticoagulation Forum);

Stock Ownership:

Royalties: Allison Burnett (Wolters-Kluwer); Daniel M. Riche (McGraw-Hill); Honoraria (Merck); Sara Vazquez (UpToDate)

Grants: Anastasia Armbruster (ACCP); Jessica Bente (New Jersey Society of Health-System Pharmacists); Gregory Castelli
(American Board of Family Medicine); Kevin Cowart (University of South Florida Taneja College of Pharmacy); Ralph J. Riello
III (AstraZeneca)

Honoraria: Anastasia Armbruster (AstraZeneca); John Bucheit (Association of Diabetes Care & Education Specialists); Nancy M.
Nix (Coherus; Pfizer; AstraZeneca); Ralph J. Riello III (Alexion; AstraZeneca; Janssen)

Other:

Nothing to disclose: Katherine Aymond, Eugene N. Bush, Nicholas W. Carris, Stephanie Dwyer Kaluzna, Lindsey Federle, Beth-
any A. Ford, Stormi E. Gale, Jaclynne R. Gowen, Glenn Herrington, Christine Ji, Amy L. Lehnert, Nilam R. Naik, Brenda Pahl, Joel
J. Peterson, A. Joshua Roberts, Kelly M. Rudd, Ashley Schenk, Susan M. Smith, Elisabeth M. Wang, Toby C. Trujillo, Barbara Wig-
gins, Leslie Wooten, Eman El Sayed Younis

ROLE OF BPS: The Board of Pharmacy Specialties (BPS) is an autonomous division of the American Pharmacists Association (APhA).
To maintain its strict, independent standards for certification, BPS does NOT endorse or provide review information, preparatory
courses, or study guides for Board Certification Examinations. The Board, through its specialty councils, is responsible for spe-
cialty examination content, administration, scoring, and all other aspects of its certification programs. BPS is totally separate
and distinct from ACCP. PSAP has been approved by BPS for use in BCPS recertification. Information about the BPS recertifica-
tion process is available online.

Questions regarding BPS specialty recertification should be directed to:

Board of Pharmacy Specialties

2215 Constitution Avenue NW
Washington, DC 20037
(202) 429-7591
Continuing Pharmacy Education
and Recertification Instructions
Continuing Pharmacy Education (CPE) Credit: The American College of Clinical Pharmacy is accredited by the
Accreditation Council for Pharmacy Education (ACPE) as a provider of CPE.

PSAP Target Audience: The target audience for PSAP 2022 Book 1 (Cardiology) is pharmacotherapy specialists and advanced
level clinical pharmacists encountering diverse cardiovascular patient populations.

Available CPE credits: Purchasers who successfully complete all posttests for PSAP 2022 Book 1 (Cardiology) can earn 21.5 contact
hours of CPE credit. The universal activity numbers are as follows: Cardiology I – 0217-0000-22-002-H01-P, 5.0 contact hours;
Cardiology II – 0217-0000-22-003-H01-P, 6.0 contact hours; Cardiology III – 0217-0000-22-004-H01-P, 5.0 contact hours; and
Cardiology IV – 0217-0000-22-005-H01-P, 5.5 contact hours. You may complete one or all available modules for credit. Tests may
not be submitted more than one time.

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The passing point to earn BCPS recertification credit is based on an expert analysis of the assessment items in each posttest
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Interactive Case: Hyperlipidemia
Management for Special Populations
By Glenn Herrington, Pharm.D., AACC, BCCP, BCPS, CDCES; and Daniel M. Riche, Pharm.D.,
FCCP, CLS, ASH-CHC

Reviewed by Elisabeth M. Wang, Pharm.D., BCCP; Jessica A. Bente, Pharm.D., BCPS, BCGP; and Eman Elsayed Younis, Pharm.D., BCPS-AQ
Cardiology

LEARNING OBJECTIVES

1. Evaluate cardiovascular risk and complications to apply pharmacologic management strategies for hyperlipidemia in
older adult patients.
2. Apply pharmacologic management strategies for hyperlipidemia in patients of various racial/ethnic backgrounds.
3. Apply pharmacologic management strategies for hyperlipidemia in patients with HIV infection.
4. Apply pharmacologic management strategies for familial hyperlipidemia.

ABBREVIATIONS IN THIS FEATURE

ASCVD Atherosclerotic cardiovascular BASELINE KNOWLEDGE STATEMENTS
disease
Readers of this feature are presumed to be familiar with the
CAC Coronary artery calcium
following:
CVD Cardiovascular disease
FH Familial hypercholesterolemia
• General knowledge of the pathophysiology of lipid
disorders
HeFH Heterozygous familial
hypercholesterolemia
• Goal-oriented, drug-oriented, and evidence-oriented strate-
gies for the treatment of lipid disorders
HoFH Homozygous familial
hypercholesterolemia • Drug knowledge of the oral and injectable pharmacologic
agents used to treat lipid disorders
PCE Pooled cohort equations
PCSK9 Proprotein convertase subtilisin/
• Statin dosing and pharmacokinetic and pharmacodynamic
parameters
kexin type 9
PLWH People living with HIV • Basic understanding of the impact of age, race, sex, genet-
ics, and concomitant diseases on lipid disorders
STEMI ST-segment elevation myocardial
infarction Table of common laboratory reference values.
T2DM Type 2 diabetes mellitus

Table of other common abbreviations. ADDITIONAL READINGS

The following free resources have additional background infor-

mation on this topic:
• Wilson PWF, Polonsky TS, Miedema MD, et al. Systematic
review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/
ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the man-
agement of blood cholesterol: a report of the American
College of Cardiology/American Heart Association Task
Force on clinical practice guidelines. Circulation 2019;
139:e1144-61.

PSAP 2022 Book 1 • Cardiology 187 Interactive Case: Hyperlipidemia Management


• Chastain DB, Stover KR, Riche DM. Evidence-based
review of statin use in patients with HIV on antiretro-
viral therapy. J Clin Transl Endocrinol 2017;8:6-14.
• Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/
ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/
ASPC/NLA/PCNA guideline on the management of
blood cholesterol: executive summary: a report of the
American College of Cardiology/American Heart
Association task force on clinical practice guidelines
[published correction appears in J Am Coll Cardiol
2019;73:3234-7]. J Am Coll Cardiol 2019;73:3168-209.
• Sarkar S, Brown TT. Lipid Disorders in People with
HIV. In: Feingold KR, Anawalt B, Boyce A, et al., eds.
Endotext [Internet]. South Dartmouth (MA): MDText.
com, Inc.; 2000. Table 5. Interaction of Antiretroviral
Therapy and Statins.
• McGowan MP, Hosseini Dehkordi SH, Moriarty PM,
et al. Diagnosis and treatment of heterozygous
familial hypercholesterolemia. J Am Heart Assoc
2019;8:e013225.
• Virani SS, Morris PB, Agarwala A, et al. 2021 ACC
expert consensus decision pathway on the manage-
ment of ASCVD risk reduction in patients with persistent
hypertriglyceridemia: a report of the American Col-
lege of Cardiology solution set oversight committee.
J Am Coll Cardiol 2021;78:960-93.
• Goldberg AC, Hopkins PN, Toth PP, et al. Familial
hypercholesterolemia: screening, diagnosis and man-
agement of pediatric and adult patients: clinical guid-
ance from the National Lipid Association expert
panel on familial hypercholesterolemia. J Clin Lipidol
2011;5:S1-8.
INTERACTIVE CASE:
HYPERLIPIDEMIA MANAGEMENT
FOR SPECIAL POPULATIONS
• Click here to start this PSAP activity.
REFERENCES
Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA
guideline on the primary prevention of cardiovascular
disease: a report of the American College of Cardiology/
American Heart Association Task Force on Clinical
Practice Guidelines. J Am Coll Cardiol 2019;74:e177-e232.
Baigent, C, Blackwell, L, Emberson, J, et al. Efficacy and
safety of more intensive lowering of LDL cholesterol:
a meta-analysis of data from 170 000 participants in
26 randomised trials. Lancet. 2010;376:1670–81
Birmingham BK, Bujac SR, Elsby R, et al. Rosuvastatin
pharmacokinetics and pharmacogenetics in white and
Asian subjects residing in the United States. Eur J Clin
Pharmacol 2015;71:329–40.
PSAP 2022 Book 1 • Cardiology
Practice Points
• Cardiovascular disease (CVD) is the leading cause of
mortality worldwide. Almost 18 million people die of CVD
every year, according to the WHO. Eighty-five percent of
these deaths are a result of atherosclerotic cardiovascu-
lar disease (ASCVD), including myocardial infarction and
stroke. Over 18 million U.S. adults have coronary artery
disease, according to the CDC. In addition, each year,
655,000 U.S. adults die of heart disease, accounting for
one in four deaths.
• Atherogenic lipoproteins are thought to be a strong
contributor to the development of ASCVD. Lipid-lowering
drugs, primarily statins, have shown efficacy in reducing
the risk of ASCVD; however, despite strong recommenda-
tions from several professional societies, many people at
risk of death from ASCVD are not receiving appropriate
medication therapy. Statin-associated adverse effects, lack
of response, or insufficient response to maximally tolerat-
ed statins are common treatment barriers. Patient-specific
characteristics, such as age, race/ethnicity, sex, genetics,
and concomitant disease states (e.g., HIV), may increase
a patient’s risk of ASCVD and affect the risk-benefit of
lipid-lowering drugs. Clinical pharmacists should be aware
of the characteristics and risk assessment (e.g., ASCVD
risk calculator) in special populations in order to guide
medication therapy recommendations and improve patient
outcomes.
Bohula EA, Morrow DA, Giugliano RP, et al. Atherothrombotic
risk stratification and ezetimibe for secondary prevention.
J Am Coll Cardiol 2017;69:911–21.
Carnethon MR, Pu J, Howard G, et al. Cardiovascular
health in African Americans: a scientific statement
from the American Heart Association. Circulation
2017;136:e393–423.
Conomos MP, Laurie CA, Stilp AM, et al. Genetic diversity
and association studies in US Hispanic/Latino popula-
tions: applications in the Hispanic Community Health
Study/Study of Latinos. Am J Hum Genet 2016;98:165–84.
Currier JS, Lundgren JD, Carr A, et al. Epidemiological evi-
dence for cardiovascular disease in HIV-infected patients
and relationship to highly active antiretroviral therapy.
Circulation 2008;118:e29–e35.
Daviglus ML, Pirzada A, Talavera GA. Cardiovascular disease
risk factors in the Hispanic/Latino population: lessons
from the Hispanic Community Health Study/Study of
Latinos (HCHS/SOL). Prog Cardiovasc Dis 2014;57:230–6.
Daviglus ML, Pirzada A, Durazo-Arvizu R, et al. Prevalence
of low cardiovascular risk profile among diverse Hispanic/
Latino adults in the United States by age, sex, and level
of acculturation: the Hispanic Community Health Study/
Study of Latinos. J Am Heart Assoc 2016;5:e003929.
Ford ES, Li C, Zhao G. Prevalence and correlates of metabolic
syndrome based on a harmonious definition among adults
in the US. J Diabetes 2010;2:180–93.
188 Interactive Case: Hyperlipidemia Management
Frank, AT, Zhao, B, Jose, PO, et al. Racial/ethnic differences
in dyslipidemia patterns. Circulation. 2014;129:570–9.
Garfinkel D, Ilhan B, Bahat G. Routine deprescribing of
chronic medications to combat polypharmacy. Ther Adv
Drug Saf 2015;6:212–33.
Gnjidic D, Le Couteur DG, Blyth FM, et al. Statin use
and clinical outcomes in older men: a prospective
population-based study. BMJ Open 2013;3:e002333.
Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/
AHA guideline on the assessment of cardiovascular
risk: a report of the American College of Cardiology/
American Heart Association Task Force on Practice
Guidelines. Circulation 2014;129:S49–73.
Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/
AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/
NLA/PCNA guideline on the management of blood
cholesterol: executive summary: a report of the American
College of Cardiology/American Heart Association
Task Force on Clinical Practice Guidelines. J Am Coll
Cardiol 2019;73:3168-209.
Gujral UP, Vittinghoff E, Mongraw-Chaffin M, et al. Car-
diometabolic abnormalities among normal-weight persons
from five racial/ethnic groups in the United States: a
cross-sectional analysis of two cohort studies. Ann Intern
Med 2017;166:628–36.
Hata J, Kiyohara Y. Epidemiology of stroke and coronary
artery disease in Asia. Circ J 2013;77:1923–32.
Hutchinson RN, Shin S. Systematic review of health
disparities for cardiovascular diseases and associ-
ated factors among American Indian and Alaska Native
populations. PLoS One 2014:9;e80973.
Kutner JS, Blatchford PJ, Taylor DH Jr, et al. Safety and
benefit of discontinuing statin therapy in the setting
of advanced, life-limiting illness: a randomized clinical
trial. JAMA Intern Med 2015;175:691–700.
Lambert CT, Sandesara P, Isiadinso I, et al. Current
treatment of familial hypercholesterolaemia. Eur Cardiol
2014;9:76–81.
Liao JK. Safety and efficacy of statins in Asians. Am J
Cardiol 2007;99:410–4.
Mahabadi AA, Mohlenkamp S, Lehmann N, et al. CAC score
improves coronary and CV risk assessment above statin
indication by ESC and AHA/ACC primary prevention
guidelines. JACC Cardiovasc Imaging 2017;10:143–53.
McGowan MP, Hosseini Dehkordi SH, Moriarty PM, Duell PB.
Diagnosis and treatment of heterozygous familial hyper-
cholesterolemia. J Am Heart Assoc 2019;8(24):e013225.
Molina JM, Andrade-Villanueva JEchevarria J, et al. Once-
daily atazanavir/ritonavir compared with twice-daily
lopinavir/ritonavir, each in combination with tenofovir
and emtricitabine, for management of antiretroviral-naïve
HIV-1-infected patients: 96-week efficacy and safety
results of the CASTLE study. J Acquir Immune Defic Syndr
2010;53:323–32.
PSAP 2022 Book 1 • Cardiology
Mortensen MB, Falk E. Primary prevention with statins in the
elderly. J Am Coll Cardiol 2018;71:85–94.
Muntner P, Colantonio LD, Cushman M, et al. Validation of
the atherosclerotic cardiovascular disease Pooled Cohort
risk equations. JAMA 2014;311:1406–15.
Pejic RN. Familial hypercholesterolemia. Ochsner J 2014
Winter;14:669-72.
Pilotto A, Panza F, Copetti M, et al. Statin treatment and
mortality in community-dwelling frail older patients
with diabetes mellitus: a retrospective observational
study. PLoS One 2015:10;e0130946.
Pu J, Romanelli R, Zhao B, et al. Dyslipidemia in special
ethnic populations. Cardiol Clin 2015;33:325–33.
Qi K, Reeve E, Hilmer SN, et al. Older peoples’ attitudes
regarding polypharmacy, statin use and willingness to
have statins deprescribed in Australia. Int J Clin Pharm
2015;37:949–57.
Qureshi WT, Kaplan RC, Swett K, et al. American College of
Cardiology/American Heart Association (ACC/AHA) class
I guidelines for the treatment of cholesterol to reduce
atherosclerotic cardiovascular risk: implications for US
Hispanics/Latinos based on findings from the Hispanic
Community Health Study/Study of Latinos (HCHS/SOL).
J Am Heart Assoc 2017:6;e005045.
Rana JS, Tabada GH, Solomon MD, et al. Accuracy of the
atherosclerotic cardiovascular risk equation in a large
contemporary, multiethnic population. J Am Coll Cardiol
2016;67:2118–30.
Rao G, Powell-Wiley TM, Ancheta I, et al. Identification of
obesity and cardiovascular risk in ethnically and racially
diverse populations: a scientific statement from the
American Heart Association. Circulation 2015;132:457–72.
Rasheed S, Yan JS, Lau A, Chan AS. HIV replication
enhances production of free fatty acids, low density
lipoproteins and many key proteins involved in lipid
metabolism: a proteomics study, PLoS ONE 2008;3:e3003.
Riddler SA, Smit E, Cole SR, et al. Impact of HIV infection and
HAART on serum lipids in men. JAMA 2003;289:2978–82.
Rodriguez F, Maron DJ, Knowles JW, et al. Association
between intensity of statin therapy and mortality in
patients with atherosclerotic cardiovascular disease.
JAMA Cardiol 2017;2:47–54.
Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab
and clinical outcomes in patients with cardiovascular
disease. N Engl J Med 2017;376:1713–22.
Savarese G, Gotto AM Jr, Paolillo, S, et al. Benefits of statins
in elderly subjects without established cardiovascular
disease: a meta-analysis. J Am Coll Cardiol
2013;62:2090–9.
Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and
cardiovascular outcomes after acute coronary syndrome.
N Engl J Med 2018;379:2097-107.
189 Interactive Case: Hyperlipidemia Management
Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in
elderly individuals at risk of vascular disease (PROSPER):
a randomised controlled trial. Lancet 2002;360:1623–30.
Tebas P, Henry WK, Matining R, et al. Metabolic and immune
activation effects of treatment interruption in chronic
HIV-1 infection: implications for cardiovascular risk. PLoS
ONE 2008;3:e2021.
Teng M, Lin L, Zhao YJ, et al. Statins for primary prevention
of cardiovascular disease in elderly patients: systematic
review and meta-analysis. Drugs Aging 2015;32:649–61.
Thai M, Reeve E, Hilmer SN, et al. Prevalence of statin-drug
interactions in older people: a systematic review. Eur J
Clin Pharmacol 2016;72:513–21.
Tikkanen, MJ, Holme, I, Cater, NB, et al. Comparison of
efficacy and safety of atorvastatin (80 mg) to simvastatin
(20 to 40 mg) in patients aged <65 versus >65 years with
coronary heart disease (from the Incremental DEcrease
through Aggressive Lipid Lowering [IDEAL] study) Am J
Cardiol. 2009;103:577–82
PSAP 2022 Book 1 • Cardiology
Volgman AS, Palaniappan LS, Aggarwal NT, et al. Atheroscle-
rotic cardiovascular disease in South Asians in the United
States: epidemiology, risk factors, and treatments: a
scientific statement from the American Heart Association.
Circulation 2018;138:e1–34.
Wilson PWF, Polonsky TS, Miedema MD, et al. System-
atic review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/
ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the
management of blood cholesterol: a report of the Amer-
ican College of Cardiology/American Heart Association
Task Force on Clinical Practice Guidelines. Circulation
2019;139:e1144–61. 
Writing Committee, Virani SS, Morris PB, Agarwala A, Bal-
lantyne CM, et al. 2021 ACC Expert Consensus Decision
Pathway on the Management of ASCVD Risk Reduction
in Patients With Persistent Hypertriglyceridemia:
A Report of the American College of Cardiology Solution
Set Oversight Committee. J Am Coll Cardiol. 2021 Jul
22:S0735-1097(21)05323-7.
190 Interactive Case: Hyperlipidemia Management
Self-Assessment Questions
Questions 1 and 2 pertain to the following case.
M.J., an 83-year-old white woman with type 2 diabetes melli-
tus (T2DM) and hypertension, is referred to a pharmacist-led
lipid clinic for management of hyperlipidemia. The referral
from her primary care provider indicates that her LDL choles-
terol is “not at goal” and includes previous adverse drug reac-
tions to atorvastatin, rosuvastatin, and simvastatin. M.J.’s
most recent lipid panel shows TC 205 mg/dL, LDL cholesterol
124 mg/dL, HDL cholesterol 48 mg/dL, and TG 88 mg/dL. Her
A1C is 6.1% and blood pressure is 118/68 mm Hg. M.J.’s only
current medication is pitavastatin 1 mg daily. She admits that
she often skips doses because of myalgias that limit her abil-
ity to work in her garden. She refuses to try another statin
because of severe myalgias with previous statin therapy. M.J.
would prefer to manage her atherosclerotic cardiovascular
disease (ASCVD) risk with diet and exercise.
1. Which one of the following best assesses M.J.’s 10-year
ASCVD risk?
A. Less than 7.5%
B. 7.5% to less than 20%
C. At least 20%
D. Cannot estimate because of her age
2. Which one of the following is best to recommend for
management of M.J.’s hyperlipidemia?
A. Discontinue pitavastatin.
B. Continue pitavastatin and add ezetimibe.
C. Discontinue pitavastatin and initiate pravastatin
10 mg once daily.
D. Discontinue pitavastatin and initiate ezetimibe.
Questions 3 and 4 pertain to the following case.
S.M., a 76-year-old African American man, is seen for
a 1-month follow-up after hospitalization for an acute
ST-segment elevation myocardial infarction (STEMI). His
medical history includes T2DM and hypertension. S.M.’s LDL
cholesterol at the time of the STEMI was 155 mg/dL. Rosu-
vastatin 40 mg daily was initiated during his hospitalization.
3. S.M. has never taken a lipid-lowering agent and voices
concerns about newly prescribed rosuvastatin after
hearing of potential adverse drug effects from his neigh-
bors. Which one of the following is the best educational
point to share with S.M. regarding rosuvastatin?
A. Statin therapy is recommended because of his very
high risk of another ASCVD event.
B. Statin therapy is not recommended because of lack
of evidence in patients older than 75.
PSAP 2022 Book 1 • Cardiology
C. Ezetimibe may be preferred to a statin because of its
lower risk of adverse effects.
D. Statin therapy should be avoided because of the
potential for worsening control of diabetes.
4. Which one of the following is the best goal LDL choles-
terol to recommend for S.M.?
A. Cannot determine because of his age
B. Less than 70 mg/dL
C. Less than 100 mg/dL
D. 50% reduction from baseline
5. A 53-year-old man of South Asian ancestry has a medical
history of hypertension (currently treated with amlodip-
ine 5 mg once daily). His blood pressure today is 118/68
mm Hg. A lipid panel includes TC 185 mg/dL, HDL cho-
lesterol 30 mg/dL, LDL cholesterol 130 mg/dL, and TG
128 mg/dL. The patient is not a smoker. He asks about
lipid-lowering medications because his father died of a
MI at 53 years of age. According to the ACC/AHA pooled
cohort equations (PCE), the patient’s 10-year ASCVD risk
is 6.9%. Which one of the following is best to recommend
for managing this patient’s blood cholesterol?
A. No medication changes are indicated.
B. Initiate rosuvastatin 5 mg daily.
C. Initiate rosuvastatin 20 mg daily.
D. Initiate evolocumab 140 mg every 14 days.
6. A 65-year-old Japanese American woman has a medical
history that includes hypertension and T2DM. Simvasta-
tin 20 mg once daily was initiated 2 weeks ago. Today,
she presents to the ED with new-onset, severe bilateral
cramping of the deltoids. Her CK concentration is within
normal limits. Which one of the following is best to rec-
ommend regarding this patient’s myalgia?
A. Continue simvastatin.
B. Change simvastatin to atorvastatin 20 mg once daily.
C. Change simvastatin to rosuvastatin 20 mg once daily.
D. Change simvastatin to ezetimibe.
7. A 51-year-old man moved to the mainland United States
from Puerto Rico after losing his home in a tropical
storm. He is referred to cardiology because of a recent
diagnosis of severe primary hypercholesterolemia with
coronary artery disease. The patient has taken rosuvas-
tatin 40 mg once daily for several years. His lipid panel
today includes TC 247 mg/dL, HDL cholesterol 41 mg/dL,
LDL cholesterol 198 mg/dL, and TG 105 mg/dL. The car-
diologist wants to initiate a proprotein convertase sub-
tilisin/kexin type 9 (PCSK9) inhibitor; however, there is
concern about its cost because the patient is unem-
ployed and has no prescription insurance. Which one
191 Interactive Case: Hyperlipidemia Management
 of the following is best to recommend for this patient’s
hypercholesterolemia?
A. Provide an evolocumab manufacturer’s co-pay card.
B. Initiate ezetimibe rather than a PCSK9 inhibitor.
C. Change rosuvastatin 40 mg once daily to
atorvastatin 80 mg once daily.
D. Help the patient apply to the evolocumab
manufacturer’s patient assistance foundation.
Questions 8 and 9 pertain to the following case.
K.M., a 50-year-old African American man, presents to car-
diometabolic clinic for a follow-up. His medical history is
significant for newly diagnosed HIV infection, controlled
mitochondrial myopathy, and controlled hypertension.
K.M.’s lipid panel today shows HDL cholesterol 38 mg/dL,
TG 200 mg/dL, and LDL cholesterol 188 mg/dL, consistent
with the laboratory values at his first appointment 3 months
ago. The patient’s medication history includes darunavir/
cobicistat/emtricitabine/tenofovir alafenamide (Symtuza)
and hydrochlorothiazide. In addition, because of a low CD4
count, K.M. takes trimethoprim/sulfamethoxazole and fluco-
nazole for primary opportunistic infection prophylaxis.
8. Which one of the following is best to recommend initiat-
ing to help reduce K.M.’s LDL cholesterol and ASCVD risk?
A. Atorvastatin 40 mg/day
B. Pitavastatin 2 mg/day
C. Pravastatin 40 mg/day
D. Fluvastatin 20 mg/day
9. K.M. started the recommended statin therapy. He returns
to your clinic after being discharged from the hospital
5 days ago for hypertriglyceridemia-induced acute pan-
creatitis. His inpatient laboratory test results included
TG 401 mg/dL and LDL cholesterol 172 mg/dL. None
of K.M.’s medications before the hospitalization were
changed at discharge, and he was referred back to your
clinic for outpatient follow-up and medication manage-
ment. Which one of the following is best to recommend
for K.M. regarding statin?
A. Change to atorvastatin 40 mg/day and add fish oil.
B. Change to rosuvastatin 20 mg/day and add
fenofibrate.
C. Change to simvastatin 20 mg/day and add
ezetimibe.
D. Change to rosuvastatin 20 mg/day and add
gemfibrozil.
10. A 42-year-old African American man presents to the
clinic for his 3-month follow-up. His medical history is
significant for heterozygous familial hypercholesterol-
emia (HeFH), T2DM, and a recent hospital admission for
a Helicobacter pylori infection. The patient’s home drugs
include metformin 1000 mg twice daily, semaglutide
PSAP 2022 Book 1 • Cardiology
1 mg subcutaneously once weekly, olmesartan 40 mg
once daily, rosuvastatin 40 mg once daily, ezetimibe
10 mg once daily, and 4 days remaining of triple ther-
apy with clarithromycin 500 mg twice daily, amoxicillin
1000 mg twice daily, and pantoprazole 40 mg twice daily.
His LDL cholesterol today is 197 mg/dL, which remains
above goal. The patient worries about remembering
to take another medication because he says he barely
remembers to even take his current medications. Which
one of the following is best to recommend to help further
reduce this patient’s LDL cholesterol?
A. Niacin
B. Colesevelam
C. Fish oil
D. Alirocumab
Questions 11 and 12 pertain to the following case.
R.W., a 23-year-old white woman, presents to your cardiomet-
abolic clinic for a follow-up. Her medical history is significant
for HeFH caused by a mutation in the LDL receptor protein.
R.W. has not had an ASCVD event. Today, R.W.’s LDL choles-
terol is 230 mg/dL and TG are 298 mg/dL. She currently takes
rosuvastatin 40 mg/day, ezetimibe 10 mg/day, and ethinyl
estradiol/etonogestrel vaginal ring.
11. Although she has previously discussed starting a PCSK9
inhibitor, R.W. is still resistant because of her fear of nee-
dles. She wants to know what other oral options are avail-
able. Which one of the following is best to recommend
adding to R.W.’s current therapy?
A. Bempedoic acid
B. Evolocumab
C. Fenofibrate
D. Niacin
12. Six months later, R.W. returns to the clinic for a follow-up.
Her LDL cholesterol has improved to 198 mg/dL but TG
are 304 mg/dL. She announces that she recently became
pregnant (currently second trimester). R.W. takes rosu-
vastatin 40 mg/day, ezetimibe 10 mg/day, colesevelam
3.75 g/day, and a prenatal vitamin. After counseling,
R.W. wants to prioritize as little harm as possible to the
pregnancy. In addition to incorporating lifestyle changes
focused on maintaining a diet low in fats and cholesterol,
which one of the following is best to recommend for R.W.?
A. Continue current regimen; add evolocumab for
further LDL cholesterol lowering.
B. Discontinue rosuvastatin; continue ezetimibe and
colesevelam.
C. Discontinue rosuvastatin and ezetimibe; continue
colesevelam.
D. Discontinue rosuvastatin, ezetimibe, and
colesevelam; initiate lipoprotein apheresis.
192 Interactive Case: Hyperlipidemia Management
Learner Feature Evaluation: Interactive Case: Hyperlipidemia Management
for Special Populations
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material’s quality and usefulness, as well as the achieve-
ment of learning objectives. Rate each item using this 5-point
scale:
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1. The content of the feature met my educational needs.
2. The content of the feature satisfied my expectations.
3. The author presented the feature content effectively.
4. The content of the feature was relevant to my practice
and presented at the appropriate depth and scope.
5. The content of the feature was objective and balanced.
6. The content of the feature is free of bias, promotion, and
advertisement of commercial products.
PSAP 2022 Book 1 • Cardiology
7. The content of the feature was useful to me.
8. The teaching and learning methods used in the feature
were effective.
9. The active learning methods used in the feature were
effective.
10. The learning assessment activities used in the feature
were effective.
11. The feature was effective overall.
12. The activity met the stated learning objectives.
13. If any objectives were not met, please list them here.
OTHER COMMENTS
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provide any additional comments regarding this feature:
193 Interactive Case: Hyperlipidemia Management
Interactive Case: Anticoagulation in
Special Populations
By Allison E. Burnett, Pharm.D., CACP; and Kelly M. Rudd, Pharm.D., FCCP, BCPS, CACP

Reviewed by Sara R. Vazquez, Pharm.D., BCPS, CACP; and Nancy Nix, Pharm.D., BCPS, BCOP

LEARNING OBJECTIVES

1. Evaluate available evidence pertaining to the use of oral anticoagulants in patients with antiphospholipid syndrome
(APS).
2. Apply appropriate diagnostic modalities and construct an anticoagulant therapy plan for patients with suspected or
confirmed heparin-induced thrombocytopenia.
3. Evaluate the risk-benefit of vitamin K antagonist and direct oral anticoagulant (DOAC) therapies in patients with renal
impairment.
4. Assess the role of DOAC therapy in patients at extremes of weight.

ABBREVIATIONS IN THIS FEATURE

AC Anticoagulant/anticoagulation BASELINE KNOWLEDGE STATEMENTS

aCL Anticardiolipin antibody Readers of this feature are presumed to be familiar with the
AF Atrial fibrillation following:
APLA Antiphospholipid antibody • Physiology of immune system function
APS Antiphospholipid syndrome • Normal coagulation physiology
β2GPI β2 glycoprotein I
• General knowledge of anticoagulants (ACs) and associ-
CAPS Catastrophic APS ated dosing regimens
CFX Chromogenic factor X • General knowledge of pathophysiologic conditions requir-
CKD Chronic kidney disease ing AC therapy
CRNMB Clinically relevant nonmajor • General guideline recommendations for the treatment of
bleeding conditions requiring AC therapy
DOAC Direct oral anticoagulant
Table of common laboratory reference values
DVT Deep venous thrombosis
ECMO Extracorporeal membrane
oxygenation ADDITIONAL READINGS
ELISA Enzyme-linked immunosorbent
assay The following resources have additional background informa-
ESRD End-stage renal disease tion on these topics:
HIPA Heparin-induced platelet aggrega- • EULAR recommendations for the management of
tion assay antiphospholipid syndrome in adults. Ann Rheum Dis
HIT Heparin-induced 2019;78:1296-304.
thrombocytopenia • Diagnosis and management of the antiphospholipid
HITT HIT with thrombosis syndrome. N Engl J Med 2018;378:2010-21.
IVC Inferior vena cava • Use of DOACs in obesity for treatment and prevention of
LA Lupus anticoagulant venous thromboembolism: updated communication from
the ISTH SSC Subcommittee on Control of
LAAO Left atrial appendage occlusion
Anticoagulation. J Thromb Haemost 2021;19:1874-82.
MB Major bleeding
NVAF Nonvalvular atrial fibrillation

PSAP 2022 Book 1 • Cardiology 195 Interactive Case: Anticoagulation

 OAC Oral anticoagulant
PCI Percutaneous coronary intervention
PE Pulmonary embolism
PTCP Pretest clinical probability
RCT Randomized controlled trial
SLE Systemic lupus erythematosus
TTR Time in therapeutic INR range
VTE Venous thromboembolism
Table of other common abbreviations.
INTERACTIVE CASE:
ANTICOAGULATION IN SPECIAL
POPULATIONS
• Click here to start this PSAP activity
Practice Points
• Hypercoagulable conditions such as antiphospholipid
syndrome (APS) and heparin-induced thrombocytopenia
(HIT) are associated with complex diagnostic workups and
may require use of different management approaches from
those used for routine thromboembolic events such as
deep venous thrombosis (DVT) and pulmonary embolism
(PE).
• Pharmacists should have good familiarity with who should
and should not be tested for APS and HIT, interpretation of
laboratory results, and appropriate pharmacotherapeutic
options specific to these conditions.
• Obese and renal impairment populations have been un-
derrepresented in the large randomized controlled trials
(RCTs) comparing direct oral anticoagulants (DOACs) with
warfarin for venous thromboembolism (VTE) and non-
valvular atrial fibrillation (NVAF), but emerging evidence
suggests DOACs and warfarin are reasonable for treating
and preventing thrombosis in these populations.
• Pharmacists play an essential role in stewardship over
high-risk antithrombotic therapies, especially in special
populations of patients who may be more vulnerable to
adverse events and poor outcomes.
REFERENCES
Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the
treatment of acute venous thromboembolism. N Engl J
Med 2013;369:799-808.
Ahuja T, Sessa K, Merchan C, et al. Oral factor Xa inhibitors
versus warfarin for the treatment of venous thromboem-
bolism in advanced chronic kidney disease. Adv Hematol
2021;2021:e8870015.
Arepally GM, Padmanabhan A. Heparin-induced thrombocy-
topenia: a focus on thrombosis. Arterioscler Thromb Vasc
Biol 2021;41:141-52.
PSAP 2022 Book 1 • Cardiology
• Chronic kidney disease and cerebrovascular disease:
consensus and guidance from a KDIGO Controver-
sies Conference. Stroke 2021;52:e328-e346.
• Oral anticoagulation for patients with atrial fibrilla-
tion on long-term dialysis. JACC 2020;75:273-85.
• American Society of Hematology guideline for man-
agement of venous thromboembolism: heparin-in-
duced thrombocytopenia. Blood Adv 2018;2:3360-92.
Bansal VK, Herzog CA, Sarnak MJ, et al. Oral anticoagu-
lants to prevent stroke in nonvalvular atrial fibrillation in
patients with CKD stage 5D: an NKF-KDOQI Controversies
Report. Am J Kidney Dis 2017;70:859-68.
Barlow A, Barlow B, Reinaker T, et al. Potential role of
direct oral anticoagulants in the management of hep-
arin-induced thrombocytopenia. Pharmacotherapy
2019;39:837-53.
Boersma LV, Ince H, Kische S, et al. Evaluating real-world
clinical outcomes in atrial fibrillation patients receiving
the WATCHMAN left atrial appendage closure technol-
ogy: final 2-year outcome data of the EWOLUTION trial
focusing on history of stroke and hemorrhage. Circulation
Arrhythmia and Electrophysiology 2019;12:e006841
Boonyawat K, Caron F, Li A, et al. Association of body
weight with efficacy and safety outcomes in phase III
randomized controlled trials of direct oral anticoagu-
lants: a systematic review and meta-analysis. J Thromb
Haemost 2017;15:1322-33.
Boriani G, Ruff CT, Kuder JF, et al. Relationship between
body mass index and outcomes in patients with atrial
fibrillation treated with edoxaban or warfarin in the
ENGAGE AF-TIMI 48 trial. Eur Heart J 2019;40:1541-50.
Brodsky SV, Satoskar A, Chen J, et al. Acute kidney injury
during warfarin therapy associated with obstructive
tubular red blood cell casts: a report of 9 cases. Am J
Kidney Dis 2009;54:1121-6.
Brouwer TF, Whang W, Kuroki K, et al. Net clinical benefit of
left atrial appendage closure versus warfarin in patients
with atrial fibrillation: a pooled analysis of the randomized
PROTECT-AF and PREVAIL studies. J Am Heart Assoc
2019;8:e013525.
Camm AJ, Cools F, Virdone S, et al. Mortality in patients
with atrial fibrillation receiving nonrecommended
doses of direct oral anticoagulants. J Am Coll Cardiol
2020;76:1425-36.
Cervera R, Piette JC, Font J, et al. Antiphospholipid
syndrome: clinical and immunologic manifestations
and patterns of disease expression in a cohort of 1,000
patients. Arthritis Rheum 2002;46:1019-27.
Cervera R, Rodríguez-Pintó I, Colafrancesco S, et al. 14th
International Congress on Antiphospholipid Antibodies
196 Anticoagulation in Special Populations
 Task Force Report on Catastrophic Antiphospholipid
Syndrome. Autoimmun Rev 2014;13:699-707.
Cervera R, Serrano R, Pons-Estel GJ, et al. Morbidity and
mortality in the antiphospholipid syndrome during a
10-year period: a multicentre prospective study of 1000
patients. Ann Rheum Dis 2015;74:1011-8.
Chang M, Yu Z, Shenker A, et al. Effect of renal impairment
on the pharmacokinetics, pharmacodynamics, and safety
of apixaban. J Clin Pharmacol 2016;56:637-45.
Cohen H, Efthymiou M, Isenberg DA. Use of direct oral
anticoagulants in antiphospholipid syndrome. J Thromb
Haemost 2018;16:1028-39.
Cohen H, Isenberg DA. How I treat anticoagulant-refrac-
tory thrombotic antiphospholipid syndrome. Blood
2021;137:299-309.
Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus
warfarin in patients with atrial fibrillation. N Engl J Med
2009;361:1139-51.
Cuker A, Arepally GM, Chong BH, et al. American Society of
Hematology 2018 guidelines for management of venous
thromboembolism: heparin-induced thrombocytopenia.
Blood Adv 2018;2:3360-92.
Cuker A, Cines DB. How I treat heparin-induced
thrombocytopenia. Blood 2012a;119:2209-18.
Cuker A, Gimotty PA, Crowther MA, et al. Predic-
tive value of the 4Ts scoring system for hepa-
rin-induced thrombocytopenia: a systematic review and
meta-analysis. Blood 2012b;120:4160-7.
de Groot PG, Lutters B, Derksen RHWM, et al. Lupus
anticoagulants and the risk of a first episode of deep
venous thrombosis. J Thromb Haemost 2005;3:1993-7.
Dentali F, Manfredi E, Crowther M, Ageno W. Long-duration
therapy with low molecular weight heparin in patients with
antiphospholipid antibody syndrome resistant to warfarin
therapy. J Thromb Haemost. 2005 Sep;3(9):2121-3.
De Vriese AD, Caluwé R, Meersch HVD, et al. Safety and
efficacy of vitamin K antagonists versus rivaroxaban
in hemodialysis patients with atrial fibrillation: a
multicenter randomized controlled trial. J Am Soc Nephrol
2021;32:1474-83.
De Vriese AS, Caluwé R, Bailleul E, et al. Dose-finding study
of rivaroxaban in hemodialysis patients. Am J Kidney Dis
2015;66:91-8.
Devreese KMJ, de Groot PG, de Laat B, et al. Guidance from
the Scientific and Standardization Committee for lupus
anticoagulant/antiphospholipid antibodies of the Interna-
tional Society on Thrombosis and Haemostasis. J Thromb
Haemost 2020;18:2828-39.
Di Minno MND, Lupoli R, Di Minno A, et al. Effect of
body weight on efficacy and safety of direct oral
anticoagulants in the treatment of patients with acute
venous thromboembolism: a meta-analysis of randomized
controlled trials. Ann Med 2015;47:61-8.
PSAP 2022 Book 1 • Cardiology
Dias C, Moore KT, Murphy J, et al. Pharmacokinetics, phar-
macodynamics, and safety of single-dose rivaroxaban in
chronic hemodialysis. Am J Nephrol 2016;43:229-36.
Dobesh PP, Kernan MM, Lueshen JJ. Direct oral anticoagu-
lants in the treatment of venous thromboembolism: use in
patients with advanced renal impairment, obesity, or other
weight-related special populations. Semin Respir Crit Care
Med 2021;42:233-49.
Doré M, Frenette A, Chagnon I, et al. Interrater agreement for
two systems used to determine the probability of hepa-
rin-induced thrombocytopenia. Am J Health Syst Pharm
2014;71:2045-52.
Douketis JD, Spyropoulos AC, Spencer FA, et al.
Perioperative management of antithrombotic therapy:
Antithrombotic Therapy and Prevention of Thrombosis,
9th ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines. Chest
2012;141(2 suppl):e326S-e350S.
Dreisbach AW. The influence of chronic renal failure on
drug metabolism and transport. Clin Pharmacol Ther
2009;86:553-6.
EINSTEIN-PE Investigators, Büller HR, Prins MH, et al. Oral
rivaroxaban for the treatment of symptomatic pulmonary
embolism. N Engl J Med 2012;366:1287-97.
Erkan D, Espinosa G, Cervera R. Catastrophic antiphospho-
lipid syndrome: updated diagnostic algorithms. Autoim-
mun Rev 2010;10:74-9.
Fanikos J, Burnett AE, Mahan CE, et al. Renal function
considerations for stroke prevention in atrial fibrillation.
Am J Med 2017a;130:1015-23.
Fanikos J, Burnett AE, Mahan CE, et al. Renal function and
direct oral anticoagulant treatment for venous thrombo-
embolism. Am J Med 2017b;130:1137-43.
Gallagher D, Visser M, Sepúlveda D, et al. How useful is body
mass index for comparison of body fatness across age,
sex, and ethnic groups? Am J Epidemiol 1996;143:228-39.
Galli M, Luciani D, Bertolini G, et al. Lupus anticoagulants are
stronger risk factors for thrombosis than anticardiolipin
antibodies in the antiphospholipid syndrome: a systematic
review of the literature. Blood 2003;101:1827-32.
Garcia D, Erkan D. Diagnosis and management of the anti-
phospholipid syndrome. N Engl J Med 2018;378:2010-21.
Garza-Mayers AC, Shah R, Sykes DB, et al. The successful
use of apixaban in dialysis patients with calciphylaxis who
require anticoagulation: a retrospective analysis. Am J
Nephrol 2018;48:168-71.
Gebhart J, Posch F, Koder S, et al. Increased mortality in
patients with the lupus anticoagulant: the Vienna Lupus
Anticoagulant and Thrombosis Study (LATS). Blood
2015;125:3477-83.
Ghoshal S, Freedman BI. Mechanisms of stroke in
patients with chronic kidney disease. Am J Nephrol
2019;50:229-39.
197 Anticoagulation in Special Populations
Goto S, Angchaisuksiri P, Bassand J, et al. Management and
1-year outcomes of patients with newly diagnosed atrial
fibrillation and chronic kidney disease: results from the
prospective GARFIELD-AF Registry. J Am Heart Assoc
2019;8:e010510.
Granger CB, Alexander JH, McMurray JJV, et al. Apixaban
versus warfarin in patients with atrial fibrillation. N Engl
J Med 2011;365:981-92.
Greinacher A. Heparin-induced thrombocytopenia. N Engl
J Med 2015;373:252-61.
Gulseth MP, Wittkowsky AK, Fanikos J, et al. Safety and
efficacy of vitamin K antagonists versus rivaroxaban
in hemodialysis patients with atrial fibrillation: a multi-
center randomized controlled trial. Pharmacotherapy
2011;31:1232-49.
Hanni C, Petrovitch E, Ali M, et al. Outcomes associated with
apixaban vs warfarin in patients with renal dysfunction.
Blood Adv 2020;4:2366-71.
Herndon K, Guidry TJ, Wassell K, et al. Characterizing the
safety profile of apixaban versus warfarin in moderate to
severe chronic kidney disease at a Veterans Affairs hospi-
tal. Ann Pharmacother 2020;54:554-60.
Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines
for the diagnosis and management of atrial fibrillation
developed in collaboration with the European Association
for Cardio-Thoracic Surgery (EACTS): the task force for
the diagnosis and management of atrial fibrillation of the
European Society of Cardiology (ESC) developed with the
special contribution of the European Heart Rhythm Asso-
ciation (EHRA) of the ESC. Eur Heart J 2021;42:373-498.
Htet S, Hayes L, Leung T. Strong lupus anticoagulant (LA)
as a cause for prolonged prothrombin time (PT), activated
partial thromboplastin time (APTT) and abnormally low
intrinsic factor (IF) levels. Pathology (Phila) 2015;47:S90.
January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS
focused update of the 2014 AHA/ACC/HRS guideline for
the management of patients with atrial fibrillation: a report
of the American College of Cardiology/American Heart
Association Task Force on Clinical Practice Guidelines and
the Heart Rhythm Society in Collaboration with the Soci-
ety of Thoracic Surgeons. Circulation 2019;140:e125-e151.
Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for
VTE disease: CHEST guideline and expert panel report.
Chest 2016;149:315-52.
Kelkar AH, Rajasekhar A. Inferior vena cava filters: a
framework for evidence-based use. Hematology Am Soc
Hematol Educ Program 2020;2020:619-28.
Kelly DM, Ademi Z, Doehner W, et al. Chronic kidney dis-
ease and cerebrovascular disease: consensus and guid-
ance from a KDIGO Controversies Conference. Stroke
2021;52:e328-e346.
Khamashta MA, Cuadrado MJ, Mujic F, et al. The manage-
ment of thrombosis in the antiphospholipid-antibody
syndrome. N Engl J Med 1995;332:993-7.
PSAP 2022 Book 1 • Cardiology
Kidney Disease: Improving Global Outcomes (KDIGO). CKD
Evaluation and Management. 2021.
Kooiman J, van der Hulle T, Maas H, et al. Pharmacokinet-
ics and pharmacodynamics of dabigatran 75 mg b.i.d. in
patients with severe chronic kidney disease. J Am Coll
Cardiol 2016;67:2442-4.
Krnic-Barrie S, O’Connor CR, Looney SW, et al. A retrospec-
tive review of 61 patients with antiphospholipid syndrome.
Analysis of factors influencing recurrent thrombosis. Arch
Intern Med 1997;157:2101-8.
Kubitza D, Becka M, Mueck W, et al. Effects of renal impair-
ment on the pharmacokinetics, pharmacodynamics and
safety of rivaroxaban, an oral, direct factor Xa inhibitor.
Br J Clin Pharmacol 2010;70:703-12.
Kubitza D, Becka M, Zuehlsdorf M, et al. Body weight has
limited influence on the safety, tolerability, pharmacokinet-
ics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in
healthy subjects. J Clin Pharmacol 2007;47:218-26.
Kuno T, Takagi H, Ando T, et al. Oral anticoagulation for
patients with atrial fibrillation on long-term dialysis. J Am
Coll Cardiol 2020;75:273-85.
Liesenfeld KH, Lehr T, Dansirikul C, et al. Population pharma-
cokinetic analysis of the oral thrombin inhibitor dabiga-
tran etexilate in patients with non-valvular atrial fibrillation
from the RE-LY trial. J Thromb Haemost 2011;9:2168-75.
Limdi NA, Beasley TM, Baird MF, et al. Kidney function influ-
ences warfarin responsiveness and hemorrhagic compli-
cations. J Am Soc Nephrol 2009;20:912-21.
Linkins LA, Dans AL, Moores LK, et al. Treatment and preven-
tion of heparin-induced thrombocytopenia: Antithrombotic
Therapy and Prevention of Thrombosis, 9th ed: American
College of Chest Physicians Evidence-Based Clinical Prac-
tice Guidelines. Chest 2012;141(2 suppl):e495S-e530S.
Lockshin MD, Kim M, Laskin CA, et al. Prediction of adverse
pregnancy outcome by the presence of lupus anticoagu-
lant, but not anticardiolipin antibody, in patients with anti-
phospholipid antibodies. Arthritis Rheum 2012;64:2311-8.
Love PE, Santoro SA. Antiphospholipid antibodies: anti-
cardiolipin and the lupus anticoagulant in systemic
lupus erythematosus (SLE) and in non-SLE disorders.
Prevalence and clinical significance. Ann Intern Med
1990;112:682-98.
Lutz J, Menke J, Sollinger D, et al. Haemostasis in chronic
kidney disease. Nephrol Dial Transplant 2014;29:29-40.
Malec K, Broniatowska E, Undas A. Direct oral anticoagu-
lants in patients with antiphospholipid syndrome: a cohort
study. Lupus 2020;29:37-44.
Martin K, Beyer-Westendorf J, Davidson BL, et al. Use of
direct oral anticoagulants in patients with obesity for
treatment and prevention of venous thromboembolism:
updated communication from the ISTH SSC Subcommit-
tee on Control of Anticoagulation. J Thromb Haemost
2021;19:1874-82.
198 Anticoagulation in Special Populations
Mavrakanas TA, Garlo K, Charytan DM. Apixaban versus no
anticoagulation in patients undergoing long-term dialy-
sis with incident atrial fibrillation. Clin J Am Soc Nephrol
2020;15:1146-54.
Mavrakanas TA, Samer CF, Nessim SJ, et al. Apixaban phar-
macokinetics at steady state in hemodialysis patients.
J Am Soc Nephrol 2017;28:2241-8.
McAlister FA, Wiebe N, Jun M, et al. Are existing risk scores
for nonvalvular atrial fibrillation useful for prediction or
risk adjustment in patients with chronic kidney disease?
Can J Cardiol 2017;33:243-52.
McDonnell T, Wincup C, Buchholz I, et al. The role of
beta-2-glycoprotein I in health and disease associating
structure with function: more than just APS. Blood Rev
2020;39:100610.
McGlasson DL, Romick BG, Rubal BJ. Comparison of a chro-
mogenic factor X assay with international normalized ratio
for monitoring oral anticoagulation therapy. Blood Coagul
Fibrinolysis 2008;19:513-7.
Minet V, Dogné JM, Mullier F. Functional assays in the diag-
nosis of heparin-induced thrombocytopenia: a review.
Molecules 2017;22:617.
Miyakis S, Lockshin MD, Atsumi T, et al. International
consensus statement on an update of the classification
criteria for definite antiphospholipid syndrome (APS).
J Thromb Haemost 2006;4:295-306.
Molnar AO, Bota SE, McArthur E, et al. Risk and complica-
tions of venous thromboembolism in dialysis patients.
Nephrol Dial Transplant 2018;33:874-80.
Molshatzki N, Orion D, Tsabari R, et al. Chronic kidney
disease in patients with acute intracerebral hemorrhage:
association with large hematoma volume and poor
outcome. Cerebrovasc Dis 2011;31:271-7.
Nagler M, Bakchoul T. Clinical and laboratory tests for the
diagnosis of heparin-induced thrombocytopenia. Thromb
Haemost 2016;116:823-34.
Nilius H, Kaufmann J, Cuker A, et al. Comparative
effectiveness and safety of anticoagulants for the
treatment of heparin-induced thrombocytopenia.
Am J Hematol 2021;96:805-15.
Ortel T. Antiphospholipid syndrome laboratory testing and
diagnostic strategies. Am J Hematol 2012;87(suppl 1):
S75-S81.
Ortel TL, Neumann I, Ageno W, et al. American Society of
Hematology 2020 guidelines for management of venous
thromboembolism: treatment of deep vein thrombosis and
pulmonary embolism. Blood Adv 2020;4:4693-738.
Ovbiagele B, Wing JJ, Menon RS, et al. Association of
chronic kidney disease with cerebral microbleeds in
patients with primary intracerebral hemorrhage. Stroke
2013;44:2409-13.
Parasrampuria DA, Marbury T, Matsushima N, et al. Phar-
macokinetics, safety, and tolerability of edoxaban in
PSAP 2022 Book 1 • Cardiology
end-stage renal disease subjects undergoing haemodialy-
sis. Thromb Haemost 2015;113:719-27.
Parasrampuria DA, Truitt KE. Pharmacokinetics and pharma-
codynamics of edoxaban, a non-vitamin K antagonist oral
anticoagulant that inhibits clotting factor Xa. Clin Pharma-
cokinet 2016;55:641-55.
Pastori D, Menichelli D, Cammisotto V, et al. Use of direct
oral anticoagulants in patients with antiphospho-
lipid syndrome: a systematic review and comparison
of the international guidelines. Front Cardiovasc Med
2021;8:715878.
Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus
warfarin in nonvalvular atrial fibrillation. N Engl J Med
2011;365:883-91.
Pavord S, Myers B. Bleeding and thrombotic complications
of kidney disease. Blood Rev 2011;25:271-8.
Pengo V, Ruffatti A, Legnani C, et al. Clinical course of high-
risk patients diagnosed with antiphospholipid syndrome.
J Thromb Haemost 2010;8:237-42.
Pengo V, Ruffatti A, Legnani C, et al. Incidence of a first
thromboembolic event in asymptomatic carriers of high-
risk antiphospholipid antibody profile: a multicenter pro-
spective study. Blood 2011;118:4714-8.
Pokorney S. RENal hemodialysis patients ALlocated apix-
aban versus warfarin in Atrial Fibrillation. November 2019.
Proietti M, Boriani G. Obesity paradox in atrial fibrilla-
tion: implications for outcomes and relationship with
oral anticoagulant drugs. Am J Cardiovasc Drugs
2020;20:125-37.
Proietti M, Guiducci E, Cheli P, et al. Is there an obesity para-
dox for outcomes in atrial fibrillation? A systematic review
and meta-analysis of non-vitamin K antagonist oral anti-
coagulant trials. Stroke 2017;48:857-66.
Randhawa MS, Vishwanath R, Rai MP, et al. Association
between use of warfarin for atrial fibrillation and out-
comes among patients with end-stage renal disease: a
systematic review and meta-analysis. JAMA Netw Open
2020;3:e202175.
Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the
treatment of cancer-associated venous thromboembo-
lism. N Engl J Med 2018;378:615-24.
Reddel SW, Krilis SA. Testing for and clinical significance
of anticardiolipin antibodies. Clin Diagn Lab Immunol
1999;6:775-82.
Reed D, Palkimas S, Hockman R, et al. Safety and effec-
tiveness of apixaban compared to warfarin in dialysis
patients. Res Pract Thromb Haemost 2018;2:291-8.
Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran
plasma concentrations and patient characteristics on the
frequency of ischemic stroke and major bleeding in atrial
fibrillation patients: the RE-LY trial (Randomized Evalu-
ation of Long-Term Anticoagulation Therapy). J Am Coll
Cardiol 2014;63:321-8.
199 Anticoagulation in Special Populations
Rosove MH, Brewer PM. Antiphospholipid thrombosis: clin-
ical course after the first thrombotic event in 70 patients.
Ann Intern Med 1992;117:303-8.
Ruiz-Irastorza G, Hunt BJ, Khamashta MA. A systematic
review of secondary thromboprophylaxis in patients
with antiphospholipid antibodies. Arthritis Rheum
2007;57:1487-95.
Rumbaut R, Thiagarajan P. Platelet-Vessel Wall Interactions
in Hemostasis and Thrombosis. Morgan & Claypool Life
Sciences, 2010.
Sammaritano LR. Antiphospholipid syndrome. Best Pract
Res Clin Rheumatol 2020;34:101463.
Sandhu RK, Ezekowitz J, Andersson U, et al. The “obe-
sity paradox” in atrial fibrillation: observations from the
ARISTOTLE (Apixaban for Reduction in Stroke and Other
Thromboembolic Events in Atrial Fibrillation) trial. Eur
Heart J 2016;37:2869-78.
Saran R, Robinson B, Abbott KC, et al. US Renal Data System
2018 annual data report: epidemiology of kidney disease
in the United States. Am J Kidney Dis 2019;73:A7-A8.
Sarnak MJ, Amann K, Bangalore S, et al. Chronic kidney
disease and coronary artery disease. J Am Coll Cardiol
2019;74:1823-38.
Sarratt SC, Nesbit R, Moye R. Safety outcomes of apixaban
compared with warfarin in patients with end-stage renal
disease. Ann Pharmacother 2017;51:445-50.
Schafer JH, Casey AL, Dupre KA, et al. Safety and effi-
cacy of apixaban versus warfarin in patients with
advanced chronic kidney disease. Ann Pharmacother
2018;52:1078-84.
Schenkeveld L, Magro M, Oemrawsingh RM, et al. The
influence of optimal medical treatment on the “obesity
paradox,” body mass index and long-term mortality in
patients treated with percutaneous coronary intervention:
a prospective cohort study. BMJ Open 2012;2:e000535.
Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of
acute venous thromboembolism with dabigatran or warfa-
rin and pooled analysis. Circulation 2014;129:764-72.
Schulman S, Svenungsson E, Granqvist S. Anticardiolipin
antibodies predict early recurrence of thromboembolism
and death among patients with venous thromboembolism
following anticoagulant therapy. Duration of Anticoagula-
tion Study Group. Am J Med 1998;104:332-8.
Schunemann H, Cushman M, Burnett AE, et al. American
Society of Hematology 2018 guidelines for management
of venous thromboembolism: prophylaxis for hospitalized
and nonhospitalized medical patients. Blood Advances
2018; 2 (22): 3198-3225.
Sebaaly J, Kelley D. Direct oral anticoagulants in obesity:
an updated literature review. Ann Pharmacother
2020;54:1144-58.
Siontis KC, Zhang X, Eckard A, et al. Outcomes associated
with apixaban use in end-stage kidney disease patients
PSAP 2022 Book 1 • Cardiology
with atrial fibrillation in the United States. Circulation
2018;138:1519-29.
Song S, Kang D, Halim A, et al. Population pharmacokinet-
ic-pharmacodynamic modeling analysis of intrinsic FXa
and bleeding from edoxaban treatment. J Clin Pharmacol
2014;54:910-6.
Sood MM, Bota SE, McArthur E, et al. The three-year
incidence of major hemorrhage among older adults
initiating chronic dialysis. Can J Kidney Health Dis
2014;1:21.
Spyropoulos AC, Brohi K, Caprini J, et al. Scientific and
Standardization Committee Communication: guidance
document on the periprocedural management of patients
on chronic oral anticoagulant therapy: recommendations
for standardized reporting of procedural/surgical bleed
risk and patient-specific thromboembolic risk. J Thromb
Haemost 2019;17:1966-72.
Stangier J, Clemens A. Pharmacology, pharmacokinet-
ics, and pharmacodynamics of dabigatran etexilate,
an oral direct thrombin inhibitor. Clin Appl Thromb
2009;15(1_suppl):9S-16S.
Stangier J, Rathgen K, Stähle H, et al. Influence of renal
impairment on the pharmacokinetics and pharmacody-
namics of oral dabigatran etexilate. Clin Pharmacokinet
2010;49:259-68.
Stanton BE, Barasch NS, Tellor KB. Comparison of the
safety and effectiveness of apixaban versus warfarin in
patients with severe renal impairment. Pharmacotherapy
2017;37:412-9.
Tektonidou MG, Andreoli L, Limper M, et al. EULAR
recommendations for the management of anti-
phospholipid syndrome in adults. Ann Rheum Dis
2019;78:1296-304.
Tittl L, Endig S, Marten S, et al. Impact of BMI on clinical
outcomes of NOAC therapy in daily care – results of the
prospective Dresden NOAC Registry (NCT01588119).
Int J Cardiol 2018;262:85-91.
Tripodi A, Chantarangkul V, Clerici M, et al. Laboratory con-
trol of oral anticoagulant treatment by the INR system in
patients with the antiphospholipid syndrome and lupus
anticoagulant. Results of a collaborative study involv-
ing nine commercial thromboplastins. Br J Haematol
2001;115:672-8.
Upreti VV, Wang J, Barrett YC, et al. Effect of
extremes of body weight on the pharmacokinetics,
pharmacodynamics, safety and tolerability of apixaban in
healthy subjects. Br J Clin Pharmacol 2013;76:908-16.
van Rein N, Heide-Jørgensen U, Lijfering WM, et al. Major
bleeding rates in atrial fibrillation patients on single,
dual, or triple antithrombotic therapy. Circulation
2019;139:775-86.
Wang HH, Hung SY, Sung JM, et al. Risk of stroke in long-
term dialysis patients compared with the general
population. Am J Kidney Dis 2014;63:604-11.
200 Anticoagulation in Special Populations
Wang X, Tirucherai G, Marbury TC, et al. Pharmacokinetics, Washam JB, Holmes DN, Thomas LE, et al. Pharmacotherapy
pharmacodynamics, and safety of apixaban in subjects for atrial fibrillation in patients with chronic kidney
with end-stage renal disease on hemodialysis. J Clin disease: insights from ORBIT-AF. J Am Heart Assoc
Pharmacol 2016;56:628-36. 2018;7:e008928.

Warkentin TE. Laboratory diagnosis of heparin-induced Wattanakit K, Cushman M. Chronic kidney disease
thrombocytopenia. Int J Lab Hematol 2019;41(suppl 1): and venous thromboembolism: epidemiology and
15-25. mechanisms. Curr Opin Pulm Med 2009;15:408-12.

Warkentin TE, Anderson JAM. How I treat patients with a Winkelmayer WC, Patrick AR, Liu J, et al. The increasing
history of heparin-induced thrombocytopenia. Blood prevalence of atrial fibrillation among hemodialysis
2016;128:348-59. patients. J Am Soc Nephrol 2011;22:349-57.

Warkentin TE, Sheppard JI, Moore JC, et al. Quantitative World Health Organization (WHO). Obesity: preventing
interpretation of optical density measurements using and managing the global epidemic. Report of a WHO
PF4-dependent enzyme-immunoassays. J Thromb consultation. World Health Organ Tech Rep Ser 2000;
Haemost 2008;6:1304-12. 894:i-xii, 1-253.

PSAP 2022 Book 1 • Cardiology 201 Anticoagulation in Special Populations

Self-Assessment Questions
13. You are evaluating a patient with a recent deep venous
thrombosis (DVT) for a potential diagnosis of anti-
phospholipid syndrome (APS) who has elevated anti-
cardiolipin antibody (aCL) levels (IgG) greater than 40
GPL/MPL units. Which one of the following is best to rec-
ommend regarding this patient’s antiphospholipid anti-
body (APLA) laboratory assessment?
A. Abnormal APLA laboratory assessments should
be confirmed in 12–14 days to complete the APS
diagnosis.
B. Abnormal APLA laboratory assessments should
be confirmed in 12 weeks to complete the APS
diagnosis.
C. Abnormal APLA antibody assessments do not need
to be reconfirmed to complete the APS diagnosis.
D. After abnormal APLA laboratory assessments, a
dilute Russell viper venom time is recommended
within 2 weeks to complete the APS diagnosis.
14. Which one of the following patients with APS at low
bleeding risk would most likely benefit from warfarin
therapy with a target INR of 3.5 (goal 3.0–4.0)?
A. 25-year-old man with a first provoked venous
thrombotic event (venous thromboembolism [VTE])
with obesity who is positive for lupus anticoagulant
(LA)
B. 32-year-old woman with one episode of obstetric
APS 18 months ago being seen today for
preconception counseling
C. 35-year-old man with a high-risk APLA profile but no
personal history of thrombosis
D. 42-year-old woman with secondary APS presenting
with a recurrent DVT on warfarin at an INR of 2.6
15. The primary care provider for a 45-year-old man with a
new episode of VTE requests an anticoagulation (AC)
consult because there is high suspicion for APS. Which
one of the following best evaluates the current evidence
for use of rivaroxaban in treating and preventing throm-
boembolism if this patient is confirmed to have APS?
A. Has high-quality safety and efficacy data in patients
with low-risk APS, and data are promising in high-
risk APS.
B. Has limited safety and efficacy in both low- and high-
risk APS, with current guidance to avoid use in APS.
C. Was shown noninferior to warfarin in patients
with triple-positive thrombotic APS as a safe and
effective therapeutic option.
D. Was shown superior to warfarin in patients with
triple-positive thrombotic APS as a safe and
effective therapeutic option.
PSAP 2022 Book 1 • Cardiology
16. A 52-year-old woman with secondary APS, systemic
lupus erythematosus (SLE), and end-stage renal dis-
ease (ESRD) receiving dialysis takes warfarin for second-
ary thromboprophylaxis (target INR 3.0, goal 2.5–3.5).
During dialysis, she develops symptoms consistent with
a transient ischemic attack and is transferred to the ED.
Her INR is 2.5. Which one of the following best evaluates
the effectiveness of this patient’s AC therapy?
A. If the chromogenic factor X (CFX) is 99%, she has
adequate AC to current goal.
B. If the CFX is 33%, she has adequate AC to current
goal.
C. If the activated PTT (aPTT) is 1.5 times the
laboratory normal, her AC is adequate.
D. If the LA is positive, her AC is inadequate because
the LA interferes with INR accuracy.
Questions 17–19 pertain to the following case.
D.A. is a 62-year-old woman in the medical ICU. On rounds, it
is noted that her Plt values have decreased from 110,000/mm3
to 87,000/mm3 overnight. The team suspects heparin-induced
thrombocytopenia (HIT) and wants to order laboratory
testing. You remind D.A.’s care team that it would be best to
use the 4T score to determine the need for HIT testing.
17. Which one of the following best justifies use of the 4T
score for D.A.?
A. It has a high positive predictive value and is good for
ruling in HIT.
B. It is the most validated pretest clinical probability
(PTCP) score for HIT.
C. It ranges from 0 to 8 points, depending on highly
objective criteria.
D. A score of 3 is considered moderate risk and
warrants enzyme-linked immunosorbent assay
(ELISA) testing.
18. D.A.’s care team calculates her 4T score as 4, and testing
is recommended. Which one of the following is best to
recommend regarding laboratory testing for HIT type 2
in D.A.?
A. Serotonin release assay (SRA) is a highly specific
functional assay and is considered the gold
standard.
B. Heparin-induced platelet aggregation assay (HIPA)
is an immunoassay that detects platelet factor 4
(PF4)/heparin antibodies.
C. ELISA is a highly specific functional assay that is
reported in optical density (OD).
D. SRA has a rapid turnaround time and should be used
first line.
202 Anticoagulation in Special Populations
19. D.A. is stable but requires AC therapy while the team catheter-directed thrombolysis and is transferred from
awaits laboratory results. On the basis of the ASH 2018 the cardiac ICU to the progressive care ward on hospi-
HIT guidelines, which one of the following is best to rec- tal day 4. Your antithrombosis stewardship service is
ommend for D.A.? consulted for recommendations on oral anticoagulant
(OAC) therapies for this patient. On interview, the patient
A. Argatroban is preferred for initial therapy in all
describes having what sounds like an unprovoked prox-
patients with HIT because it is FDA approved.
imal DVT last year. He was prescribed warfarin at that
B. Direct oral anticoagulants (DOACs) are preferred to
time; however, he took it for only a few weeks because
warfarin, but regimens used for isolated HIT differ
he lives more than 130 miles from the nearest medical
from those used in clinic trials.
facility and could not make frequent trips to get his INR
C. Patients with suspected HIT should immediately be
checked. He sees a primary care provider at a rural clinic
initiated on prophylactic-intensity non-heparin AC
two or three times per year who prescribes his medica-
therapy.
tions, including glipizide, furosemide, losartan, and ator-
D. All patients with HIT should receive 3–6 months of
vastatin. He is otherwise ready for discharge and eager
AC therapy.
to go home. Which one of the following is best to recom-
20. A 78-year-old woman (height 66 inches, weight 61 kg) mend for this patient’s recurrent unprovoked VTE?
presents to the urgent care clinic for shortness of breath
A. Place a retrievable inferior vena cava (IVC) filter and
and a feeling of “butterflies” in her chest that began this
have him follow up with his primary care provider in
morning while doing laundry. A 12-lead ECG reveals atrial
3 months for evaluation for removal.
flutter with heart rate 102 beats/minute. The patient’s
B. Discontinue heparin and prescribe apixaban 5 mg
medical history includes hypertension, diabetes, glau-
orally twice daily for a total duration of 3 months
coma, stage 5 CKD, and peripheral arterial disease
with monthly follow-up.
requiring a femoral-popliteal bypass graft in 2017. She
C. Discontinue heparin and prescribe apixaban 10
also reports occasional hemorrhoid-associated bleed-
mg orally twice daily for 3 more days, then 5 mg
ing. She currently takes aspirin 81 mg daily, lisinopril
twice daily for at least 3 months followed by regular
5 mg daily, atorvastatin 20 mg, basal and bolus insulin,
assessment for tolerance.
and latanoprost; her SCr is 1.9 mg/dL. Through shared
D. Keep him in the hospital for continued
decision-making, she expresses significant concern
heparinization as a bridge to warfarin until his
about having a stroke and would prefer preventive ther-
INR is greater than 2 and tell him to arrange self-
apy. Which one of the following is best to recommend for
management of INR at home.
this patient?
22. As the AC stewardship pharmacist for your hospital, you
A. Continue aspirin for both stroke prevention and
have been asked to provide medical grand rounds on the
peripheral arterial disease.
current use of DOACs in the treatment of atrial fibrillation
B. Initiate apixaban 2.5 mg twice daily and discuss
(AF) and VTE events. Which one of the following best
aspirin with her vascular surgeon.
describes the current data for DOAC use in patients at
C. Initiate apixaban 5 mg twice daily and discuss
extremes of weight?
aspirin with her vascular surgeon.
D. Initiate warfarin and continue aspirin. A. Large, well-controlled randomized clinical trials
(RCTs) have been conducted to evaluate DOAC
21. A 48-year-old man (height 67 inches, weight 88 kg, BMI
safety and efficacy.
30.4 kg/m2) with ESRD not yet on dialysis as well as dia-
B. The number of underweight patients and patients
betes and hypertension is transferred from an outside
with obesity included in phase III clinical trials have
hospital to your ED by MedFlight for bilateral submas-
been limited to less than 10% and 40%, respectively.
sive pulmonary embolisms (PEs). He was initiated on a
C. The definitions of obesity were homogeneous in the
heparin infusion at the outside hospital, but no throm-
currently available clinical trial data.
bolytics were administered. Laboratory tests confirm an
D. All trials included formal, standardized safety
elevated BNP of 2260 pg/mL and increased troponins.
and efficacy evaluations as a primary end point in
A CT chest and cardiac echocardiogram reveal a right
patients at weight extremes.
ventricular/left ventricular ratio of 1.8, and his esti-
mated CrCl is 13 mL/minute. He successfully undergoes

PSAP 2022 Book 1 • Cardiology 203 Anticoagulation in Special Populations

23. A 63-year-old man (weight 182 kg, BMI 56 kg/m2) devel-
ops proximal DVT following emergency orthopedic sur-
gery after an acute ankle fracture with surgical repair. He
has no history of thrombotic events. His baseline creat-
inine and hematologic profile are normal. The patient is
adamantly against the use of warfarin. Which one of the
following is the best rivaroxaban dosing to recommend
fo this patient?
A. Rivaroxaban 10 mg orally once daily
B. Rivaroxaban 15 mg orally once daily
C. 15 mg orally twice daily for 3 weeks, then lower to 10
orally once daily
D. 15 mg orally twice daily for 3 weeks, then lower to 20
orally once daily
PSAP 2022 Book 1 • Cardiology
24. A 66-year-old man (height 69 inches, weight 55 kg, BMI
19.5 kg/m2) presents to his primary care provider with
chief concerns of shortness of breath and tachycardia
and is subsequently diagnosed with AF. The patient’s
medical history includes hypertension and mild hyperlip-
idemia, both being treated appropriately. His renal func-
tion is normal (CrCl 70 mL/minute), and he is at average
bleeding risk. Which one of the following is best to rec-
ommend for this patient’s initial AC therapy?
A. Apixaban 2.5 mg orally twice daily
B. Aspirin 650 mg orally twice daily
C. Edoxaban 30 mg orally once daily
D. Warfarin 5 mg orally daily (goal INR 2.0–3.0)
204 Anticoagulation in Special Populations
Learner Feature Evaluation: Interactive Case: Anticoagulation in Special
Populations
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PSAP 2022 Book 1 • Cardiology
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205 Anticoagulation in Special Populations
Interactive Case: Cardiovascular
Diseases in Pregnancy
By Lindsey Federle, Pharm.D., BCCP, BCPS

Reviewed by Jessie Dunne, Pharm.D., BCPS, BCCP; and Leslie Wooten, Pharm.D., BCPS

LEARNING OBJECTIVES

1. Evaluate patient risk factors for cardiovascular complications during pregnancy and stratify according to the modified
WHO pregnancy risk classes.
2. Distinguish the physiologic and pharmacokinetic changes that occur in pregnancy.
3. Assess hypertensive disorders of pregnancy and devise treatment plans throughout pregnancy.
4. Develop an appropriate medical regimen for peripartum cardiomyopathy.
5. Design safe and effective anticoagulant regimens during pregnancy.
6. Develop pharmacotherapy to manage acute arrhythmia in the pregnant patient.

ABBREVIATIONS IN THIS FEATURE

ACOG American College of Obstetricians
and Gynecologists
CVD Cardiovascular disease
HDP Hypertensive disorder of
pregnancy
LVEF Left ventricular ejection fraction
PPCM Peripartum cardiomyopathy
SMM Severe maternal morbidity
SVT Supraventricular tachycardia
Table of other common abbreviations.
BASELINE KNOWLEDGE STATEMENTS
Readers of this feature are presumed to be familiar with the
following:
• Terminology in pregnancy
• Basic pharmacokinetic and pharmacodynamic principles,
including absorption, bioavailability, metabolism and
transport, and excretion
• General knowledge of cardiovascular medication dosing,
adverse effects, and pharmacokinetics
• Management of hypertension, heart failure, venous throm-
boembolism, valvular heart disease, and arrhythmias in a
non-pregnant population
Table of common laboratory reference values

ADDITIONAL READINGS

The following resources have additional background informa-

tion on this topic:
• Halpern DG, Weinberg CR, Pinnelas R, et al. Use of medica-
tion for cardiovascular disease during pregnancy: JACC
state-of-the-art review. J Am Coll Cardiol 2019;73:457-76.
• Mehta LS, Warnes CA, Bradley E, et al. Cardiovascular con-
siderations in caring for pregnant patients: a scientific
statement from the American Heart Association. Circula-
tion 2020;141:e884-e903.
• Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, et al.
2018 ESC guidelines for the management of cardiovascular
diseases during pregnancy. Eur Heart J 2018;39:3165-241.
• Online Appendix

PSAP 2022 Book 1 • Cardiology 207 Interactive Case: Cardiovascular Diseases in Pregnancy

Practice Points
• Pregnancy causes significant physiologic and pharmacoki-
netic changes. Medication management of cardiovascular
disease (CVD) in pregnancy presents many challenges.
• Women who have underlying CVD or who develop cardio-
vascular conditions are at an increased risk of morbidity
and mortality and should be assessed before pregnancy for
counseling, medication management, and stabilization of
underlying disease state.
• Hypertensive disorders of pregnancy (HDPs) are a hetero-
geneous group of disorders that can worsen at any time.
No consensus exists regarding blood pressure goals in
managing HDPs.
• If preeclampsia develops, gestational age and presence of
severe features will guide management decisions regarding
delivery of care and initiation of magnesium sulfate.
• Until the pathophysiology of peripartum cardiomyopathy
(PPCM) is better understood, medical management will
overlap with that for other types of heart failure to achieve
goals of improving left ventricular function and preventing
morbidity and mortality. Unique considerations for PPCM
include stage of pregnancy (i.e., antepartum or postpar-
tum), whether there is a desire to breastfeed, and whether
bromocriptine or anticoagulation should be prescribed.
• Anticoagulation in pregnancy presents a challenge in bal-
ancing therapeutic efficacy with antithrombotic safety for
both the patient and the developing fetus. When possible,
anticoagulation planning should begin before conception
to allow for patient and provider discussion and documen-
tation of plan, particularly for patients with mechanical
heart valves.
• New-onset arrhythmia in pregnancy should prompt an
evaluation for underlying conditions. Antiarrhythmic agents
should be avoided, if possible; however, when used, the
lowest recommended dose should be initiated, with ad-
justments made according to response. If maternal cardiac
arrest occurs, causes of arrest should be considered and
the clinician should not hesitate to administer medications,
given the gravity of the situation.
INTERACTIVE CASE:
CARDIOVASCULAR DISEASES IN
PREGNANCY
• Click here to start this PSAP activity.
REFERENCES
Altman D, Carroli G, Duley L, et al. Do women with preeclamp-
sia, and their babies, benefit from magnesium sulphate?
The Magpie trial: a randomised placebo-controlled trial.
Lancet 2002;359:1877-90.
American College of Obstetricians and Gynecologists
(ACOG) Practice Bulletin: thromboembolism in pregnancy.
Obstet Gynecol 2018;132:e1-e17.
American College of Obstetricians and Gynecologists (ACOG)
Practice Bulletin: chronic hypertension in pregnancy.
Obstet Gynecol 2019a;133:e26-e50.
PSAP 2022 Book 1 • Cardiology
American College of Obstetricians and Gynecologists (ACOG)
Practice Bulletin: pregnancy and heart disease. Obstet
Gynecol 2019b;133:e320-56.
American College of Obstetricians and Gynecologists (ACOG)
Practice Bulletin: gestational hypertension and
preeclampsia. Obstet Gynecol 2020;135:e237-60.
Bayer-Westendorf J, Marten S. Reproductive issues in women
on direct oral anticoagulants. Res Pract Thromb Haemost
2021;5:e12512.
Caruso G, Scopelliti A, Scaramuzzino S, et al. Cabergoline
as an adjuvant to standard heart failure treatment in peri-
partum cardiomyopathy: a case report and review of the
literature. Case Rep Womens Health 2021;29:e00277.
Casele HL, Laifer SA, Woelkers DA, et al. Changes in the
pharmacokinetics of the low-molecular-weight hepa-
rin enoxaparin sodium during pregnancy. Am J Obstet
Gynecol 1999;181(5 pt 1):1113-7.
Centers for Disease Control and Prevention (CDC). Preg-
nancy Mortality Surveillance System. 2020. Available
at https://www.cdc.gov/reproductivehealth/maternal-­
mortality/pregnancy-mortality-surveillance-system.htm.
Centers for Disease Control and Prevention (CDC) Foundation.
Building U.S. Capacity to Review and Prevent Maternal
Deaths. 2018. Report from Nine Maternal Mortality Review
Committees. Available at https://www.cdcfoundation.org/
sites/default/files/files/ReportfromNineMMRCs.pdf.
Drenthen W, Boersma E, Balci A, et al. Predictors of pregnancy
complications in women with congenital heart disease.
ZAHARA Investigators. Eur Heart J 2010;31:2124-32.
D’Souza R, Ostro J, Shah PS, et al. Anticoagulation for preg-
nant women with mechanical heart valves: a systematic
review and meta-analysis. Eur Heart J 2017;38:1509-16.
Duley L, Gulmezoglu AM, Henderson-Smart DJ, et al. Mag-
nesium sulphate and other anticonvulsants for women
with pre-eclampsia. Cochrane Database Syst Rev
2010;11:CD000025.
Duley L, Meher S, Hunter KE, et al. Antiplatelet agents for
preventing preeclampsia and its complications. Cochrane
Database Syst Rev 2019;10:CD004659.
Hilfiker-Kleiner D, Haghikia A, Berliner D, et al. Bromocriptine
for the treatment of peripartum cardiomyopathy: a multi-
centre randomized study. Eur Heart J 2017;38:2671-9.
Hoffman MK, Goudar SS, Kodkany BS, et al.; ASPIRIN Study
Group. Low-dose aspirin for the prevention of preterm
delivery in nulliparous women with a singleton pregnancy
(ASPIRIN): a randomised, double-blind, placebo-controlled
trial. Lancet 2020;395:285-93.
Hofmeyr GJ, Lawrie TA, Atallah AN, et al. Calcium supple-
mentation during pregnancy for preventing hypertensive
disorders and related problems. Cochrane Database Syst
Rev 2018;10:CD001059.
Jeejeebhoy FM, Zelop CM, Lipman S, et al. Cardiac arrest
in pregnancy: a scientific statement from the American
Heart Association. Circulation 2015;132:1747-73.
208 Interactive Case: Cardiovascular Diseases in Pregnancy
Koczo A, Marino A, Jeyabalan A. Breastfeeding, cellular
immune activation, and myocardial recovery in peripartum
cardiomyopathy. JACC Basic Transl Sci 2019;4:291-300.
Magee LA, von Dadelszen P, Rey E, et al. Less-tight versus
tight control of hypertension in pregnancy. N Engl J Med
2015;372:407-17.
Magee LA, von Dadelszen P, Singer J, et al. The CHIPS ran-
domized controlled trial (Control of Hypertension in
Pregnancy Study): is severe hypertension just an elevated
blood pressure? Hypertension 2016;68:1153-9.
Malhame I, Danilack VA, Raker CA, et al. Cardiovascu-
lar severe maternal morbidity in pregnant and postpar-
tum women: development and internal validation of risk
prediction models. BJOG 2021;128:922-32.
Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA
guideline for the management of patients with valvular
heart disease. Circulation 2021;143:e72-e227.
Ozkan M, Cakal B, Karakoyun S, et al. Thrombolytic therapy
for the treatment of prosthetic heart valve thrombosis
in pregnancy with low-dose, slow infusion of tissue-type
plasminogen activator. Circulation 2013;128:532-40.
Parikh NI, Gonzalez JM, Anderson CAM, et al. Adverse preg-
nancy outcomes and cardiovascular disease risk: unique
opportunities for cardiovascular disease prevention in
women: a scientific statement from the American Heart
Association. Circulation 2021;143:e903-16.
Pfaller B, Sathananthan G, Grewal J, et al. Preventing compli-
cations in pregnant women with cardiac disease.
J Am Coll Cardiol 2020;75:1443-52.
Pinheiro EA, Stika CS. Drugs in pregnancy: pharmacologic
and physiologic changes that affect clinical care. Semin
Perinatol 2020;44:151221.
Rashba EJ, Zareba W, Moss AJ, et al. Influence of pregnancy
on the risk for cardiac events in patients with heredi-
tary long QT syndrome. LQTS Investigators. Circulation
1998;97:451-6.
Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, et al.
2018 ESC guidelines for the management of cardio-
vascular diseases during pregnancy. Eur Heart J
2018;39:3165-241.
Rolnik DL, Wright D, Poon LC, et al. aspirin versus placebo in
pregnancies at high risk for preterm preeclampsia. N Engl
J Med 2017;377:613-22.
PSAP 2022 Book 1 • Cardiology
Rosenbloom JI, Sabol BA, Chung C, et al. Improving medi-
cation error identification with an inpatient maternal-fetal
medicine pharmacist. Poster presented at: 39th Annual
Pregnancy Meeting, Society for Maternal-Fetal Medicine;
February 2019; Las Vegas, NV.
Scaffidi J, Mol BW, Keelan JA. The pregnant women as a
drug orphan: a global survey of registered clinical trials
of pharmacological interventions in pregnancy. BJOG
2017;124:132-40.
Silversides CK, Grewal J, Mason J, et al. Pregnancy out-
comes in women with heart disease: the CARPREG II
study. J Am Coll Cardiol 2018;71:2419-30.
Sliwa K, Blauwet L, Tibazarwa K, et al. Evaluation of bro-
mocriptine in the treatment of acute severe peripartum
cardiomyopathy: a proof-of-concept pilot study. Circula-
tion 2010;121:1465-73.
Stephenson ML, Serra AE, Neeper JM. A randomized con-
trolled trial of differing doses of post-cesarean enoxa-
parin thromboprophylaxis in obese women. J Perinatol
2016;36:95-9.
Thorne S, MacGregor A, Nelson-Piercy C. Risks of
contraception and pregnancy in heart disease. Heart
2006;92:1520-5.
von Dadelszen P, Payne B, Li J, et al. Prediction of adverse
maternal outcomes in pre-eclampsia: development and
validation of the fullPIERS model. Lancet 2011;377:219-27.
Yaméogo NV, Kagambèga LJ, Seghda A, et al. Bromocriptine
in management of peripartum cardiomyopathy: a random-
ized study on 96 women in Burkina Faso. J Cardiol Clin
Res 2017;5:1098-106.
Yucel E, Yeh DD. Pregnancy in women with congenital heart
disease. Curr Treat Options Cardiovasc Med 2017;19:73.
Wolfe DS, Hameed AB, Taub CC, et al. Addressing mater-
nal mortality: the pregnant cardiac patient. Am J Obstet
Gynecol 2019;220:167.e1-8.
Zeisler H, Llurba E, Chantraine F, et al. Predictive value of the
sFlt-1:PlGF ratio in women with suspected preeclampsia.
N Engl J Med 2016;374:130-22.
209 Interactive Case: Cardiovascular Diseases in Pregnancy
Self-Assessment Questions
Questions 25–27 pertain to the following case.
R.W., a 28-year-old woman with a medical history of severe
rheumatic mitral stenosis with valve replacement 2 months
ago, is contemplating pregnancy. Her home drugs include
metoprolol 25 mg orally twice daily, and warfarin 5 mg
alternating with 2.5 mg each day. R.W.’s ECHO after sur-
gery revealed ejection fraction (EF) 45%, well-functioning
mechanical mitral valve, and mild aortic stenosis. Her vital
signs are stable, and she is in no apparent distress. R.W.’s
laboratory values include INR 2.6 and SCr 0.6 mg/dL.
25. Which one of the following is the best frequency of moni-
toring by a cardiologist to recommend throughout R.W.’s
pregnancy?
A. Weekly
B. Every 2 weeks
C. Monthly
D. Once each trimester
26. For which one of the following physiologic alterations is
R.W. most at risk during her pregnancy?
A. Increases in total body volume and cardiac output
will alter her valve gradients and worsen stenotic
physiology.
B. Anticoagulation during pregnancy will increase her
risk of anemia requiring iron replacement.
C. Physiologic changes of pregnancy will alter her
warfarin pharmacokinetics and decrease her dose
requirement.
D. Hypercoagulable state of pregnancy will increase
her risk of valve-related thrombosis.
27. Which one of the following educational points regarding
anticoagulation management during pregnancy is best
to provide to R.W.?
A. Changing to enoxaparin 1 mg/kg subcutaneously
every 12 hours now will minimize the risk of
teratogenicity.
B. Continuing warfarin throughout pregnancy to target
an INR of 2.5–3.5 will minimize the risk of valvular
thrombosis.
C. Targeting an INR of 1.5–2.5 throughout pregnancy
can minimize the risk of teratogenicity and prevent
valvular thrombosis.
D. Placing a bioprosthetic valve will minimize the
maternal risk of thrombosis and fetal toxicity from
anticoagulation during pregnancy.
PSAP 2022 Book 1 • Cardiology
28. Which one of the following women is at highest risk
of maternal morbidity and mortality when becoming
pregnant?
A. 27-year-old with long QT syndrome and history of
ventricular tachycardia
B. 28-year-old with unrepaired severe asymptomatic
aortic stenosis
C. 35-year-old with a history of peripartum
cardiomyopathy (PPCM) (current EF 25%)
D. 40-year-old with hypertension undergoing assisted
reproduction
29. A 25-year-old woman with congenital long QT syndrome
is 8 weeks pregnant. Her vital signs include blood pres-
sure 106/62 mm Hg and heart rate 72 beats/minute.
Which one of the following is best to recommend initiat-
ing in this patient?
A. Metoprolol
B. Atenolol
C. Carvedilol
D. Propranolol
Questions 30–32 pertain to the following case.
H.T., a 42-year-old woman (height 68 inches, weight 77 kg),
has a medical history that includes a single pulmonary embo-
lism (PE), a factor V Leiden homozygote, and hypertension.
She is nulliparous and 5 weeks pregnant after in vitro fertil-
ization. H.T.’s home drugs include apixaban 5 mg twice daily
and nifedipine 30 mg daily. Her vital signs include blood pres-
sure 145/88 mm Hg and heart rate 84 beats/minute. Her labo-
ratory values include BUN 18 mg/dL, SCr 0.8 mg/dL, Hgb 15.2
g/dL, Plt 208,000/mm3, and protein/creatinine ratio 0.2
mg/dL.
30. Which one of the following is best to recommend to man-
age H.T.’s anticoagulation?
A. Continue apixaban 5 mg twice daily for all
trimesters.
B. Administer enoxaparin 40 mg subcutaneously every
12 hours for all trimesters.
C. Administer enoxaparin 80 mg subcutaneously every
12 hours for all trimesters.
D. Administer enoxaparin 80 mg subcutaneously
every 12 hours for the first trimester, then change to
warfarin in the second and third trimesters.
210 Interactive Case: Cardiovascular Diseases in Pregnancy
31. H.T., now 28 weeks 4 days pregnant, visits the office for a
blood pressure check with no other concerns. Her medi-
cations include nifedipine 60 mg daily and labetalol 400
mg three times daily. Her vital signs include blood pres-
sure 154/92 mm Hg and heart rate 92 beats/minute. Her
laboratory values include SCr 1.1 mg/dL, Hgb 13.6 g/dL,
Plt 154,000/mm3, AST 36 U/L, ALT 20 U/L, LDH 186 U/L,
and protein/creatinine ratio 0.23 mg/dL. Which one of
the following best assesses H.T.’s hypertensive disorder
of pregnancy (HDP)?
A. Chronic hypertension
B. Chronic hypertension with superimposed
preeclampsia
C. Gestational hypertension
D. Preeclampsia
32. H.T., now 34 weeks 2 days pregnant, has been monitor-
ing her blood pressure and reports a result of 172/110
mm Hg and a similar value repeated after 15 minutes.
She had a headache this morning, but acetaminophen
resolved her symptoms. Her medications include nifed-
ipine 90 mg daily and labetalol 400 mg three times daily.
Which one of the following is best to recommend for
managing H.T.’s blood pressure?
A. Methyldopa
B. Intravenous hydralazine
C. Intravenous magnesium sulfate
D. Immediate-release nifedipine
33. A 32-year-old nulliparous woman (height 66 inches,
weight 86 kg) is 12 weeks 2 days’ gestation. Her medical
history includes type 1 diabetes, hypertension, and a pro-
thrombin G20210A mutation heterozygote. Her grand-
mother had a PE at age 42; the patient has no history
of venous thromboembolism (VTE). Today’s examination
shows the patient has blood pressure 135/85 mm Hg and
heart rate 80 beats/minute. Her home drugs include con-
tinuous glucose monitoring with an insulin pump and
labetalol 200 mg twice daily. Which one of the following
is best to recommend to improve this patient’s maternal
outcomes?
A. Add aspirin 81 mg daily.
B. Add calcium carbonate 500 mg three times daily.
C. Add enoxaparin 40 mg subcutaneously daily.
D. Increase labetalol to 300 mg twice daily.
Questions 34–36 pertain to the following case.
J.R. is a 22-year-old woman with no contributory medi-
cal history. She was being treated for preeclampsia with
severe features when she gave birth at 36 weeks 2 days by
PSAP 2022 Book 1 • Cardiology
vaginal delivery. Immediately after delivery, a maternal car-
diac arrest was called for ventricular fibrillation. Before the
cardiac arrest, J.R. was being treated for preeclampsia with a
magnesium sulfate continuous infusion 2 g/hour and labeta-
lol 100 mg twice daily. She is currently 6 minutes into car-
diopulmonary resuscitation and has received defibrillation
twice, epinephrine 1 mg intravenously every 3 minutes, and
amiodarone 300 mg intravenously once; magnesium sulfate
was discontinued.
34. Which one of the following is best to recommend to J.R.’s
maternal cardiac arrest team?
A. Amiodarone should only be administered after other
medications have failed.
B. Central access must be above the diaphragm for
medication administration.
C. Vasopressin 40 units once is preferred to assist with
uterine contraction.
D. Calcium chloride 1 g intravenously should be
administered.
35. J.R. achieves return of spontaneous circulation after 9
minutes, and her neurologic function is intact. Workup
of her cardiac arrest reveals an EF of 20% and pulmonary
edema on chest radiography, with no coronary artery dis-
ease seen on coronary angiogram. Her laboratory values
are SCr 0.6 mg/dL, K 4.6 mEq/L, magnesium 5.6 mEq/L,
and N-terminal pro–brain natriuretic peptide 16,204
pg/mL (range 15–450 pg/mL). J.R.’s vital signs include
blood pressure 146/84 mm Hg, heart rate 110 beats/min-
ute, respiratory rate 24 breaths/minute, and Sao2 89%.
Which one of the following, together with furosemide 40
mg intravenously once, is best to recommend initiating
for suspected PPCM in J.R.?
A. Hydralazine 10 mg intravenously once
B. Nitroglycerin infusion 5–200 mcg/minute
C. Metoprolol 5 mg intravenously once
D. Milrinone infusion 0.25 mcg/kg/minute
36. Which one of the following educational points is best to
share with J.R. regarding bromocriptine use for PPCM?
A. Bromocriptine will improve left ventricular function
and decrease mortality.
B. Breastfeeding will not be feasible if prescribed
bromocriptine.
C. Longer durations of bromocriptine show superior
outcomes in improving EF.
D. Anticoagulation will not be needed if she does not
use bromocriptine.
211 Interactive Case: Cardiovascular Diseases in Pregnancy
Learner Feature Evaluation: Interactive Case: Cardiovascular Diseases
in Pregnancy
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PSAP 2022 Book 1 • Cardiology
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212 Interactive Case: Cardiovascular Diseases in Pregnancy