Heart Failure Topic Discussion

Maha Muzaffar, PharmD, PGY1 Pharmacy Resident

Background
• Primary diagnosis in over 1 million hospitalizations each year
• Heart failure occurs when the heart is not able to supply sufficient oxygen-rich blood to the
body, because of impaired ability of the ventricle to either fill or eject blood
• Causes of HF: ischemic heart disease and myocardial infarction (MI), hypertension, and
valvular heart disease (VHD)
Diagnosis
• Symptoms of HF are usually related to fluid overload, which commonly presents as shortness
of breath (SOB) and edema
• An ultrasound of the heart (echocardiography or echo) is performed when HF is suspected to
provide an estimate of the left ventricular ejection fraction (LVEF)
• LVEF is a measurement of how much blood is pumped out of the left ventricle with each
contraction
EF Term Primary Problem
55-70% Normal Normal
≥ 50% Heart Failure with Preserved EF Impaired ventricular relaxation
(HFpEF) and filling during diastole
Diastolic Dysfunction
41-49% Heart Failure with Mildly Likely mixed systolic and
Reduced EF (HFmrEF) diastolic dysfunction
≤ 40% Heart Failure with Reduced EF Impaired ability to eject blood
(HFrEF) during systole
Systolic Dysfunction
≤ 40% at baseline, then a ≥ 10% Heart Failure with Improved EF EF improved with treatment;
increase and second EF > 40% (HFimpEF) classified separately because
treatments for HFrEF should be
continued, despite higher EF
Classification Systems
• 2 classification systems are recommended for HFrEF
• The ACC/AHA staging system is used to guide treatment in order to slow progression of
structural heart disease (LVH, low EF, valvular disease, previous MI) in asymptomatic patients
(stages A and B) or in symptomatic patients (stages C and D)
• HF can also be classified by the level of limitation in physical functioning using the New York
Heart Association (NYHA) classification system
 Signs and Symptoms of Systolic Heart Failure
• Labs and Biomarkers:
o Increased BNP (B-type natriuretic peptide): normal is <100 pg/mL
o Increased NT-proBNP (N-terminal pro-B-type natriuretic peptide): normal is <300
pg/mL
o BMP and proBNP are used to distinguish between cardiac and non-cardiac causes of
dyspnea
• Left-Sided Signs and Symptoms
o Orthopnea: SOB when lying flat
o Paroxysmal nocturnal dyspnea (PND): nocturnal cough and SOB
o Bibasilar rales: crackling lung sounds heard on lung exam
o S3 gallop: abnormal heart sound
o Hypoperfusion (renal impairment, cool extremeities)
• General Signs and Symptoms
o Dyspnea (SOB at rest or upon exertion)
o Cough
o Fatigue, weakness
o Reduced exercise capacity
• Right-Sided Signs and Symptoms
o Peripheral edema
o Ascites: abnormal fluid accumulation
o Jugular venous distension (JVD): neck vein distention
o Hepatojugular reflux (HJR): neck vein distension from pressure placed on the
abdomen
o Hepatomegaly: enlarged liver due to fluid congestion
Compensatory Mechanisms

• HFrEF is a low cardiac output state, the body compensates by activating the neurohormonal
pathways to increase blood volume or the force or speed of contractions
• This can temporarily increase CO, but chronically leads to myocyte damage and cardiac
remodeling→ hypertrophy
• The main pathways that are activated in HF are the renin-angiotensin aldosterone system
(RAAS, the sympathetic nervous system (SNS) and vasopressin)
• The neurohormones that normally balance these systems (e.g. natriuretic peptides) become
insufficient
Lifestyle Management
 • Patients with HF should be instructed to:
o Monitor and document body weight daily, in the morning after voiding and before
eating
o Notify the provider if weight increased by 2-4 pounds in one day or 3-5 pounds in one
week, or is symptoms worsen (e.g. SOB with activity)
o Restrict sodium intake to <1,500 mg/day in stage A and B HF
o Restrict fluid (1.5-2L/day) in stage D HF
o Stop smoking. Limit alchohol intake. Do not use illicit drugs.
o Obtain recommended vaccines
o Reduce weight to BMI <30 kg/m2 to decrease the heart’s workload and preserve
function
o Exercise (or performing regular physical activity, if able)
Drugs That Cause Or Worsen Heart Failure
• Dipeptidyl peptidase 4 inhibitors: alogliptin, saxagliptan
• Immunosupressants: TNF inhibiotrs (adalimumab, etanercept) and interferons
• Non-DHP CCBs: dilitazem and verapamil (in systolic HF)
• Antiarrhythmics: Class I agents (e.g. quinidine, flecainide, and dronedarone)
• Amiodarone and dofetilide are preffered in patients with HF
• TZD’s: increased risk of edema
• Itraconazole
• Oncology drugs: anthracyclines (doxorubicin, daunorubicin)
• NSAID’s: All (including celecoxib)
Drug Treatments
Initial medications, recommended for all patients without contraindications:
• ACE inhibitors, angiotensin receptor blockers (ARBs) or angiotensin receptor and neprilysin
inhibitor (ARNI)
o Decreased mortality in HFrEF
o ARNI is preferred over an ACEi/ARB to further reduce morbidity and mortality
• Beta-Blockers (BB)
o Provide benefit in controlling heart rate and reducing arrhyhtmia risk, decrease
mortality in HFrEF
• Loop Diuretics
o Reduce blood volume, which decreased edema and congestion; most HF patients
need a loop diuretic for symptom relief
Secondary medications, add on in select patients:
• Aldosterone receptor antagonists (ARAs)
o Decrease morbidity and mortality in NYHA Class II-IV
o Provide added diuresis; improve symptoms and HF
o Must meet eGFR criteria for use
• Sodium-glucose co-transporter 2 (SGLT2) inhibitors
o Initially approved for type 2 diabetes; select agents found to decrease morbidity and
mortality in NYHA Class II-IV HFrEF with or without DM
o Must meed eGFR criteria for use
• Hydralazine and nitrates (BiDil)
o Decrease morbidity and mortality in black patients with NYHA Class III-IV, when
added to an ACEi/ARB and BB, or in other patients who cannot tolerate an ACEi/ARB
 o Recommended in persistently symptomatic black patients with NYHA Class III-IV,
despite treatment with ARNI, BB, ARA, SGLT2 Inhibitor
• Ivabridine
o Decreased risk of hospitilization in patients with stable NYHA Class II-III HF in normal
sinus rhythm with a resting HR ≥ 70 bpm on maximally tolerated dose of BB
Additonal medications
• Digoxin
o Provides a small increase in cardiac output, improves symptoms and decreases
cardiac hospitilizations (does not decrease mortality)
• Vericiguat, a soluble guanylate cyclase (sGC) stimulator
o Decreases risk of hospitilization and CV death after HF hospitilization or need for IV
diurectics; not yet included in treatment guidelines
ACEi/ARBs

MOA: ACEis block the conversion of angiotensin I to angiotensin II, resulting in decreased
vasoconstriction and aldosterone secretion. Block the degredation of bradykinin, which may
contribute to the vasodilatory effects and the side effects of cough and angioedema. ARBs block Ang
II from binding to the angiotensin II type-1 (AT1) receptor. These drugs decrease RAAS activation,
resulting in a reduced preload and afterload. They reduce cardiac remodeling, improve left ventricular
function and decrease morbidity and mortality.

Clinical Pearls for ACEI’s:

• BBW: can cause injury and death to the developing fetus when used in the 2nd and 3rd
trimesters; discontinue as soon as pregnancy is detected
• CI: do not use with history of angioedema, do not use within 36 hours of sacubitril/valsartan
(Entresto), do not use with aliskiren in DM
 • Warnings: angioedema, hyperkalemia, hypotension, renal impairment, bilateral renal artey
stenosis (avoid use)
• Side Effects: Generally well tolerated, can cause cough, hyperkalemia, increased SCr,
hypotension/dizziness, headache
• Monitoring: BP, K, renal function, s/sx of HF and angioedema
Clinical Pearls for ARB’s
• Less cough
• Less angioedema
• No washout period required with sacubitril/valsartan (Entresto)
ARNI
Initial dose Target dose Mean doses

MOA: combination of neprilysin inhibitor (sacubitril) and an ARB (valsartan). Neprilysin in the enzyme
responsible for degredation of several beneficial vasodilatory peptides, including natriuretic peptides,
adernmedullin, substance P, and bradykinin. These peptides counteract the effects of RAAS activation
and cause vasodilation and diuresis. An ARNI is indicated in NYHA Class II-IV patients to reduce HF
hospitilizations and cardiovascular death. It is a preferred first-line treatment in all patients with
HFrEF, andwould be used in place of an ACEI or other ARB.

Clinical Pearls for ARNI:

• BBW: can cause injry and death to the developing fetus when used in the 2nd and 3rd
trimesters; discontinue as soon as pregnancy is detected
• CI: Do not use with or within 36 hours of ACEi, do not use with history of angioedema, Do not
use with aliskirin in DM
• Warnings: angioedema, hyperkalemia, hypotension, renal impairment, bilateral renal artery
stenosis
• SE: cough, hyperkalemia, increased SCr, hypotension/dizziness, headache
• Monitor: BP, K, renal function, s/sx of HF and angioedema
• NO washout period when switching from an ARB; take the first dose when the next ARB dose
was due
Beta Blockers
MOA: Atagonize the effects of catecholamines (especially NE) at the beta-1, beta-2 and/or alpha-1
adrenergic receptors. They decrease vasoconstriciton, improve cardiac function, and decrease
morbidity and mortality. They are recommended for all HF patients. Only discontinue beta-blockers
during acute decompensated HF if hypotension or hypoperfusion is present

Clinical Pearls for Beta-1 Selective Beta-Blockers (metoprolol,bisoprolol):

• BBW: Do not discontinue abruptly (particularly in patient with CHD/IHD); gradually taper over
1-2 weeks to avoid acute tachycardia, HTN, and/or ischemia
• CI: Severe bradycardia, 2nd or 3rd degree AV block or sick sinus syndrome (unless a permanent
pacemaker is in place); overt cardiac failure or cardiogenic shock
• Warnings: caution in DM; can worsen hyperglycemia or hypoglycemia, and mask
hypoglycemic symptoms, use caution with bronchospastic diseases (asthma, COPD), use
caution with Raynaud’s/other peripheral vascular diseases and pheochromocytoma, can
masks signs of hyperthyroidism (e.g. tachycardia), can worsen CNS depression
• SE: bradycardia, fatigue, hypotension, dizziness, impotence, cold extremities (can exacerbate
Raynaud’s)
• Monitoring: HR (decrease dose if HR <55 bpm), BP, s/sx of HF
Clinical Pearls for Non-selective Beta-Blocker and Alpha-1 Blocker (carvedilol):
• CI: severe hepatic impairment
• Warning: interopertive floppy iris syndrome has occurred in cataract eye surgery patiets who
were on or were previously treated with an alpha-1 blocker
• SE: edema, weight gain
Loop Diuretics
Furosemide (Lasix) Oral: 20-40 daily or BID
Tablet, Injection Max 600 mg/day
Bumetanide (Bumex) Oral: 0.5-1mg
Tablet, Injection Max 10 mg/day
Torsemide Oral: 10-20 mg daily
Tablet Max: 200 mg/day
Ethacrynic acid (Edecrin) Oral: 50-200 mg daily or divided
Tablet, Injection Max: 400 mg/day
MOA: block sodium and chloride reabsorption in the thick ascending limb of the loop of Henle. They
increase excretion of Na,K,Cl,Mg,Ca, and water. The decrease in fluid volume makes it easier for the
heart to pump, reduces congestive symptoms (decreases preload) and restores euvolemia (dry
weight). They do not improve survival, but are often required for symptom control. If response to
look diuretics is poor, adding a thiazide-type diuretic, such as metolazone, can be useful.
Clinical Pearls:
• BBW: can cause profound diuresis resulting in fluid and electrolyte depletion
• CI: anuria
• Warnings: sulfa allergy (not likely to cross-react); does not apply to ethacrynic acid
• SE: decrease electrolytes: K, Mg, Na, Cl, Ca (different than thiazides which increase Ca), Can
increase HCO3 (metabolic acidosis), UA, BG, TGs, TC; ototoxicity, orthostatic hypotension,
photosensitivity, myalgias
• Monitoring: renal function, fluid status (input/output, weight), BP, electrolytes, audiology
testing (with high doses or rapid IV administration), s/sx of HF
• Dose conversions: furosemide 40mg=torsemide 20mg=bumetanide 1mg=ethacrynic acid
50mg
Aldosterone Antagonist

MOA: compete with aldosterone at receptor sites in the distal convoluted tubule and collecting ducts
of the nephron. Spironolactone is non-selective; it also blocks androgen and exhibits endocrine side
effects. Eplerenone is selective and does not exhibit endocrine side effects. ARAs decrease sodium
and water retention, cardiac remodeling (espeically myocardial fibrosis) and the risk of suddon
cardiac death. ARAs decrease morbidity and mortality and should be added to ARNI (or ACEi or ARB)
and beta-blockers in patients with NYHA Class II-IV HF.

Clinical Pearls:
• CI: do not use if hyperkalemia, severe renal impairment, Addison’s disease (spironolactone) or
taking strong CYP3A4 inhibitors (eplerenone)
• Warnings: do not initiate for HF if K>5 mEq/L (>5.5 mEq/L for eplerenone), CrCl (eGFR)≤30 or
Scr>2.0 mg/dL (females) or SCr>2.5 mg/dL (males)
• Side Effects: HyperK, Increased SCr, dizziness, hypercholremic metabolic acidosis (rare).
Spironolocatone: gynecomastia, breast tenderness, impotence, irregular menses,
amernorrhea. Eplerenone: Increased TG
• Monitoring: BP, K, renal function, fluid status, s/sx of HF
SGLT2i’s

MOA: reduce glucose reabsorption in the proximal renal tubules. Reduced sodium
reabsorption,diuresis, and results in a decrease in preload and/or afterload.

Clinical Pearls for SGLT2i’s:

• CI: dialysis
 • Warnings: ketoacidosis, hypotension, AKI, genital mycotic infections, urinary tract infections,
necrotizing fascitis of the perineum
• SE: weight loss, increase urination, increase thirst, hypoglycemia
• Dapagliflozin: Do not initiate if eGFR<30 ml/min
• Empagliflozin: Do not initiate if eGFR<20 ml/min
Hydralazine/Nitrates

MOA: direct arterial vasodilator, which decreases afterload. Nitrates increase the availability of nitric
oxide, causing venous vasodilation and decreased preload. The combo improves survival in HF (but to
lesser degree than ACEi) and can be used as an alternative in patients who cannot tolerate ACEi or
ARBs due to poor renal function,angioedema, or hyperkalemia. The combo product BiDil is indicated
in self-identified black patients with NYHA Class III or IV who are symptomatic despite optimal
treatment with with ARNI (or ACEI or ARBs), beta-blockers, ARAs, and SGLT2i’s.

Clinical Pearls for hydralazine:

• CI: mitral valve stenosis, CAD
• Warning: drug-induced lupus erythematosus (DILE-dose and duration related), peripheral
neuritis, blood dyscrasias, hypotension
• SE: peripheral edema, HA, flushing, palpitations, reflex tachycardia, N/V
• Monitoring: HR, BP, s/sx of HF, ANA titer
Clinical Pearls for ISDN:
• CI: do not use with PDE-5 inhibitors or riociguat
• SE: hypotension, HA, dizziness, lightheadedness, flushing, tachyphlaxis (need 10-12 hour
nitrate-free trial), syncope
• Monitoring: HR, BP, s/sx of HF
Ivabridine

MOA: Disrupts the “funny” current (If) in the SA node, resulting in a reduced rate of firing and
ultimately decreases HR. Reduces the risk of hospitilizations for worsening HF, but does not affect
mortality. Recommended as an adjunct treatment in symptomatic (NYHA Class II-III) stable chronic EF
(EF≤35%). Patients must already be on mortality-reducing medications, including target or maximally-
tolerated doses of beta-blockers (or contraindication to use), and be in sinus rhythm with a resting
HR≥70 bpm.

Clinical pearls:
 • CI: ADHR, sick sinus syndrome, SA block or 3rd degree AV block (unless a permanent
pacemaker in place); clinically significant hypotension or bradycardia; HR maintained
exclusively by a pacemaker; severe hepatic impairment; use with stong CYP3A4
• Warnings: can cause bradycarida which can increase risk of QT prolongation and ventricular
arrhythmias; not recommended in 2nd degree AV block, increased risk of atrial fibrillation,
fetal toxicity (females should use effective contraception)
• SE: bradycardia, hypertension, atrial fibrillation, luminous phenomena (phosphenes-seeing
flashes of light)
• Monitor: HR, ECG, BP
Soluble guanylate cyclase stimulators

MOA:
• Digoxin: inhibits Na-K-ATPase pump= causing a positive intropic effect (increased CO), and
exerts a parasympathetic effect, which causes negative chronotropy (decreased HR). Does not
improve survival, but can reduce HF related hospitilizations
• Vericiguat: increases cyclic GMP which leads to smooth muscle relaxation and vasodilation.
Can be used as an add-on therapy for HF, but not yet included in the HF guidelines

Clinical pearls for digoxin:

• CI: ventricular fibrillation
• Warnings: 2nd/3rd degree heart block without a pacemaker, Wolff-Parkinsons-White syndrome
with AFib, vesicant (avoid extravasation)
• SE: dizziness, mental disturbances, headache, N/V, diarrhea
• Monitoring: electrolytes, renal function, HR, ECG, BP, and digoxin level (draw 12-24 hours
after dose)
• Toxicity: initial s/sx: N/V, loss of appetite and bradycardia; severe s/sx: blurred/double vision,
greenish-yellow halos around lights or objects, altered color perception, abdominal pain,
confusion, delerium, arrhythmias
Clinical pearls for vericiguat:
• BBW: do not use if pregnant. Contraception required during use and for one month after
stopping treatment
• CI: do not use with riociguat (another soluble guanylate cyclase inhibitor)
• SE: hypotension, anemia, dyspepsia
HFpEF
Goals & Treatment Approach:
• Lack of objective data exists to guide therapy
• Alleviation of congestion (at rest or with exertion)-> diuretics
• Manage precipitating factors:
o HTN-> effectice antihypertensive therapy
o Afib-> rate control
o Myocardial ischemia-> beta-blockers
 • Eliminate or reduce the factors responsible for the underlying microvascular inflammation
o Control blood pressure-> effective antihypertensive therapy
o Reduce heart rate-> beta-blockers, non-DHP CCBs

Resources:

American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines, Heart Failure Society of America.
(2022). 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart
Association Joint Committee on Clinical Practice Guidelines. Journal of the American College of Cardiology, 81(17), e937-e983. doi:
10.1016/j.jacc.2022.02.047.

2022 Naplex Course Book.

2021 update to the 2017 ACC expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answer to 10 Pivotal Issues
About Heart Failure with Reduced Ejection Fraction. J AM Coll Cardiol.2021;77(6):772-810.