REVIEW

Pharmacological Therapy Optimization for Heart

Failure: A Practical Guide for the Internist
Michelle Dimza, DO, Varsha Kurup, MD, Catarina Canha, MD, Arlene Jimenez, MD, Mohammad Al-Ani, MD,
Alex M. Parker, MD, Juan R. Vilaro, MD, Mustafa M. Ahmed, MD, Juan M. Aranda Jr, MD
Division of Cardiovascular Medicine, University of Florida College of Medicine, Gainesville..

ABSTRACT

Heart failure carries significant morbidity and mortality and affects a large population of patients cared for
predominantly by primary care physicians. The complexity of managing heart failure patients is increasing
as new therapies continue to emerge. This review outlines important clinical pearls and proposes strategies
for optimization of medical therapy.
Ó 2023 Elsevier Inc. All rights reserved.  The American Journal of Medicine (2023) 136:745−752

KEYWORDS: Guideline-directed medical therapy; Heart failure; Medical treatment; Titration

Approximately 6.2 million people have heart failure in the
United States.1 Fifty percent of these patients have heart
failure with reduced ejection fraction (HFrEF), and 50%
have heart failure with preserved ejection fraction (HFpEF).
Heart failure patients see on average 15 to 23 physicians per
year and will take a minimum 6.8 prescriptions per day.2
Current health care models suggest that the majority of care
received by these patients is provided by family medicine
and internal medicine physicians.3,4 Therefore, it is impera-
tive that the internal medicine physician play a significant
role in titration and optimization of heart failure guideline-
directed medical therapy (GDMT).
Current heart failure guidelines highlight the use of 4
drug classes for the management of symptomatic HFrEF.5
The combination of renin-angiotensin-aldosterone system
(RAAS) blockers, angiotensin-receptor neprilysin inhibitors
(ARNIs), beta-blockade, mineralocorticoid receptor antago-
nists (MRAs), and sodium-glucose cotransporter 2 inhibi-
tors (SGLT2is) have been estimated to reduce all-cause
mortality by 73%.6 Benefits of quality of life, symptom
relief, and altering the remodeling process occur. These
Funding: None.
Conflict of Interest: Each author declares that they have no known
competing financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Authorship: All authors had access to the data and a role in writing
this manuscript.
Requests for reprints should be addressed to Michelle Dimza, DO,
1329 SW 16th Street, P.O. Box 100288, Gainesville, FL 32610-0288.
E-mail address: Michelle.Dimza@medicine.ufl.edu
benefits are associated with specific dosages that are well
established in clinical trials. A strategy for initiating and
titrating current medications to appropriate dosages poses
several clinical challenges. This review aims to provide the
internist with strategies and clinical pearls to optimize med-
ical therapies in HFrEF.
RENIN-ANGIOTENSIN-ALDOSTERONE BLOCKERS
Both angiotensin-converting-enzyme inhibitors (ACEIs)
and angiotensin II receptor blockers (ARBs) have been
shown in large randomized control trials to improve hemo-
dynamics and provide neurohormonal blockade, while
reducing hospitalization and improving mortality.7-12
Angiotensin-converting-enzyme inhibitors decrease the
conversion of angiotensin I to angiotensin II, which alters
the negative remodeling effects of angiotensin II. There is a
strong association between angiotensin II and increased
blood pressure (BP), sympathetic tone, aldosterone levels,
hypertrophy, and fibrosis. Angiotensin-converting-enzyme
inhibitors also decrease the degradation of bradykinin,
which promotes vasodilation and natriuresis.7 Angiotensin
II receptor blockers block angiotensin II from binding to
AT-1 receptors, without any effect on bradykinin.
Clinical Pearls
Common barriers to initiation and titration of ACEIs and
ARBs are rise in serum creatinine and hypotension. Several
trials have demonstrated an expected rise in serum

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https://doi.org/10.1016/j.amjmed.2023.04.033

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746 The American Journal of Medicine, Vol 136, No 8, August 2023

creatinine up to 30% in the first 2 weeks due to the vasodila- discharge. Pre-discharge initiation of beta-blockade
tion effect of RAAS blockade on the efferent arteriole of the improves the use of beta-blockade at 60 days without
glomeruli. The initial rise in creatinine and change in glo- increasing side effects or length of stay.20
merular filtration rate (GFR) should stabilize over several
weeks. If the serum creatinine rise is greater than 30%,
MINERALOCORTICOID RECEPTOR ANTAGONISTS
ACEIs should be held and undergo evaluation for volume
Mineralocorticoid receptor antagonists have shown
depletion, concurrent use of nonsteroidal medications, or
improvement in all-cause mortality, reduced heart failure
bilateral renal artery stenosis.13 A meta-analysis of several
hospitalizations, and reduced incidence of sudden cardiac
randomized control trials showed modest BP lowering
death in patients with HFrEF and New York Heart Associa-
effect with RAAS blockade of 8 mm hg systolic BP and
tion (NYHA) class II to IV symp-
5 mm hg diastolic BP.14
toms.21-23 Aldosterone results in
CLINICAL SIGNIFICANCE sodium and fluid retention, myo-
BETA-BLOCKERS  Hospitalists and primary care physi- cardial fibrosis, vascular stiffen-
Bisoprolol, metoprolol succinate, and ing, endothelial dysfunction, and
cians provide most of the care to
carvedilol have been shown to reduce catecholamine release, which all
patients with heart failure. have negative impacts on the fail-
mortality, sudden cardiac death, and
 The most recent guidelines for heart ing heart.
heart failure hospitalization while
improving ventricular function and failure management highlight 4 major
quality of life. 15-17
The use of beta- drug classes, including beta-blockers,
Clinical Pearls
blockers in heart failure are not a angiotensin-receptor neprilysin inhibi-
After initiating MRAs, renal func-
class effect, as individual beta-block- tors, mineralocorticoid receptor tion and potassium should be
ers have different receptor blocking antagonists, and sodium-glucose checked at 72 hours, 1 week, 4
properties that can be beneficial or cotransporter 2 inhibitors. weeks, and every 6 months. For
detrimental in heart failure. In gen-  Evaluation of volume status, heart patients with a GFR of 31 to 49
eral, metoprolol succinate and biso- rate, blood pressure, and kidney func- ml/min/1.73m2, the dose should
prolol offer selective beta 1 receptor tion help direct initiation and titration be reduced by half. For patients
blockade, whereas carvedilol blocks of medical therapy in hospital and out- with chronic kidney disease or
beta 1, beta 2, and alpha 1 receptors. borderline hyperkalemia, ongoing
patient settings.
Beta 2 blockade reduces sympathetic investigations for the use of potas-
tone while providing vasodilatory sium binders with uninterrupted
effect. The dose equivalent to obtain MRAs and RAAS inhibition are promising; however, clini-
the same heart rate reduction between carvedilol and meto- cal outcome data are still pending.24,25 Eplerenone has
prolol succinate is 2:l. Therefore, 25 mg twice daily of car- higher selectivity to aldosterone receptor than spironolac-
vedilol and 100 mg daily of oral metoprolol succinate tone and therefore is preferred for patients who experience
provide the same heart rate reduction.18 gynecomastia or vaginal bleeding with spironolactone.

Clinical Pearls ANGIOTENSIN RECEPTOR-NEPRILYSIN

Initiation of beta-blockers may be associated with initial
worsening of heart failure, bradycardia, or hypotension. For
this reason, beta-blockers are better tolerated when the
patient is decongested. Beta-blockers should not be initiated
in acute heart failure decompensation. Conversely beta-
blockade should not be discontinued in acute decompensa-
tion unless the patient is hypotensive or in shock.19 A his-
tory of reactive airway disease is not a contradiction to
beta-blocker therapy. Cardioselective beta-blockers such as
metoprolol succinate and bisoprolol are well tolerated in
reactive airway disease. The dose of beta-blockade should
be titrated every 1 to 2 weeks. Titration should be based on
resting heartrate (HR) to achieve a goal less than 70 bpm.
Data suggest that EF begins to increase with carvedilol at a
dose of 6.25 mg orally twice per day with a target dose of
25 mg orally twice per day.15 Target dose of metoprolol
succinate should be 150 mg to 200 mg orally daily. In the
hospitalized patient, beta-blockade should be initiated
when the patient is euvolemic and started prior to hospital
INHIBITORS
Angiotensin-receptor neprilysin inhibitors reduce compos-
ite cardiovascular death and heart failure hospitalization up
to 20% compared with ACEIs in patients with symptomatic
NYHA class II or III heart failure.26 In addition to RAAS
blockade, ARNIs target the neprilysin enzyme, which
breaks down natriuretic peptides. Natriuretic peptides are
neurohormones that are secreted in response to volume and
pressure overload in the heart. Angiotensin-receptor nepri-
lysin inhibitors promote diuresis and natriuresis while
diminishing sympathetic tone, BP, and myocardial fibrosis.
Multiple clinical trials suggest ARNIs can be started de
novo in new HFrEF and their effect on lowering natriuretic
peptides is seen in the first 2 weeks.27
Clinical Pearls
Patients with newly diagnosed symptomatic HFrEF should
be started on an ARNI if BP allows. Initial BP may be a

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Dimza et al Pharmacological Therapy Optimization for Heart Failure
limiting factor since ARNIs may lower systolic BP by 5-
7 mm hg in the first week.26 Pearls to successfully initiate
ARNIs include starting low dose and avoiding over diuresis
at time of initiation. It is essential that volume status be
evaluated. ARNIs will have a diuretic effect by blocking
the degradation of B-type natriuretic peptide. Thus, they
are tolerated with initial congestion but as the patient
approaches euvolemia, diuretics may need to be adjusted to
avoid hypotension and hypovolemia.
SODIUM-GLUCOSE COTRANSPORTER 2
INHIBITORS
Sodium-glucose cotransporter 2 inhibitors reduce glucose
absorption in the proximal tubule of the kidney. They have
been used in type 2 diabetes and have been associated with
reduced heart failure hospitalizations.28-30 Heart failure
clinical trials with SGLT2is have shown approximately
25% reduction in heart failure hospitalization and cardio-
vascular death compared with placebo in patients with
symptomatic HFrEF already on GDMT.31 The mechanism
of this cardiovascular benefit is incompletely understood.
Multiple contributing biochemical pathways have been
described involving SGLTi and the effects on the kidneys,
myocardium, vasculature, and sympathetic nervous system.
Sodium-glucose cotransporter 2 inhibitors may have down-
stream effects on cardiac energy metabolism, natriuresis,
and decreasing cardiac inflammation.32
Clinical Pearls
Sodium-glucose cotransporter 2 inhibitors provide a
diuretic effect; therefore, upon initiation other diuretic med-
ications must be reevaluated. If a patient is congested, then
SGLT2is can be initiated with no change in diuretics. If the
patient is euvolemic, then SGLT2is offer the opportunity to
discontinue diuretics. In patients that have HFrEF and dia-
betes, SGLT2is provide dual benefit. Although the risk of
hypoglycemia is low, there is always a concern about the
interaction of SGLT2is with other diabetic medications.
One strategy is to measure hemoglobin A1c and if elevated,
the SGLT2i can be added to current diabetic medications. If
the hemoglobin A1c is controlled, the guidelines suggest
reducing insulin by 50%. Sodium-glucose cotransporter 2
inhibitors are well tolerated with metformin but should be
used with caution with oral hypoglycemic agents.
ADDITIONAL THERAPIES
If symptoms persist with optimal GDMT, there are addi-
tional therapies to consider. Ivabradine, digoxin, vericiguat,
and omega-3 polyunsaturated fatty acid can be used to
reduce hospitalization.5 Additionally, patients with symp-
tomatic HFrEF despite GDMT therapy should undergo
early referral to advanced heart failure centers.
Ivabradine blocks the “funny” sodium channel in the
sinus node and reduces heart rate. It has a class IIa indica-
tion for HFrEF patients who have NYHA class II-III
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747
symptoms, normal sinus rhythm, HR >70 bpm, and who
are on maximum tolerated beta-blocker. It is important that
this medication is not a substitute for beta-blockade. Beta-
blockers reduce mortality while ivabradine does not. Ivab-
radine is not to be used in atrial fibrillation.33
Digoxin currently has a class IIb indication for HFrEF.
Digitalis has been associated with reduction of heart failure
hospitalizations. Important clinical pearls include using
low-dose digoxin and not titrating to drug levels. Digoxin
has a narrow therapeutic window with adverse complica-
tions associated with high levels. Patients with enlarged
hearts, tachycardia (atrial fibrillation or sinus tachycardia)
tend to benefit the most.34
Vericiguat is an oral soluble guanylate cyclase stimulator
that reduces hospitalization in HFrEF. Soluble guanylate
cyclase is an enzyme that consumes nitric oxide to produce
cyclic guanosine monophosphate at the level of the cardiomyo-
cyte. Cyclic guanosine monophosphate is responsible for vaso-
relaxation, inhibiting platelet aggregation, remodeling, and
inflammation. Vericiguat helps to regulate this nitric oxide-sol-
uble guanylate cyclase-cyclic guanosine monophosphate sig-
naling pathway.35 It is important to note that in clinical trials
with vericiguat the use of ARNIs and SGLT2is was very low.
Therefore, maximizing GDMT with ARNIs and SGLT2is
should be considered before use of vericiguat.
Finally, omega-3 polyunsaturated fatty acids have been
associated with reduction of hospitalization for cardiovas-
cular reasons. Clinical trials have demonstrated a small
benefit in terms of mortality and hospitalization for cardio-
vascular cause.36,37 The benefit derives from improvement
of endothelial dysfunction and inflammation.36
DIURETICS
Diuretics are used to treat vascular congestion in heart fail-
ure exacerbation. Loop diuretics work by inhibiting reab-
sorption of sodium and chloride at the loop of Henle, thus
promoting natriuresis and water loss. In acute heart failure
exacerbation, the decision of route and dosing of diuretic
can be challenging.
In acute decompensation, IV loop diuretic is preferred
over oral because gastrointestinal absorption can be altered
with congestion. A logarithmic relationship exists between
loop diuretic dose and natriuresis. In heart failure, the phar-
macokinetics curve of diuretics is shifted to the right,
requiring higher doses to reach the threshold for sodium
excretion and volume loss. Therefore, initiation of IV loop
diuretic 2.5 times the home oral dose is recommended.38,39
Assessment of diuretic response and subsequent redosing
can be informed by urine output (UOP) or spot urine
sodium. If UOP is >150 ml/hr, then the current dose of IV
loop diuretic can be repeated every 6-12 hours.38 Alterna-
tively, if UOP is <150 ml/hr, then the dose of IV loop
diuretic should be doubled until appropriate UOP is
achieved. Also, urine sodium >50 to 70 mmol/L suggests
adequate secretion of sodium. If urine sodium is <50-
70 mmol/L, then the dose of IV loop diuretic should be
748 The American Journal of Medicine, Vol 136, No 8, August 2023

Figure 1 Inpatient initiation of guideline-directed medical therapy (GDMT) using blood pres-
sure, heart rate (HR), and volume status to ensure starting doses of BB and RAAS inhibitors and,
when appropriate, SGLT2i and MRA prior to discharge. ACEI = angiotensin-converting enzyme
inhibitor; ARB = angiotensin II receptor blocker; ARNI = angiotensin-receptor neprilysin inhibi-
tor; BB = beta-blockers; MRA = mineralocorticoid receptor antagonist; RAAS = renin-angioten-
sin-aldosterone system; SBP = systolic blood pressure; SGLT2i = sodium glucose cotransporter
2 inhibitor.

doubled.40 Chronic administration of loop diuretics can
result in hyperactive reabsorption of sodium in the distal
convoluted tubule that can be blocked by thiazide diu-
retics.41 Thus, combination nephron blockage with a thia-
zide, such as metolazone, can be used to increase sodium
secretion. Combination diuretic therapy is not first line due
to concern for severe electrolyte derangements and worsen-
ing renal function. However, it can be used to counteract
diuretic resistance.
elevation of creatinine associated with cardiorenal syn-
drome. Elevated filling pressures are most commonly
responsible for the decrease in GFR. Decongestion in this
scenario will improve GFR. Finally, diuretics do not
improve mortality but do improve symptoms. If a patient is
euvolemic, warm and dry with normal B-type natriuretic
peptide, diuretic regimen reduction or discontinuation can
be attempted with excellent outcomes.

INPATIENT GDMT ALGORITHM

Clinical Pearls Inpatient initiation of GDMT requires evaluation of systolic
It is imperative to identify congestion and use appropriate BP, heart rate, and the presence of congestion. Most
diuretic dose. Hypervolemia must be treated despite patients will have congestion and tachycardia on initial

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Dimza et al Pharmacological Therapy Optimization for Heart Failure 749

evaluation. Systolic BP will determine ability to tolerate
ARNIs over ACEis or ARBs (Figure 1). If SBP is
<100 mm hg, it is reasonable to start ACEIs or ARBs and
consider an ARNIs trial later.26 After 24-48 hours of ade-
quate IV diuresis, reevaluation of ongoing congestion will
dictate the next step in management. If the patient has mini-
mal congestion, it is preferred to start an evidence-based
beta-blocker as soon as possible. If the patient has contin-
ued signs of congestion, systolic BP and electrolytes will
determine addition of SGLT2is and MRAs. Once the
patient is deemed euvolemic and on an adequate dose of
oral diuretic, starting doses of any GDMT not present up
until this point should be initiated. Highest priority should
be placed on starting beta-blockers and ARNIs due to great-
est mortality benefit.15-17,26 If the patient has not been able
to tolerate ARNIs due to hypotension, it is reasonable to
discharge on ACEIs or ARBs and consider an outpatient
ARNIs trial. It is important to note that if ACEIs are started,
a wash-out period of 36 hours is necessary before starting
ARNIs.
OUTPATIENT GDMT ALGORITHM
The outpatient titration of pharmacologic therapy begins in
the first clinic visit 7 to 10 days after hospital discharge.5 At
that visit, evaluation of volume status, tolerance of dis-
charge medications, and transition from hospital to home
lifestyle is imperative. Heart failure clinical profile such as
heart rate, BP, volume status, and kidney function will
determine an individualized titration schedule (Figure 2).
The heart failure patient ideally will be discharged on an
ARNI or an ACEI or ARB with beta-blockade.42 SGLT2is
or MRAs may have been included on discharge. If BP and
kidney function allow, this clinic visit should result in

Figure 2 Outpatient titration algorithm. Outpatient titration of guideline-directed medical therapy (GDMT)
using blood pressure (BP), heart rate (HR), kidney function, and volume status to optimize BB, RAAS, MRA,
and SGLT2i. ARNI = angiotensin-receptor neprilysin inhibitor; BB = beta-blockers; MRA = mineralocorticoid
receptor antagonist; RAAS = renin-angiotensin-aldosterone system; SBP = systolic blood pressure;
SGLT2i = sodium glucose cotransporter 2 inhibitor.

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750
Table Medications with Unproven Benefit or Harm in Heart Failure2,5
Hypertension medications COR LOE
Dihydropyridine CCB* 3 A
-Amlodipine No benefit
-Felodipine
Nondihydropyridine CCB 3 A
-Diltiazem Harm
-Verapamil
Alpha blockers n/a B Dipeptidyl peptidase-4 (DDP-4) inhibitors
-Doxazosin
A = high-quality evidence; B = moderate-quality evidence; CCB = calcium channel blocker; COR = class of recommendation; COX = cyclo-oxygenase;
LOE = level of evidence.
*Dihydropyridine CCBs have no benefit in heart failure but can be used for hypertension management in heart failure patients after maximizing guide-
line-directed medical therapy.
completion of the 4 neurohormonal blockers to the patient’s
regimen. The addition of SGLT2is is efficacious and safe in
patients with HFrEF taking or not taking MRAs, supporting
the use of both drugs together along with ARNIs and beta-
blockers.43 If the patient has mild hypervolemia or is euvo-
lemic, the addition of SGLT2is may require reduction or
discontinuation of diuretics as these agents result in further
diuresis.32
Pharmacological therapy titration can occur every 1 to 2
weeks.5 Once the patient is stabilized on the 4 classes of
pharmacologic therapy with stable diuretic dosage, the phy-
sician can begin to optimize dosages of ARNIs and beta-
blockers. There is not much optimization required of
SGLT2is and MRAs.
The physician should focus on ARNI and beta-blocker
titration. The hemodynamic profile that must be reevaluated
is the patient’s HR, BP, and volume status. Both dose esca-
lations of ARNIs and beta-blockers are associated with bet-
ter outcomes and greater positive remodeling of the
myocardium.44-46 If the patient is euvolemic with HR >70
bpm and systolic blood pressure >100 mmHg, then the
beta-blocker should be titrated first.47 Optimal beta-blocker
doses include metoprolol succinate (150 mg orally daily),
carvedilol (25 mg orally twice per day), and bisoprolol
(10 mg orally daily).15,16,48,49
As the dosage of beta-blocker increases so does EF.15
Although beta-blocker dosages are important, meta-analy-
ses including over 19,000 patients suggest the magnitude of
HR reduction is most beneficial rather than beta-blocker
dose.15 Data suggest that for every 5 bpm reduction in HR,
mortality improves (HR 0.82 (0.71−0.97) per 5 bpm).50
Therefore, it is recommended to titrate beta-blockers to a
HR goal of 70 bpm.33
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The American Journal of Medicine, Vol 136, No 8, August 2023
Non-hypertension medications COR LOE
Class IC antiarrhythmic 3 A
-Flecainide Harm
-Propafenone
Dronedarone
Thiazolidinediones 3 A
-Rosiglitazone Harm
-Pioglitazone
3 B
-Saxagliptin Harm
-Alogliptin
COX selective and non-selective inhibitors 3 B
-Ketorolac Harm
-Ibuprofen
-Naproxen
-Celecoxib
If HR is near or below 70 bpm or the patient is hypervo-
lemic then the ARNI dose should be increased first. Higher
ARNI dosages are associated with greater reverse remodel-
ing.51 Clinical pearls to improve chances of ARNI up titra-
tion include avoidance of dehydration or overuse of
diuretics that may lower BP. Up titration of ARNI twice
daily over 3 to 6 weeks is well tolerated.52
Each individual patient may have limitations for opti-
mal titration based on HR, BP, and renal function. The
first objective should be to get the patient on the 4 clas-
ses of drugs for HFrEF. The second objective should be
to titrate beta-blockers and ARNI based on HR, BP, kid-
ney function, and congestion. The second objective is
more achievable if dehydration and over-diuresis are
avoided. Thus, diuretics must be constantly readdressed.
The best outcomes in heart failure occur when the
patient is warm and dry with optimal GDMT and no
diuretics.53 Lastly, it is important to be cognizant of
common medications with unproven benefit or harm in
heart failure (Table).
Once GDMT is achieved with the initial 4 classes of
pharmacological therapy, patient symptoms and ventric-
ular function should be reevaluated. If symptoms of
heart failure persist and the left ventricular ejection frac-
tion is <40%, additional therapies are warranted.5 Afri-
can American patients with persistent NYHA class III-
IV heart failure are candidates for hydralazine and
nitrates, which portends additional morbidity and mor-
tality benefit.5,54 African American patients should not
be denied ARNI therapy in favor of hydralazine and
nitrates. Hydralazine and nitrate therapy is an add-on
therapy for African American patients with symptoms
on GDMT, which includes ARNI.5
Dimza et al Pharmacological Therapy Optimization for Heart Failure
SUMMARY
 All patients with symptomatic HFrEF should be consid-
ered for the 4 classes of medications: mortality benefit-
beta-blockers, ARNIs, MRAs, and SGLT2is.
 Initiation and titration of GDMT starts in hospitalized
patients and continues in outpatient setting using volume
status, HR, BP, and renal function
 Hypervolemic patients tolerate titration of RAAS inhibi-
tion better, whereas beta-blockade should be titrated in
euvolemic patients with HR > 70 bpm
 For patients who continue to be symptomatic on GDMT,
additional therapies and referral to advanced heart fail-
ure centers are indicated.
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