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

0002-9343/© 2023 Elsevier Inc. All rights reserved.

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
INHIBITORS
this reason, beta-blockers are better tolerated when the Angiotensin-receptor neprilysin inhibitors reduce compos-
patient is decongested. Beta-blockers should not be initiated ite cardiovascular death and heart failure hospitalization up
in acute heart failure decompensation. Conversely beta- to 20% compared with ACEIs in patients with symptomatic
blockade should not be discontinued in acute decompensa- NYHA class II or III heart failure.26 In addition to RAAS
tion unless the patient is hypotensive or in shock.19 A his- blockade, ARNIs target the neprilysin enzyme, which
tory of reactive airway disease is not a contradiction to breaks down natriuretic peptides. Natriuretic peptides are
beta-blocker therapy. Cardioselective beta-blockers such as neurohormones that are secreted in response to volume and
metoprolol succinate and bisoprolol are well tolerated in pressure overload in the heart. Angiotensin-receptor nepri-
reactive airway disease. The dose of beta-blockade should lysin inhibitors promote diuresis and natriuresis while
be titrated every 1 to 2 weeks. Titration should be based on diminishing sympathetic tone, BP, and myocardial fibrosis.
resting heartrate (HR) to achieve a goal less than 70 bpm. Multiple clinical trials suggest ARNIs can be started de
Data suggest that EF begins to increase with carvedilol at a novo in new HFrEF and their effect on lowering natriuretic
dose of 6.25 mg orally twice per day with a target dose of peptides is seen in the first 2 weeks.27
25 mg orally twice per day.15 Target dose of metoprolol
succinate should be 150 mg to 200 mg orally daily. In the Clinical Pearls
hospitalized patient, beta-blockade should be initiated Patients with newly diagnosed symptomatic HFrEF should
when the patient is euvolemic and started prior to hospital 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 747

limiting factor since ARNIs may lower systolic BP by 5- symptoms, normal sinus rhythm, HR >70 bpm, and who
7 mm hg in the first week.26 Pearls to successfully initiate are on maximum tolerated beta-blocker. It is important that
ARNIs include starting low dose and avoiding over diuresis this medication is not a substitute for beta-blockade. Beta-
at time of initiation. It is essential that volume status be blockers reduce mortality while ivabradine does not. Ivab-
evaluated. ARNIs will have a diuretic effect by blocking radine is not to be used in atrial fibrillation.33
the degradation of B-type natriuretic peptide. Thus, they Digoxin currently has a class IIb indication for HFrEF.
are tolerated with initial congestion but as the patient Digitalis has been associated with reduction of heart failure
approaches euvolemia, diuretics may need to be adjusted to hospitalizations. Important clinical pearls include using
avoid hypotension and hypovolemia. 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
SODIUM-GLUCOSE COTRANSPORTER 2 hearts, tachycardia (atrial fibrillation or sinus tachycardia)
INHIBITORS tend to benefit the most.34
Sodium-glucose cotransporter 2 inhibitors reduce glucose Vericiguat is an oral soluble guanylate cyclase stimulator
absorption in the proximal tubule of the kidney. They have that reduces hospitalization in HFrEF. Soluble guanylate
been used in type 2 diabetes and have been associated with cyclase is an enzyme that consumes nitric oxide to produce
reduced heart failure hospitalizations.28-30 Heart failure cyclic guanosine monophosphate at the level of the cardiomyo-
clinical trials with SGLT2is have shown approximately cyte. Cyclic guanosine monophosphate is responsible for vaso-
25% reduction in heart failure hospitalization and cardio- relaxation, inhibiting platelet aggregation, remodeling, and
vascular death compared with placebo in patients with inflammation. Vericiguat helps to regulate this nitric oxide-sol-
symptomatic HFrEF already on GDMT.31 The mechanism uble guanylate cyclase-cyclic guanosine monophosphate sig-
of this cardiovascular benefit is incompletely understood. naling pathway.35 It is important to note that in clinical trials
Multiple contributing biochemical pathways have been with vericiguat the use of ARNIs and SGLT2is was very low.
described involving SGLTi and the effects on the kidneys, Therefore, maximizing GDMT with ARNIs and SGLT2is
myocardium, vasculature, and sympathetic nervous system. should be considered before use of vericiguat.
Sodium-glucose cotransporter 2 inhibitors may have down- Finally, omega-3 polyunsaturated fatty acids have been
stream effects on cardiac energy metabolism, natriuresis, associated with reduction of hospitalization for cardiovas-
and decreasing cardiac inflammation.32 cular reasons. Clinical trials have demonstrated a small
benefit in terms of mortality and hospitalization for cardio-
Clinical Pearls vascular cause.36,37 The benefit derives from improvement
Sodium-glucose cotransporter 2 inhibitors provide a of endothelial dysfunction and inflammation.36
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 DIURETICS
patient is euvolemic, then SGLT2is offer the opportunity to Diuretics are used to treat vascular congestion in heart fail-
discontinue diuretics. In patients that have HFrEF and dia- ure exacerbation. Loop diuretics work by inhibiting reab-
betes, SGLT2is provide dual benefit. Although the risk of sorption of sodium and chloride at the loop of Henle, thus
hypoglycemia is low, there is always a concern about the promoting natriuresis and water loss. In acute heart failure
interaction of SGLT2is with other diabetic medications. exacerbation, the decision of route and dosing of diuretic
One strategy is to measure hemoglobin A1c and if elevated, can be challenging.
the SGLT2i can be added to current diabetic medications. If In acute decompensation, IV loop diuretic is preferred
the hemoglobin A1c is controlled, the guidelines suggest over oral because gastrointestinal absorption can be altered
reducing insulin by 50%. Sodium-glucose cotransporter 2 with congestion. A logarithmic relationship exists between
inhibitors are well tolerated with metformin but should be loop diuretic dose and natriuresis. In heart failure, the phar-
used with caution with oral hypoglycemic agents. 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
ADDITIONAL THERAPIES diuretic 2.5 times the home oral dose is recommended.38,39
If symptoms persist with optimal GDMT, there are addi- Assessment of diuretic response and subsequent redosing
tional therapies to consider. Ivabradine, digoxin, vericiguat, can be informed by urine output (UOP) or spot urine
and omega-3 polyunsaturated fatty acid can be used to sodium. If UOP is >150 ml/hr, then the current dose of IV
reduce hospitalization.5 Additionally, patients with symp- loop diuretic can be repeated every 6-12 hours.38 Alterna-
tomatic HFrEF despite GDMT therapy should undergo tively, if UOP is <150 ml/hr, then the dose of IV loop
early referral to advanced heart failure centers. diuretic should be doubled until appropriate UOP is
Ivabradine blocks the “funny” sodium channel in the achieved. Also, urine sodium >50 to 70 mmol/L suggests
sinus node and reduces heart rate. It has a class IIa indica- adequate secretion of sodium. If urine sodium is <50-
tion for HFrEF patients who have NYHA class II-III 70 mmol/L, then the dose of IV loop diuretic should be

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

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 trial. It is important to note that if ACEIs are started,
ARNIs over ACEis or ARBs (Figure 1). If SBP is a wash-out period of 36 hours is necessary before starting
<100 mm hg, it is reasonable to start ACEIs or ARBs and ARNIs.
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- OUTPATIENT GDMT ALGORITHM
mal congestion, it is preferred to start an evidence-based The outpatient titration of pharmacologic therapy begins in
beta-blocker as soon as possible. If the patient has contin- the first clinic visit 7 to 10 days after hospital discharge.5 At
ued signs of congestion, systolic BP and electrolytes will that visit, evaluation of volume status, tolerance of dis-
determine addition of SGLT2is and MRAs. Once the charge medications, and transition from hospital to home
patient is deemed euvolemic and on an adequate dose of lifestyle is imperative. Heart failure clinical profile such as
oral diuretic, starting doses of any GDMT not present up heart rate, BP, volume status, and kidney function will
until this point should be initiated. Highest priority should determine an individualized titration schedule (Figure 2).
be placed on starting beta-blockers and ARNIs due to great- The heart failure patient ideally will be discharged on an
est mortality benefit.15-17,26 If the patient has not been able ARNI or an ACEI or ARB with beta-blockade.42 SGLT2is
to tolerate ARNIs due to hypotension, it is reasonable to or MRAs may have been included on discharge. If BP and
discharge on ACEIs or ARBs and consider an outpatient 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 The American Journal of Medicine, Vol 136, No 8, August 2023

Table Medications with Unproven Benefit or Harm in Heart Failure2,5

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

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Dimza et al Pharmacological Therapy Optimization for Heart Failure 751

SUMMARY inhibitors and angiotensin receptor blockers: a multinational cohort

study. Hypertension 2021;78:591–603.
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dose-related improvements in left ventricular function and survival in
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ered for the 4 classes of medications: mortality benefit- 1996;94:2807–16.
beta-blockers, ARNIs, MRAs, and SGLT2is. 16. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/
 Initiation and titration of GDMT starts in hospitalized XL Randomised Intervention Trial in Congestive Heart Failure
(MERIT-HF). Lancet 1999;353:2001–7.
patients and continues in outpatient setting using volume
17. A randomized trial of beta-blockade in heart failure. The Cardiac
status, HR, BP, and renal function Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and
 Hypervolemic patients tolerate titration of RAAS inhibi- Committees. Circulation 1994;90:1765–73.
tion better, whereas beta-blockade should be titrated in 18. Poole-Wilson PA, Swedberg K, Cleland JG, et al. Comparison of car-
euvolemic patients with HR > 70 bpm vedilol and metoprolol on clinical outcomes in patients with chronic
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(COMET): randomised controlled trial. Lancet 2003;362:7–13.
additional therapies and referral to advanced heart fail- 19. Jondeau G, Neuder Y, Eicher JC, et al. B-CONVINCED: Beta-blocker
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