EXECUTIVE SUMMARY

Heart failure affects more than 6.2 million patients in the United States and about 26 million patients globally. Approximately 50% of patients with heart failure have reduced ejection fractions.

  • Morbidity and mortality are altered favorably with the use of guideline-directed medical therapy, with multiple drug therapies having informed evidence-based therapies for the treatment.
  • Drug classes of common disease-modifying agents from inotropic agents to a wide variety of agents including angiotensin II converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers, beta-adrenoceptor blockers, mineralocorticoid receptor antagonists, combination vasodilator therapy, sodium/potassium If channel blocker, angiotensin II receptor-neprilysin inhibitors, sodium-glucose co-transporter-2 (SGLT2) inhibitors, soluble guanylate cyclase stimulators, and cardiac myosin activators.
  • Comprehensive quadruple guideline-directed medical therapy should be initiated immediately upon diagnosis and optimized over two weekly intervals, along with a multidisciplinary team approach.

Heart failure is a widely prevalent medical condition with a high burden of morbidity and mortality. It affects more than 6.2 million patients in the United States and approximately 26 million patients globally.1 (See Figure 1.) Approximately 50% of patients with heart failure have heart failure with reduced ejection fraction (HFrEF).1 HFrEF morbidity and mortality are altered favorably with the use of guideline-directed medical therapy (GDMT). Multiple drug therapies have informed evidence-based therapies for the treatment of HFrEF.

Figure 1. Congestive Heart Failure

Until recently, triple therapy (beta-blockade, angiotensin-converting enzyme inhibitor [ACEI]/angiotensin receptor-neprilysin inhibition [ARNI], and mineralocorticoid receptor antagonism [MRA]) formed the basis of HFrEF pharmacotherapy.2 The addition of hydralazine and isosorbide dinitrate combination after optimal doses of triple therapy, particularly in African Americans, also was advocated in the guidelines.2 The compelling evidence of the mortality and morbidity benefits of the novel sodium-glucose co-transporter-2 (SGLT2) inhibitors beyond benefits derived from triple therapy (with or without diabetes)3 has led to expert recommendations for the incorporation of these medications in HFrEF treatment algorithms.4 Even with the optimal use of GDMT, patients with HFrEF have variable periods of clinical stability and persistent residual risk for further deterioration and sudden death.5 Concomitant use of SGLT2 inhibitors and triple therapy led to significant improvements in HFrEF survival and morbidity.6 SGLT2 inhibitors, particularly dapagliflozin and empagliflozin, join a class of HFrEF pharmacotherapies with established mortality and morbidity benefits that justify their inclusion in foundational HFrEF therapies. This article discusses the evolution of foundational HFrEF pharmacotherapies, the new role of SGLT2 inhibitors in HFrEF with and without diabetes, and the challenges of navigating these advances in HFrEF pharmacotherapy. This article also will explore other recent novel supplemental therapies with improved morbidity outcomes in HFrEF.

The Basis of Current HFrEF Medical Therapy

Neurohormonal Antagonism as the Basis of HFrEF Therapy

HFrEF progression is explained pathophysiologically by maladaptive responses of the sympathetic system activation and the renin-angiotensin-aldosterone system (RAAS) to an initial cardiac injury. Neurohormonal antagonism of these biologic pathways has been established to attenuate HFrEF progression.7-9 In some cases, inhibition of these neurohormonal pathways can reverse cardiovascular remodeling.10 Neurohormonal blockade of the sympathetic system and RAAS has been the basis of contemporary GDMT.2

Left Ventricular Ejection Fraction as a Basis of HFrEF Therapy

Left ventricular ejection fraction (EF) is a measure of cardiac contractility and function. It has been used widely for categorization of heart failure phenotypes into HFrEF (EF < 40%), heart failure with midrange ejection fraction (HFmrEF; EF 40% to 49%), and heart failure with preserved ejection fraction (HFpEF; EF 50%). These heart failure categories have been used extensively as key criteria in many clinical trials involving heart failure patients. Accordingly, heart failure management guidelines employ EF thresholds to articulate therapeutic recommendations.2,11

Recent proteomic studies demonstrated significant heterogeneity in biologic traits across the spectrum of EF categories.12,13 Further, patients within a shared etiology of heart failure (e.g., ischemic cardiomyopathy) also show significant overlap in these biologic traits.12 These findings may explain the observed variability of therapeutic response in heart failure and raise questions about the validity and utility of EF in guiding heart failure therapy.13 Despite these findings, it is well established that therapeutic response to medical therapy varies with left ventricular EF; patients with HFrEF benefit the most from currently available pharmacotherapy.14-16 Left ventricular EF offers a pragmatic and reliable tool for risk stratification, prediction, and determination of therapeutic response in heart failure.17

Evolution of HFrEF Pharmacotherapy

Historical Perspective on HFrEF Pharmacotherapy

Medical management of HFrEF has evolved significantly over the last three decades. The last 30 years saw a shift from a focus on drug therapies aimed at increasing contractile mechanics (digoxin and inotropes) to disease-modifying therapies. Mortality and morbidity benefits from pharmacotherapy in HFrEF first were demonstrated with vasodilator therapy. A combination of the vasodilators hydralazine and isosorbide dinitrate was associated with increased survival.18 This was followed by clinical trials demonstrating the mortality and morbidity benefit with the use of ACEIs and a confirmation of similar benefit with the use of angiotensin receptor blockers (ARBs) in a later trial of HFrEF.7,19,20

Subsequent clinical trials, predominantly on background ACEI as standard therapy, showed incremental mortality and morbidity benefit from the addition of a beta-blocker and MRA.8,21,22 Triple combination therapy with a beta-blocker, ACEI/ARB, and MRA was the standard GDMT for some time. In addition to this triple regimen, combination vasodilator (hydralazine and isosorbide dinitrate) therapy was strongly recommended based on survival and morbidity benefit in a later trial comprising African American patients with advanced heart failure despite optimal GDMT.23

Later, ivabradine, an inhibitor of the potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 receptor, showed lower incidence of hospitalization in HFrEF when added to maximally tolerated beta-blocker therapy in patients with sinus rhythm and resting heart rate greater than 70 beats per minute (bpm).24 Recently, sacubitril-valsartan, an ARNI, demonstrated superior outcomes of cardiovascular mortality and hospitalization in HFrEF compared to enalapril (an ACEI).25

Another recent addition to the therapeutic armamentarium of HFrEF are the SGLT2 inhibitors. In the Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) trial, the addition of dapagliflozin to GDMT resulted in incremental mortality and morbidity benefits independent of diabetes mellitus status.3 Similar results also were replicated in the Empagliflozin Outcome Trial in Patients with Chronic HFrEF (EMPEROR-Reduced) using another SGLT2 inhibitor, empagliflozin, among HFrEF patients with or without diabetes on GDMT.26

Most recently, vericiguat, a novel oral soluble guanylate cyclase stimulator, was shown to decrease the risk of cardiovascular death and hospitalization when added to GDMT in patients with recent hospitalization for heart failure (EF 45%) and/or recent use of intravenous diuretics.27

Class Effects for HFrEF Pharmacotherapies

The rationale for the multidrug therapeutic framework in HFrEF is to target different biologic pathways to modify the trajectory of HFrEF. The following are the classes of important disease-modifying therapies for patients with HFrEF.

Renin-Angiotensin-Aldosterone Inhibitors (ACEIs)

This class of drugs antagonizes the deleterious cardiovascular effects of the RAAS in HFrEF. Inhibition of angiotensin-converting enzyme leads to decreased serum angiotensin II and aldosterone, afterload reduction, and reversal of cardiac remodeling, which slow the progression of HFrEF.19 ACEIs improve mortality, heart failure symptoms, hospitalization, and quality of life in patients with HFrEF.7 These benefits have been observed even with lower dosages of ACEIs,28 although efforts should be made to replicate target clinical trial dosages for optimal clinical benefits.

ARBs block angiotensin II at its receptors and have comparable mortality and morbidity benefits to ACEIs in HFrEF.20 Given a lack of superiority to ACEIs, ARBs should be used only if a patient is intolerant of an ACEI.2

The CHAMP-HF (Medical Therapy for Heart Failure with Reduced Ejection Fraction) registry of outpatients in the United States revealed low ACEI/ARB use (27%). Predischarge initiation of an ACEI or ARB for hospitalized patients with HFrEF is associated with improved short-term and long-term mortality and hospitalization.29 Hitherto, ACEIs generally were considered as first-line therapy in de novo HFrEF, but now have been supplanted by ARNI based on recent expert consensus recommendations.4 It must be noted that, if there are barriers to access (e.g., cost), then ACEIs still are a viable therapeutic choice.

Beta-Blockers

Beta-adrenoceptor blockade in HFrEF allows for modulation of adrenergic hyperactivity, reversal of cardiac remodeling, and improvement of left ventricular function.10,30 Beta-adrenoreceptor blockade with carvedilol, metoprolol succinate, and bisoprolol has been demonstrated to improve HFrEF symptoms, hospitalization, and mortality.8,21,31

However, there is low uptake of beta-blockers in patients with HFrEF in the United States.32 Despite the potential to worsen cardiac hemodynamics and heart failure symptoms initially, evidence-based beta-blockers can be initiated safely as soon as a patient with HFrEF is hemodynamically stable.33,34 Predischarge initiation of beta-blockers in HFrEF is well tolerated, improves short-term and long-term survival, and is associated with greater beta-blocker uptake and retention than post-discharge initiation (91% vs. 73%, P < 0.0001).33,34 Heart failure guidelines suggest the initiation of beta-blockers at lower dosages and gradual escalation to target trial dosages to allow for better tolerability and retention.2

Mineralocorticoid Receptor Antagonists

Increased serum aldosterone in HFrEF causes both cardiovascular remodeling through its proinflammatory effects and sodium/water retention. MRAs attenuate these pathophysiological effects, leading to improved outcomes in HFrEF. MRAs improve HFrEF hospitalization and mortality when added to background therapy of ACEI/ARB and beta-blockers in patients with mild to severe HFrEF.22,35 The CHAMP-HF registry revealed disappointingly low MRA prescription (only 33% of eligible patients with HFrEF received a prescription) in eligible outpatients with HFrEF in the United States.32

Concern for potential deterioration in renal function and hyperkalemia when used alongside ACEI/ARB/ARNI may explain the inertia associated with MRA prescription, although clinical trial evidence has revealed lower HFrEF hospitalization in patients receiving a combination of MRA and ACEI or ARB.36 Novel therapies for management of acute and chronic hyperkalemia likely will improve uptake and tolerability of GDMT, including MRAs, for patients with HFrEF.4,15 Patients initiated on MRAs must be monitored closely for electrolytes (especially potassium) and renal function, at least two to three days following initiation, seven days after either initiation or titration, monthly thereafter for three months, and then every three months, depending on the clinical status.2,4

Combination Vasodilator Therapy

Heart failure is associated with decreased bioavailability of nitric oxide, oxidative stress, cardiovascular remodeling, and endothelial dysfunction.37 Combination vasodilator therapy with hydralazine (antioxidant) and isosorbide dinitrate (nitric oxide donor) is associated with improved heart failure mortality, hospitalization, and quality of life.18,23 More robust clinical benefits (all-cause mortality, heart failure hospitalization, and health quality scores) were seen with the addition of fixed-dose hydralazine-isosorbide dinitrate to standard heart failure therapy in African American patients with New York Heart Association (NYHA) class III-IV HFrEF.23 (See Table 1.)

Table 1. ACC/AHA Staging and NYHA Classification of HF

ACC/AHA Stages of HF

NYHA Classes of HF

A

At risk for HF, but without structural heart disease or symptoms of HF

I

No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF.

B

Structural heart disease, but without signs or symptoms of HF

II

Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF.

C

Structural heart disease with prior or current symptoms of HF

III

Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF.

D

Refractory HF requiring advanced therapies/interventions

IV

Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest.

ACC: American College of Cardiology; AHA: American Heart Association; HF: heart failure

The addition of hydralazine-isosorbide dinitrate, either as fixed individual medications or as a fixed combination, therefore, is recommended for African American patients with NYHA class III-IV HFrEF after achieving target doses or maximally tolerated doses of GDMT (beta-blocker, ARNI/ACEI/ARB, and MRA).2 Patients should be monitored for hypotension, and consideration should be made for up-titration to optimal doses every two weeks until target doses are achieved.2

ARNIs

ARNIs allow for simultaneous angiotensin II receptor blockade and neprilysin inhibition (which prevents degradation of natriuretic peptides and other vasoactive substances). The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) study demonstrated the superiority of sacubitril-valsartan in decreasing cardiovascular mortality and heart failure hospitalization in patients with HFrEF on background GDMT including an ACEI or ARB.25 ARNI therapy causes reversal of cardiac remodeling.38 More recent studies have demonstrated the safety, tolerability, and efficacy of predischarge ( 12 to 24 hours before discharge) initiation of sacubitril-valsartan in hemodynamically stable patients with HFrEF decompensation or acute de novo HFrEF.39-41 In patients receiving an MRA in the PARADIGM-HF trial, sacubitril-valsartan was associated with lower risks of severe hyperkalemia (K > 6.0; 3.1 per 100 patient-years vs. 2.2 per 100 patient-years; hazard ratio [HR], 1.37; P = 0.02).42

The recent update to the 2017 heart failure guidelines recommends transitioning patients previously on ACEI/ARB to ARNI in the absence of access barriers.2,4 When considering transitioning from ACEI, a 36-hour washout period is recommended prior to starting the ARNI to avoid hypotension and angioedema. From a dosing perspective, if a patient is taking an equivalent dose of less than 10 mg daily of enalapril or the equivalent of 160 mg or less of valsartan daily, then the recommended dose of sacubitril-valsartan is 24 mg to 26 mg twice daily. On the other hand, for patients on an equivalent dose of enalapril of greater than 10 mg or an equivalent dose of valsartan more than 160 mg daily, then the initiating dose of 49 mg to 51 mg twice a day would be recommended. Dose titration to a target dose of 97 mg/103 mg is recommended based on tolerability of blood pressure and renal function.2,4

SGLT2 Inhibitors

Initially designed for glycemic control in patients with type 2 diabetes mellitus, SGLT2 inhibitors emerged as potential therapeutic agents for HFrEF after demonstrating favorable cardiovascular and renal outcomes in type 2 diabetes patients with heart failure.43 The mechanisms behind the HFrEF benefits of SGLT2 inhibitors are not fully understood. There is evidence to suggest that SGLT2 inhibitor benefits in HFrEF probably are mediated through direct preload and afterload reduction, cardiometabolic effects including ketogenesis, and anti-inflammatory effects.44 SGLT2 inhibitor-induced osmotic diuresis and natriuresis improves both circulatory and interstitial fluid overload, which likely explains their benefit in heart failure hopitalizations.45 Given the prognostic value of renal function in HFrEF,46 favorable renal hemodynamics44 and improved cardiorenal interactions from SGLT2 inhibitors are likely to contribute to beneficial HFrEF outcomes.

The DAPA-HF trial showed that the addition of dapagliflozin to background GDMT in NYHA class II-IV HFrEF patients with and without diabetes was associated with a lower risk for the composite outcome of worsening HFrEF or cardiovascular death (16.3% dapagliflozin group vs. 21.2% placebo group; HR, 0.74; 95% confidence interval [CI], 0.65-0.85; P < 0.001).3 In terms of individual clinical endpoints, dapagliflozin was associated with reductions in the risks of a first episode of worsening heart failure (10% dapagliflozin vs. 13.7% placebo; HR, 0.70; 95% CI, 0.59-0.83), cardiovascular death (9.6% dapagliflozin vs. 11.5% placebo; HR, 0.82; 95% CI, 0.69-0.98), and all-cause death (11.6% dapagliflozin vs. 13.9% placebo; HR, 0.83; 95% CI, 0.71-0.97).3 The Dapagliflozin Effects on Biomarkers, Symptoms and Functional Capacity in Patients with Heart Failure with Reduced Ejection Fraction (DEFINE-HF) trial extended the potential role of SGLT2 inhibitors in HFrEF by showing improvements in healthcare quality scores in HFrEF patients with or without diabetes.47 The favorable effects of dapagliflozin on quality of care scores in HFrEF were not accompanied by improvements in N-terminal pro B-type natriuretic peptide measures.47 Further, the EMPEROR-Reduced trial demonstrated improvement in the composite outcome of cardiovascular death or heart failure hospitalization with the addition of empagliflozin to GDMT in HFrEF patients with and without diabetes (19.4% empagliflozin vs. 24.7% placebo; HR, 0.75; 95% CI, 0.65-0.86; P < 0.001).26 Additionally, heart failure hospitalization and the annual rate of decline in glomerular filtration rate (GFR) were lower in the empagliflozin group compared to placebo (HR, 0.70; 95% CI, 0.58-0.85; P < 0.001; and -0.55 mL/1.73m2 of body surface per year vs. -2.28 mL/1.73m2 of body surface per year; P < 0.001, respectively).26 The performance of SGLT2 inhibitors in HFrEF patients with glomerular filtration rates less than 20 mL/min/1.73m2 has not yet been assessed. Meta-analysis of SGLT2 inhibitor clinical trials supports the consistency of these favorable cardiorenal outcomes, including heart failure hospitalization, cardiovascular death, and renoprotection.48,49 Quadruple therapy (a combination of ARNI, beta-blockers, MRA, and SGLT2 inhibitor) is associated with greater reductions in cardiovascular death and/or heart failure hospitalization in HFrEF when compared to conventional therapy (combination ACEI or ARB and beta-blocker).6 These favorable HFrEF outcomes call for SGLT2 inhibitor inclusion in foundational disease-modifying agents for HFrEF. Accordingly, the American College of Cardiology Expert Consensus and the Heart Failure Collaboratory panels recommend SGLT2 inhibitors in patients with HFrEF.4,16

Other Novel Therapies in HFrEF

Some recent clinical trials have demonstrated benefit in heart failure morbidity (heart failure hospitalization and quality of life, rather than survival benefit).

Sodium/Potassium If Channel Blockers

Beta-blocker trials have revealed the prognostic value of resting heart rates in HFrEF. Higher resting heart rates ( 60 bpm) are associated with increased mortality in HFrEF.50,51 Ivabradine slows sinoatrial nodal conduction through specific inhibition of the If current.24 In the Systolic HF Treatment with the If Inhibitor Ivabradine (SHIFT) trial, the addition of ivabradine to GDMT in patients with symptomatic stable heart failure and EF
35% resulted in fewer heart failure hospitalizations or cardiovascular death than placebo (24% vs. 29% placebo; HR, 0.82; 95% CI, 0.75-0.90; P < 0.0001).24 This was driven primarily by decreases in heart failure hospitalizations (21% vs. 16% placebo; HR, 0.74; 95% CI, 0.66-0.83).24 The use of ivabradine was associated with a higher incidence of symptomatic bradycardia (5% vs. 1% placebo; P < 0.0001) and transient visual blurring (3% vs. 1% placebo; P < 0.0001).24 Adjunctive use of ivabradine is recommended for patients with HFrEF (EF  35%) in sinus rhythm who have resting heart rates greater than 70 bpm while on GDMT, including the maximal tolerated doses of a beta-blocker.2 Heart rate should be reassessed after two to four weeks of initiation of or titration of therapy. The starting dose in patients younger than age 75 years is 5 mg twice daily with food. If the heart rate still is more than 60 bpm in two to four weeks, then the dose could be increased by 2.5 mg twice daily to a maximum dose of 7.5 mg twice daily. The heart rate should be monitored after each increase in dose. Dose reduction is necessitated if the heart rate goes below 50 bpm. Discontinuation of the medication is recommended if the heart rate is less than 50 bpm at the 2.5 mg twice daily with food dose. For patients older than age 75 years, the starting dose is 2.5 mg twice daily with food.

Soluble Guanylate Cyclase Stimulators

Soluble guanylate cyclase (sGC) stimulators modulate the nitric oxide-soluble guanylate cyclase pathway through production of the second messenger cyclic guanosine monophosphate and were first approved for use in pulmonary arterial hypertension.52 Activation of sGC by its endogenous ligand nitric oxide results in the generation of cyclic guanosine monophosphate (cGMP), which modulates cardiovascular function through the downstream effects of vasodilation, inhibition of smooth muscle proliferation, platelet aggregation, leukocyte recruitment, and reversal of vascular remodeling.53 In HFrEF, endothelial dysfunction and oxidative stress cause decreased bioavailability of nitric oxide and relative deficiency of sGC, leading to decreased cGMP production.54 Vericiguat stimulates sGC through a nitric oxide independent binding site and sensitizes it to endogenous nitric oxide, leading to increased cGMP production.55 The Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) assessed the effects of adding vericiguat, a novel sGC stimulator, to GDMT in patients with NYHA class II-IV heart failure and EF < 45% after recent hospitalization or use of intravenous diuretics.27 The incidence of the composite outcome of cardiovascular death or first hospitalization for heart failure was lower in the vericiguat group compared to placebo (35.5% vs. 38.5% placebo; HR, 0.90; 95% CI, 0.82-0.98; P = 0.02).27 Adverse events, including symptomatic hypotension (9.1% vs. 7.9%, P = 0.12) and syncope (4.0% vs. 3.5%, P = 0.13), were more common than placebo in the vericiguat group. Vericiguat was approved recently by the Food and Drug Administration (FDA) for the treatment of patients with heart failure and EF < 45% to reduce the risk of cardiovascular death and heart failure hospitalization after recent hospitalization or the need for outpatient intravenous diuretics.

Cardiac Myosin Activators

Selective cardiac myosin activators improve myocardial contractility and function by enhancing myosin-actin cross-bridges within cardiomyocytes.56 Unlike previously studied inotropes, this class of pharmaceutical products was demonstrated to increase the duration of cardiac systole and ejection fraction.56 The addition of omecamtiv mecarbil, a selective cardiac myosin activator, to GDMT in patients with symptomatic heart failure and EF < 35% was associated with a lower incidence of a composite outcome of a heart failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes compared to placebo (37.0% vs. 39.1% placebo; HR, 0.92; 95% CI, 0.86-0.99; P = 0.03). There was no difference in heart failure symptoms, and there was a nonsignificant trend toward increased mortality in the omecamtiv mecarbil group compared to placebo (19.6 vs. 19.4 placebo; HR, 1.01; 95% CI, 0.92-1.11).57 Omecamtiv mecarbil has not yet been approved for use in HFrEF.

Drug Selection in HFrEF

New advances in HFrEF pharmacotherapy inspire hope, but also make management of HFrEF more complex. A lack of both direct incremental and head-to-head clinical trials to compare the performance of currently available HFrEF disease-modifying agents against each other complicates the medical management of HFrEF. Increasingly, clinicians must contend with the question of what therapeutic agent to prioritize and what sequence to follow to achieve optimal GDMT. Expert consensus pathways suggest a multipronged approach. Individual patient factors, including clinical context, comorbidities, race, sex, age, frailty, and socioeconomic factors, including insurance and access, can help inform drug selection. Consideration also must be given to the unique adverse effects profile of each therapeutic agent to allow for tailored therapy where GDMT-limiting adverse effects may arise. (See Table 2.) Although it is challenging, and not pragmatic enough to apply universally, therapeutic agents must be used in tandem with the clinical trial inclusion and exclusion criteria.

Table 2. Common Disease-Modifying Therapeutic Agents in HFrEF

Drug Class

Dosage

Potential Drug Class Adverse Effects

Angiotensin II Converting-Enzyme Inhibitors (ACEIs)

Captopril

6.25 mg to 50 mg tid

Hypotension, renal dysfunction, hyperkalemia, ACEI-induced dry cough, angioedema

Enalapril

2.5 mg to 20 mg bid

Fosinopril

5 mg to 40 mg qd

Lisinopril

2.5 mg to 40 mg qd

Perindopril

2 mg to 16 mg qd

Quinapril

5 mg to 20 mg bid

Ramipril

1.25 mg to 10 mg qd

Trandolapril

1 mg to 4 mg qd

Angiotensin II Receptor Blockers

Candesartan

4 mg to 32 mg qd

Hypotension, renal dysfunction, hyperkalemia, cough

Losartan

25 mg to 150 mg qd

Valsartan

20 mg to 160 mg bid

Evidence-Based Beta-Adrenoceptor Blockers

Bisoprolol

1.25 mg to 10 mg qd

Sinus bradycardia, atrioventricular blockade, hypotension, worsening heart failure

Carvedilol/Carvedilol CR

3.125 mg to 50 mg bid/10 mg to 80 mg qd

Metoprolol succinate

12.5 mg to 200 mg qd

Mineralocorticoid Receptor Antagonistsa

Spironolactone22

12.5 mg to 50 mg qd

Renal dysfunction, hyperkalemia, gynecomastia (spironolactone)

Eplerenone35

25 mg to 50 mg qd

Combination Vasodilator Therapy

Hydralazine/isosorbide
dinitrate23

37.7 mg/20 mg to 75 mg/40 mg tid

Hypotension, dizziness, headaches, tachycardia, drug-induced lupus

Sodium/Potassium If Channel Blocker

Ivabradine24

5 mg to 7.5 mg bid

Symptomatic bradycardia, QT prolongation, transient visual blurring

Angiotensin II Receptor-Neprilysin Inhibitorsb

Sacubitril/valsartan25

24 mg/26 mg to 97 mg/103 mg bid

Hypotension, angioedema, hyperkalemia, renal dysfunction

Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitorsc

Dapagliflozin3

10 mg qd*

Volume depletion, euglycemic diabetic ketoacidosis, limb amputations, mycotic urinary tract infections, Fournier’s gangrene

Empagliflozin26

10 mg qd*

Soluble Guanylate Cyclase Stimulatorsn

Vericiguat27

2.5 mg starting dose; 2.5 mg to 10 mg qd*

Symptomatic hypotension, syncope, anemia, renal dysfunction

Cardiac Myosin Activatorsn

Omecamtiv mecarbil57**

25 mg to 50 mg bid

Elevated troponin, potential for myocardial ischemia at higher doses

HFrEF: heart failure with reduced ejection fraction; qd: once daily; bid: twice daily; tid: three times daily

a contraindicated in patients with creatinine > 2.5 mg/dL and/or eGFR < 30 mL/min/1.73m2; b high risk of angioedema with concomitant ACEI use — a washout period of 36 hours must be observed, and smaller starting doses of ARNI used when initiating therapy in patients on low-dose ACEI therapy; c caution must be exercised with initiation of dapagliflozin and empagliflozin in HFrEF and eGFR ≤ 30mL/min/1.73m2 and ≤ 20 mL/min/1.73m2, respectively; n novel therapy; * target doses in drug trial; ** product does not have an expected release to market date

Comprehensive (quadruple) GDMT must be initiated immediately when a patient is diagnosed with HFrEF and optimized over two weekly intervals to clinical trial dosages or maximal tolerated dosages.4 Predischarge initiation of GDMT promotes the uptake and retention of GDMT, although one must consider the clinical context, including the existence of congestive symptoms, hypotension, and renal dysfunction. Small drug dosages at initiation of therapy and gradual up-titration to target clinical trial or maximally tolerated dosages may be more practical and tolerable in patients, such as the elderly, in whom hypotension, renal dysfunction, and frailty commonly accompany HFrEF. A multidisciplinary team approach to the management of HFrEF and a timely referral of HFrEF patients to advanced heart failure cardiologists can help mitigate the challenge of managing a rapidly changing landscape of HFrEF pharmacotherapy and potentially help clinical outcomes.4

Summary

There is a rapid evolution in the landscape of disease-modifying pharmacotherapies in HFrEF. However, adoption and uptake of these evidence-based therapies has been and remains low.

There is a need for clinicians to evolve with these rapidly changing times and champion the implementation of new scientific evidence to improve clinical outcomes in patients with HFrEF.

References

  1. 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-e596.
  2. 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-e161.
  3. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008.
  4. Writing Committee; Maddox TM, Januzzi JL Jr, 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; Jan 4. doi:10.1016/j.jacc.2020.11.022. [Online ahead of print].
  5. Greene SJ, Fonarow GC, Butler J. Risk profiles in heart failure: Baseline, residual, worsening, and advanced heart failure risk. Circ Heart Fail 2020;13:e007132.
  6. Vaduganathan M, Claggett BL, Jhund PS, et al. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: A comparative analysis of three randomised controlled trials. Lancet 2020;396:121-128.
  7. SOLVD Investigators; Yusuf S, Pitt B, Davis CE, et al. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293-302.
  8. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996;334:1349-1355.
  9. Butler J, Anstrom KJ, Felker GM, et al. Efficacy and safety of spironolactone in acute heart failure: The ATHENA-HF randomized clinical trial. JAMA Cardiol 2017;2:950-958.
  10. Hall SA, Cigarroa CG, Marcoux L, et al. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade. J Am Coll Cardiol 1995;25:1154-1161.
  11. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129-2200.
  12. Adamo L, Yu J, Rocha-Resende C, et al. Proteomic signatures of heart failure in relation to left ventricular ejection fraction. J Am Coll Cardiol 2020;76:1982-1994.
  13. Liu PP, Al-Khalaf M, Blet A. Time to reframe ejection fraction in light of new pathophysiological insights into heart failure. J Am Coll Cardiol 2020;76:1995-1998.
  14. Solomon SD, Vaduganathan M, Claggett BL, et al. Sacubitril/valsartan across the spectrum of ejection fraction in heart failure. Circulation 2020;141:352-361.
  15. Seferovic PM, Ponikowski P, Anker SD, et al. Clinical practice update on heart failure 2019: Pharmacotherapy, procedures, devices and patient management. An expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology. Eur Heart J Fail 2019;21:1169-1186.
  16. Bhatt AS, Abraham WT, Lindenfeld J, et al. Treatment of HF in an era of multiple therapies: Statement from the HF Collaboratory. JACC Heart Fail 2021;9:1-12.
  17. Bristow MR, Kao DP, Breathett KK, et al. Structural and functional phenotyping of the failing heart: Is the left ventricular ejection fraction obsolete? JACC Heart Fail 2017;5:772-781.
  18. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314:1547-1552.
  19. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429-1435.
  20. Konstam MA, Neaton JD, Poole-Wilson PA, et al. Comparison of losartan and captopril on heart failure-related outcomes and symptoms from the losartan heart failure survival study (ELITE II). Am Heart J 2005;150:123-131.
  21. [No authors listed]. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in-Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001-2007.
  22. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-717.
  23. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351:2049-2057.
  24. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study. Lancet 2010;376:875-885.
  25. McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.
  26. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413-1424.
  27. Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in patients with heart failure and reduced ejection fraction. N Engl J Med 2020;382:1883-1893.
  28. Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation 1999;100:2312-2318.
  29. Sanam K, Bhatia V, Bajaj NS, et al. Renin-angiotensin system inhibition and lower 30-day all-cause readmission in Medicare beneficiaries with heart failure. Am J Med 2016;129:1067-1073.
  30. Bristow MR. Beta-adrenergic receptor blockade in chronic heart failure. Circulation 2000;101:558-569.
  31. [No authors listed]. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomised trial. Lancet 1999;353:9-13.
  32. 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;72:351-366.
  33. Gattis WA, O’Connor CM, Gallup DS, et al. Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure: Results of the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) trial. J Am Coll Cardiol 2004;43:1534-1541.
  34. Fonarow GC, Abraham WT, Albert NM, et al. Carvedilol use at discharge in patients hospitalized for heart failure is associated with improved survival: An analysis from Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF). Am Heart J 2007;153:82.e1-82.e11.
  35. Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11-21.
  36. Hernandez AF, Mi X, Hammill BG, et al. Associations between aldosterone antagonist therapy and risks of mortality and readmission among patients with heart failure and reduced ejection fraction. JAMA 2012;308:2097-2107.
  37. Sharma R, Davidoff MN. Oxidative stress and endothelial dysfunction in heart failure. Congest Heart Fail 2002;8:165-172.
  38. Januzzi JL, Prescott MF, Butler J, et al. Association of change in N-terminal pro-B-type natriuretic peptide following initiation of sacubitril-valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction. JAMA 2019;322:1-11.
  39. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med 2019;380:539-548.
  40. Wachter R, Senni M, Belohlavek J, et al. Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: Primary results of the randomised TRANSITION study. Eur Heart J Fail 2019;21:998-1007.
  41. Pascual-Figal D, Wachter R, Senni M, et al. NT-proBNP response to sacubitril/valsartan in hospitalized heart failure patients with reduced ejection fraction: TRANSITION Study. JACC Heart Fail 2020;8:822-833.
  42. Desai AS, Vardeny O, Claggett B, et al. Reduced risk of hyperkalemia during treatment of heart failure with mineralocorticoid receptor antagonists by use of sacubitril/valsartan compared with enalapril: A secondary analysis of the PARADIGM-HF trial. JAMA Cardiol 2017;2:79-85.
  43. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: A systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31-39.
  44. 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;75:422-434.
  45. Hallow KM, Helmlinger G, Greasley PJ, et al. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metab 2018;20:479-487.
  46. Hillege HL, Nitsch D, Pfeffer MA, et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation 2006;113:671-678.
  47. Nassif ME, Windsor SL, Tang F, et al. Dapagliflozin effects on biomarkers, symptoms, and functional status in patients with heart failure with reduced ejection fraction: The DEFINE-HF trial. Circulation 2019;140:1463-1476.
  48. 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;396:819-829.
  49. Johansen ME, Argyropoulos C. The cardiovascular outcomes, heart failure and kidney disease trials tell that the time to use sodium glucose cotransporter 2 inhibitors is now. Clinical Cardiol 2020;43:1376-1387.
  50. Li SJ, Sartipy U, Lund LH, et al. Prognostic significance of resting heart rate and use of β-blockers in atrial fibrillation and sinus rhythm in patients with heart failure and reduced ejection fraction: Findings from the Swedish Heart Failure Registry. Circ Heart Fail 2015;8:871-879.
  51. McAlister FA, Wiebe N, Ezekowitz JA, et al. Meta-analysis: Beta-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med 2009;150:784-794.
  52. Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369:330-340.
  53. Derbyshire ER, Marletta MA. Structure and regulation of soluble guanylate cyclase. Annu Rev Biochem 2012;81:533-559.
  54. Follmann M, Ackerstaff J, Redlich G, et al. Discovery of the soluble guanylate cyclase stimulator vericiguat (BAY 1021189) for the treatment of chronic heart failure. J Med Chem 2017;60:5146-5161.
  55. Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation 2011;123:2263-2273.
  56. Cleland JG, Teerlink JR, Senior R, et al. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: A double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet 2011;378:676-683.
  57. Teerlink JR, Diaz R, Felker GM, et al. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N Engl J Med 2021;384:105-116.