. 2023 Dec 4;2(6Part B):101206. doi: 10.1016/j.jscai.2023.101206

Table 1.

A comprehensive summary of the mainstay agents in the treatment of chronic HFrEF, evidenced by a conglomerate of landmark trials and the current clinical practice guideline recommendation.

Drug class	Mechanism of action	Physiologic response	Indication	Landmark RCTs	Pivotal evidence	2022 AHA/ACC/HFSA Class of Recommendation (COR) / Level of Evidence (LOE)
ARNI	Inhibition of angiotensin II receptor type 1 (AT1 receptor) [ARB component] + Inhibition of breakdown of natriuretic peptides [Neprilysin inhibitor component]	↑ Natriuresis, diuresis, and vasodilation ↓ Extracellular fluid ↓ NT-proBNP concentration ACEI/ARB effects as below	• All patients with chronic HFrEF and NYHA II-IV • Preferred over ACEI/ARB; can be started de novo	PARADIGM-HF⁷ PIONEER-HF⁸	Compared to ACEI: • Reduction in composite of CV death or first hospitalization for worsening HF (HR, 0.80; 95% CI, 0.73-0.87; P < .001)⁷ • Reduction in mortality (HR, 0.84; 95% CI, 0.76-0.93; P < .001)⁷ • Reduction in HFH (HR, 0.81; 95% CI, 0.71-0.89; P < .001)⁷ • Reduction in NT-proBNP concentration (Ratio of change 0.71 [95% CI, 0.63-0.81])⁸	COR 1 / LOE A
ACEI	Inhibition of ACE → ↓ conversion of angiotensin I to angiotensin II	↓ Vasoconstriction ↓ Aldosterone secretion → ↓ reabsorption of Na⁺ and water ↓ BP ↑ renal plasma flow → ↓ GFR → ↓ filtration fraction ↓ Afterload ↓ Preload Promote reverse cardiac remodeling	• All patients with chronic HFrEF, NYHA II-IV when ARNI is not feasible	CONSENSUS⁹ SOLVD¹⁰ SOLVD II¹¹	• 40.0% reduction in mortality (52.0% vs 36.0%; P = .002)⁹ • Improvement in NYHA classification in ACEI group⁹ • 16.0% reduction in mortality (39.7% vs 35.2%; P = .004)¹⁰ • 26% reduction in death or HFH (P < .0001)¹⁰ • 36.0% reduction in HFH (18.7% vs 12.9%; P=.001)¹¹	COR 1 / LOE A
ARB	Inhibition of angiotensin II receptor type 1 (AT1 receptor)		• All patients with chronic HFrEF, NYHA II-IV who are intolerant of ACEI due to cough or angioedema and when use of ARNI is not feasible	CHARM-Added¹² Val-HeFT¹³	• Reduction in combined end point of CV death and HFH (HR, 0.85; 95% CI, 0.75-0.96)¹² • 13.2% reduction in combined end point (morbidity & mortality, cardiac arrest, HFH, intravenous inotropic or vasodilator therapy) in ARB group vs placebo (HR, 0.87; 95% CI, 0.77-0.97)¹³	COR 1 / LOE A
BB (bisoprolol, metoprolol succinate, or carvedilol)	Competitively bind to and block β-adrenergic receptors	↓ BP ↓ Heart rate ↓ Cardiac contractility ↓ Myocardial O₂ demand ↑ coronary perfusion Promote reverse cardiac remodeling	• All patients with chronic HFrEF • Should be continued even if asymptomatic or improving symptoms	CIBIS-II¹⁴ MERIT-HF¹⁵ COPERNICUS¹⁶	• Bisoprolol: 31% reduction in combined risk of death or HFH; reduced mortality (HR, 0.66; 95% CI, 0.54-0.81; P < .001); reduction in HFH (HR, 0.64; 95% CI, 0.53-0.79; P < .001)¹⁴ • Metoprolol succinate: 31% reduction in all-cause mortality (7.2% vs 11%; RR, 0.66; 95% CI, 0.53-0.81)¹⁵ • Carvedilol: 35% reduction in all-cause mortality (HR, 0.66; 95% CI, 0.54-0.81); 24.0% reduction in composite of HF death (12.0% vs 15.0%; P < .001)¹⁶	COR 1 / LOE A
MRA	Competitively bind to aldosterone receptors in the late distal convoluted tubule and the collecting duct	↓ Aldosterone effects → ↓ Na⁺ reabsorption and K⁺ excretion ↑ Diuresis Prevent adverse cardiac remodeling	• All patients with chronic HFrEF, NYHA II-IV, if eGFR >30 mL/min/1.73 m² and serum potassium <5.0 mEq/L	RALES¹⁷ EMPHASIS-HF¹⁸	• 30.0% reduction in mortality (RR, 0.70; 95% CI, 0.60-0.82; P < .001)¹⁷ • 35.0% reduction in HF (RR, 0.65; 95% CI, 0.54-0.77; P < .001)¹⁷ • Improved NYHA class (P < .001)¹⁷ • Reduction in composite of mortality and HF (HR, 0.63; 95% CI, 0.54-0.74; P < .001)¹⁸ o Reduction in mortality (HR, 0.76; 95% CI, 0.61-0.93; P = .008)¹⁸ o Reduction in HF (HR, 0.58; 95% CI, 0.47-0.70; P < .001)¹⁸	COR 1 / LOE A
SGLT2i	Reversible inhibition of SGLT2 in the proximal tubule of the kidney	↑ Osmotic diuresis ↑ Natriuresis ↑ Glycosuria and polyuria ↓ BP Improve myocardial contractility	• All patients with symptomatic chronic HFrEF, irrespective of presence of T2DM	DAPA-HF¹⁹ EMPEROR-Reduced²⁰ SOLOIST-WHF²¹	Reduction in primary composite end point of HFH or CV death: • HR, 0.74; 95% CI, 0.65-0.85; P < .001¹⁹ o HF events (HR, 0.70; 95% CI, 0.59-0.83)¹⁹ o CV death (HR, 0.82; 95% CI, 0.69-0.98)¹⁹ • HR, 0.75; 95% CI, 0.65-0.86; P < .001²⁰ o HF events (HR, 0.70; 95% CI, 0.58-0.85)²⁰ • Reduction in composite of CV death and HF events (HR, 0.67; 95% CI, 0.52-0.85; P < .001), benefit retained across HFrEF and HFpEF subgroups²¹	COR 1 / LOE A
Hydralazine-isosorbide dinitrate (H-ISDN)	Increase release of cGMP [Hydralazine] + Increase of nitric oxide [ISDN]	↑ Smooth muscle relaxation → ↑ vasodilation → ↓ preload ↓ Afterload ↓ BP ↓ Myocardial wall tension ↓ Myocardial O₂ demand ↑ Myocardial perfusion	• Self-identified African Americans with NYHA III-IV HFrEF receiving optimal GDMT • In patients with symptomatic HFrEF who cannot be given first-line GDMT due to drug intolerance or renal insufficiency	V-HeFT I²² A-HeFT²³	• 34% decrease in mortality at 2 y²² • 43% reduction in all-cause mortality²³	COR 1 / LOE A: Self-identified African Americans COR 2b / LOE C-LD: Symptomatic HFrEF patients intolerant to first-line GDMT
Ivabradine	Selectively inhibits I_f channel in the pacemaker cells of the SA node → prolongs slow depolarization (phase 4)	↓ Heart rate ↓ Myocardial O₂ demand ↑ Coronary perfusion Lengthen diastole	• All patients with stable chronic HFrEF, NYHA II-III who are receiving GDMT including a maximally tolerated BB and are in NSR with HR ≥70 bpm	SHIFT²⁴	Composite end point of HFH or CV death: • HR, 0.82; 95% CI, 0.75-0.90; P < .0001²⁴	COR 2a / LOR B-R
Soluble guanyl cyclase simulator (vericiguat)	Simulate soluble guanyl cyclase, increasing cGMP production	↑ Smooth muscle relaxation → ↑ vasodilation → ↓ preload ↑ Endothelial function ↓ Cardiac fibrosis Promote reverse cardiac remodeling	• Selected high-risk patients with HFrEF and recent worsening HF on optimal GDMT	VICTORIA²⁵	Composite end point of HFH or CV death: • HR, 0.90; 95% CI, 0.82-0.98²⁵	COR 2b /LOE B-R

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; AT1, angiotensin II receptor type 1; BB, β-blocker; BP, blood pressure; CV, cardiovascular; eGFR, estimated glomerular filtration rate; GDMT, guideline-directed medical therapy; HF, heart failure; HFH, heart failure hospitalization; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; MRA, mineralcorticoid receptor antagonist; NSR, normal sinus rhythm; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; RCT, randomized control trial; RR, relative risk; SGLT2i, sodium-glucose cotransporter 2 inhibitor; T2DM, type 2 diabetes mellitus.