Table 1.

Modes of action of currently available therapies for HFrEF

	Drugs with proven morbidity or mortality benefit						Drugs with symptomatic benefit but no proven mortality benefit
Class/ molecular mode of action	Angiotensin‐converting enzyme inhibitors	Angiotensin II receptor type 1 antagonists	Beta‐1‐adrenoceptor antagonists/ blockers	Mineralo‐corticoid receptor antagonists	Angiotensin receptor‐neprilysin (neutral endopeptidase) inhibitor	Combination of isosorbide dinitrate (ISDN) and hydralazinea	Na+/K+ ATPase inhibitors	Inhibition of water/sodium reabsorption in the kidney	Organic nitric oxide donors	If blockers
Class short name	ACEI	AT1‐RA/ ARB	BB	MRA	ARNI	Nitrate plus direct arterial vasodilator	Digitalis	Natriuretics/ Diuretics	Nitrates	Selective sinus node inhibitor
Postulated mechanism in HF	Inhibition of the detrimental long‐term effects of RAAS activation	Blockade of detrimental long‐term effects of elevated angiotensin II levels	Reduced sympathetic nervous system activity, reduced renin production and release	Synergistic hemodynamic and natriuretic effects with ACEIs, reduced RAAS effects via reduction of tissue ACE activity and the AT1 receptor density	Simultaneous inhibition of angiotensin II via AT1 blockade and increase of beneficial vasoactive substrates including NPs via inhibition of neprilysin	Combination of preferential venous pooling with subsequent pre‐load reduction through ISDN and afterload reduction via direct vasodilation through hydralazine	Positive inotrope through increase of intracellular Ca2+ in cardiomyocytes	Increased excretion of sodium and water to reduce congestion and decrease preload to heart	Increased availability of NO, leads to afterload and preferential preload reduction, venous pooling to reduce congestion and volume overload of the heart	Inhibition of a selective sinoatrial pacemaker current reduces heart rate
Examples	Captopril, Enalapril, Lisinopril, Ramipril	Losartan, Olmesartan, Candesartan, Valsartan	Metoprolol, Bisoprolol, Nebivolol, Carvedilol	Spironolactone Eplerenone	Sacubitril/ valsartan	BiDila	Digoxin, Digitoxin	Furosemide Torasemide, Hydrochloro‐thiazide, Indapamide	Glyceryl trinitrate, Isosorbide‐mononitrate	Ivabradine

ACE, angiotensin converting enzyme; ACEI, angiotensin converting enzyme inhibitor; ARNI, angiotensin receptor‐neprilysin inhibitor; ATI, angiotensin II receptor type 1; BB, beta‐blockers; HFrEF, heart failure and reduced ejection fraction; MRA, mineralocorticoid receptor antagonist; NO, nitric oxide; NP, natriuretic peptide; RA/ARB, renin‐angiotensin/angiotensin receptor blocker; RAAS: renin‐angiotensin‐aldosterone system; NEP, neutral endopeptidase/neprilysin.

^aEfficacy demonstrated for self‐identified African‐Americans in the A‐HeFT study.34