Table 2. Characteristics, inclusion criteria, and efficacy of major trials of HFsrEF.

Characteristics	Inclusion/exclusion criteria									Events
Class of drug	Name of trial	Drug name	Number of patient	EF (%)	SBP (mmHg)	HR (bpm)	Cr (mg/dL)	eGFR (mL/min)	K (meq/L)	All-cause death	CV death + HHF	CV death	HHF
Foundational therapy
ACEI	CONSENSUS33	Enalapril	253	NR	NR	NR	≤ 3.7	NR	NR	↓	NR	↓	NR
	SOLVD34	Enalapril	2569	≤ 35	NR	NR	≤ 2	NR	NR	↓	↓	↓	↓
ARB	Val-HeFT39	Valsartan	5010	≤ 40	≥ 90	NR	≤ 2.5	NR	NR	↔	↓	↔	↓
	CHARM-Alternative40	Candesartan	2028	≤ 40	NR	NR	< 3	NR	< 5.5	↔	↓	↓	↓
BB	US Carvedilol49	Carvedilol	1094	≤ 35	≥ 85	≥ 68	NR	NR	NR	↓	↓	↓	↓
	MERIT-HF3	Metoprolol succinate	3991	≤ 40	≥ 100	≥ 68	NR	NR	NR	↓	↓	↓	↓
	CIBIS-II51	Bisoprolol	2647	≤ 35	≥ 100	≥ 60	NR	NR	NR	↓	↓	↓	↓
	COPERNICUS50	Carvedilol	2289	≤ 25	≥ 85	≥ 68	≤ 2.8	NR	3.5-5.2	↓	↓	↓	↓
	SENIORS52	Nebivolol	2128	≤ 35	≥ 90	≥ 60	NR	NR	NR	↔	↓	↔	↔
MRA	RALES4	Spironolactone	1663	≤ 35	NR	NR	≤ 2.5	NR	≤ 5	↓	↓	↓	↓
	EMPHASIS-HF55	Eplerenone	2737	≤ 35	NR	NR	NR	≥ 30	≤ 5	↓	↓	↓	↓
ARNI	PARADIGM-HF6	Sacubitril/valsartan	8442	≤ 40	≥ 100	NR	NR	≥ 30	≤ 5.2	↓	↓	↓	↓
SGLT2 i	DAPA-HF7	Dapagliflozin	4744	≤ 40	≥ 95	NR	NR	≥ 30	NR	↓	↓	↓	↓
	EMPEROR-Reduced8	Empagliflozin	3730	≤ 40	≥ 100	NR	NR	≥ 20	NR	↔	↓	↔	↓
	SOLOIST-WHF9	Sotagliflozin	1222	NL	≥ 100	NR	NR	≥ 30	NR	↔	↓	↔	↓
Additional therapy
Digoxin	DIG72	Digoxin	6800	≤ 45	NR	NR	NR	NR	NR	↔	NR	↔	↓
Vasodilator	V-HeFT I76	Hydralazine/isosorbide dinitrate	642	< 45	NR	NR	NR	NR	NR	↓	NR	NR	NR
	A-HeFT78	Isosorbide/hydralazine	1050	≤ 35	NR	NR	NR	NR	NR	↓	NR	NR	↓
Sinus node inhibitor	SHIFT79	Ivabradine	6558	≤ 35	≥ 85	≥ 70	NR	NR	NR	↔	↓	↔	↓
sGC stimulator	VICTORIA10	Vericiguat	5050	≤ 45	≥ 100	NR	NR	≥ 15	NR	↔	↓	↔	↓

ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; BB, beta-blocker; bpm, beat per minute; Cr, serum creatinine; CV, cardiovascular; EF, ejection fraction; eGFR, estimated glomerular filtration rate; HFsrEF, heart failure with severely reduced ejection fraction; HHF, heart failure hospitalization; HR, heart rate; K, potassium; MRA, mineralocorticoid receptor antagonist; NL, no limit; NR, not reported; SBP, systolic blood pressure; sGC, soluble guanylate cyclase; SGLT2 i, sodium-glucose co-transporter 2 inhibitor.