Table 1.

Trials of pharmacotherapies in HFpEF

Study	Year, size, and population	Randomization (study arms)	Median follow‐up	Primary outcomes	Results a
CHARM‐Preserved Yusuf et al. 29	2003 N = 3023, HFpEF	Candesartan vs. placebo	36.6 months	CVD death or HF hospitalization	HR 0·86 (0·74–1·00) P = 0.051
SENIORS Flather et al. 30	2005 N = 2128, HFpEF	Nebivolol vs. placebo	21 months	‐ All‐cause mortality or CVD hospitalization ‐ All‐cause mortality	‐ HR 0.86 (0.74–0.99) P = 0.039 ‐ HR 0.88 (0.71–1.08) P = 0.21
PEP‐CHF Cleland et al. 31	2006 N = 850, HFpEF	Perindopril vs. placebo	2.1 years	All‐cause mortality and HF hospitalization	HR 0.919 (0.700–1.208) P = 0.545
DIG ancillary trial Ahmed et al. 32	2006 N = 988, HFpEF	Digoxin vs. placebo	37 months	HF hospitalization or HF mortality	HR 0.82 (0.63–1.07) P = 0.136
I‐PRESERVE Massie et al. 33	2008 N = 4128, HFpEF	Irbesartan vs. placebo	49.5 months	All‐cause mortality or CVD hospitalization	HR 0.95 (0.86–1.050) P = 0.35
HK‐DHF Yip et al. 34	2008 N = 150, HFpEF	Diuretics alone vs. diuretics plus irbesartan vs. diuretics plus ramipril	1 year	Recurrent hospitalization	Rates were similar in all groups (12.2%, 11.1%, 11.4%)
ALL‐HAT Grimm et al. 35	2009 N = 1479 with heart failure (LVEF >35%)	‐ Lisinopril vs. chlorthalidone ‐ Amlodipine vs. chlorthalidone ‐ Doxazosin vs. chlorthalidone	1 year	HF hospitalization	‐ OR 1.33 (0.65–2.74) P =0.44 ‐ OR 1.08 (0.53–2.21) P =0.83 ‐ OR 1.33 (0.65–2.74) P =0.44
J‐DHF Yamamoto et al. 36	2013 N = 245, HFpEF	Carvedilol vs. no carvedilol	3.2 years	CVD death and HF hospitalization	HR 0.902 (0.546–1.48) P = 0.6854
RELAX Redfield et al. 37	2013 N = 216, HFpEF	Sildenafil vs. placebo	24 weeks	‐ Changes in VO2 max ‐ Changes in 6MWT distance	‐ Changes in VO2 max P =0.90 ‐ Changes 6MWT P = 0.92
Aldo‐DHF Edelmann et al. 38	2013 N = 422, HFpEF	Spironolactone vs. placebo	12 months	‐ Diastolic function (E/e′) ‐ Peak VO2 (mL/min/kg)	‐ −1.5 (−2.0 to −0.9) P = 0.001 ‐ +0.1 (−0.6 to +0.8) P =0.8.
TOPCAT Pitt et al. 39	2014 N = 3445, HFpEF	Spironolactone vs. placebo	3.3 years	CVD death, aborted SCA, or HF hospitalization	HR 0.89 (0.77–1.04) P = 0.14
EMPA‐REG OUTCOME Zinman et al. 50	2015 N = 7020 (T2DM + CVD risk)	Empagliflozin vs. placebo	3.1 years	CVD death, non‐fatal MI or non‐fatal stroke	HR 0.86 (0.74–0.99) P = 0.04 for superiority
Meta‐analysis Bavishi et al. 48	2015 N = 27 099 (17 studies), HFpEF	Beta‐blocker vs. placebo/no beta‐blocker	At least 1 year	Observational studies: ‐ All‐cause mortality ‐ HF hospitalization	‐ RR 0.81 (0.72–0.90) P < 0.001 ‐ RR 0.79 (0.57–1.10) P > 0.05
				RCTs only: ‐ All‐cause mortality ‐ HF hospitalization	‐ RR 0.94 (0.67–1.32) P = 0.72 ‐ RR 0.90 (0.54–1.49) P = 0.68
Meta‐analysis Khan et al. 40	2017 N = 17 284 (13 studies), HFpEF	ACEI or ARB vs. placebo or standard therapy	24.8 months	All‐cause mortality ‐RCTs only ‐Observational studies	‐ RR 1.02 (0.93–1.11) P = 0.68 ‐ RR 0.91 (0.87–0.95) P = 0.005
Meta‐analysis Zheng et al. 41	2017 N = 18 101 (25 RCTs), HFpEF	‐ Beta‐blocker vs. placebo ‐ ACE‐Is vs. placebo ‐ ARBs vs. placebo ‐ MRA vs. placebo	‐	All‐cause mortality	‐ RR: 0.78 (0.65–0.94) P = 0.008 ‐ RR: 1.10 (0.85–1.43) P = 0.46 ‐ RR: 1.02 (0.93–1.12) P = 0.71 ‐ RR: 0.92 (0.79–1.08) P = 0.32
CANVAS trials Neal et al. 51	2017 N = 10 142 (T2DM + CVD risk)	Canagliflozin vs. placebo	188.2 weeks	CVD death, non‐fatal MI or non‐fatal stroke	HR 0.86 (0.75–0.97) P < 0.001 (non‐inferiority); P = 0.02 (superiority)
PARAGON‐HF Solomon et al. 42	2019 N = 4822, HFpEF	Sacubitril–valsartan vs. valsartan	35 months	HF hospitalization and CVD death	Rate ratio 0.87 (0.75–1.01) P = 0.06
DECLARE‐TIMI 58 Wiviott et al. 52	2019 N = 17 160, T2DM + CVD risk (HF N = 1724)	Dapagliflozin or placebo	4.2 years	‐ MACE ‐ CVD death or HF hospitalization	‐ Dapagliflozin non‐inferior to placebo (P < 0.001) ‐ HR 0.83 (0.73–0.95) P = 0.005
VITALITY‐HFpEF Armstrong et al. 64	2020 N = 789, HFpEF	Vericiguat 15 and 10 mg/d vs. placebo	24 weeks	‐ KCCQ PLS least‐squares mean difference ‐ 6‐MW distance mean scores	‐ Vericiguat 15 and 10 mg/d vs. placebo (P = 0.47 and P = 0.80) ‐ P = 0.45 (15 mg/d) and P = 0.81 (10 mg/d)
SOLOIST‐WHF Bhatt DL et al. 59	2021 N = 1222 (T2DM + HF) (LVEF ≥50%, N = 256 patients)	Sotagliflozin vs. placebo	9.0 months	CVD death, HF hospitalization or urgent visit	‐ All patients: HR 0.67 (0.52–0.85) P < 0.001 ‐ LVEF ≥50%: HR 0.48 (0.27–0.86)
SCORED Bhatt et al. 60	2021 N = 10 584 (T2DM + CKD + CVD risk); (HF N = 3283, LVEF ≥50%, N = 1667)	Sotagliflozin vs. placebo	16 months	CVD death, HF hospitalization or urgent visit	‐ All patients: HR 0.74 (0.63–0.88) P < 0.001 ‐ LVEF ≥50%: HR 0.72 (0.52–0.99)
Pooled data SOLOIST‐WHF and SCORED, presented at ESC 2021 Bhatt 59 , 60	2021 N = 11 784	Sotagliflozin vs. placebo	24 months	CVD death, HF hospitalization or urgent visit	HFpEF: HR 0.73 (0.45–0.89) P = 0.009 All patients: HR 0.72 (0.63–0.82) P = 0.000002
EMPEROR‐Preserved Anker et al. 57	2021 N = 5988, HFpEF	Empagliflozin (10 mg once daily) vs. placebo	26.2 months	‐ CVD death or HF hospitalization ‐ CVD death ‐ HF hospitalization	‐ HR 0.79 (0.69–0.90) P < 0.001 ‐ HR 0.91 (0.76–.09) ‐ HR 0.73 (0.61–0.88) P < 0.001
NCT03030235 Nassif et al. 65	2021 N = 324, HFpEF	Dapagliflozin or placebo	12 weeks	‐ Improvement in KCCQ‐CS ‐ Improvement 6MWT	‐ Improved KCCQ‐CS (P = 0.001) ‐ Improved 6MWT (P = 0.007)
DELIVER Solomon et al. 58	2022 N = 6263, HFpEF	Dapagliflozin vs. placebo	2.3 years	‐ Worsening HF or CVD death ‐ Worsening HF ‐ CVD death	‐ HR 0.82 (0.73–0.92) P < 0.001 ‐ HR 0.79 (0.69–0.91) ‐ HR 0.88 (0.74–1.05)

6MMT, 6‐min walk test; ACEI, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; CVD, cardiovascular disease; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HR, hazard ratio; KCCQ‐CS, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid antagonist; OR, odds ratio; RR, relative risk; SCA, sudden cardiac arrest; T2DM, type 2 diabetes mellitus.

^a Results are effect size and 95% confidence intervals (in brackets).