Table 2.

Clinical characteristics of HFpEF in Negative Clinical Trials to Date

First Author/Trial	Japanese-DHF¹²⁶	ELANDD¹²⁷	I-PRESERVE¹²⁹	DIG-PEF⁴³	ALDO-DHF³⁶	RAAM-PEF¹³⁰	RELAX³⁵	TOPCAT^{34, 117}
Intervention	Carvedilol	Nebivolol	Irbesartan	Digoxin	Spironolactone	Eplerenone	Sildenafil	Spironolactone
Sample size	245	116	4128	988	422	44	216	3445
Inclusion Criteria	LVEF > 40%;	LVEF > 45%; diastolic dysfunction by Doppler echo; NYHA class II-III	LVEF > 45%; NYHA II-IV; hospitalization for HF within past 6mo	LVEF > 45%; clinical signs/sx of HF; normal sinus rhythm	LVEF > 50%; NYHA II-III, evidence of diastolic dysfunction	LVEF > 50%, NYHA II-III; elevated BNP	LVEF >50; elevated NT-pro BNP; reduced exercise capacity	LVEF > 45%; controlled HTN (SBP <140mmHg or <160mmHg if on 3+ medication; serum potassium < 5.0mmol; history of hospitalization for HF in past 12 months or elevated BNP/NT-proBNP
Primary Endpoint	Composite CV death and unplanned hospitalization for HF	Change in 6MWT	Composite CV death from any cause or hospitalization for CV cause	Combined HF hospitalization or HF mortality	Changes in diastolic function (E/e’) and max exercise capacity (peak Vo2)	Change in 6MWT	Change in peak oxygen consumption	Composite of death from CV causes, aborted cardiac arrest, or hospitalization for HF
Outcome	Negative	Negative	Negative	Negative	Improved diastolic function; did not improve exercise capacity	Negative	Negative	Negative; lower hospitalization for HF in spironolactone group
One yr survival (%)	Placebo 90^; treatment 90^		Placebo, 90^; treatment 90^	Placebo 77; treatment 77	Placebo 100; treatment >99		6 month survival: Placebo, 100; treatment 97	Placebo >90; treatment >90
Patient Characteristics (means or %)
Age, yr	73	67	72	67	67	72	68	69
Women, %	43	65	59	42	52	5	43	52
Caucasian, %			94	86			90	89
African American, %			2
NYHA Class, %	I (18), II (69), III (11), IV (2)	II (77), III (21)	II (21), III (77), IV (3)	I (19), II (59), III (20), IV (1)	II (85), III (15)	II (67), III (33)	II (49), III (51)	I (3), II (63), III (33), IV (0.4)
Comorbidities
Hypertension, %	80	86	89	62	92	100	80	91
CAD, %	28	17	38	50	43	67	42	59
Diabetes, %	28	21	28	27	61	62	42	32
CKD, %			31	48			56	39
Left ventricular hypertrophy, %							48
Vital signs
SBP, mmHg	134	134	137		135	130	124 (median)	129
DBP, mmHg	75	81	79		79	71		76
Body mass index, kg/m²	24	30	29.7		29	30	33 (median)	32
Admission Data
BNP, pg/mL	219					255		234 (median)
N-terminal pro-BNP, pg/mL			360		179 (median)		757 (median)	950 (median)
Serum creatinine, mg/dl	1.0		1.0			1.6	1.3	1.1
LV mass (g), or LVMI (g/m²)	126 g/m²				108 g/m²	49 g/m^2.7	77 g/m²
Medications
Diuretic, %	63	49	82	82	55	95	88	82
ACE-inhibitor, %	24	75 (ACE-I or ARB)	26	86	78	95 (ACE-I or ARB)	65 (ACE-I or ARB)	65
ARB, %	51							20
Beta-blocker, %			59		69	76	77	78
Digoxin, %	19		14
Aldosterone antagonist, %	21		15				12
Statin, %		46	32		53		63	53

Japanese-DHF: Japanese Diastolic Heart Failure; ELANDD: Effects of Nebivolol on Clinical Symptoms, Exercise Capacity, andLeft ventricular Function in Diastolic Dysfunction; I-PRESERVE: Irbesartan in Heart Failure with Preserved Ejection Fraction; DIG-PEF: Digitalis Intervention Group-Preserved Ejection Fraction; ALDO-DHF: Effect of Spironolactone on Diastolic Function and Exercise Capacity in Heart Failure with Preserved Ejection Fraction; RAAM-PEF: Randomized Aldosterone Antagonism in Heart Failure with Preserved Ejection Fraction; RELAX: Spironolactone for Heart Failure with Preserved Ejection Fraction; TOPCAT: Treatment of Preserved Cardiac Function with an Aldosterone Antagonist; LVEF: left ventricular ejection fraction; HF: heart failure; CV: cardiovascular; NYHA: New York Heart Association; 6MWT: six minute walk test; HTN: hypertension; SBP: systolic blood pressure: BNP: B-type natriuretic peptide; NT-proBNP: N-terminal pro-B-type natriuretic peptide; CAD: coronary artery disease; CKD: chronic kidney disease; ACE-inhibitor: angiotensin converting enzyme-inhibitor; ARB: angiotensin receptor blocker; LVMI: Left ventricular mass index (LV mass/body surface area).

Estimated survival based on Kaplan-Meier curves