Diagnosis and treatment of heart failure with preserved left ventricular ejection fraction

Table 6 Pharmacologic studies in heart failure with preserved ejection fraction

Ref.	Drug vs control	Drug half-life hours	Number patients	Duration	LVEF	Results
Beta-blockers
Swedish Heart Failure Registry[81]	All BBs (prescribed at discharge	6-h Atenolol; 12-19 h Nevibolol	8244	755 d	LVEF 49%-50% and LVEF > 50%	β-blockers decreased mortality but not combined all-cause mortality or hospitalizations
SWEDIC Trial[82]	Carvedilol	6-10 h	97	6 mo	LVEF ≥ 40%	E/A ratio improved but no other measures of diastolic function
J-DHF Trial[83]	Carvedilol	6-10 h	245	38 mo	LVEF ≥ 40%	Standard dose, but not low dose, carvedilol reduced; CV mortality and hospitalizations
COHERE Registry[84]	Carvedilol	6-10 h	4280	12 mo	LVEF > 40%	Carvedilol had no mortality benefit but decreased hospitalization
SENIORS[85,86]	Nebivolol	2.5-20 h	643	21 mo	LVEF > 35%	Nebivolol did not decrease CV hospitalizations or mortality
ELANDD Trial[87]	Nebivolol	2.5-20 h	116	21 mo	LVEF ≥ 45%	Nebivolol did not increase exercise capacity
CIBIS-ELD Trial[88]	Bisoprolol vs Carvedilol	9-12 vs 6-10 h	250	3 mo	LVEF ≥ 45%	Bisoprolol and carvedilol had no effect on established and prognostic markers of diastolic function
El-Refai et al[89]	Beta Blocker (bisoprolol, carvedilol, metoprolol, labetalol, and atenolol)	6-7 h (Atenolol); 9-12 h (Bisoprolol)	741	25 mo	LVEF ≥ 50%	Beta blockers decreased mortality and HF rehospitalizations
β-PRESERVE[90]	Metoprolol succinate vs control	3-9 h	1200	24 mo	LVEF ≥ 50%	Trial Results not available
OPTIMIZE-HF[91]	All BBs (prescribed at discharge)	6-7 h Atenolol 12-19 h Nebivolol	21149	3 mo	LVEF 40%-49% and ≥ 50%	Beta blockers had no effect on mortality and rehospitalization
Calcium channel blockers
Setaro et al[92]	Verapamil vs placebo	4.5-12 h	20	1 mo	LVEF ≥ 45%	Verapamil increased exercise capacity clinicoradio-graphic score. No change in LVEF.
Hung et al[93]	Verapamil vs placebo	4.5-12 h	15	3 mo	Normal LVEF	Verapamil increased exercise time and LV diastolic function
ACE inhibitors
Aronow et al[94]	Enalapril vs control (diuretics alone)	11 h	21	3 mo	LVEF ≥ 50%	Enalapril increased exercise time and LVEF
PEP-CHF trial[95]	ACE inhibitor (perindopril) vs placebo	3-10 h with prolonged terminal elimination	207	12 mo	LVEF ≥ 45%	Perindopril increased 6 min walk distance but did not decrease mortality
Angiotensin II receptor blockers
I-PRESERVE[96]	Irbesartan vs placebo	11-15 h	4563	24 mo	LVEF ≥ 45%	No decrease in hospitalization or mortality
CHARM-Preserved[97]	Candesartan vs control medication (ACE Inhibitor, BB, CCB)	9 h	3023	37 mo	LVEF ≥ 40%	Candesartan slightly decreased hospitalizations but did not decrease mortality
Angiotensin receptor blocker/nephrilysin inhibitors
PARAMOUNT Trial[98]	Sacubitril/valsartan vs valsartan	11.5 h	301	3 and 8-9 mo	LVEF ≥ 45%	Sacubiril Valsartan reduced NT-proBNP
PARAGON-HF Governmental Trial NCT01920711	Sacubitril/valsartan vs valsartan	11.5	4300	57 mo	LVEF ≥ 45%	Sacubitril/valsartan not superior to valsartan alone in decreasing hospitalization or cardiovascular mortality
Ivabradine
Kosmala et al[99]	Ivabradine vs placebo	11 h	61	7 d	LVEF ≥ 50%	Ivabradine increased exercise time, peak oxygen uptake, and decreased E/e’
EDIFY trial[100]	Ivabradine vs placebo	11 h	179	8 mo	LVEF ≥ 45%	No improvement in 6 min walk, E/e’, or NT-proBNP
Statins
Fukuta et al[101]	Standard HF therapy with a statin vs without a statin	2 h (lovastatin)-19 h (rosuvastatin)	137	21 mo	LVEF ≥ 50%	Statin therapy associated with reduced mortality
Ouzounian et al[102]	Standard HF therapy with a statin vs without a statin	2 h (lovastatin)-19 h (rosuvastatin)	6451	38 mo	LVEF ≥ 50%	Statins did not decrease morbidity or mortality in patients with HF without CAD
Animal model of heart ailure (rats)[103]	Standard HF therapy with rosuvastatin vs without rosuvastatin	19 h	46	19 mo	Preserved EF	Statins had no benefit
Digoxin
(DIG) trial[104]	Digoxin vs placebo	36-48 h	988	37 mo	LVEF ≥ 45%	Digoxin had no effect on all-cause and CV mortality, heart failure hospitalizations
Phosphodiesterase-5 inhibitors
RELAX trial[105]	Sildenafil vs placebo	3-4 h	216	24 mo	LVEF ≥ 50%	No improvement in 6 min walk distance, clinical status, or peak O2 consumption
Nitrates
NEAT-HFpEF trial[106]	Isosorbide mononitrate vs placebo	2.5-5.1 h	110	22 mo	LVEF ≥ 50%	No improvement in 6 min walk distance or NT-proBNP
INDIE-HFpEF[107,108]	Inhaled inorganic nitrite vs placebo	0.7 h	105	4 wk	LVEF ≥ 50%	No significant improvement in exercise tolerance, NY Heart Association Class, E/e’, NT-proBNP
Governmental trial NCT02840799	Oral KNO3 vs KCL	1.2 h	26	1 mo	LVEF ≥ 50%	KNO3 trial is in progress

LVEF: Left ventricular ejection fractions; HF: Heart failure; EF: Ejection fraction.