V-HeFT II: Vasodilator – Heart Failure Trial

1. V-HeFT II: Vasodilator–Heart Failure Trial Purpose To compare the efficacy of the ACE inhibitor enalapril with that of hydralazine plus isosorbide dinitrate in patients with chronic congestive heart failure Reference Cohn JN, Johnson G, Ziesche S et al. A comparison of enalapril with hydralazine–isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303–10.

2. V-HeFT II: Vasodilator–Heart Failure Trial- TRIAL DESIGN - Design: Multicenter, randomized, double-blind Patients: 804 patients, aged 18–75 years, with evidence of cardiac dysfunction in association with reduced exercise tolerance, receiving digoxin and diuretic therapy; patients with MI in previous 3 months or angina pectoris limiting exercise excluded Follow up and primary endpoint: Primary endpoint: all-cause mortality. Mean 2.5 years follow up. Treatment: Patients randomized to either: • Enalapril 10 mg twice daily, placebo matching hydralazine and placebo matching isosorbide dinitrate, or • Hydralazine 75 mg and isosorbide dinitrate 40 mg, both four times daily, and placebo matching enalapril

3. V-HeFT II: Vasodilator–Heart Failure Trial- RESULTS - • Mortality in enalapril arm, compared with hydralazine–isosorbide: • significantly lower at 2 years (18 vs. 25%, P=0.016) • lower over entire trial period (0.5–5.7 years), but not significantly so (32.8 vs. 38.2%, P=0.08) • differences attributed to significantly fewer sudden deaths • Left ventricular ejection fraction significantly higher in both arms over 3 years (P=0.0001), and significantly more so with hydralazine–isosorbide than with enalapril at 13 weeks (P=0.026) • O2 consumption at peak exercise levels significantly increased above baseline by hydralazine–isosorbide at 13 weeks and 6 months (by 0.6 and 0.8 mL/kg/min, respectively, both P<0.0001) but not by enalapril, declining after 1 year • Incidence of hypotension and cough significantly higher with enalapril; headache significantly higher with hydralazine–isosorbide

4. Enalapril Hydralazine– isosorbide dinitrate V-HeFT II: Vasodilator–Heart Failure Trial- RESULTS continued- Cumulative mortality Cumulative 0.75 mortality 0.50 0.25 0 0 12 24 36 48 60 Months after randomization Cohn et al. N Engl J Med 1991; 325:303–10.

5. Cardiac 112 (85) – 137 (89) – – Sudden, no warning 41 (37) 16 63 (46) 25 0.015 Sudden, with warning 16 (14) 7 29 (21) 12 0.032 Due to pump failure 50 (5) 23 40 (29) 19 0.44 Other or unknown 5 (5) – 5 (4) – – Noncardiac 20 11 16 9 0.63 Cancer 9 – 9 – – V-HeFT II: Vasodilator–Heart Failure Trial- RESULTS continued- Cause of death Hydralazine – isosorbide Enalapril (n=403) dinitrate (n=401) P Deaths Cumulative Deaths Cumulative No. (%)* mortality, % No. (%)* mortality, % All 132 – 153 – 0.08 Other 11 – 7 – – * Percentage of cardiac deaths Cohn et al. N Engl J Med 1991; 325:303–10.

6. V-HeFT II: Vasodilator–Heart Failure Trial- RESULTS continued- Mean change in left ventricular ejection fraction Change in 0.05 ejection fraction 0.04 0.03 0.02 Enalapril 0.01 Hydralazine – isosorbide 0 dinitrate 13 weeks 1 year 2 years Time after randomization Cohn et al. N Engl J Med 1991; 325:303–10.

7. V-HeFT II: Vasodilator–Heart Failure Trial- SUMMARY - In patients with chronic congestive heart failure: • Enalapril conferred greater reduction in mortality than hydralazine–isosorbide for at least 2 years, due to lower incidence of sudden death • Treatment with either enalapril or hydralazine–isosorbide increased left ventricular ejection fraction • Hydralazine–isosorbide increased O2 consumption at peak exercise levels for the first year