Lessons from V-HeFT: questions for V-HeFT II and the future therapy of heart failure

V-HeFT, the first mortality trial in patients with heart failure, has provided important insights regarding trial design, including patient selection and efficacy criteria. Planning of V-HeFT II, the trial comparing hydralazine-isosorbide dinitrate and enalapril, has raised additional issues regarding the power to detect mortality effects and the relative value of non-mortality endpoints for efficacy. V-HeFT has demonstrated that some vasodilator regimens can prolong life in heart failure. Hydralazine + isosorbide dinitrate reduced mortality by 27% compared to placebo in patients treated with digoxin and diuretics. The possibility of a non-vasodilator mechanism for long-term benefit of these interventions is raised by the apparently poor relationship between the magnitude of vasodilation and the favorable long-term effects. These issues need to be explored in subsequent trials. In future long-term trials, however, the need for background therapy with drugs that have been effective in reducing mortality will make the identification of life prolongation from new therapies more difficult to demonstrate.