Effect of Vasodilator Therapy on Mortality in Chronic Congestive Heart Failure

Abstract

To evaluate the effects of vasodilator therapy on mortality among patients with chronic congestive heart failure, we randomly assigned 642 men with impaired cardiac function and reduced exercise tolerance who were taking digoxin and a diuretic to receive additional double-blind treatment with placebo, prazosin (20 mg per day), or the combination of hydralazine (300 mg per day) and isosorbide dinitrate (160 mg per day). Follow-up averaged 2.3 years (range, 6 months to 5.7 years). Mortality over the entire follow-up period was lower in the group that received hydralazine and isosorbide dinitrate than in the placebo group. This difference was of borderline statistical significance. For mortality by two years, a major end point specified in the protocol, the risk reduction among patients treated with both hydralazine and isosorbide dinitrate was 34 percent (P less than 0.028). The cumulative mortality rates at two years were 25.6 percent in the hydralazine--isosorbide dinitrate group and 34.3 percent in the placebo group; at three years, the mortality rate was 36.2 percent versus 46.9 percent. The mortality-risk reduction in the group treated with hydralazine and isosorbide dinitrate was 36 percent by three years. The mortality in the prazosin group was similar to that in the placebo group. Left ventricular ejection fraction (measured sequentially) rose significantly at eight weeks and at one year in the group treated with hydralazine and isosorbide dinitrate but not in the placebo or prazosin groups. Our data suggest that the addition of hydralazine and isosorbide dinitrate to the therapeutic regimen of digoxin and diuretics in patients with chronic congestive heart failure can have a favorable effect on left ventricular function and mortality.

Drugs That May Cause or Exacerbate Heart Failure

“…72 Additionally, in VeHFT (Veterans Heart Failure Trial-1), hydralazine combined with isosorbide dinitrate decreased mortality and improved LVEF compared with placebo, whereas prazosin did not. 73 …”

“…In the case of the nonuroselective agents, which have greater systemic α-blockade effects, much of the evidence has been extrapolated from the results of ALLHAT and Ve-HFT-1. 71,73 In a retrospective analysis of 388 patients with HF and benign prostatic hypertrophy receiving prazosin, terazosin, doxazosin, or tamsulosin, Dhaliwal et al 281 found no significant increase in all-cause mortality and HF rehospitalization in those receiving β-blockers. However, in those not receiving β-blockade, α-blockade exposure was associated with an increase in HF hospitalization (HR, 1.94; 95% CI, 1.14-3.32).…”

Present and future pharmacotherapeutic agents in heart failure: an evolving paradigm

“…The V‐HeFT I trial compared hydralazine and ISDN versus prazosin with placebo in 642 men with impaired systolic function and demonstrated a 34% relative risk reduction at 2 years ( P  < 0.028) (Cohn et al ., 1986). V‐HeFT II was undertaken in 1991 to compare this combination with and without enalapril, with significant mortality benefit seen in the enalapril arm (Cohn et al ., 1991).…”

Unbelievable Folly of Clinical Trials in Heart Failure

“…Ironically, the combination of hydralazine and isosorbide dinitrate actually proved to be nearly inferior to an ACE inhibitor on survival in the patients with mild-to-moderate heart failure enrolled in the V-HeFT II trial, 20 even though the effects of an ACE inhibitor on mortality in such patients are known to be modest (when compared with placebo). 21 Interestingly, the effect of hydralazine and isosorbide dinitrate on the risk of death and heart failure hospitalizations was not a prespecified end point in either V-HeFT I or V-HeFT II, 20,22 and the combined data from V-HeFT I and V-HeFT II were sufficiently confusing that the FDA declined to approve the combination for the treatment of chronic heart failure when the initial application for its commercial use was made in 1997. 23 At the same time, the guideline process has been silent on 2 drugs that were approved for the treatment of heart failure in the United States >6 months ago, ivabradine and sacubitril/valsartan.…”