V-HeFT

Published

Cohn JN, et al. "Effect of vasodilator therapy on mortality in chronic congestive heart failure". The New England Journal of Medicine. 1986. 314(24):1547-52.
PubMed • Full text • PDF

Clinical Question

In patients with dilated cardiomyopathy and systolic heart failure, does vasodilator therapy with isosorbide dinitrate (ISDN)/hydralazine confer a survival benefit?

Bottom Line

In the era before beta-blockers and ACE inhibitors, ISDN/hydralazine showed a trend towards improved survival among patients with systolic heart failure.

Major Points

In the early 1980s, vasodilator therapy was in reasonably wide use among individuals with symptomatic systolic heart failure, based upon its favorable hemodynamic effects. However, its effect on mortality had not been studied until the VA Cooperative Study investigators undertook the V-HeFT trial.

Published in 1986, and therefore predating the use of ACE inhibitors and beta-blockers, the Vasodilator Heart Failure Trial (V-HeFT) randomized 642 patients with symptomatic chronic compensated systolic heart failure to combination isosorbide dinitrate (ISDN)/hydralazine, prazosin, or placebo. At a mean follow-up of 2.3 years, there was no statistically significant difference in mortality between the three groups (38.7% vs. 49.7% vs. 44.0%), although there was a trend towards improved survival with ISDN/hydralazine compared to placebo (P=0.053). Despite employing multiple statistical methods, however, the authors could not obtain a P<0.05 for this comparison. In addition to demonstrating a trend towards improved survival, the ISDN/hydralazine group also had statistically significant improvement in LVEF at 8 weeks and 1 year. There was no significant mortality or hemodynamic benefit with the alpha-antagonist prazosin, which actually showed a trend towards harm.

The main takeaway from this trial was the post hoc subgroup analysis published separately that suggested improved survival with ISDN/hydralazine among self-identified black patients, prompting the subsequent (and positive) A-HeFT trial (2004). The subsequent V-HeFT II trial was undertaken to compare ISDN/hydralazine vs. enalapril, and showed that the ACE inhibitor conferred a survival benefit over ISDN/hydralazine.

Guidelines

AHA/ACCF Heart Failure Guidelines (2013, adapted)

• Recommendation of nitrates/hydralazine for self-described African American patients with NYHA III-IV HFrEF on OMT with ACE-inhibitors and beta blockers unless contraindicated (class I, level A)
• Suggestion of nitrates/hydralazine for all patients with current or previous symptomatic HFrEF who can't tolerate ACE-inhibitor or ARB therapy unless contraindicated (class IIa, level B)

Design

• Multicenter, double-blind, parallel group, randomized, placebo-controlled trial
• N=642
  • ISDN/hydralazine (n=186)
  • Prazosin (n=183)
  • Placebo (n=273)
• Setting: 11 VA centers in the US
• Enrollment: 1980-1985
• Mean follow-up: 2.3 years
• Analysis: Intention-to-treat
• Primary outcome: Mortality

Population

Inclusion Criteria

• Age 18-75 years
• Dilated cardiomyopathy
  • Cardiomegaly (cardiothoracic ratio >0.55 on CXR) or LV internal diastolic diameter >2.7cm/m² on TTE
  • LVEF <45% by radionuclide scan
• Reduced exercise tolerance (peak oxygen consumption <25mL/kg/min)

Exclusion Criteria

• Exercise tolerance limited by chest pain rather than dyspnea or fatigue
• Significant CAD or MI within prior 3 months
• Significant valvular disease
• Chronic lung disease
• Other disease likely to limit 5-year survival
• Patients requiring long-acting nitrates for angina, CCBs, ß-blockers, or antihypertensive agents other than diuretics
• Contraindication to study drug

Baseline Characteristics

Comparisons are ISDN/hydralazine vs. prazosin vs. placebo.

• Mean age: 58.4 years
• Duration of HF symptoms:
  • <6 months: 18.2%
  • 6 months-1.5 years: 26.3%
  • 1.5-4 years: 24.4%
  • >4 years: 31.1%
• Alcoholism: 40.0%
• Hypertension: 41.2%
• Diabetes: 17.2% vs. 18.7% vs. 24.5%
• CAD: 44.2%
• Prior MI: 41.5%
• Prior CABG: 12.9%
• Prior valve replacement: 4.9%
• HR: 82 bpm
• BP: 119/76
• Cardiothoracic ratio: 0.53
• LVIDD: 3.5 cm/m²
• EF: 30%
• Exercise duration: 9.6 mins
• Oxygen consumption: 14.7 ml/kg/min

Baseline Medications

• Vasodilators: 37.8
• Antiarrhythmics: 26.9%
• Sublingual nitroglycerin: 18.7%
• Anticoagulants: 19.1%

Interventions

• Randomized to isosorbide dinitrate (37.5mg QID) plus hydralazine (20mg QID), prazosin (2.5mg daily), or matching placebo
  • Mean daily dosages: ISDN 136mg, hydralazine 270mg, prazosin 18.6mg
• If ncecessary, digoxin and diuretic therapy were adjusted

Outcomes

Comparisons are ISDN/hydralazine vs. prazosin vs. placebo, unless otherwise specified. Dagger (†) indicates outcomes with P<0.05 when compared to placebo.

Primary Outcomes

Mortality

38.7% vs. 49.7% vs. 44.0% (P=0.093 by log-rank test, P=NS by Wilcoxon test)

Secondary Outcomes

Mortality by year

(Comparisons are ISDN/hydralazine vs. placebo.)

Year 1: 12.1% vs. 19.5% (RR 0.62, P not specified)

Year 2: 25.6% vs. 34.3% (RR 0.75, P<0.028)

Year 3: 36.2% vs. 46.9% (RR 0.77, P=0.053)

Year 4: 49.7% vs. 53.6% (RR 0.93, P not specified)

Ejection fraction

8 weeks: +2.9%† vs. +0.7% vs. +0.4%

1 year: +4.2%† vs. +1.4% vs. -0.1%

Change in SBP

8 weeks: +0.0 vs. -4.1† vs. +0.2 mm Hg

1 year: +0.6 vs. -4.6 vs. -0.3 mm Hg

Discontinuation of therapy

17% vs. 23% vs. 17%

(Includes side effects, clinical deterioration, nonfatal cardiac event, or patient preference.)

Subgroup Analysis

A subgroup analysis published separately demonstrated a statistically significant benefit of ISDN/hydralazine among self-identified black patients.

Criticisms

• Given the borderline significance of the survival benefit seen with ISDN/hydralazine, this should not be interpreted as a positive trial. (Of note, the FDA did not approve the drug combination for heart failure as a result of this study.)

Funding

Funded by the Cooperative Studies Program of the Medical Research Study of the VA Central Office in Washington, DC.