A-HeFT, V-HeFT, V-HeFT - Hydralazine+nitrate in HFrEF

A-HeFT: Taylor AL, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351:2049-57.

V-HeFT: Cohn JN, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. N Engl J Med 1986;314:1547-52.

V-HeFT II: Cohn JN, 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.

Patients

Interventions

Results in context

V-HeFT was the first trial demonstrating a mortality benefit with any drug for heart failure. It was published prior to studies showing benefits of ACEI/ARB, beta-blocker, and mineralocorticoid receptor antagonists
- V-HeFT demonstrated that hydralazine/ISDN improved outcomes in HF, & that this was not due to a generic "vasodilator" effect, as demonstrated by an INCREASE in mortality with prazosin
V-HeFT II came hot off the heels of CONSENSUS (published in 1987), which demonstrated a great benefit to ACEI in NYHA class IV HF
- Although the results of the comparison of enalapril to hydralazine/ISDN in V-HeFT II were not "statistically" significant, with a p=0.08 for mortality, it provided convincing evidence of the superiority of RAAS inhibition with an ACEI over hydralazine/ISDN
- After V-HeFT II, hydralazine/ISDN was put on the sideline & no further outcome RCTs were conducted until A-HeFT
In 1999, subgroup analyses of the two V-HeFT trials demonstrated borderline race-based differences in response to hydralazine/ISDN (p=0.09-0.11 for interaction by race) & formed the basis to conduct A-HeFT
- Mortality in V-HeFT according to race
  - Black: Hydralazine/ISDN 9.7%, placebo 17.3% (NNT 14)
  - White: Hydralazine/ISDN 16.9%, placebo 18.8%
- Mortality in V-HeFT II according to race
  - Black: Enalapril 12.8%, hydralazine/ISDN 12.9%
  - White: Enalapril 11.0%, hydralazine/ISDN 14.9% (NNT 26)
- Of note, these analyses were underpowered to rule out a benefit of hydralazine/ISDN in whites
A-HeFT demonstrated a large reduction in mortality with hydralazine/ISDN in black HFrEF patients with mostly NYHA functional class III
- Hydralazine/ISDN therefore has a role as add-on therapy to ACEI/ARB in symptomatic black HFrEF patients who can tolerate additional vasodilator therapy
- It's unclear based on the available evidence if the results of A-HeFT can translate to non-black HFrEF patients. Given the borderline subgroup analyses noted above, hydralazine/ISDN likely still has a role for non-black patients as a 3rd line agent in those who cannot tolerated an ACEI or ARB due to hyperkalemia or renal dysfunction.