Oral Nitrates and Hydralazine

The Vasodilator Heart Failure Trial (V-HeFT) was the first major randomized HF trial and was conducted in Veterans Administration hospitals throughout the US. Patients who remained symptomatic with mild to severe symptoms of HF despite treatment with diuretics and digoxin were randomized to a combination of hydralazine and isosorbide dinitrate or prazosin or placebo. The combination of hydralazine and isosorbide dinitrate was associated with a reduction in all-cause mortality compared to both placebo and prazosin that was of borderline statistical significance (P=.053).79 In V-HeFT II, the combination of hydralazine and isosorbide dinitrate was compared with enalapril in a population similar to V-HeFT I.80 All-cause mortality was 28% lower with enalapril than with the hydralazine isosorbide dinitrate combination. However, quality of life and peak exercise capacity as measured by peak oxygen consumption were better with hydralazine-isosorbide dinitrate.

The African-American Heart Failure Trial (A-HeFT) enrolled 1050 self-identified African-American patients who had NYHA class III or IV HF with dilated ventricles and reduced LVEF.81 In this placebo-controlled, blinded, and randomized trial, subjects were randomly assigned to receive a fixed combination of isosorbide dinitrate plus hydralazine or placebo in addition to standard therapy for HF. The primary end point was a composite score made up of weighted values for death from any cause, a first hospitalization for HF, and change in the quality of life. The study was terminated early because of a significantly higher mortality rate in the placebo group than in the group given the fixed combination of isosorbide dinitrate plus hydralazine (10.2% vs 6.2%, P=.02). The mean primary composite score was significantly better in the group given isosorbide dinitrate plus hydralazine than in the placebo group, as were its individual components: 43% reduction in the rate of death from any cause, 33% relative reduction in the rate of first hospitalization for HF, and an improvement in the quality of life. These results taken together constitute a strong recommendation for the addition of the fixed combination of isosorbide dinitrate/hydralazine to the standard medical regimen for HF in African Americans. Data cannot exclude a benefit of the isosorbide dinitrate/hydralazine combination in non-African Americans when added to the standard medical regimen for HF.