Effects of Nitrates and Hydralazine in Heart Failure: Clinical Evidence Before the African American Heart Failure Trial

The initial rationale for use of organic nitrates and hydralazine (HYD) in combination was their complementary “nitroprussidelike” hemodynamic effect caused by the predominant venodilatory action of organic nitrates and the arterial-dilatory effect of HYD. This combination leads to a significant improvement in cardiac function, with a concomitant reduction in right and left ventricular filling pressures and augmentation of cardiac output. Based on this hemodynamic profile, the Vasodilator Heart Failure Trial (V-HeFT) was designed to examine the effect of this drug combination on the outcome of patients with congestive heart failure (CHF). Results from V-HeFT I showed improvements in left ventricular ejection fraction (LVEF), exercise tolerance, and survival in patients treated with isosorbide dinitrate (ISDN) and HYD compared with those treated with placebo. A retrospective analysis of V-HeFT I and V-HeFT II showed that the benefit of ISDN-HYD was seen mainly in African Americans. This observation led to the design of the African American Heart Failure Trial (A-HeFT), which confirmed the benefit of these drugs in combination in African American patients with CHF. There are a number of potential mechanisms responsible for the beneficial therapeutic effects of combination ISDN-HYD in patients with CHF, including favorable hemodynamic effects and improvement in left ventricular systolic function. Data from V-HeFT II showed a significant improvement in LVEF with combination ISDN-HYD, greater than the effect of the angiotensin-converting enzyme inhibitor enalapril. This increase in LVEF was associated with a favorable effect on survival. Prevention of nitrate tolerance with HYD may also be responsible for the favorable therapeutic effects of combination ISDN-HYD. Frequent administration of ISDN has been shown to result in the early development of nitrate tolerance. Concomitant use of HYD with a nitrate, both in an animal model and in patients with CHF, has been shown to prevent the development of nitrate tolerance and maintain the favorable hemodynamic effect of nitrates.