Isosorbide dinitrate/hydralazine: its role in the treatment of heart failure

Despite the advances in pharmacotherapy for heart failure due to reduced left ventricular function, mortality still remains high and many patients are hospitalized over time due to worsening heart failure symptoms. There is some experimental evidence that vasoconstriction and nitric oxide (NO) deficiency in the vasculature play a role in aggravating the symptoms of heart failure, especially in patients of African-American origin. Treatment with high doses of isosorbide dinitrate (ISDN) has been shown to increase symptom-free walking time, but tolerance to the hemodynamic effects of ISDN develops rapidly. Experimental data suggests that hydralazine, given concomitantly, attenuates the development of hemodynamic tolerance to ISDN and may increase bioavailability of NO in the vasculature. In a racially mixed population, treatment with a combination of ISDN and hydralazine reduced mortality compared to placebo to a nearly statistically significant extent in the first Vasodilator Heart Failure Trial (V-HeFT I) but was inferior to treatment with angiotensin-converting enzyme (ACE) inhibitor enalapril in the V-HeFT II study. Subgroup retrospective analysis of published data, however, suggested that ISDN/hydralazine had a substantial effect in black patients and was apparently as effective as treatment with the ACE inhibitor, enalapril, in the same population, but had a much smaller, if any, effect in white patients. A recent placebocontrolled study showed that in self-identified black patients with heart failure, ISDN/hydralazine, given in addition to current state-of-the-art pharmacotherapy for heart failure, reduces mortality and first hospitalizations due to heart failure and improves quality of life. The usefulness of ISDN/hydralazine in ethnic groups other than self-identified blacks is unknown at present and is considered off-label use. This review focuses on ISDN/hydralazine for the management of patients with heart failure due to left ventricular dysfunction and the adverse effects which may be encountered with therapy.