A review of isosorbide dinitrate and hydralazine in the management of heart failure in black patients, with a focus on a new fixed-dose combination

Background: It is estimated that 25% to 30% of patients with heart failure (HF) in the United States are black. Compared with nonblack patients, black patients have a reduced ability to produce endogenous nitric oxide, which may be associated with enhanced responsiveness to drugs that increase the delivery of nitric oxide, such as nitrates. When used with nitrates, hydralazine (HYD) acts as an antioxidant and prevents development of nitrate tolerance. Objective: This article reviews the clinical pharmacology of isosorbide dinitrate (ISDN) and HYD and clinical trials of their use in the treatment of HF, with a particular focus on the new fixed-dose combination for the treatment of HF in black patients. Methods: Articles or abstracts reporting the results of randomized, double-blind, controlled studies of ISDN and HYD in HF were identified through a search of the English-language literature indexed on MEDLINE and Current Contents/Clinical Medicine from 1966 to February 5, 2005, using the terms hydralazine, isosorbide dinitrate, nitrates, and heart failure. The reference lists of identified articles were reviewed for additional publications. Selected information provided by the manufacturer was also reviewed. Results: The combination of ISDN and HYD was studied in 3 large randomized controlled trials, the first and second Vasodilator in Heart Failure trials (V-HeFT 1 and V-HeFT 11), which included similar to 27% black men, and the African-American Heart Failure Trial (A-HeFT), which included 100% self-identified black patients of both sexes. In V-HeFT 1, which compared ISDN 40 mg QID and HYD 75 mg QID with prazosin 20 mg/d or placebo in 642 patients with mild to severe HF (New York Heart Association [NYHA] class II-III), those receiving ISDN and HYD had a 34% reduction in mortality risk compared with those receiving placebo (P < 0.038). In V-HeFT 11, which compared the same dosages of ISDN and HYD with enalapril 20 mg/d in 804 patients with NYHA class II-IV HF, those receiving enalapril had a 28% reduction in mortality risk compared with those receiving ISDN and HYD (P = 0.016). A predetermined subanalysis of V-HeFT I and V-HeFT 11 found that black patients receiving ISDN and HYD had a 47% reduction in relative mortality risk compared with nonblack patients (hazard ratio = 0.53 vs 130, respectively; P = 0.04). In A-HeFT, which compared combination ISDN/HYD 40/75 mg TID with placebo in 1050 patients with moderate to severe HF (NYHA class III-IV), ISDN/HYD was associated with fewer deaths compared with placebo (32 vs 54, respectively; P = 0.02), a lower incidence of first hospitalizations for HF (85 vs 130; P = 0.002), and a larger number of patients with marked improvement ( > 10 units) in quality-of-life scores, as measured on the Minnesota Living with Heart Failure Questionnaire (180 vs 166; P = 0.01). In A-HeFT, adverse events occurring with a greater incidence in the ISDN/HYD group than the placebo group were headache (49.5% vs 21.1%, respectively), dizziness (30.1% vs 13.7%), nausea and vomiting (9.7% vs 6.1%), hypotension (7.9% vs 4.4%), sinus congestion (4.3% vs 1.7%), and tachycardia (4.1% vs 2.7%). A pharmacoeconomic analysis based on health care resource utilization in A-HeFT found the ISDN/HYD combination product to be cost-effective over a wide range of acquisition costs (up to $12/d). Conclusions: The findings of these 3 large controlled clinical trials support the efficacy of ISDN and HYD in patients with HE Using a composite end point of mortality, HF hospitalization, and quality of life, the A-HeFT study found benefits to adding the fixed-dose ISDN/HYD combination product to standard therapy in self-identified black patients of African descent with moderate to severe HF.