Effects of ACE inhibitors or β-blockers in patients treated with the fixed-dose combination of isosorbide dinitrate/hydralazine in the African-American heart failure trial

Background: In the A-HeFT (African-American Heart Failure Trial), treatment of African-American patients with New York Heart Association (NYHA) class III/IV heart failure (HF) with fixed-dose combination (FDC) of isosorbide dinitrate/hydralazine (I/H) reduced mortality and morbidity and improved patient reported functional status compared with standard therapy alone. Objective: To examine the benefit of FDC I/H in subgroups based on baseline drug therapy and to investigate whether ACE inhibitors and/or angiotensin receptor antagonists (angiotensin receptor blockers) [ARBs] or β-adrenoceptor antagonists (β-blockers) provided additional benefit in FDC I/H-treated African-American patients with HF. Study design: The A-HeFT was a double-blind, placebo-controlled study enrolling 1050 patients stabilized on optimal HF therapies and with NYHA class III/IV HF with systolic dysfunction conducted during the years 2001-4 with up to 18 months follow-up. The primary endpoint was a composite of mortality, first HF hospitalization, and improvement of quality of life at 6 months. Secondary endpoints included mortality, hospitalizations, and change in quality of life. Prospective Kaplan-Meier survival analyses were used for differences between FDC I/H and placebo groups and retrospective analyses were conducted within FDC I/H-treated and placebo groups. Results: Subgroup analysis for mortality, event-free survival (death or first HF hospitalization), and HF hospitalization showed that FDC I/H, compared with placebo, was effective with or without ACE inhibitors or β-blockers or other standard medications with all-point estimates favoring the FDC I/H group. Within the placebo-treated group, β-blockers or ACE inhibitors and/or ARBs were efficacious in improving survival (hazard ratio [HR] 0.33; p < 0.0001 for β-blocker use and HR 0.39; p = 0.01 for ACE inhibitor and/or ARB use). However, within the FDC I/H-treated group, use of β-blockers, but not ACE inhibitors and/or ARBs, provided additional significant benefit for survival (HR 0.44; p = 0.029 and HR 0.60; p = 0.34, respectively), event-free survival (HR 0.62; p = 0.034 and HR 0.72; p = 0.29, respectively) and the composite score of death, HF hospitalization and change in quality of life (p = 0.016 and p = 0.13, respectively). Conclusion: Based on the analysis of baseline medication use in the A-HeFT, FDC I/H was superior to placebo with or without β-blockers or ACE inhibitor. However, β-blockers but not ACE inhibitors and/or ARBs provided additional significant benefit in African-Americans with HF treated with FDC I/H. These analyses are hypotheses generating and their confirmation in clinical trials needs to be considered.