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

Jalal K. Ghali, S. William Tam, Keith C. Ferdinand, Jo Ann Lindenfeld, Michael L. Sabolinski, Anne L. Taylor, Manuel Worcel, Charles L. Curry, Jay N. Cohn

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)373-380
Number of pages8
JournalAmerican Journal of Cardiovascular Drugs
Issue number5
StatePublished - 2007

Bibliographical note

Funding Information:
The A-HeFT trial was funded by NitroMed, Inc. Authors are either consultants of NitroMed, Inc. (JKG, KCF, JL, ALT, JNC) or are/were employees of NitroMed (MW, MLS, SWT). Dr Cohn has a royalty relationship with NitroMed based on his patents of the drug combination. Drs Ferdinand, Lindenfield, and Taylor have also received consultancies/honoraria from AstraZeneca, Merck, Wyeth, Novartis, or Medtronics.


  • ACE inhibitors, therapeutic use
  • Angiotensin receptor antagonists, therapeutic use
  • Beta adrenergic receptor antagonists, therapeutic use
  • Heart failure, treatment
  • Hydralazine/isosorbide dinitrate, therapeutic use
  • Mortality
  • Quality of life


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