Effects of ACE inhibitors or beta-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 beta-adrenoceptor antagonists (beta-blockers) provided additional benefit in FDC I/H-treated African-American patients with HF.


METHODS
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 beta-blockers or other standard medications with all-point estimates favoring the FDC I/H group. Within the placebo-treated group, beta-blockers or ACE inhibitors and/or ARBs were efficacious in improving survival (hazard ratio [HR] 0.33; p<0.0001 for [beta]-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 beta-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).


CONCLUSIONS
Based on the analysis of baseline medication use in the A-HeFT, FDC I/H was superior to placebo with or without beta-blockers or ACE inhibitor. However, beta-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.
University Health Center, Wayne State University, Detroit, MI 48201, USA. jghali@med.wayne.edu
Jalal K
JK
Ghali
S William
SW
Tam
Keith C
KC
Ferdinand
JoAnn
J
Lindenfeld
Michael L
ML
Sabolinski
Anne L
AL
Taylor
Manuel
M
Worcel
Charles L
CL
Curry
Jay N
JN
Cohn
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D001741:Black or African American; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000208:ethnology; D006801:Humans; D006830:Hydralazine / Q000627:therapeutic use*; D007548:Isosorbide Dinitrate / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000627:therapeutic use*
D000319:Adrenergic beta-Antagonists; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D014665:Vasodilator Agents; D006830:Hydralazine; D007548:Isosorbide Dinitrate