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African-American Heart Failure Trial - A-HeFT
Description:
The goal of the African-American Heart Failure Trial (A-HeFT) was to evaluate treatment with a fixed dose of isosorbide dinitrate plus hydralazine compared with placebo among black patients with advanced heart failure.
Hypothesis:
Treatment with a fixed dose of isosorbide dinitrate plus hydralazine will be associated with an improvement in clinical outcomes compared with placebo among black patients with advanced heart failure.
Study Design
Study Design:
Patients Enrolled: 1,050
NYHA Class: Class III 96%; Class IV 4%
Mean Follow Up: 18 months (mean duration 10 months)
Mean Patient Age: Mean age 57 years
Female: 41
Mean Ejection Fraction: Mean 24% at baseline
Patient Populations:
Age ≥18 years, black race, NYHA class III or IV heart failure for ≥3 months, receiving standard therapy for heart failure, and evidence of left ventricular dysfunction within prior six months
Exclusions:
Acute myocardial infarction, acute coronary syndrome, or stroke within prior three months; cardiac surgery or percutaneous coronary intervention within the prior three months; presence of clinically significant valvular heart disease, or hypertrophic or restrictive cardiomyopathy, acute myocarditis or uncontrolled hypertension; need for cardiac transplantation; cardiac arrest or arrhythmias in prior three months; use of parenteral inotropic agents within prior month; symptomatic hypotension; likely death from another illness during study period; or contraindication to nitrate or hydralazine therapy
Primary Endpoints:
Composite score was made up of weighted values for death from any cause, a first hospitalization for heart failure, and change in the quality of life.
Secondary Endpoints:
Individual components of the primary composite score, death from cardiovascular causes, total number of hospitalizations for heart failure and for any reason, total number of days hospitalized, quality of life, number of unscheduled emergency room and office or clinic visits, change in B-type natriuretic peptide level at six months, new need for cardiac transplantation, and a change in the left ventricular ejection fraction, the left ventricular internal diastolic dimension, and the left ventricular wall thickness at six months
Drug/Procedures Used:
Patients were randomized to fixed dose of isosorbide dinitrate plus hydralazine (n=518) or placebo (n=532). Randomization was stratified by baseline use of beta-blocker therapy. Initial dose was 20 mg of isosorbide dinitrate and 37.5 mg of hydralazine. Dosing was increased to a total daily dose of 120 mg of isosorbide dinitrate and 225 mg of hydralazine.
Concomitant Medications:
Baseline therapy: diuretics (90%), angiotensin-converting enzyme inhibitor (69%), angiotensin-receptor blocker (17%), and beta-blocker (74%)
Principal Findings:
There were more females (44.2% vs. 36.1%) and more diabetics (44.8% vs. 37.0%) in the isosorbide dinitrate plus hydralazine group compared with placebo. The large majority of patients in the trial had New York Heart Association (NYHA) class III at baseline (96%). Cause of heart failure was ischemic heart disease in 23% of patients, hypertension in 38%, and idiopathic in 26%. The study was terminated for a mortality benefit after 1,050 of the planned 1,100 patients had been randomized.
Mortality was significantly lower in the combination therapy group (6.2% vs. 10.2%, hazard ratio 0.57, p=0.01). The survival differences began at approximatley six months after randomization and continued to diverge through follow-up. The primary composite score was significantly improved in the combination therapy group compared with placebo (-0.1 ± 1.9 vs. -0.5 ± 2.0, p=0.01). Individual components of the composite score were also significantly improved in the combination therapy group, including death (data above), first hospitalization for heart failure (16.4% vs. 24.4%, p=0.001), and change in quality of life score at six months (-5.6 ± 20.6 vs. -2.7 ± 21.2, p=0.02).
Target dose was given in 68.0% of patients in the combination therapy group and 88.9% of patients in the placebo group (p<0.001). Blood pressure (BP) was lower in the combination therapy group compared with placebo (systolic BP -1.9 mm Hg vs. +1.2 mm Hg for placebo, p=0.02; diastolic BP -2.4 mm Hg vs. +0.8 mm Hg for placebo, p<0.001). Adverse events of headache (47.5% vs. 19.2%, p<0.001) and dizziness (29.3% vs. 12.3%, p<0.001) were higher in the combination therapy group, but exacerbations of CHF were lower, including all exacerbations (8.7% vs. 12.8%, p=0.04) and severe exacerbations (3.1% vs. 7.0%, p=0.005).
Interpretation:
Among black patients with advanced heart failure, treatment with nitric oxide-enhancing therapy (a fixed dose of isosorbide dinitrate plus hydralazine) was associated with a reduction in the primary composite endpoint and in all-cause mortality compared with placebo.
Subgroup analysis of prior randomized trials suggested combination therapy with isosorbide dinitrate plus hydralazine was particularly beneficial in black patients, but since the analyses were of subgroups, the findings were considered exploratory and not conclusive. No prior study of this therapy had been conducted exclusively in black patients. Heart failure disproportionately affects African-Americans, further highlighting the importance of identifying effective therapies for this population.
References:
Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351:2049-57.
Presented by Anne L. Taylor at the American Heart Association Scientific Sessions, November 2004, New Orleans, LA.
Keywords: Myocardial Ischemia, Blood Pressure, Headache, Vasodilator Agents, Nitric Oxide, Isosorbide Dinitrate, Drug Combinations, Hydralazine, Dizziness, Quality of Life, Nitrates, Heart Failure, Ventricular Dysfunction, Left, Hospitalization, Hypertension, Diabetes Mellitus
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