BiDil® A-HeFT TRIAL

A-HeFT
The African American Heart Failure Trial (A-HeFT) – co-sponsored by NitroMed and the Association of Black Cardiologists, Inc. – was the first study conducted in a heart failure population in which all of the participants identified themselves as black.  This Phase III trial commenced in May  2001 and evaluated the effects of BiDil® (isosorbide dinitrate/hydralazine hydrochloride) – a fixed-dose combination of isosorbide dinitrate (I) and hydralazine hydrochloride (H) – in self-identified blacks when taken in addition to standard heart failure therapies.  After a unanimous recommendation from the independent Data and Safety Monitoring Board (DSMB) and Steering Committee in July 2004, A-HeFT was halted early due to a significant survival benefit seen with the drug as compared to standard therapy alone.

Why A-HeFT?
A-HeFT was designed to study the effect of BiDil among self-identified black patients with heart failure, based on the retrospective analyses of the Veteran’s Affairs Vasodilator Heart Failure Trials  (V-HeFT I and II), conducted from 1980 through 1991, that suggested a positive effect on survival in black patients taking an I/H combination, but showed little evidence of a survival benefit  in white patients.  The U.S. Food and Drug Administration (FDA) determined that the results of the V-HeFT trials were not adequate to support approval of BiDil at that time.  However, when NitroMed presented the retrospective data to the FDA in 2000, the FDA indicated that a clearly positive trial in African Americans could provide a basis for approval of BiDil for this particular heart failure population.

A-HeFT Design
The A-HeFT study used a unique composite endpoint of mortality, first hospitalization for heart failure and patient reported functional status in patients receiving BiDil in addition to a variety of current standard therapies compared to patients receiving these current therapies plus placebo.  Most patients in the trial received, in addition to BiDil or placebo, a loop diuretic, an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker, and a beta blocker, and many also received a cardiac glycoside and/or an aldosterone antagonist. 

A-HeFT was a randomized, double-blind, placebo-controlled study that enrolled 1,050 self-identified black patients with New York Heart Association class III or IV heart failure at 169 clinical research sites.  The classification system means that patients had marked limitation of physical activity (NYHA Class III) or were unable to carry out any physical activity without discomfort (NYHA Class IV).  Participants in A-HeFT were required to be receiving standard heart failure therapy at the time of the beginning of the trial, per their physicians. 

A-HeFT patients were evaluated every three months to assess clinical status and self-reported functional status.  Follow-up with patients continued throughout their duration in the study, up to a maximum of eighteen months.  No patients were lost to follow-up for vital status.

A-HeFT Results
The results of A-HeFT were exceptionally strong.  Clinical trial results demonstrated that in the BiDil treatment group versus patients taking placebo, there was:

• A statistically significant decrease of 43 percent in the risk of mortality (P=.012; Absolute mortality rate: BiDil, 6.2% vs. placebo, 10.2%)
• A statistically significant reduction of 39 percent in the risk of first hospitalization for heart failure (P<.001; Absolute first hospitalization for heart failure rate: BiDil, 16.4% vs. placebo, 24.4%)
• Substantial improvement at most time points in response to the Minnesota Living with Heart Failure questionnaire.  This questionnaire provides a self-report of patients’ physical symptoms, functionality and emotional attributes.

Adverse events reported in the trial and seen more frequently in the group given BiDil included symptoms of headache (50 percent in BiDil patients vs. 21 percent in placebo patients) and dizziness (32 percent in BiDil patient vs. 14 percent in placebo patients).  

BiDil is contraindicated in patients who are allergic to organic nitrates.  Augmentation of the vasodilatory effects of isosorbide dinitrate by phosphodiesterase inhibitors such as sildenafil, vardenafil, or tadalafil could result in severe hypotension.  Complete safety information is included in the BiDil label which can be viewed  at www.bidil.com.

The results from A-HeFT were presented at the American Heart Association’s 2004 Scientific Sessions and were published in the November 11,  2004 issue of the New England Journal of Medicine.