A-HeFT: ISDN-hydralazine cuts mortality in black Americans on standard HF meds

November 08, 2004

New Orleans, LA - A dual-drug vasodilator regimen on top of standard medications significantly cut the risk of death and other important clinical events in African Americans with HF, reported investigators from the randomized African-American Heart Failure Trial (A-HeFT).[1] Based on those results, the fixed-dose combination of two long-available vasodilators, isosorbide dinitrate (ISDN) and hydralazine, is expected to win FDA market approval for the A-HeFT indication with little resistance.

The trial's formal publication was released online this morning by the New England Journal of Medicine and will appear in its November 11, 2004 issue. The A-HeFT results were also scheduled to be presented today at the American Heart Association 2004 Scientific Sessions by Dr Anne L Taylor (University of Minnesota, Minneapolis), chair of the A-HeFT steering committee.

 
The reduction in mortality is consistent with the existence of an alternative mechanism controlling the progression of heart failure.
 

A landmark trial in several ways, A-HeFT points to likely important roles for peripheral vascular dysfunction in the pathogenesis of HF and ventricular remodeling and for the use of specific drug therapies based on self-reported race.

"The 43% reduction in the mortality rate in the group given isosorbide dinitrate plus hydralazine occurred among patients who were well treated with a background regimen of neurohormonal-inhibitor drugs," write Taylor and her colleagues. "Thus, the reduction in mortality is consistent with the existence of an alternative mechanism controlling the progression of heart failure."

Trial halted early

The trial randomized 1050 men and women who classified themselves as African American and who had NYHA class 3-4 HF and reduced LV function to receive a fixed-dose combination of ISDN-hydralazine or a placebo. They were required to have an LVEF of <35%; it could be <40% if they also had echocardiographic evidence of LV dilatation.

Actively treated patients initially received a tablet containing 20 mg of the nitrate and 37.5 mg of hydralazine (BiDil®, NitroMed) three times daily; depending on side effects, the dosage could be increased to two such tablets tid at the physicians' discretion. All patients were receiving standard HF medications that overwhelmingly included diuretics, beta blockers, and ACE inhibitors or angiotensin receptor blockers.

The trial was halted before the planned 1100 patients had been randomized, following the data monitoring board's observation of a significant mortality increase in the placebo group. The reported outcomes are for a mean follow-up of 10 months, with some patients followed up to 18 months.

A-HeFT: Outcomes of the primary composite end point and its components (intention-to-treat)


End point
ISDN-hydralazine (n=518)
Placebo (n=532)
p

-0.1
-0.5
0.01

6.2
10.2
0.02

16.4
24.4
0.001

-5.5
-2.7
0.02

*Composite end point includes all-cause mortality, first HF hospitalization, and change in quality-of-life. See the sidebar for the scoring system.

**Lower scores indicate better quality of life.

"Fascinating issues" raised
 
Endothelial function and bioavailability of nitric oxide may be less robust in blacks than in whites.
 

"This trial raises fascinating issues regarding heart-failure therapeutics and variations in drug susceptibility among populations," writes Dr Joshua M Hare (Johns Hopkins University, Baltimore, MD) in an editorial accompanying the A-HeFT publication.[2] Whereas ISDN stimulates nitric-oxide signaling in the promotion of endothelial function, hydralazine is a vasodilator and antioxidant that seems to enhance the effects of the organic nitrate, he observes. Moreover, the trial focused on a population based on perceived race that had previously shown signs of gaining special benefit from a specific drug regimen. A-HeFT grew out of a finding that the vasodilator combination appeared to improve HF outcomes in African Americans without showing a striking effect in the larger overall population in a post hoc analysis of the Vasodilator Heart Failure Trial.[3]

Other data suggested organic nitrates produce their vasodilatory effects by functioning as nitric-oxide donors and that "endothelial function and bioavailability of nitric oxide may be less robust in blacks than in whites," write Taylor and colleagues in their paper.

 
We need not shy away from the potential benefits of race-conscious therapeutics, but we should manage its downside risks.
 

Thus, the A-HeFT trial's design avoided at least one of the potential pitfalls of conventional trials that encompass large heterogeneous populationsa take-home message based on average results that "may obscure therapeutic efficacy in some subgroups and the lack of such efficacy in others," Taylor and colleagues write.

The trial raises some potentially thorny social and regulatory issues, observes Dr M Gregg Bloche (Johns Hopkins University, Baltimore, MD) in a Perspective published simultaneously with the A-HeFT report.[4] "We need not shy away from the potential benefits of race-conscious therapeutics, but we should manage its downside risks," he writes. Among those risks:

  • Once a pharmaceutical company has obtained patent protection and FDA approval for a race-based drug indication, it may have "little incentive to sponsor research aimed at elucidating the relevant genetic variations" for which race is a crude marker, according to Bloche.

  • Because "blackness" is a culturally defined term "poorly connected to underlying population genetics," blacks as defined in A-HeFT are heterogeneous with respect to the genetic basis for the treatment's effectiveness, Bloche writes. This underscores the potential value of more specific genetic markers to replace race-based treatment criteria.

  • Finally, "group differences in pathophysiology and responses to treatment are not necessarily genetic. . . . A miasma of psychosocial, economic, cultural, environmental, and other determinants affects human physiology in ways that are poorly understood." As these factors may be disproportionately represented in one racial group or another, they may play a role in variable treatment response by race, Bloche notes.

Adverse effects in A-HeFT


End point
ISDN-hydralazine (n=518) (%)
Placebo (n=532) (%)
p
HF exacerbations
8.7
12.8
0.04

3.1
7.0
0.005
Headache
47.5
19.2
<0.001
Dizziness
29.3
12.3
<0.001



A-HeFT's primary end point defined

A-HeFT used a novel primary end point consisting of weighted values for all-cause death, first hospitalization for HF, and change in quality of life according to the Minnesota Living with Heart Failure questionnaire. Patients accrued points ranging from -6 to +2, with lower scores indicating more adverse developments, according to the following scheme.

A-HeFT scoring system

End point
Points
Death
-3
Survival to end of trial
0
First HF hospitalization
-1
No hospitalizations
0
Six-month change in quality of life

+2

+1

0

-1

-2
Possible score
-6 to +2

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