A-Heft analysis: Improved HF outcome related to favorable effects on LV remodeling

Fixed-dose of isosorbide dinitrate and hydralazine associated with significant reductions in LV chamber diameter and increases in ejection fraction.

BOCA RATON, Fla. — An analysis of A-Heft data found that the combination of isosorbide dinitrate and hydralazine, as a nitric oxide donor, induces regression of left ventricular remodeling in black patients with moderate to severe heart failure who are already being treated with standard heart failure therapies.

The data were presented at a late-breaking clinical trial presentation by Jay N. Cohn, MD, at the Heart Failure Society of America 9th Annual Scientific Meeting. Cohn is a member of Cardiology Today’s Editorial Board on the Myocardial Disorders, HF and Transplantation section.

The African American Heart Failure (A-Heft) study, which showed a mortality and morbidity benefit with isosorbide dinitrate and hydralazine (BiDil, NitroMed Inc.), was terminated early in July 2004 when patients taking the combination drug had an absolute mortality rate of 6.2% compared to a 10.2% mortality rate in the placebo arm. The FDA approved the drug combination earlier this year for treatment of HF in blacks.

Echocardiographic data

For the analysis, echocardiographic data and BMP levels were examined at baseline and at six months after randomization in A-Heft to determine whether isosorbide dinitrate and hydralazine, which had a dramatic improvement on survival, could also improve LV structure and function.

The echos were all carried out in the study centers, but all echos were digitalized and then analyzed by the same cardiologists in a core laboratory.

“Keep in mind that the echos that determined eligibility for entrance into the trial were not the same echos that were performed at baseline,” Cohn said.

Regression in remodeling

The EF, which averaged 35% at baseline, rose significantly by 2.8 units in the isosorbide dinitrate and hydralazine arm at six months compared to 0.8 units in the placebo group.

“This difference in response was highly significant,” Cohn said. “Furthermore, the left ventricular chamber size was reduced significantly more in the drug combination arm than in the placebo group.”

There was also a greater reduction in B-type natriuretic peptide levels at six months in the isosorbide dinitrate and hydralazine arm than in the placebo arm, Cohn said.

“These data support the conclusion that this drug combination favorably affects left ventricular structure and function,” he said.

“So in summary, the benefit of the fixed-dose of isosorbide dinitrate and hydralazine on mortality and morbidity in African-American patients with moderate to severe HF is accompanied by significant reductions in LV chamber diameter and increases in EF — a regression in remodeling.”

This effect was observed in patients who primarily were already treated with ACE inhibitors or AII receptor antagonists and beta-blockers. The data, then, suggest an independent mechanism of action through enhanced nitric oxide, according to Cohn. – by Suzanne Bryla

Cohn has a financial interest in BiDil.

For more information:

• Cohn JN. Fixed-dose combination of isosorbide dinitrate and hydralazine Inhibits LV remodeling in well-treated severe HF in African Americans: A-Heft. Late-breaking trial presented at the Heart Failure Society of America 9th Annual Scientific Meeting, Sept. 18-21, 2005. Boca Raton, Fla.