First race-based drug receives FDA approval

Washington -- The heart failure drug BiDil has become a flashpoint for debate and discussion.

Now, it will likely become even more of a hot topic because this fixed-dose, single pill, a combination of isosorbide dinitrate and hydralazine, shown in clinical trials to be helpful in treating heart failure in African-American patients, gained Food and Drug Administration approval on June 23.

The trick for physicians will be to determine when it is indicated. And the key questions: Is it just for African-American patients? Or perhaps it's helpful for all patients who share an as-yet-unrecognized genetic trait?

An FDA advisory committee voted unanimously on June 17 in favor of agency approval after sifting through the evidence. The FDA approval came just days later.

The majority of committee members also agreed with BiDil's manufacturer, NitroMed of Lexington, Mass., that the medication label should indicate it is intended for black patients.

Nearly 5 million Americans are living with heart failure, and 550,000 new cases are diagnosed each year, according to the American Heart Assn. The condition is particularly common among black patients, affecting about 3% of all adult African-Americans.

African-American patients also develop symptoms of heart failure at an earlier age than do patients of other races, according to the heart association, possibly because they are more likely to have hypertension and diabetes than others and because they more frequently exhibit sodium retention, ventricular hypertrophy and vascular injury. Lack of access to quality health care may also play a role. However, coronary artery disease is less common in blacks with heart failure than in whites with this condition.

The issue of whether a combination of physical traits makes BiDil particularly effective for certain people is driving some of the back and forth over who should receive it.

"I would suggest that clinicians look at patients who may fit some of the criteria seen in the study that were independent of skin color," said Keith Ferdinand, MD, an investigator in a trial that demonstrated BiDil's effectiveness and a professor of clinical pharmacology at Xavier University in New Orleans.

Among the traits suggested by Dr. Ferdinand: middle age, obesity, hypertension, idiopathic heart failure and diabetes.

He would prefer that the label not single out blacks as the group that would benefit the most from BiDil. "I think it's too restrictive," he said. Restrictive labels have not been proposed for the popular statin drugs, he noted, even though most of the trials were conducted with whites.

A-HeFT trial results

BiDil was shown to be effective in a trial of 1,050 black patients with heart failure who were already receiving standard therapy. Results from the African-American Heart Failure Trial, or A-HeFT, published in the Nov. 11, 2004, New England Journal of Medicine, showed a significant improvement in mortality and hospitalizations among heart failure patients who took BiDil rather than a placebo.

The trial was a follow-up to earlier studies that showed a possible benefit to black patients but no overall benefit among those using the drug.

BiDil combines 20 mg of isosorbide dinitrate and 37.5 mg of hydralazine in one tablet. Although both component medications have been available separately for decades, they had fallen from favor in treating heart failure after the introduction of newer medications thought to be more effective, said Winston Price, MD, president of the National Medical Assn.

"I think physicians who take care of patients of African-American descent with congestive heart failure should be thrilled [with the news about BiDil]," he said.

Clyde W. Yancy, MD, an investigator on the A-HeFT trial and a professor of medicine at the University of Texas Southwestern Medical Center in Dallas, would like to tell physicians three things about BiDil.

"The first is that BiDil represents a new treatment for heart failure," he said.

"Also, when you see your patient who is best described as African-American and is already on effective therapy but remains symptomatic, this is a great intervention," he said.

"I would also tell physicians that this may be a brand-new way of looking at cardiovascular disease. We may begin talking about nitric oxide and oxidative stress as a way to define disease," he said.

Evidence suggests that African-American patients with heart failure produce lower levels of nitric oxide in their coronary and peripheral vasculature, wrote M. Gregg Bloche, MD, co-director of Georgetown-Johns Hopkins Joint Program in Law and Public Health, in the same NEJM issue that contained the A-HeFT findings. Isosorbide dinitrate increases nitric oxide.

But most agree that using race to determine who should be prescribed a medication is far from perfect. "It is our hope that as our research continues, we'll discover other patient populations and/or discover what it is in the African-American race that might be applicable to others that explains the benefit," said Dr. Yancy. "We don't believe that it is race only."

Rather than becoming embroiled in a controversy over race-based medicines, it's important to keep an eye on the bottom line, said Robert S.D. Higgins, MD, director of the heart transplantation program at Rush University Medical Center in Chicago. "Realistically, what are we trying to do here? We are trying to provide patients with options that can potentially save lives."

The discovery of BiDil's effectiveness is to be applauded, said Stephen Liggett, MD, director of the cardiopulmonary research center at the University of Cincinnati. "Heart failure response in African-Americans is worse than in Caucasians ... and something needs to be done."