A study showing that a new drug combination dramatically improves outcomes for black patients with heart failure is expected to lead to federal approval of the medication specifically for that group. While some doctors applaud this development, others question its validity and worry about its ethical implications, fearing it will usher in a wave of race-based drug treatments driven more by marketing than by science.
The study, published in the Nov. 11 edition of the New England Journal of Medicine, was halted nine months early when researchers noticed 43 percent fewer deaths among people taking the new drug than among those given a placebo. The test participants were 1,050 people who identified themselves as black, all of whom also took other medications (including diuretics, ACE inhibitors and beta blockers) typically prescribed for heart failure.
"It's the largest reduction in mortality that's ever been achieved in a heart failure trial," said Jay Cohn, a University of Minnesota cardiologist who co-authored of the study.
The drug, named BiDil, represents a "race-based therapy" approach that many doctors said they expect to see increase, at least partly because such treatments represent a potentially faster route to drug approval. But some doctors say the approach misrepresents race as an easily distinguished biological trait. Studies have shown genetic variation within any racial group exceeds that between two groups.
Race-based therapy is a "bad idea," said Patricia Davidson, a cardiologist at Washington Hospital Center. For a doctor to employ this type of treatment, the practitioner would have to ask a patient, "How much African American blood do you have" in you? she said. "We have to be very careful with that."
Like some other critics, she also expressed worry that approving and marketing a drug to one group only could hurt other patients who might have benefited from the same treatment. A lack of data about a drug's effects on the wider population could leave doctors without sufficient guidance on whether to broaden its use.
NitroMed, the Massachusetts-based company that made BiDil and funded the trial, plans to apply for Food and Drug Administration (FDA) approval by the end of the year, said Manuel Worcel, the company's chief medical officer. It hopes for approval sometime in 2005.
Heart failure, a condition in which the heart loses the ability to pump enough blood through the body, is often associated with coronary artery disease, high blood pressure and diabetes, according to the National Heart, Lung, and Blood Institute. Of the roughly 5 million people nationwide who had heart failure in 2001 -- the most recent year for which data is available, said Cohn, some 1 million were black. In 2001, about 9 percent of the 52,828 people for whom heart failure was listed as the primary cause of death were black, according to the American Heart Association.
BiDil is a combination of two drugs -- hydralazine and isosorbide dinitrate (also known as nitroglycerin) -- that have been available for decades in generic forms.
Hydralazine, often used to treat hypertension in the 1960s, went out of favor with the development of newer, more profitable drugs, such as ACE inhibitors and beta blockers.
"We now know that hydralazine not only acts to lower blood pressure, but it is an antioxidant . . . [and] protects arteries in the heart," Cohn said.
Isosorbide dinitrate is still commonly prescribed to treat chest pain, doctors said. The drug relaxes the arteries and veins, helping to deliver nitric oxide to the body, Cohn said.
Previous trials suggest that some black people may have a nitric oxide deficiency that BiDil helps to correct. Black patients have also been found to be less responsive to ACE inhibitor therapy for hypertension and heart failure, the study's authors said in telephone interviews.
NitroMed plans to conduct further research to see if other patients might also benefit from BiDil, according to Worcel, a cardiologist.
"Do we believe that only blacks have nitric oxide deficiency? Absolutely not," Worcel said. "The issue here is how to identify those patients that are going to be helped by drugs like [BiDil.]" The drug company hopes to identify other, less "crude" biomarkers, he said, to help them identify other patients who would respond well to BiDil.
Cohn said he has prescribed the two components of BiDil individually for many of his own patients with heart failure since 1980, when an earlier study showed benefits for patients of all races. "Many of my colleagues who have been around a long time are using the combination and have been for many years," he said.
New Route to Approval
The study that touched off the controversy began in June 2001, said lead author Anne Taylor, a professor of medicine and cardiology at the University of Minnesota. The 1,050 black patients who were randomly assigned to take BiDil or a placebo had an average age of 56. The BiDil group was about 55 percent male, and the placebo group was 63 percent male.
The trial, co-sponsored by the Association of Black Cardiologists, was supposed to end in 2005. But researchers stopped it in July, when benefits to the BiDil group were so great that the researchers could not defend withholding the drug from the placebo group. When the trial was stopped, 54 of the 532 patients in the placebo group had died, compared with 32 of the 518 patients in the BiDil group. That translated to a 43 percent improvement in survival among patients taking BiDil, according to the study.
Researchers also found a 33 percent reduction in the rate of first hospitalizations for heart failure among patients taking BiDil compared with those taking placebo. Patients taking the new drug also reported improved quality of life. BiDil also helped lower some patients' blood pressure, the authors wrote.
The trial, dubbed the African American Heart Failure Trial, followed an unsuccessful 1980s attempt to get the FDA to approve BiDil for all racial groups.
"The reason they turned [the earlier bid] down was not because they didn't think BiDil worked," said Jonathan Kahn, a law professor at Hamline University in Minnesota, who wrote an article for the Yale Journal of Health Policy, Law and Ethics about the history of BiDil and the controversy surrounding race-based treatments.
The problem was, said Kahn, researchers didn't design the trial to meet the kind of tests the FDA applies when new medications are submitted for approval. Taylor said researchers were conducting exploratory research -- to see if the drug, as theorized, might decrease the heart's workload, thereby helping it pump more efficiently.
Researchers later reanalyzed the data and found that black patients seemed to respond more favorably to BiDil than did whites. They published a study in 1999 in the Journal of Cardiac Failure that combined the results of two heart failure trials involving 395 black men and 1,024 white men. In one of those trials, black men taking the two components of BiDil had a slightly lower mortality rate than those on placebo; white patients taking the drugs saw no effect. The authors called for additional trials "involving large numbers of black patients" to further investigate their response to the drugs.
The data reported in the most recent study means almost certain FDA approval for BiDil use in black patients, doctors said. That expected approval would allow NitroMed to hold exclusive rights to the drug until 2022. The earliest BiDil could be on the market would be sometime in 2005.
But Kahn said the drug did not have to be tied to race to be approved.
"You come to realize how really terribly unfortunate it is that it [BiDil] became entangled with race, and that race -- in my mind -- is really being used here much more as marketing concept than as a medical concept," Kahn said. "And that's my real concern."
Taylor said she expects that other racial groups will benefit from BiDil as well. "We think that there will be [positive] effects in other groups of patients. What you need are sizable groups [in clinical trails] to show that," she said.
Without such proof, doctors said, official FDA approval will not likely be broadened. That means doctors wanting to use it for patients of other races will have to prescribe it "off label" -- the term for uses not specifically approved by the FDA, said M. Gregg Bloche, a Georgetown University law professor and an adjunct professor at the Johns Hopkins School of Public Health.
But identifying good candidates for BiDil by race could be tricky, said Bloche, since many people have backgrounds that include several different ethnicities. Color of skin, he said, is not an accurate marker of racial background.
"The concept of race is based on a tiny number of genetic characteristics," said Bloche. What matters more, Bloche said, are specific genetic patterns that affect how people respond to medications and other therapies. Members of any number of races may have these genetic characteristics. Environmental factors can make a difference, too, he said.
Kahn, the author of the study criticizing the association between BiDil and race, also expressed discomfort with the new study.
"It sends the message that because it was done only in African Americans that somehow African Americans are different genetically than everybody else. And that is a very dangerous message to be sending," Kahn said. "It's one that doesn't need to be sent in order to bring this drug to market."