New drug combo intensifies race-based medicine debate

A recent study shows positive outcomes for African-American patients treated with a new therapy for heart failure.

By — Posted Dec. 6, 2004

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When it comes to health care access, outcomes and even treatment issues, it is clear that race matters. A new heart drug therapy is now further complicating this reality and raising some awkward questions.

The African-American Heart Failure Trial found a drug combination of isosorbide dinitrate and hydralazine, known as BiDil, to be effective in reducing mortality and hospitalizations among black patients with heart failure, raising the possibility of medications that treat a single racial group.

If the Food and Drug Administration approves BiDil specifically for treating black patients, it would be the first time a race-specific drug is given the nod. But it also would follow years of troubling negative associations with race, based on well-documented disparities in quality and access to health care.

"Are we moving into a new era of race-based therapeutics?" asks M. Gregg Bloche, MD, co-director of Georgetown-Johns Hopkins Joint Program in Law and Public Health, in his Nov. 11 New England Journal of Medicine editorial. The BiDil trial findings were published in the same issue.

Whether the study represents an attempt to gain rapid approval from the FDA for a medication that is essentially a combination of two older drugs, or a marketing ploy, or a genuine effort to find effective treatments for blacks with heart failure is a matter of dialogue. Part of the debate centers on whether race and ethnicity might, in this light, prove to be positive variables, rather than factors that historically have made the field uneven. In other words, does a drug like BiDil function to close the treatment gap for minorities, or will it ultimately widen it further?

For physicians in the trenches, however, the approval of BiDil might have another impact. It could lead to a range of new race-centered discussions with patients as well as the likelihood that BiDil will move higher on the list of treatment options for patients, especially black patients, with heart failure.

More than skin deep

Physicians have known for a long time that patients of different races respond differently to cardiovascular medications, said Sally Satel, MD, a resident scholar at the American Enterprise Institute, a Washington, D.C., think tank that hosted a Nov. 12 symposium, "Race, Medicine and Public Policy." "Disease is not color-blind, and doctors shouldn't be, either," she said.

Responses of blacks and whites to drugs such as ACE inhibitors and beta-blockers mark only one therapeutic distinction. As a staff psychiatrist at a methadone clinic, Dr. Satel sees many patients who have hepatitis C, and, "for reasons we don't understand, African-American patients, on average, unfortunately don't respond well to standard therapy."

In addition, it is becoming apparent that African-Americans should initially be prescribed lower doses of antidepressants because, on average, they tend to metabolize those medications more slowly than do white patients, she said.

A study in the November Nature Genetics pointed to other such patterns, identifying 29 medicines, or combinations of medicines, that have different safety and/or efficacy profiles among different racial or ethnic groups.

Many researchers believe that genetics are driving those differences. Some are troubled by a possible overreliance on race or ethnicity as a proxy for those as-yet-undiscovered genetic pathways. This issue is one of the major scientific concerns as medicine wrestles with how and why some drugs work for some groups.

Keith Ferdinand, MD, one of the BiDil study authors who spoke at the symposium, cautioned that, while the data indicate a benefit to the drug for African-Americans, it does not necessarily prove that there is a genetic basis for this effect.

Thus, some physicians fear that pinpointing specific medications as more appropriate for certain races could lead to even greater health care disparities for minorities. Such targeting could lead to grave errors, because humans are far more nuanced genetically than is reflected in skin color, geneticists argue.

And genetics aside, Dr. Ferdinand noted, there are still conditions that need improvement when considering appropriate care for minorities. Culture and socioeconomic status play large roles, as does the historic distrust of the health care system that continues to linger decades after the infamous Tuskegee experiment.

Enormous interest is being focused on resolving health disparities, with the Dept. of Health and Human Services, medical colleges and physicians' groups all working to that end.

"The elimination of racial and ethnic disparities in health care is an issue of the highest priority for the AMA," said AMA President John C. Nelson, MD, MPH. "African-Americans suffer a disproportionate incidence of cardiovascular disease, and the AMA supports evidence-based approaches that address this problem."

But there is even a hope that over time, the concept of race will be dropped from the picture as genetic understanding expands.

Stephen Liggett, MD, director of the cardiopulmonary research center at the University of Cincinnati, has researched the genetics of heart disease. "Rather than define a person by skin color, we tried to make the case that we need to move as quickly as possible if there is a wide variability in response to a drug to find out what the genetic signature of that is and dispense with just using race."

The route to this discovery might not be all that long, he predicted. "We know the general pathways. We know the enzymes and the receptors involved. We can look at the genetic differences of the responders and the nonresponders, and we may get a hit right there."

In the case of BiDil, though, there is still more to be learned.

The drug could be found to work well for groups other than African-Americans and, conversely, it might not work well among all African-Americans with heart failure, Dr. Liggett said. "There may be a polymorphism or a series of polymorphisms that may be more predominant in individuals of African descent, but there will be plenty of individuals without that polymorphism who will look black."

Of course, for now, the physician has nothing but skin color to go on, he acknowledged.

It is for that reason and the fact that cardiovascular disease, especially congestive heart failure, wrecks such havoc among black populations that the BiDil findings are being applauded.

The drug demonstrated such clear benefit that the trial was halted early, Dr. Ferdinand noted.

Winston Price, MD, president of the National Medical Assn., said his group was "thrilled" with the finding and will now work toward helping African-Americans who can benefit from the medication to gain information on it and access to it.

The drug not only cut mortality nearly in half but also improved quality of life and reduced the chance of patients ending up in the hospital, he said. Because of such improved outcomes, the study should be viewed as a step toward resolving disparities in health care rather than as a means to raise the "ugly" issue of race-based medicine and race-based studies, he noted.

Criticism over the enrollment of only African-Americans is also not valid, he added. "Through the history of American medicine, African-Americans, as well as other minorities -- Native Americans, Pacific Islanders and Latinos -- repeatedly have had to rely on medications that were studied in Caucasians as an indication that this was a good treatment for them because it was studied and it worked. It shouldn't be the reverse concern because this study happened to be in African-Americans."

Randall Starling, MD, associate medical director of the Kaufman Center for Heart Failure at the Cleveland Clinic, also regarded the study findings as a gain. "I think that physicians should be encouraged that the combination of isosorbide dinitrate and hydralazine can be used with perhaps more confidence and enthusiasm than it has in the past."

The findings also could point the way to a more definitive genetic profile of which patients, regardless of race, might respond well to BiDil. "That, I think, is really the future," Dr. Starling said.

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African-American Heart Failure Trial

Findings: Patients who took BiDil -- a fixed-dose combination of isosorbide dinitrate and hydralazine -- with standard heart failure therapy experienced a 43% improvement in survival compared with patients who received standard therapy plus placebo. During the trial's 18-month run, 54 patients in the placebo arm died compared with 32 who took BiDil. BiDil is thought to enhance the production and utilization of nitric oxide.

Design: The randomized, double-blinded, placebo-controlled trial of 1,050 patients was halted after 18 months because of the higher mortality rate among those receiving the placebo.

Sponsors: NitroMed Inc., the manufacturer of BiDil, and the Assn. of Black Cardiologists.

Next steps: NitroMed has submitted a new drug application to the Food and Drug Administration and expects a product launch next year.

Sources: The New England Journal of Medicine and NitroMed

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External links

"Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure," The New England Journal of Medicine, Nov. 11, in pdf (link)

AMA on health disparities (link)

AMA's Ethics Standards Group on health disparities (link)

AMA's Minority Affairs Consortium (link)

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