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Two years after the Food and Drug Administration (FDA) approved BiDil—a heart failure drug indicated specifically for African Americans—only a relatively small percentage of the nation's estimated 750,000 black patients with this condition are being treated with the drug. Last year, the drug's first full year after its 2005 FDA approval, physicians wrote about 84,000 prescriptions for it, reports BiDil's manufacturer, Massachusetts-based NitroMed Inc.
Some physicians say cost is a factor. "BiDil has been farther down the [formulary] chain with most insurance carriers, so coverage for the medicine without a substantial co-pay has been a problem, and the medication is expensive," says Andrew L. Smith, MD, medical director of heart failure and transplantation at Emory Healthcare in Atlanta.
Some insurers don't cover it at all. Fewer than 100 of Smith's patients are taking BiDil. He says most others, who cannot afford or are unwilling to shoulder the burden of higher out-of-pocket expenses, rely on two generic drugs—isosorbide dinitrate and hydralazine hydrochloride—which are the key ingredients in BiDil.
BiDil is a fixed-dose, single-pill combination of the two generics. A recent cost analysis finds it is twice as expensive as either of its components.1 However, Jane A. Kramer, NitroMed's vice president for corporate affairs, says the drug is "affordably accessible on the major commercial, Part D, and Medicaid formularies at co-pays ranging from $15 to $25.
"Typically generic drugs carry a $10 co-payment," she says. "In many cases, BiDil is actually less costly than shelling out $20 for two prescriptions, which will not deliver the mortality benefit demonstrated with BiDil" (for a breakdown of generic versus BiDil costs, see "FYI").
RESEARCH UNDERPINNINGS
The medication is designed as adjunctive therapy for heart failure in self-identified black patients. Doctors typically prescribe it, in addition to standard treatment, to delay hospitalization, improve functional status, and reduce mortality. Physicians frequently try to achieve those same goals using the generic pills, says Smith, who is also a professor in the cardiology division at Emory University School of Medicine.
But he acknowledges "it's not possible to exactly mimic the BiDil combination with the use of separate generic medications."
The man behind BiDil is cardiologist Jay N. Cohn, MD, a professor at University of Minnesota Medical School in Minneapolis. He developed the drug in the late 1970s and prescribes it in his current practice.
"It is being prescribed and used, but not nearly to the extent it should be," Cohn says. "This probably reflects inadequacy of marketing and deficiencies in educating physicians and patients."
Cohn, who has signed a royalty arrangement with NitroMed and thus has a financial stake in the company, believes NitroMed's size may be adversely affecting sales. "NitroMed is a very small company without adequate resources to market the drug," he says. "They had hoped that data itself would sell the drug, but, unfortunately, aggressive advertising and marketing are essential."
Cohn organized and chaired the first long-term U.S. trials in heart failure, the Veterans Affairs Cooperative Vasodilator-Heart Failure Trial (V-HeFT) in the 1990s.2 He and other physicians contend that BiDil remains the most effective medication studied in black patients with heart failure, attaining a 43% decrease in all-cause mortality, 8% fewer first hospitalizations, and a highly significant reduction in overall scores on the Minnesota Living With Heart Failure (MLHF) questionnaire at 12 months compared with placebo. These favorable findings resulted in early termination of the African-American Heart Failure Trial (A-HeFT), also led by Cohn, enabling the placebo group in this trial to commence the BiDil regimen.3
A-HeFT had enrolled 1,050 self-identified black male and female patients with stable symptomatic heart failure—defined as impaired cardiac function and limited exercise tolerance—across 169 U.S. sites. In addition to maintaining standard therapy with digitalis glycosides and diuretics, 518 participants were randomized to receive BiDil and 532 to receive placebo for as long as 18 months.
The FDA based its June 2005 approval on the results of A-HeFT and two other trials: the placebo-controlled clinical trial V-HeFT I and the active-controlled clinical trial V-HeFT II, which compared BiDil with enalapril.4,5 In both cases, retrospective reviews showed that efficacy correlated with self-identified race.
"A-HeFT was not just done out of the clear blue," says Elijah Saunders, MD, an A-HeFT collaborator and professor of medicine in the cardiology division at University of Maryland School of Medicine in Baltimore. "There were some suggestions from the earlier studies that black patients who received [BiDil] would do better than they would do with standard therapy."
Saunders and others speculate that black patients may benefit more from the drug than those in other ethnic groups due to a difference in the bioavailability of nitric oxide. The presence of the compound plays an important role in combating heart failure. "In a population that may be low in the substance already, you might expect to get better results," he explains. "That is the leading theory."
In Cohn's view, "personalized medicine is the future. Identifying individual responsiveness to therapy will be critical, whether it be based on genotype, geographic origin, ethnicity, environment, or other factors. Race is currently a `placeholder' for more specific markers."
Some ethicists have criticized the tailoring of a medication for a racial group, but Saunders believes the research into BiDil is justified. He has prescribed the medicine for about 10 patients, all of whom, he says, "are doing well." Although it is too early to predict the long-term effects, Saunders says the patients have reported less shortness of breath and swelling than before they took the drug.
However, the drug doesn't work for everybody. About 20% of Smith's Emory patients discontinued BiDil because of side effects like headaches and dizziness. Still, side effects usually improve over time with dose adjustment, Smith notes.
THE RACE-BASED QUESTION
BiDil sets a precedent employing race as a predictor of drug response, says Susanne B. Haga, PhD, assistant research professor at Duke University's Institute for Genome Sciences & Policy in Durham, N.C. But she doesn't expect the trend to continue for a category "as imprecise as race." Rather, she foresees the day genetics-based, individualized assessment will play a larger role in drug customization.
Quantitative measurements, such as those based on genetic analysis, would serve as more accurate and reliable indicators of particular drug outcomes, she has argued in several papers—one of them concerning BiDil.6,7
"The overall study design was fine in that it accomplished its objectives in determining that BiDil was superior and equally safe compared with standard of care treatment for heart failure in a very selective population," Haga says. "Therein also lies its weakness, in that anyone could have self-identified as African-American, and therefore this inclusion criterion was imprecise, unquantifiable, and potentially inaccurate."
Haga notes that, at the FDA advisory committee meeting about the A-HeFT
data, a woman of apparent Asian ancestry asked whether she would have been
admitted to the study if she'd self-identified as black and met clinical
criteria. The study investigators responded, "Yes." 
Footnotes
BiDil costs about $1.80 a pill, which is about 10 times the cost of its generic combination of isosorbide dinitrate and hydralazine hydrochloride.
Source: Bibbins-Domingo K, Fernandez A: BiDil for heart failure in black patients: Implications of the U.S. Food and Drug Administration approval. Ann Intern Med 146: 52-56, 2007.
Available online at www.annals.org/cgi/content/full/146/152?ck=nck.
References
2. Carson P, Ziesche S, Johnson G, et al.: Racial differences in response to therapy for heart failure: Analysis of the vasodilator-heart failure trials. J Card Fail 4:178–187, 1999.
3. Taylor AL, Zeische S, Yancy C, et al.: Combination of isosorbide
dinitrate and hydralazine in blacks with heart failure. N Engl J
Med 351:2049–2057, 2004.
4. Cohn JN, Archibald DG, Ziesche S, et al.: Effect of vasodilator therapy on mortality in chronic congestive heart failure: Results of a Veterans Administration Cooperative Study. N Engl J Med 314:1547–1552, 1986.[Abstract]
5. Cohn JN, Johnson G, Ziesche S, et al.: A comparison of enalapril with hydralazineisosorbide dinitrate in the treatment of chronic congestive heart failure: V-HeFT II. N Engl J Med 325: 303–310, 1991.[Abstract]
6. Haga SB, Venter JC: FDA races in wrong direction.
Science 301:466, 2003.
7. Haga SB, Ginsburg GS: Prescribing BiDil: Is it black and white?
J Am Coll Cardiol 48:12–14, 2006.
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