FDA approves heart failure drug specifically for black patients
Calls action step toward promise of personalized medicine’
The FDA has approved a drug for the treatment of heart failure specifically in self-identified black patients, the first time an approval has targeted a racial group. In an announcement, the FDA said the approval represented a step toward the "promise of personalized medicine."
BiDil, a fixed-dose combination of the older, generic drugs isosorbide dinitrate and hydralazine hydrochloride, is indicated to improve survival, prolong time to hospitalization for heart failure, and improve patient-reported functional status, as an adjunct to current standard heart failure therapy in self-identified black patients.
The approval was based in part on the results from the recent African American Heart Failure Trial (A-HeFT), which was halted early, in July 2004, because of significant survival benefit seen with the drug. A-HeFT looked at 1,050 self-identified black patients who had New York Heart Association Class III or IV heart failure with dilated ventricles. The patients were randomly assigned to receive a fixed dose of isosorbide dinitrate plus hydralazine or placebo in addition to standard therapy for heart failure. The standard therapy included a loop diuretic, an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, and a beta-blocker. Many patients also received a cardiac glycoside or an aldosterone antagonist.
The patients on the isosorbide dinitrate/hydralazine combination experienced a 43% reduction in death and a 39% decrease in hospitalization for heart failure compared to placebo, and reported a decrease of their symptoms of heart failure.
Two previous studies had evaluated the safety and efficacy of the combination of isosorbide dinitrate/hydralazine combination in the treatment of heart failure — Vasodilator-Heart Failure Trial I and II (V-HeFT I and V-HeFT II). Medco Research originally had submitted the overall results for V-HeFT I and V-HeFT II in the original new drug application (NDA) and received a not approvable letter in 1997 from the FDA requesting additional clinical research.
NitroMed subsequently acquired the NDA. Investigators conducted retrospective reanalyses of the results from V-HeFT I and II and hypothesized that the observed benefit of the isosorbide dinitrate/hydralazine combination occurred primarily in black patients. "Through V-HeFT I and II, we had two clear-cut cases where it appeared that BiDil had a better response in blacks than in whites in the treatment of heart failure," says Manuel Worcel, MD, FAHA, chief medical officer for NitroMed in Lexington, MA.
NitroMed approached the FDA with this retrospective data and asked for an approval based on the reanalyses. The FDA told NitroMed that the data of the reanalyses was suggestive of a differential effect in blacks. If the company could provide a prospectively designed heart failure trial exclusively in blacks with confirmatory results, the FDA would consider an approval, Worcel says. NitroMed subsequently designed the A-HeFT trial, which was conducted between 2001 and 2004.
The precise reason that the isosorbide dinitrate/hydralazine combination works better in blacks is unknown. One suggestion is that the pill increases the body’s levels of nitric oxide; African-Americans more commonly have this deficiency.
"At the end, what counts is that we have seen a very significant and very impressive effect with this BiDil combination on clinical endpoints for heart failure patients," Worcel says.
Critics who charge that this approval may lend credence to the notion of biologic difference between races are misleading, he says. "[The approval] talks to a biologic difference between white and black patients with heart failure [in these trials]."
Environment plays an important role, Worcel explains. Access to medical care, lack of insurance, and lower educational level all have effects on the patient’s health as well as whether he or she smokes and is overweight.
Courting the black patient
NitroMed entered unchartered territory when it conducted the first clinical trial exclusively with African American patients, Worcel says. "We didn’t know how difficult this would be."
Organizations such as the Association of Black Cardiologists (ABC) in Atlanta and the National Medical Association in Washington, DC, supported the research. ABC co-sponsored A-HeFT and issued a statement in favor of the drug’s FDA approval. "The approval of BiDil is a major step toward eliminating existing cardiovascular-related health disparities affecting African Americans, a population that is disproportionately burdened by heart failure," said B. Waine Kong, PhD, JD, chief executive officer of the ABC, in a statement.
NitroMed used their assistance to identify experienced investigators and to create an ethnically sensitive message on what the trial meant and what benefits patients may receive from participating. The company had a challenge in that African Americans have not previously been a large presence in heart failure trials. The black patients included in V-HeFT I, V-HeFT II, and A-HeFT make up 40% of all the African American patients ever included in heart failure trials in the world, Worcel claims. He says is especially pleased that the trial didn’t lose any patient throughout its course.
Details about dosage
The isosorbide dinitrate/hydralazine combination is orally administered and is initiated at a dose of one tablet, three times per day, and may be increased to a maximum of two tablets, three times per day, based on patient tolerance, the company says. Adjustments to maximum dosage may occur in three to five days; however, adverse side effects, which may include headaches and dizziness, may require that some patients take more time to reach their highest tolerated dose.
Nitromed surprised some by pricing its isosorbide dinitrate/hydralazine pill at a wholesale acquisition cost of $1.80 per tablet. It will be supplied to pharmacists in bottles of 180 tablets. If one pill is taken three times a day, the cost will be at least $5.40 per day for the patient. Analysts told news agencies that they had expected the cost to be about half that much.
NitroMed, however, is offering a patient assistance program (PAP) that may blunt some of the criticism about the price. Through the BiDil PAP, NitroMed expects to make its isosorbide dinitrate/hydralazine pill available free of charge to patients without insurance coverage whose annual household incomes are up to three times the poverty level. For all others without insurance coverage, NitroMed expects to make isosorbide dinitrate/hydralazine pill available for $25 per prescription, which the company says is consistent with the copayment typically charged by private insurance for Tier II, or preferred branded drugs.
One concern has been whether physicians might take the two generic drugs, hydralazine and isosorbide dinitrate, and try to make their own combination therapy at a much lower cost, even though NitroMed’s pill is a fixed dose.
Neither component by itself has been shown to be effective in improving heart failure related to clinical endpoints, Worcel says. Many patients who will be taking this pill will also be taking multiple additional medications. If they decide not to take one of the components, they will lose all the benefits of the combination. "I would not advise anyone to do that," he says. "It doesn’t make sense."
The FDA has approved a drug for the treatment of heart failure specifically in self-identified black patients, the first time an approval has targeted a racial group. In an announcement, the FDA said the approval represented a step toward the promise of personalized medicine.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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