BIDIL, a Heart Drug Targeted at African Americans, Stirs Complex Controversy

The Food and Drug Administration (FDA) approved the combination of the two old drugs, hydralazine with isosorbide dinitrate (BIDIL), on June 23, 2005 for the treatment of heart failure in African-American patients. Hydralazine (APRESOLINE) was first marketed for high blood pressure in January 1953 and isosorbide dinitrate (ISORDIL) in January 1968 to manage chest pain (angina).

BiDil is produced by NitroMed, Inc. of Lexington, Mass. Its two components are available as generics.

The FDA approval of BiDil grabbed headlines across the United States, not so much for its medical importance but because it is the first drug ever approved with the intention of its being used by one racial group — African Americans. While some experts, including African-American cardiologists, greeted the approval of BiDil as a positive step, others were concerned that it could reinforce ideas about racial differences that have justified discrimination.

In general, Public Citizen is deeply skeptical about the idea that medications can be effectively targeted toward specific racial groups. Racial categories are social constructs and are not, for the most part, based on biology. People of all races have the vast majority of their genetic makeup in common, and we have no strong reason to think that, except for particular rare conditions, people’s self-identified race is correlated very much with their biological makeup.

Another concern raised by the BiDil approval is that drug companies may use racially targeted marketing to extend the patent on certain products, keeping drug prices high and boosting corporate profits. The patent for BiDil would normally expire in 2007, but if the drug is marketed specifically to African Americans, the patent can be extended to 2020.

Specifically, BiDil is approved for the treatment of heart failure in addition to standard treatment in self-identified black patients to improve survival, to prolong time to hospitalization for heart failure, and to improve patient-reported functional status. In the clinical trial supporting the approval of BiDil, the African American Heart Failure Trial (known by its acronym A-HeFT) most patients were also being treated with a loop diuretic, furosemide (LASIX), an angiotensin converting enzyme (ACE) inhibitor, such as enalapril (VASOTEC), or an angiotensin receptor blocker — losartan (COZAAR) is an example. Beta blockers such as propranolol (INDERAL) were also being used and many patients were also receiving digoxin (LANOXIN) or spironolactone (ALDACTONE), a potassium-sparing diuretic, or water pill.

The A-HeFT study was stopped early because there was a significant reduction in deaths seen in patients taking BiDil compared to those receiving a placebo. The results of A-HeFT found a 43 percent reduction in death and a 39 percent decrease in hospitalization for heart failure compared to placebo.

The 43 percent reduction in deaths and 39 percent decrease in hospitalizations for heart failure compared to placebo are relative reductions in patients taking BiDil compared to those receiving placebo. Long-time readers of Worst Pills, Best Pills News will recognize that relative reductions do not give a complete picture of the benefit of a drug. The absolute difference in risk is also needed to more completely assess the therapeutic value of a drug and place its value in a meaningful context.

The publicly available FDA reviews of BiDil presented at June 16, 2005 meeting of the agency’s Cardiovascular and Renal Drugs Advisory Committee showed that in the A-HeFT trial 32 of 518 patients (6.2 percent) taking BiDil died compared to 54 of 532 (10.2 percent) of those given placebo. This is an absolute risk difference between BiDil and placebo of 4.0 percent.

In the A-HeFT trial 85 patients (16.4 percent) on BiDil were hospitalized for heart failure. In those patients receiving the placebo, 130 (24.4 percent) were hospitalized. This is an absolute risk difference of 8.0 percent.

The FDA documents on BiDil can be found on the agency’s Web site at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4145b2_Tablepercent20ofpercent20Contents.htm   

Concerns About Lupus

One major safety concern with BiDil is the possibility of drug-induced lupus erythematosus, or SLE, from BiDil’s hydralazine component. This adverse drug reaction is an inflammatory autoimmune disorder that may affect many organ systems in the body. Older research suggests that in women receiving 200 milligrams of hydralazine per day, the incidence of drug-induced SLE was 19.4 percent after three years of use. Even at lower dosages of 50 to 100 milligrams daily, the incidence in women was 5.5 percent after three years.

Drug-induced SLE differs from SLE in that the course of the disease is usually not as severe as SLE. Usually, the symptoms resolve within a few days to weeks after stopping the drug. The symptoms of drug-induced SLE are:

• Fever
• Loss of appetite
• General discomfort, uneasiness, or ill feeling (malaise)
• Skin rash
• Joint pain
• Joint swelling
• Blurring vision
• Chest pain

The usual starting dose of BiDil is one tablet three times a day and can range up to two tablets three times a day. A single tablet of the drug contains 37.5 milligrams of hydralazine and 20 milligrams of isosorbide dinitrate. That means patients can receive 112.5 milligrams to 225 milligrams of hydralazine per day.

The A-HeFT trial was published in the Nov. 11, 2004 issue of the New England Journal of Medicine. A commentary that was published along with the trial remarked on NitroMed’s economic strategy for BiDil. The company was able to obtain a patent based on the use of the two old drugs in African Americans. This patent was a first. Never before had a patent been granted to a pre-existing drug for a new, race-specific use, with the patent blocking generic competitors from entering the market for 13 years. Shortly after the patent was granted, NitroMed went public, raising $66 million, even though isosorbide dinitrate and hydralazine are available separately as generics. Using generics, it is possible to closely approximate NitroMed’s combination at a cost of about $.44 per dose.

The New York Times reported on July 8, 2005 that NitroMed has set the price of BiDil at $1.80 per pill. This is about four times the estimated cost of the two older generic drugs purchased by themselves.

What You Can Do

You should only be using BiDil for congestive heart failure in combination with other drugs for this condition. For one-fourth of the cost, with the cooperation of your physician, you can get prescriptions for the two generically-available drugs that comprise BiDil, isosorbide dinitrate and hydralazine.