Pharmacology Update: Isosorbide Dinitrate and Hydralazine HCL Tablets (BiDilTM)
By William T. Elliott, MD, FACP, and James Chan, PhD, PharmD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Associate Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.
Drs. Chan and Elliott report no financial relationships to this field of study.
The FDA has approved the combination of isosorbide dinitrate (ISDN) and hydralazine (IH) for the treatment of heart failure (CHF) in the black (African decent) population. This represents the first approval of a drug directed at a specific ethnic population. The combination pairs 2 older drugs that have been on the market for years, although neither is approved for heart failure. NitroMed, Inc. markets the combination as BiDilTM.
Indications
IH is indicated for the treatment of heart failure as an adjunct to standard therapy in self-identified black patients.1
Dosage
The recommended dose is 20 mg of ISDN and 37.5 mg of IH 3 times a day. The dose may be titrated to a maximum dose 40 mg of ISDN and 75 mg of IH 3 times a day.1 Each tablet of BiDil contains 20 mg of ISDN and 37.5 mg of IH.
Potential Advantages
In black subjects, mainly with New York Heart Association (NYHA) class III, and some class IV heart failure, the addition of IH to standard therapy increased survival, reduced the rate of first hospitalization for heart failure, and improved quality-of-life score compared to placebo.2
Potential Disadvantages
Adverse events associated with IH compared to placebo include headache (47.5% vs 19.2%) and dizziness (29.3% vs 12.3%).2 IH has been associated with lupus erythematosus.1 Concomitant use of IH with phosphodiesterase inhibitors (eg, sildenafil) may result in extreme drop in blood pressure. The combination of IH is inferior to an ACE inhibitor (eg, enalapril) in white patients.1,4
Comments
ISDN and IH are old drugs and the combination has been evaluated in 2 heart failure studies (Vasodilator Heart Failure Trial, V-HeFT I and II).3,5 IH was more effective than placebo but less effective than enalapril. Subsequent analysis indicated that IH was comparable to enalapril in blacks but inferior to enalapril in whites.4 The benefit of the combination was verified in a black population (African-American Heart Failure Trial [A-HeFT]). This was halted early due to survival benefit seen the IH combination vs placebo when added to standard therapy.2 Black subjects with primarily NYHA class III (96%) were randomized to IH or placebo above standard therapy for heart failure. Subjects randomized to IH had a lower mortality rate (6.2% vs 10.2%; P = 0.02), lower rate of first hospitalization for heart failure (16.4% vs 22.4%; P = 0.001), and improvement in quality of life as measured by the Minnesota Living with Heart Failure questionnaire. The most common side effects were headache (47.5% vs 19.2% for placebo) and dizziness (29.3% vs 12.3%). The actual mechanisms of action of this combination have not been established. It has been suggested that in addition to the vasodilator properties of each drug, IH may mitigate the tolerance to nitrates.1
The black population appears to have a less active renin-angiotensin system and a lower bioavailability of nitric oxide which could be restored by the combination of ISDN and IH.4 The wholesale cost of IH (as BiDil) at the maximum dose (6 tablets per day) is $324 per month. The individual drugs are available as generic preparations at much lower costs. NitroMed has set up a BiDil patient assistance program
Clinical Implications
Black patients with mild-to-moderate left ventricular systolic dysfunction, in general, appear to have a higher risk of progression to heart failure and death than whites.6 Blacks with heart failure also appear to have a higher incidence of previous hypertension than coronary heart disease.4 Isosorbide dinitrate and hydralazine provides addition benefit when added-on to standard therapy in black patients with advance heart failure. It may also be an alternative to an ACE inhibitor in patients intolerant of an ACE inhibitor.
References
1. BiDil Product Information. NitroMed Inc. June 2005.
2. Taylor AL, et al. N Engl J Med. 2004;351:2049-2057.
3. Cohn JN, et al. N Engl J Med. 1991;325:303-310.
4. Carson P, et al. J Card Fail. 1999;5:178-187.
5. Cohn JN, et al. N Engl J Med. 1986;314:1547-1552.
6. Dries DL, et al. N Engl J Med. 1999;340:609-616; Erratum in: N Engl J Med. 1999;341:298.
The FDA has approved the combination of isosorbide dinitrate and hydralazine for the treatment of heart failure in the black (African decent) population.
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