On June 23, 2005, the U.S. Food and Drug Administration approved BiDil[R] (NitroMed Inc.) for the treatment of heart failure in self-identified black patients, the first such approval.
Approximately 80% of patients hospitalized with heart failure (HF) are older than age 651 and one out of 10 people age 80 and older suffers from HF. From 1979 to 2001, death from HF increased 155%. Fifty percent of patients older than age 60 with HF have an abnormal left ventricular ejection fraction (LVEF). (3-6) The prevalence of HF with normal LVEF increases with age and is higher in elderly women than in elderly men. (3-6)
In 2001, the prevalence of HF was 40% more common in black males than white males (3.5% vs 2.3%) and twice as common in black females as white females (3.1% vs 1.5%). (7) In 686 blacks with HF, mean age 79, prevalence of normal LVEF was 44% in men and 58% in women. (4)
Mortality from HF is significantly higher in persons with HF and an abnormal LVEF than in persons with HF and a normal LVEF. (5,6,8,9) The 1-year mortality of older patients with HF and an abnormal LVEF ranged from 19% to 41%. (5,8,9) In the Veterans Administration Cooperative Vasodilator-Heart Failure Trial (V-HeFT I), the 1-year mortality was 20% in men, mean age 59, treated with placebo. (10)
V-HeFT I reported that, compared with placebo, patients with HF and an abnormal LVEF randomized to hydralazine plus isosorbide dinitrate had a 38% reduction in mortality after 1 year, 25% after 2 years, and 28% after 2.3 years. (10) V-HeFT II reported that, compared with isosorbide dinitrate plus hydralazine, patients with HF and an abnormal LVEF randomized to enalapril had a 34% reduction in mortality after 1 year, 28% after 2 years, 14% after 3 years, 10% after 4 years, and 11% at the end of the follow-up period. (11)
The American College of Cardiology/American Heart Association guidelines recommend that patients with HF and an abnormal LVEF should be treated with diuretics for fluid retention and treated indefinitely with angiotensin-converting enzyme (ACE) inhibitors plus beta blockers (Class I indications). (1) These guidelines also recommend using isosorbide dinitrate plus hydralazine in patients with HF who cannot be given an ACE inhibitor or angiotensin receptor blocker because of hypotension or renal insufficiency with a Class IIa indication. (1)
Because the data from V-HeFT II suggested that blacks with HF treated with isosorbide dinitrate plus hydralazine did as well as blacks treated with enalapril, the African-American Heart Failure Trial (A-HeFT) was conducted. (12) This was a randomized, double-blind trial performed in 1,040 African Americans, mean age 57 years, with HF and an abnormal LVEF treated with diuretics, ACE inhibitors, and beta blockers who were randomized to isosorbide dinitrate plus hydralazine or to placebo. Only 23% of patients had ischemic heart disease.
At 10-month follow-up, compared with placebo, isosorbide dinitrate plus hydralazine reduced mortality 43% from 10.2% to 6.2% (p=0.02; NNT 25), reduced the rate of first hospitalization for HF 33% from 22.4% to 16.4% (p=0.001)(NNT=16.7), and improved quality-of-life score at 6 months (p=0.02). These data were submitted to the FDA as part of the approval process.
Patients treated for HF are usually older and have a higher prevalence of ischemic heart disease than the patients who were treated in A-HeFT. Patients with normal LVEF were not investigated in this study. This trial also should have included nonblack patients with HF.
We do not know from this study the effect of isosorbide dinitrate plus hydralazine in treating patients with HF who are older, who have a normal LVEF, or who are not African-American. Subgroup analyses should be performed investigating the effect of isosorbide dinitrate plus hydralazine in patients with HF with ischemic heart disease versus nonischemic heart disease and in men versus women.
The data from A-HeFT support the use of isosorbide dinitrate plus hydralazine in addition to diuretics, ACE inhibitors, and beta blockers in the treatment of African-Americans with HF in the population studied. The low mortality in this study in patients treated with isosorbide dinitrate plus hydralazine or placebo was probably due to the use of ACE inhibitors and beta blockers. This trial should also be repeated in a HF population that is not African-American.
Are we ready for race-based drug therapies? It would appear that with the approval of this drug for a self-identified racial/ethnic group, that day has arrived.
(1.) Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: Executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). Developed in collaboration with the International Society for Heart and Lung Transplantation. Endorsed by the Heart Failure Society of America. J Am Coll Cardiol 2001; 38(7):2101-13.
(2.) Kannel WB, Belanger AJ. Epidemiology of heart failure. Am Heart J 1991; 121(3 Pt 1):951-7.
(3.) Aronow WS, Ahn C, Kronzon I. Normal left ventricular ejection fraction in older persons with congestive heart failure. Chest 1998; 113(4):867-9.
(4.) Aronow WS, Ahn C, Kronzon I. Comparison of incidences of congestive heart failure in older African-Americans, Hispanics, and whites. Am J Cardiol 1999; 84(5):611-2.
(5.) Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction. J Am Coll Cardiol 1999; 33(7):1948-55.
(6.) Gottdiener JS, McClelland RL, Marshall R, et al. Outcome of congestive heart failure in elderly persons: Influence of left ventricular systolic function. The Cardiovascular Health Study. Ann Intern Med 2002; 137(8):631-9.
(7.) American Heart Association. Heart and stroke statistics--2004 update.
(8.) Pernenkil R, Vinson JM, Shah AS, Beckham V, Wittenberg C, Rich MW. Course and prognosis in patients [less than or equal to] 70 years of age with congestive heart failure and normal versus abnormal left ventricular ejection fraction. Am J Cardiol 1997; 79(2):216-9.
(9.) Aronow WS, Ahn C, Kronzon I. Prognosis of congestive heart failure after prior myocardial infarction in older men and women with abnormal versus normal left ventricular ejection fraction. Am J Cardiol 2000; 85(11):1382-4.
(10.) 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 1986; 314(24):1547-52.
(11.) Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325(5):303-10.
(12.) Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004; 351(20):2049-57.
Wilbert S. Aronow, MD
Dr. Aronow is clinical professor of medicine, department of medicine, divisions of cardiology and geriatrics, New York Medical College, Valhalla, NY.
Disclosure: The author has no real or apparent conflicts of interest related to the topic under discussion. Send comments to Dr. Sherman at email@example.com fax to 800-788-7188
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