Diseases of the heart continue to be the number one cause of death in the United States according to the Centers for Disease Control and Prevention (CDC). The published death report from 2006 shows that of the 2,426,264 deaths in the United States; 631,636 were associated attributed to diseases of the heart (CDC - DHDSP - Heart Disease Facts and Statistics, December 7, 2009). According to the Kaiser Foundation the death rate for heart disease is 190.9 per 100,000. Kentucky rates toward the last at the 42nd state with 220.9 per 100,000 deaths associated with heart disease. That statistic is even scarier when it is broken down as being the 13th highest state in terms of African American’s dying from diseases of the heart (Heart Disease Death Rate per 100,000 - Kaiser State Health Facts, n.d.). No specific data could be found in regards to heart failure only diseases of the heart. This paper will discuss pharmacological interventions specifically targeted at African American’s with heart failure.
In order to understand the treatment, the disease process should first be discussed. Heart failure can be caused by one of several mechanisms. Myocardial disease, valvular heart disease, congenital defects, and constrictive pericarditis cause impaired cardiac function. Where as increased pressure, increased volume, and increased perfusion cause excess work demands (Porth, 2005). Cheng’s description of heart failure is short and concise. “Heart failure is a
pathophysiological condition in which impaired cardiac performance leads to activation of the neurohormonal system. Reflex activation of hormones is not simply a compensatory mechanism but leads to other undesirable physiological processes such as apoptosis, endothelial dysfunction, decreased vasodilatory capacity, abnormal redistribution of blood and left ventricular remodeling” (Cheng, 2006, p. 668).
Cheng goes on to suggest that in African Americans that a deficient amount of nitrous oxide predisposed that population to hypertension and that uncontrolled hypertension leads to heart failure (Cheng, 2006).
Taylor’s description of heart failure is also a very good one. Taylor states that “left
ventricular dysfunction is associated with hemodynamic abnormalities, neurohormonal activation, and cellular alteration, which lead to the progressive vascular and myocardial remodeling that is characteristic of heart failure syndrome. Endothelial dysfunction and diminished nitrous oxide bioavailability are also associated with heart failure and contribute to the progression of vascular and myocardial remodeling in heart failure” (Taylor, 2005, p. 44i).
She goes on to state that “compared with European Americans, African Americans have a higher prevalence of heart failure, are younger at symptom onset, and are more likely to have heart failure caused by hypertension as opposed to ischemic disease” (Taylor, 2005, p. 44i).
One treatment for heart failure that has been shown to be extremely effective in African Americans is the combination of isosorbide dinitrate and hydralazine hydrochloride. This combination of medication was studied in the Vasodilator-Heart Failure Trial I and again in the Vasodilator-Heart Failure Trial II. Each study underwent subgroup analysis by ethnicity which showed that African American patients responded extremely well to the combination of isosorbide dinitrate and hydralazine (Taylor, 2005). This subgroup analysis gave rise to the African-American Heart Failure Trial and “was based on the following construct: myocardial dysfunction results in neurohormonal activation and diminished nitrous oxide availability leading to myocardial remodeling, and the relative contribution of impaired nitrous oxide bioavailability and neurohormonal blockade may vary by ethnicity” (Taylor, 2005, p. 45i).
The African American Heart Failure Trial was a randomized, placebo-controlled, double blind study used to determine the effectiveness of fixed doses of isosorbide dinitrate and hydralazine. There were a total of 1050 self identified African American patients with a diagnosis of heart failure with a classification of III or IV heart failure according to the New York Heart Association’s rating system. These patients had dilated ventricles and low ejection fractions (Taylor, 2005). The results indicate that “the addition of isosorbide dinitrate and hydralazine to a standard heart failure treatment regimen had a 43% reduction in mortality” (Hammermeister et al., 2009, p. 632). Cohn et al. goes on to elaborate that the African American Heart Failure Trial was prematurely stopped due to the high mortality rate of the placebo group and that the primary end point consisted of “a combination of mortality, hospitalization for heart failure, and quality of life measurements” (Cohn et al., 2007, p. 333). Cohn et al. also states “in the subgroups with echo measurements reported a 61% mortality reduction and a 38% improvement in event-free survival were observed” (Cohn et al., 2007, p. 333).
The results of the African American Heart Failure Trial lead the Food and Drug Administration to approve BiDil (a combination medication of isosorbide dinitrate and hydralazine hydrochloride). This medication made history because “BiDil was the FDA’s first approval of a racially targeted drug” (Yu, Goering, & Fulkerson, 2009, p. 57). However there have been some arguments to the FDA’s decision. The major argument is “that using race as a ‘descriptive’ variable can help identify differences in health and access/response to treatment that might warrant further investigation or interview” (Ellison, Kaufman, Head, Martin, & Kahn, 2008, p. 449). It appears from Ellison’s article that those authors felt the FDA’s decision was made very hastily.
Let’s now discuss each medication. Isosorbide dinitrate is classified in the nitrate family because it dilates the blood vessels allowing the blood to flow easier and the heart to pump more effectively. Hydralazine is an antihypertensive and lowers blood pressure by relaxation of the smooth muscle. It also interferes with cellular calcium metabolism. Use of hydralazine also results in decreases arterial pressure, decreases vascular resistance, increases heart rate, stroke volume, and cardiac output (Drugs.Com, 2000-2011).
Cheng describes how the combination of these two medicines works: “pharmacological modification of nitric oxide deficiency by administration of a nitric oxide donor, an antioxidant to prevent degradation of nitric oxide, or both may exert clinical benefits. Organic nitrates such as isosorbide dinitrate exert vasodilatory effects by acting as nitric oxide donors with in blood vessels, leading to improvements in nitric oxide deficiency seen in black patients” (Cheng, 2006, p. 669). Cheng also states that “when used with nitrates, hydralazine acts as an antioxidant and prevents development of nitrate tolerance” (Cheng, 2006, p. 666).
This author feels that the results of this study can best be summed up by Cohn et al. “A fixed-dose of isosorbide dinitrate and hydralazine induces further regression of left ventricular structural remodeling in black patients with heart failure already treated with renin-angiotensin-aldosterone inhibitors and sympathetic blockers. This structural effect likely accounts at least in part for the favorable effect of this drug combination in this patient population” (Cohn et al., 2007, p. 337). Hammermeister et al. adds that “the significant interactions between race/ethnicity and hydralazine and isosorbide dinitrate effects on both mortality and hospitalization for heart failure suggest that African-American patients respond differently to hydralazine and isosorbide dinitrate therapy than did white or Hispanic patients” (Hammermeister et al., 2009, p. 640).
The clinical significance of the FDA’s approval of a medication targeted specifically at a certain race because of the difference in response has far reaching effects. This could potentially give rise to further research based on any number of factors and how certain medications affect subgroups differently. This will eventually give rise to a more streamlined approach to medication administration as well as how new medications are developed and prescribed. BiDil was the first medication of its kind to be targeted to a specific subgroup of the population but probably will not be the last. The future research that can be done is virtually limitless.
Author: Jason Hawkins RN, BSN, MSN
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CDC - DHDSP - Heart Disease Facts and Statistics. (December 7, 2009). http://www.cdc.gov/heartdisease/statistics.htm
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Cohn, J. N., Tam, W., Anand, I. S., Taylor, A. L., Sabolinski, M. L., & Worcel, M. (2007). Isosorbide dinitrate and hydralazine in a fixed-dose combination produces further regression of left ventricular remodeling in a well-treated black population with heart failure: Results from a-heft. Journal of Cardiac Failure, 13(5), 331-339.
Ellison, G. T., Kaufman, J. S., Head, R. F., Martin, P. A., & Kahn, J. D. (2008). Flaws in the U.S. food and drug administration’s rationale for supporting the development and approval of BiDil as a treatment for heart failure only in black patients. Journal of Law, Medicine, & Ethics, 449-457.
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