Heart failure is a major health concern in the US and is particularly problematic in the African-American community where the disease has an earlier onset and exhibits increased mortality, even with hospitalisation. Early onset is manifested primarily in middle-aged patients, where the rates of heart failure are higher than that with a higher mortality than in whites. Between the ages of 45 and 64, African-American males have a 70% higher risk for heart failure than Caucasian males. African-American females between the ages of 45 and 54 have a 50% greater risk to develop heart failure than Caucasian females. It is estimated that there are approximately 700,000 African-Americans with heart failure in the US, and this number is expected to grow to 900,000 by 2010.
These differences between the races is possibly related to hypertension as an underlying etiology, which leads to left ventricular (LV) dysfunction in blacks more commonly than in whites. Several clinical trials have identified and investigated this phenomenon, and interesting conclusions have been found.
Lessons Learned from Clinical Trials
Based on clinical trial data, the treatment for heart failure should be essentially the same for all populations. Unfortunately, the evidence for traditional medications such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and beta-blockers is not robust in the African-American population. Primarily due to small sample sizes in some of the large randomized trials, it may also be due to some differences in terms of etiology in many African-Americans, including the predominance of hypertension as an under-lying cause, increased obesity, and perhaps salt sensitivity.
Although the ACE inhibitor trials, such as Studies of Left Ventricular Dysfunction (SOLVD) show that in African-Americans, these inhibitors have less of an effect (specifically for hospitalization), this does not necessarily mean that ACE inhibitors should not be used in black patients. However, with the administration of ACE inhibitors, there may potentially be the need to also administer diuretics or higher doses to help control blood pressure and restrict sodium to ensure that the benefits of ACE inhibition are not blunted.
The angiotensin receptor trials have only contained small sample sizes of African-Americans. However, the Candesartan in Heart Failure Assessment of Reduction in Morbidity and Mortality (CHARM) trial showed that a small number of blacks did appear to benefit from candesartan when added to conventional therapy, including ACE inhibitors.
In addition, the beta-blocker trials seem to show some evidence that this treatment is of benefit to African-Americans. Although the mortality benefits with the meta analysis of beta-blocker trials appear to have been somewhat blunted, there are some data from the US Carvedilol Heart Failure trials program that a retrospective subgroup analysis that show carvedilol gives benefit for the prevention of hospitalization and potentially for decreasing mortality. Furthermore, sub group analysis in the Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure (MERIT-HF) appeared to have some benefits for hospitalization in African-Americans, although the mortality benefits were not clearly demonstrated.
The most recent trial, the African American Heart Failure trial (AHeFT), showed a 43% reduction in mortality using a fixed dose combination of isosorbide dinitrate and hydralazine (I/H), added to conventional therapy.This at least provides some confidence that black patients would benefit from this newer approach when added to conventional therapy in terms of decreasing mortality. There was also a 39% reduction in hospitalization, and a significant improvement in quality of life as measured by the Minnesota Living with Heart Failure questionnaire.
New Drug Combinations to Address the Issue
There is now commercially available a fixed dose combination of I/H, BiDiL (Nitromed) A similar formulation was demonstrated in the Vasodilator-Heart Failure Trials (VHeFT-I and VHeFT-II). In VHeFT-I the combination of isosorbide dinitrate and hydralazine was compared to placebo and seemed to have a benefit in the African-American cohort. In V-HeFT- II there was a comparison between of I/H and enalapril. Enalapril appears to be more beneficial in the general population. However, in the subgroup of patients identified as black, there appeared to be a similar response in terms of hospitalization and mortality, with the I/H as the enalapril. The fixed dose combination was then utilized with 20mg of isosorbide dinitrate and 37.5mg of hydralazine, started at one tablet, three times a day, with an increase to two tablets, three times a day as tolerated. This combination, added to conventional therapy, appeared to provide the benefits of decreased hospitalization, improved quality of life, and overall decreased mortality. It is therefore considered appropriate and has been suggested in guidelines from the American College of Cardiology (ACC), the American Heart Association (AHA), and the Heart Failure Society of America, that this combination be used in patients self identified as black to decrease morbidity and mortality for heart failure.
Although the outcome data appeared to not be as convincing regarding ACE inhibitors, ARBs, and even beta blockers for reducing mortality in African- American patients with systolic heart failure, the A-HeFT trial was structured to add the I/H combination to conventional therapy. Currently, based on study indications and the design of the study, it is suggested that the I/H be added after ACE inhibitors, ARBs, beta-blockers, and other conventional medicines for heart failure that have been initiated in African-American patients.
Dissecting Racial Differences in the Treatment of Hear t Failure
It is unclear why black patients may have benefited in the retrospective analysis of V-HeFT-I and V-HeFT-II, when compared with white patients.The A-HeFT trials did not make a race comparison so it is difficult to maintain based on A-HeFT alone that black patients would respond to I/H better than whites.The A-HeFT trial measured a self-identified population of 1,050 African-Americans with no whites included.
Nevertheless, it has been suggested, based on other small clinical trials, that African-Americans may have more endothelial dysfunction than Caucasians. African-American patients have been shown to benefit from a nitric oxide donor and there is a potential benefit with an antioxidant in the form of hydralazine to stabilize the vascular endothelium. It may also decrease the deleterious effects of earlier, more prevalent and severe sustained hypertension, leading to heart failure.
The Future of Care for African-American Heart Failure Patients
There is a need for more research into the increased rate and mortality of heart failure in blacks; it is simply not related to a lack of medication. These disparities probably reflect early onset and poorly controlled hypertension, and an increase rate of uncontrolled risk factors for coronary heart disease. If the total burden of heart failure were to be diminished it would be more effectively done by paying attention to risk factors, both with lifestyle modification and control of risk factors with medications prior to development of heart failure. Once heart failure has developed, although the heart failure has been treated with multiple medicines and there appears to be a benefit in terms of mortality, hospitalization and quality of life, with I/H. It is at a stage where is it too late to save many of the lives, which have been unnecessarily affected by this disease because of poorly controlled risk factors as previously described, that I/H gives greatest outcome benefit.
In the future there will possibly be genetic markers that will help in deciding which patients would best benefit from various medications—not only the standard medications, ACE inhibitors, ARBs, and beta-blockers, but also I/H. Fortunately, there is a substudy of the A-HeFT trial, the Genetic Risk Assessment in Heart Failure trial (GRAHF), that has carried out a genetic analysis and found preliminarily that there are some patients who have various polymorphisms benefit from the administration of I/H. Race is actually a poor marker for any genetic differences between people and in the future genomics will help to establish which patients best respond to which medications.