If you prefer to view this article in PDF form, click here.

Race-based therapeutics: A discussion surrounding heart failure trials

Why do some illnesses affect patients of certain races differently? Why is it that some patients respond to medications in different ways than do their counterparts of a different race? Is race-based therapy the solution? Here are some answers.

Natalie Schmitz, MMSc, PA-C

The author practices at Georgia Lung Associates, Austell, Georgia. She has indicated no relationships to disclose relating to the content of this article.

According to the American Heart Association, cardiovascular disease (CVD) remains the number one killer of Americans, claiming 37.3% of deaths per year and costing $403.1 billion in related medical costs and disability.¹ A total of 71.3 million Americans have one or more forms of CVD, which include but are not limited to stroke, hypertension, and heart failure (HF).¹ Alarmingly, blacks comprise the largest percentage of those with these forms of CVD, and they die disproportionately compared to other racial groups. Three percent of blacks have HF, and those with documented HF are well known to have poorer prognoses than white patients.^2-4 In addition, mortality and morbidity rates have decreased less dramatically in black populations over the past two decades.^1,5,6

Many speculations and hypotheses have been published in an effort to explain these disparities, including differences in socioeconomic status, certain genetic polymorphisms that predispose blacks to a more severe disease progression, and altered responses to standard drug therapies. Within the past 2 decades, an increasing number of clinical trials have been designed to test the above speculations, with the outcomes most often demonstrating a combination of factors. However, it is the differences in response to drug therapies that are garnering extra attention and that have provoked a discussion regarding race-based therapies.

Research findings

Numerous clinical trials have evaluated various medications for treating HF. In more than one instance, significant discrepancies in outcomes have been observed between racial groups (see Table 1, page 26). In addition, certain classes of medications appear to have different benefits for different races.^2,4,7-14 In general, research shows that blacks have a less active renin-angiotensin system and impaired nitric oxide (NO) availability compared to persons of other races.^{2,5,10-12,15-19} Given these physiologic differences, the results of the majority of HF trials are not surprising.

V-HeFT-I The first Vasodilator-Heart Failure Trial demonstrated that black patients had a decrease in annual mortality while taking a combination of isosorbide dinitrate and hydralazine as compared to similar white patients following the same regimen.^7,9 This drug combination serves as a NO donor, thereby replenishing an important antioxidant that is diminished in blacks.

SOLVD The Studies of Left Ventricular Dysfunction matched-cohort analysis showed that enalapril, an ACE inhibitor, had more favorable outcomes for white participants as compared to their black counterparts.²

V-HeFT-II The second V-HeFT trial studied the effects of enalapril versus isosorbide dinitrate and hydralazine.^9,18 The results showed no significant difference in mortality between these two study groups. However, when differences between racial categories were examined, white patients treated with enalapril showed a decreased risk of death and hospitalization with no statistical benefit observed in the black population. Upon further analysis, blacks did show a small response to the ACE inhibitor enalapril but responded more intensely to vasodilator therapy.

Beta-blocker trials Blacks similarly demonstrate a less robust response to beta-blockade. In the Beta-Blocker Evaluation of Survival Trial (BEST), subgroup analysis showed survival benefits in nonblack patients taking bucindolol.¹³ However, the US Carvedilol Heart Failure Trials showed equal benefits in both black and nonblack participants taking that drug.³ This difference in response to bucindolol versus carvedilol is perhaps attributable to differing adrenergic actions.^3,13,20-24 Bucindolol and some other familiar beta-blockers (such as metoprolol) are nonselective, meaning that they block beta-1 and beta-2 receptors equally. Carvedilol also blocks both but has a stronger effect on beta-2 receptors. Further, unlike bucindolol, carvedilol inhibits alpha-1-adrenergic receptors. This is noteworthy because black patients, compared to whites, have a greater response to cardiac beta-2 adrenergic stimuli and peripheral alpha-1 adrenergic stimuli. This difference allows a special benefit in black patients that is not seen with other nonselective beta-blocking medications.

No lasting conclusions

Although these trials are interesting and generate hypotheses, no conclusive results attribute differing medication responses to race alone. Several notable errors in the above mentioned trials make it difficult to draw any lasting conclusions. First, blacks are underrepresented in these clinical trials.^25,26 The enrollment for blacks was highest in V-HeFT-I at 29% and lowest in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF), with less than 5% of the enrollees being black. Second, most data with subgroup analysis of race were collected in a retrospective fashion and subsequently carry inherent inaccuracies. Furthermore, subgroup analysis requires a second study to validate the results. Before 2004, no prospective HF trials had focused solely on blacks.

A-HeFT

Given the poor representation of blacks in the previous trials and the inherent inaccuracies in post hoc analysis, the African American Heart Failure Trial (A-HeFT) was designed to be the first prospective HF trial with only black participants.¹⁵ It was also the first HF trial to use a composite end point of mortality, morbidity, and quality of life. The clinical premise behind A-HeFT is multifaceted. It is known that neurohormonal inhibitors alone or in combination slow the progression of HF and that endothelial dysfunction, impaired bioavailability of NO, and increased oxidant stress occur in HF and lead to further left ventricular (LV) dysfunction.^7-10,15-19 Moreover, V-HeFT I demonstrated that NO donor isosorbide dinitrate in combination with the antioxidant hydralazine showed a significant mortality and morbidity benefit in black patients who are known to be deficient in NO bioavailability.⁷ Given this information, the researchers sought to evaluate the efficacy of isosorbide dinitrate and hydralazine in black patients with NYHA class III/IV HF who were receiving neurohormonal blockers as background therapy.

The results of the trial were remarkable. In fact, A-HeFT was discontinued early, after randomization of 1,050 of the planned 1,100 participants, because of a 43% improvement in survival in the treatment group compared to those receiving standard therapy.¹⁵ The authors concluded that adding fixed-dose isosorbide dinitrate and hydralazine to standard therapy for HF is efficacious and as such confers a survival benefit among black patients with advanced HF.

Race-based therapy

With such striking results from A-HeFT, controversies surrounding race-based therapies have been especially prominent in the recent medical literature. The largest discussion focuses on how race is defined. Currently by the US census standards, race is defined by continental divisions: black, Asian, white, Hawaiian or other Pacific Islander, and Native American or Alaskan native. However, there is 90% to 95% more genetic variation within a continental population than between continents.^27-32 In addition, according to census data from the year 2000, 7 million people in North America claim a mixed racial heritage.³³ Many argue that race is a complex mix of biological and social influences and cannot be delineated simply by superficial markers such as skin color or continental divisions. Further, the division of racial lines by arbitrary markers has no proven scientific basis. With the advent of genomics, these superficial divisions of race will be substituted for a more substantial biological and genetic definition sometime in the future. Until then, we are left with arbitrary divisions of racial lines, which are often delineated by those who identify with a specific race.

The role of genetics Even though self-defined racial categories are considered flawed at best, researchers have found that self-defined ancestry is very highly correlated with genetically defined clusters.^32,34 This point is best illustrated by examining the frequency of mutant alleles within a population. Mutant alleles with a frequency of less than 2% are nearly always race-specific and are often associated with a particular ethnic group like the Amish, Ashkenazi Jews, or European gypsies. Mutations with a frequency of 2% to 20% are prevalent in a single racial group but not in others. For example, the mutant C282Y allele associated with hemochromatosis is found in all European groups, particularly northern Europeans, but is absent in nonwhite racial groups.^32,35 Other alleles occur in all ethnic groups but with highly variable frequency. An example is the variant that causes factor V Leiden, which is seen in 5% of whites but is found in much lower frequencies in East Asians and Africans, where the disease is almost nonexistent.^32,34,36,37

Genetics plus environment The above examples illustrate that certain diseases can be attributed to single mutant alleles. However, chronic diseases such as diabetes and heart disease are more likely the result of a combination of multiple genetic as well as environmental influences. In fact, when the rates of all common chronic diseases in America are examined, it is obvious that minorities, particularly blacks, are disproportionately affected.²⁷ Could this be genetic predisposition alone? Many would say probably not. Just as race is a product of social and biologic influences, health is also influenced by multiple complex variables such as social, cultural, and moral factors as well as genetic predispositions.

In reality, variation in health status is often more related to unequal privilege and power in populations stratified along socioeconomic lines. Furthermore, socioeconomic status is strongly correlated with race and ethnic background and is a predictor of access to quality health care and education.^27,32 However, even when these variables are controlled for, differences in outcomes persist. For example, the matched-cohort analysis of the SOLVD trial matched cases with similar demographic and clinical characteristics. Even when socioeconomic status was controlled through matching, white patients continued to demonstrate better outcomes than black participants.²

Other influences Once socioeconomic status and limited access to health care are accounted for and differences persist along racial lines, other potential sources of influence must be considered. Interestingly, many of the trials mentioned earlier found on average that black patients were younger (indicating an earlier onset of HF), more likely to have hypertension, and more likely to have been hospitalized.^11,26,38 These variables seem to imply that not only is the disease progression significantly different in black patients with HF as compared to their white counterparts but also that the disease process appears to be more aggressive.

Genetic polymorphisms Certain genetic polymorphisms noted in the black population may predispose those patients to a particularly aggressive CVD process and may explain the altered responses to certain drug classes.^25,39-42 In particular, there are several known beta-1 adrenergic receptor polymorphisms. Gly-389 is an example of a polymorphism that produces a receptor with decreased affinity for beta-1 agonist. ARG-389 together with an alpha2C Del322-325 receptor mutation is associated with an increased risk of HF in blacks. In addition to predisposing patients with these defects to an increased risk, these defects may explain why black patients in general show a less robust response to nonselective beta-blocker therapies compared to their white counterparts and more of a response to strong beta-2 adrenergic blockade.

Also present in many black patients is the polymorphism involving the eNOS gene. When present, this defect is thought to trigger a subsensitive NO system. As stated previously, NO protects against myocardial and vascular remodeling; with less protection, a patient may experience more severe disease progression.^15-19 In addition, a defect in this gene also impairs the chemical response to ACE inhibitors.^43,44 These agents increase bradykinin, an agonist of nitric oxide synthetase (NOS). When NOS is activated, it improves ventricular compliance. If the NOS gene is defective, the cascade begun by the ACE inhibitors confers no benefit on ventricular function. This may explain the less vigorous response to ACE inhibitors in black patients.

Another single nucleotide polymorphism involves TGF-B1 and is associated with accelerated vascular injury and left ventricular hypertrophy (LVH).²⁶ It is known that the incidence of LVH is three times higher in blacks and shows a greater malignant pattern.^26,43 TGF-B1 is thought to stimulate the production of endothelin, a potent vasoconstrictor. More importantly, the highest levels of TGF-B1 have been found in black patients and may explain not only their increased rates of LVH but also the more malignant course of hypertension seen in this population. These are just a few of the known polymorphisms seen commonly in blacks that may explain a more severe disease course. There are other known single nucleotide polymorphisms, and additional research is underway.

Conclusion

As several HF trials have shown, blacks respond differently from whites to standard HF drug therapies, including ACE inhibitors, nonselective beta-blockers, and vasodilators. These differences seem credible and may be explained, at least partially, by genetics. However, other complex variables, such as socioeconomic status and cultural factors, also play a prominent role in health outcomes. The results of A-HeFT led to debates regarding both the possibility of the FDA approving medications for a specific race and the inherent flaws in the current racial classification system.⁴⁵ Although the current definition of race is suboptimal, it may be a stepping stone to a more in-depth and biologically significant construct in the future. Hopefully, further clinical and scientific studies will bridge the gap between genomics and medicine, leading to better treatments for patients regardless of race, socioeconomic status, or culture.

© 2007 Haymarket Media, Inc. and the American Academy of Physician Assistants. All rights reserved.
Use of jaapa.com subject to License agreement. Please read our Disclaimer and Privacy policy.