Heart Failure Management in African Americans: Meeting the Challenge

Abstract

Heart failure affects 3% of African Americans. The etiology of disease and prognosis for these patients differs substantially from those for non‐African Americans. A history of hypertension is associated with development of heart failure more often in African Americans than in non‐African Americans and it also appears that target organ involvement is more severe in African Americans with hypertension than in other patient subgroups. Reviewing the results from large‐scale clinical end point studies suggests that optimal treatment for heart failure in African Americans may differ from that of their non‐African American counterparts. More importantly, concomitant use of β blockers and angiotensin‐converting enzyme inhibitors may be as effective in African Americans as in non‐African Americans. Utilizing angiotensin–converting enzyme inhibitors alone may not represent ideal therapy. Of the drugs studied, especially among the β blockers, carvedilol may be the most effective to use for this population.

Optimal management of heart failure (HF), which affects 3% of African Americans, is an important health care priority. ¹ Optimal treatment of HF in this population is a particularly challenging clinical problem given that it may have an atypical natural history, unique epidemiology, and particularly poor prognosis. ² HF occurs at an earlier age in African Americans compared with other populations and it is more commonly associated with a history of hypertension than with epicardial coronary disease. ³ , ⁴ Hypertension plays a key role in the etiology of HF; as many as 60% of African Americans also have this condition. ⁵ The risks for mortality in African‐American men and women with HF are as much as 1.8‐ and 2.4‐fold higher, respectively, than those for other populations. ² , ⁵

The reason or reasons for these differences between African Americans and other populations are not clear, but it is worth noting that demographic information from large‐scale clinical trials suggests that socioeconomic factors probably do not play a significant role in the increased incidence and impact of HF. It is reasonable to suggest that the high prevalence of HF in African Americans is related to the higher incidence of hypertension and hypertensive heart disease. ² Severe hypertension is three to seven times more prevalent in African Americans than in whites, and left ventricular hypertrophy as well as other target organ damage is more common. ⁶ , ⁷ The prevalence of renal disease is also much higher in African Americans with hypertension than in whites. ⁷ All of these findings suggest that African Americans may have a more severe response to elevated blood pressure that results in increased target organ damage. The presence of more advanced left ventricular dysfunction and a greater severity of HF at the time of diagnosis support this view. ²

GENES, HYPERTENSION, AND HF: SIGNIFICANT EFFECTS OF RACE?

Results from several studies carried out over the past 20 years have suggested potentially significant influences of race on factors associated with the development of hypertension and HF, as well as responses to treatments for these conditions. Plasma renin activity is significantly lower in African Americans compared with whites, independent of age and blood pressure status. ⁸ The reduced activity of the renin‐angiotensin system seems to be associated with decreased responsiveness to angiotensin‐converting enzyme (ACE) inhibitor therapy in HF. For example, a post‐hoc analysis of the Studies of Left Ventricular Dysfunction (SOLVD) results indicated that enalApril treatment was significantly less effective in reducing risk for death or hospitalization for HF in African Americans than in whites. ⁵ However, when populations within the SOLVD database were matched for left ventricular function and trial participation, the racial differences were noted only as an increased frequency of hospitalization for African Americans that was not attenuated by the ACE inhibitor enalApril. In this matched cohort analysis of lower‐risk patients, there were no mortality differences as a function of race. ⁹ Results of the second Vasodilator‐Heart Failure Trial (V‐HeFT II) showed that enalApril was effective in reducing mortality in white patients compared with a regimen of isosorbide dinitrate and hydralazine. However, in African‐American patients, both regimens produced similar results, not because the ACE inhibitor was ineffective, but rather because the utilization of a nitric oxide donor and antioxidant (isosorbide dinitrate + hydralazine) was particularly effective in African‐American patients with HF. ¹⁰

Evidence supports that African Americans have attenuated nitric oxide‐mediated vasodilatory responses to methacholine and sodium nitroprusside. Although the underlying factors of this phenomenon are not completely understood, it may contribute to the higher risk of hypertension and, more importantly, hypertension‐related complications in this population. ¹¹

Recent genetic studies have provided further insight into potential reasons for the more severe response to hypertension in African‐American patients compared with white patients. Transforming growth factor‐β₁ is a fibrogenic cytokine that has been implicated in the development and progression of hypertension‐associated damage to multiple organs. Hyperexpression of transforming growth factor‐β₁ is more frequent in African Americans with hypertension than in whites, and it may be an important mediator of hypertension‐related target organ damage in this population. ¹²

There has also been growing speculation of polymorphisms of the β₁‐ and α_2c‐adrenergic receptors in progression of HF. A study done by Small et al. ¹³ examined the implication of such polymorphisms in African‐American and white subjects with transfected cells of each, both, and none of these polymorphic receptor cells. Their study revealed a substantial risk for HF in African‐American patients who were homozygous for both polymorphisms (p=0.001). They also suggested that the polymorphism associated with the α_2c genotype alone represented some degree of risk whereas the β₁ genotype alone was not associated. Continued speculation that the β₁ polymorphic genotype is a possible risk factor for HF progression continues to be studied. ¹⁴ , ¹⁵

THE ROLE OF β BLOCKERS IN THE MANAGEMENT OF PATIENTS WITH HF

The American College of Cardiology/American Heart Association have recently updated guidelines for the evaluation and management of HF (Figure 1). Patients are categorized as being at high risk for development of HF (stage A) or having asymptomatic HF (stage B), symptomatic HF (stage C), or refractory endstage HF (stage D). Recommendations for treatment vary according to stage, with β blockers being recommended for treatment of patients in stages B‐D. ¹⁶

Figure 1.

Stages of heart failure and recommended treatments. ACE=angiotensin‐converting enzyme; FHx CM=family history of cardiomyopathy; HF‐heart failure; IV‐intravenous; LV=left ventricular; MI‐myocardial infarction Adapted with permission from 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. Circulation. 2001;104:2996–3007 .

The well established utility of β blockers in the management of HF stems from the key role of sympathetic nervous system (SNS) activation in the genesis of symptoms, functional impairment, progressive ventricular dysfunction, and mortality in patients with this condition. ¹⁷ Combined analyses of results from large‐scale clinical trials have demonstrated the effectiveness of these drugs in reducing morbidity and mortality in patients with HF. ¹⁸ However, due to the limited enrollment of African Americans in some of the large clinical trials, the efficacy of β blockers in this population with HF is less clear. Results from several studies have suggested significant racial differences in the role of the SNS in the etiology of cardiovascular disease, and there are also significant genetic variations in the sensitivity and effector‐coupling of β adrenoceptors that might influence responses to SNS activation and to specific antihypertensive therapies. ¹⁹ , ²⁰ , ²¹ It is, therefore, important to explore the relative effectiveness of β blockers in African‐American compared with non‐African‐American patients with HF.

Bucindolol: The Beta‐blocker Evaluation of Survival Trial (BEST)

BEST assessed the effectiveness of bucindolol, a potent non‐selective β antagonist with mild vasodilatory properties and intrinsic sympathomimetic activity, compared with placebo in 2708 patients with New York Heart Association (NYHA) class III (92%) or IV (8%) HF and a left ventricular ejection fraction (LVEF) ≤0.35, who were also receiving an ACE inhibitor and in many cases a diuretic and/or digitalis as part of their optimal therapy. The results of this trial indicated no significant difference between active therapy and placebo in all‐cause mortality. Moreover, the null effects of bucindolol were most evident in African Americans compared with non‐African Americans (Figure 2). ²² The addition of bucindolol to ongoing therapy in the non‐African‐American cohort resulted in an 18% improvement in survival over 42 months of follow‐up. In contrast, survival decreased by 17% over the same period in African‐American patients (p=0.02 vs. non‐African‐American patients). ²³

Figure 2.

All‐cause mortality in African‐American and non‐African‐American patients in the β‐blocker Evaluation of Survival Trial (BEST). ²² There was an 18% increase in survival for non‐African Americans (p=0.01) vs. a 17% decrease in survival for African Americans (p=0.27).

US Carvedilol Heart Failure Trials Program. Carvedilol is a non‐selective β blocker with antioxidant properties and vasodilating properties that is approved for use in patients with HF. Yancy and colleagues ²⁴ specifically addressed the influence of race on the effectiveness of carvedilol in African Americans in a retrospective analysis of results from the US Carvedilol Heart Failure Trials Program. This evaluation included results from 217 African‐American and 877 non‐African‐American patients with NYHA class II‐IV HF and LVEF ≤0.35. Patients received carvedilol (6.25‐50 mg twice daily) or placebo in addition to ongoing multidrug therapy for up to 15 months. The results from this retrospective analysis (Figure 3) differed substantially from those seen with bucindolol. Addition of carvedilol to ongoing treatment decreased risk for the combined end point of all‐cause mortality and hospitalization by 48% in African‐American patients and 30% in non‐African‐American patients. Carvedilol also decreased the risk for worsening HF, defined as death, hospitalization, or a sustained increase in medical therapy, by 54% and 51%, respectively, in African‐American and non‐African‐American patients. Functional class, LVEF, and both patients' and physicians' global assessments were also improved significantly by carvedilol. Unlike the results for bucindolol, there was no significant interaction between race and treatment for any efficacy measure. ²⁴

Figure 3.

United States Carvedilol Heart Failure Study: effect of race on outcomes. The mean duration of the study was 6.5 months. *Not a primary end point Adapted with permission from N Engl J Med. 2001;344:1358–1365. ²⁴

Carvedilol Prospective Randomized Cumulative Survival(COPERNICUS)Study. The COPERNICUS study compared the addition of carvedilol and placebo to ongoing therapy in 2289 patients with severe HF (LVEF <0.25) and provided results very similar to those from the retrospective analysis summarized in the preceding section. Over an average of 10.4 months of follow‐up, carvedilol reduced risk for the combined end point of death or hospitalization for any cause by 24%, it decreased the risk for all‐cause mortality or hospitalization for cardiovascular causes by 27%, and it decreased the combined risk for death or hospitalization due to heart failure by 31%. All‐cause mortality decreased by 35% in patients who received carvedilol. Most importantly in the present context, there were no substantial differences between the effects of carvedilol treatment in African Americans and non‐African Americans (Figure 4). ²⁵ , ²⁶

Figure 4.

The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial: effect of race on outcomes. The mean duration of the study was 10.4 months. Adapted with permission from Packer M on behalf of the COPERNICUS Investigators. Effects of carvedilol on the survival of patients with severe chronic heart failure. Paper presented at: 73rd Meeting of the American Heart Association; November 11, 2000; New Orleans, LA.

Metoprolol: The Metoprolol Controlled‐Release Randomized Intervention Trial in Congestive Heart Failure (MERIT‐HF)

Metoprolol, a relatively selective β₁ adrenoceptor antagonist without intrinsic sympathomimetic activity or has vasodilating properties, has also been used extensively for the treatment of patients with HF, but results from MERIT‐HF suggested that it may be less effective in African Americans than in non‐African Americans. MERIT‐HF included 3991 patients with symptomatic chronic HF (NYHA class II‐IV, LVEF ≤0.40)—adding either metoprolol succinate or placebo to ongoing therapy—who were followed for an average of 1 year. Subgroup analysis of results from this trial (Figure 5) suggested that the efficacy of metoprolol in reducing the risk for all‐cause mortality or hospitalization for any reason was approximately the same in African Americans and non‐African Americans. In contrast, metoprolol appeared to be much less effective in decreasing total mortality or the combined end point of total mortality and hospitalization due to HF in African‐American compared with non‐African‐American patients. ²⁷ , ²⁸

Figure 5.

Subgroup analysis by race in the Metoprolol Controlled‐Release Randomized Trial in Congestive Heart Failure (MERIT‐HF). The mean duration of the study was 12 months. Adapted with permission from Am Hgeart J.>2001;142:502–511. ¹⁷

Comparison of Carvedilol and Metoprolol: The Carvedilol or Metoprolol European Trial(COMET)

Results from the large‐scale trials summarized in the preceding sections suggest that β blockers with different pharmacologic properties may differ substantially in their effectiveness in African‐American and non‐African‐American patients with HF. However, such a conclusion must be considered tentative until different drugs in this class are directly compared in a clinical trial. COMET is the first study designed to determine whether β‐blocking agents with differing pharmacologic profiles have different effects on morbidity and mortality in patients with HF. This study has enrolled 3029 patients from 15 European countries who were randomized to receive carvedilol (25 mg twice daily) or metoprolol tartrate (50 mg twice daily) in addition to their ongoing therapy. These patients were followed until a difference in events was observed, and the safety monitoring committee recommended early termination. ²⁹ The COMET Steering Committee recently announced new data revealing that carvedilol is significantly more effective than metoprolol and decreases the mortality risk by 17% in patients with HF. This suggests that carvedilol confers benefit in HF beyond that expected from β₁ receptor blockade.

CONCLUSIONS

The studies summarized here underscore the high prevalence of HF among African Americans; the etiology of HF in these patients may differ from that in non‐African Americans. Most importantly, a review of results from long‐term clinical end point studies shows that optimal therapy for HF may differ significantly between African Americans and other patients. There appear to be substantial variances in efficacy between different classes of agents (β blockers plus ACE inhibitors vs. ACE inhibitors alone) as well as for different drugs within a class (carvedilol vs. bucindolol and metoprolol). The data suggest that to effectively treat patients with HF and left ventricular systolic dysfunction, utilization of β blockers with ACE inhibitors is applicable to all patients and should be widely applied without respect to race.