Treatment of High‐Risk African American Patients: Left Ventricular Dysfunction, Heart Failure, Renal Disease, and Postmyocardial Infarction

Abstract

African Americans experience more mortality and morbidity from hypertension‐related complications than other racial groups. Although angiotensin‐converting enzyme (ACE) inhibitors have clearly been shown to reduce mortality and morbidity in hypertensive white patients with heart failure, renal dysfunction, stroke, and acute myocardial infarction, African American patients have been underrepresented in these trials. The lack of direct evidence of the benefit of ACE inhibitors in these individuals and the suggestion that ACE inhibitors are less efficacious in this group has resulted in a reluctance to use ACE inhibitors in African Americans. However, retrospective analyses in black patients with heart failure and a recent randomized clinical trial in African Americans with renal dysfunction suggest that a regimen based on ACE inhibitors is efficacious in this racial group. Although diuretics remain first‐line therapy, data now suggest that ACE inhibitors provide additional benefit and should be considered for use in patients with high‐risk complications regardless of race.

Racial minorities have, until recent years, been underrepresented in clinical trials evaluating the effect of treatment in patients with hypertension‐related complications such as heart failure, renal dysfunction, stroke, and acute myocardial infarction (MI). Because there is some evidence that there are differences in the pathophysiology of these diseases between racial groups and in their response to treatment, ¹ the overall results of many of the large clinical trials cannot necessarily be extrapolated to all ethnic populations. African Americans with heart failure have a lower incidence of associated epicardial coronary artery disease, and this is most likely to be associated with hypertension. ² In the Studies of Left Ventricular Dysfunction (SOLVD) trial, ³ hypertension was the cause of heart failure in 32% of blacks but only 4% of whites. In contrast, coronary artery disease was a less frequent cause of heart failure for African Americans than whites (36% vs. 73%). Heart failure in African Americans also occurs at an earlier age and is associated with a higher incidence of left ventricular (LV) hypertrophy. This group of patients also has more advanced LV dysfunction at diagnosis and a worse clinical class at diagnosis than whites with heart failure ² ; those with LV systolic dysfunction are at a greater risk of death from any cause than similarly treated whites. ⁴ There may also be differences in response to treatment among racial groups. Some data suggest that African Americans with LV dysfunction are less responsive to treatment with angiotensin‐converting enzyme (ACE) inhibitors as monotherapy than whites. ⁵

Despite interracial differences to treatment, the high morbidity and mortality among high‐risk patients and the evidence that ACE inhibitors decrease mortality and morbidity in African Americans argues against withholding the use of ACE inhibitors in African Americans. There are emerging data suggesting that these agents produce substantial benefits in high‐risk African American patients. This report reviews the benefits of ACE inhibitors in the treatment of high‐risk patients, and includes approaches for the treatment and/or prevention of LV dysfunction and heart failure, renal disease, stroke, and acute MI.

LV Dysfunction and Heart Failure

The role of the renin‐angiotensin system in the generation and progression of heart failure is well established, primarily through the effector molecule angiotensin II. Angiotensin II has a number of physiologic properties, including vasoconstriction, induction of sodium and water retention, and mediation of endothelial dysfunction and atherosclerosis. ⁶ ACE inhibitors inhibit the detrimental effects of angiotensin II by blocking the conversion of angiotensin I to angiotensin II in the plasma and tissues. ⁶

The role of the renin‐angiotensin system on the pathophysiology of heart failure is confirmed by the established efficacy of ACE inhibitors in the treatment of LV dysfunction and heart failure in a number of clinical trials. ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² These agents have been shown to provide symptomatic relief and to decrease morbidity and mortality in a wide variety of patients. These studies included patients with asymptomatic LV dysfunction ¹¹ and with severe heart failure. ⁸ Most importantly, ACE inhibitors have been shown in a number of studies to decrease all‐cause mortality in patients with chronic heart failure (Table I). These and other benefits of ACE inhibitors in patients with heart failure are summarized in Table II.

Table I.

Effect of ACE Inhibitors on Mortality in Patients With Left Ventricular Dysfunction and/or Heart Failure

Trial	Patients	Mortality (%)		Relative Risk (95% CI)
		ACE Inhibitors	Control
CONSENSUS 8	Severe heart failure (n=253)	39	54	0.56 (0.34–0.91)
SOLVD 12	Heart failure and reduced LVEF (n=2569)	35	40	0.82 (0.70–0.97)
SOLVD 11	Asymptomatic with reduced LVEF (n=4228)	15	16	0.92 (0.79–1.08)
AIRE 7	Post‐MI with heart failure (n=1986)	17	23	0.73 (0.60–0.89)
SAVE 10	Asymptomatic LV dysfunction after MI (n=2231)	20	25	0.81 (0.68–0.97)
TRACE 9	Post‐MI with reduced LVEF (n=1749)	35	42	0.78 (0.67–0.91)
CONSENSUS=Cooperative North Scandinavian Enalapril Survival Study; LV=left ventricular; LVEF=LV ejection fraction; AIRE=Acute Infarction Ramipril Efficacy study; MI=myocardial infarction; SAVE=Survival and Ventricular Enlargement study; TRACE=Trandolapril Cardiac Evaluation study Other trial acronyms are expanded in text.

Table II.

Benefits of ACE Inhibitors in Heart Failure

Improved cardiac function and hemodynamics

Reduction in symptoms

Increased exercise capacity

Delayed development and progression of heart failure

Reduction in hospitalizations

Reduction in the incidence of myocardial infarction/sudden death

Prolonged survival

Exner et al. ⁵ performed a retrospective analysis of data on prevention ¹¹ and treatment ¹² in the SOLVD trials to determine whether there are racial differences in response to treatment. In this analysis, white patients (n=1196) treated with the ACE inhibitor enalapril had a significant reduction in the risk of hospitalization for heart failure (49%) whereas African American patients (n=800) achieved a smaller and nonsignificant risk reduction (14%). The difference in response between groups was statistically significant (p=0.005). Treatment with enalapril produced no significant change in the risk of all‐cause mortality for either racial group. However, it has been suggested that this analysis does not provide a sufficient basis for withholding ACE inhibitor therapy from African Americans with heart failure. ¹³ Rather, it has been argued that this study suggests that African Americans benefit from ACE inhibitor therapy (although not statistically significant), but that the degree of benefit was less than it could have potentially been if these patients had received larger doses of the study drug. It has been established that African Americans require higher doses of ACE inhibitors than whites to achieve a similar therapeutic result. ¹⁴ , ¹⁵

In contrast, another analysis of the SOLVD prevention trial ¹⁶ data provides support for the use of ACE inhibitors in African Americans. Enalapril was similarly effective in this group of patients and whites in decreasing the relative risk of the development of symptomatic heart failure in patients with asymptomatic LV dysfunction. ¹⁶ In this analysis, African Americans had a 33% relative risk reduction compared with a 39% relative risk reduction for whites.

Based on these results, race does not seem to be a legitimate reason for not utilizing ACE inhibitor treatment in African American patients with LV dysfunction and/or heart failure. This is rejected in recommendations from the Heart Failure Society of America and the American College of Cardiology/American Heart Association (ACC/AHA). Guidelines published by these organizations recommend that ACE inhibitors should be routinely prescribed to all patients with heart failure due to LV dysfunction. ¹⁷ , ¹⁸ In addition, these agents are preferred over the use of angiotensin II receptor blockers or direct‐acting vasodilators. ¹⁷ , ¹⁸ The use of these agents should not be delayed until patients are found to be resistant to other drugs. ¹⁷ It should be remembered that all of these recommendations assume that the patient is also receiving a diuretic. Monotherapy is rarely fully effective in treating these patients. According to the guidelines, angiotensin II receptor blockers should be reserved for those patients who are intolerant to ACE inhibitors. Valsartan is the only angiotensin II receptor blocker that has been approved for patients with heart failure who are intolerant to ACE inhibitors.

Renal Disease

Data from several studies have shown that ACE inhibitors, usually when given with a diuretic, are effective in slowing the progression of end‐stage renal disease in patients with diabetes and proteinuric nondiabetic kidney disease. ¹⁹ , ²⁰ , ²¹ The effect seems to be at least partially independent of blood pressure lowering. Because African Americans have a substantially greater risk of hypertensive end‐stage renal disease than whites, treatment has a potentially greater benefit in African Americans. ¹

Recent data from the African American Study of Kidney Disease and Hypertension (AASK) ²² indicate that ACE inhibitors provide clinical benefit to African Americans with renal dysfunction. This study showed that a ramipril‐based treatment regimen produced a slower progression of renal disease and a reduced risk of clinical events compared with amlodipine in 1094 African Americans with mild to moderate hypertensive renal disease and proteinuria. ²² The benefit was greatest in those with the most renal dysfunction at baseline. In patients with a urinary protein/creatinine ratio >0.22 (corresponding to a protein excretion >300 mg/day), treatment with an ACE‐based program produced a 36% slower decline in glomerular filtration rate compared with amlodipine‐based‐treated patients (p=0.006). In addition, ramipril‐treated patients had a 48% reduction in the risk of a composite index of clinical end points (reduction in glomerular filtration rate >50% or 25 mL/min/1.73 m ² , end‐stage renal disease, or death). However, because patients with protein excretion >2.5 g/day were excluded from the study, the effect of treatment on this group of patients with more severe renal disease is not yet known. Nevertheless, results from this study support the use of ACE inhibitors in African American patients with mild to moderate hypertensive renal dysfunction and proteinuria.

Stroke

Stroke killed more than 167,000 people in the United States in 1999. ²³ It is the third leading cause of death behind cardiovascular disease and cancer. Stroke is more common and is associated with a higher mortality rate in African Americans than in whites. Stroke mortality rates are one third to one half higher in these individuals than in their white counterparts. ²³ , ²⁴

Antihypertensive therapy has been shown to decrease the risk of stroke in both the primary and secondary prevention settings. A recent meta‐analysis of clinical trials ²⁵ showed that antihypertensive therapy reduces the risk of stroke by 42% in patients with elevated blood pressure. For example, in the Systolic Hypertension in the Elderly Program (SHEP), ²⁶ which included 4736 individuals (14% African American), an active stepped‐care regimen including treatment with a diuretic (chlorthalidone) with or without a β blocker (atenolol) decreased the risk of stroke by 36%. Similarly, final results from the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) ²⁷ found that treatment with chlorthalidone was associated with a 15% reduction in the risk of stroke compared with lisinopril. Notably, 35% of patients in this study were African American. The 15% relative increase in stroke incidence for lisinopril must be considered in the context of heterogeneity of the results by race.

Treatment regimens based on ACE inhibitors have also been shown to reduce the risk of stroke in a wide range of patient groups. ²⁸ , ²⁹ , ³⁰ In the Heart Outcomes Prevention Evaluation (HOPE) study, there was a significant reduction in the risk for stroke in high‐risk patients with vascular disease or diabetes (n=9297). ²⁹ , ³¹ , ³² In this study, the risk of any stroke was decreased by 32% (p<0.001) in patients receiving ramipril as part of a treatment regimen compared to those receiving medications that did not include an ACE inhibitor (Figure). This was despite only modest reductions in blood pressure (3.8/2.8 mm Hg), ²⁹ although a subgroup analysis of a small group of subjects (38) suggested a greater decrease in blood pressure on ambulatory blood pressure monitoring. In addition, the relative risk of fatal stroke was reduced by 61% in the ramipril‐treated patients. A regression analysis found the benefits to be independent of baseline blood pressure, the use of other cardiovascular medications, and the presence or absence of underlying conditions (e.g., previous stroke, coronary artery disease, peripheral artery disease, or hypertension). Ramipril reduced the risk of all types of stroke, although the differences did not reach statistical significance in all instances. For example, the relative risk of ischemic stroke was reduced by a statistically significant 36% in the ramipril group (0.64; 95% confidence interval [CI], 0.50–0.82). The relative risks, however, of hemorrhagic stroke (0.74; 95% CI, 0.35–1.57) and stroke of uncertain origin (0.79; 95% CI, 0.55–1.14) were also decreased, but not to significant degrees in those treated with ramipril. The use of an ACE inhibitor as part of the treatment regimen significantly reduced the risk of stroke (0.67; 95% CI, 0.50–0.90) in the subset of 3577 patients with diabetes. ³²

Figure.

The relative risk of developing stroke in patients receiving ramipril plus other drugs compared to a regimen without an angiotensin‐converting enzyme inhibitor in the Heart Outcomes Prevention Evaluation (HOPE) study. Adapted with permission from BMJ Publishing Group. BMJ. 2002;324:699–702. ²⁹

Treatment with ramipril as part of therapy produced significant improvements in functional and cognitive outcomes in the HOPE trial. ²⁹ Fewer patients in the ramipril group had changes in cognition compared with those receiving other medications (relative risk, 0.59; 95% CI, 0.37–0.94). Ramipril‐treated patients also had significantly less facial or limb weakness (0.72; 95% CI, 0.55–0.94) and significantly less dysarthria/dysphasia (0.68; 95% CI, 0.48–0.98) than patients in the non‐ACE treated group. ²⁹ Although the number of African Americans in the study was too small to identify as a subset (n=141), the data have been extrapolated to apply to this group of patients.

The Perindopril Protection Against Recurrent Stroke Study (PROGRESS), ³⁰ conducted in Asia, Australia, and Europe, assessed the effect of blood pressure lowering with an ACE inhibitor–based regimen in 6105 patients with a history of stroke or transient ischemic attack. Again, the African American cohort was too small to be analyzed in the results. Patients were randomized to receive perindopril with or without indapamide or placebo. Active treatment was associated with a mean reduction in blood pressure of 9/4 mm Hg over the 4 years of follow‐up. The overall risk of stroke was reduced by 28% in patients receiving the ACE inhibitor regimen compared with placebo‐treated patients (p<0.0001). The risk reduction in patients who were hypertensive at baseline (32% risk reduction) was similar to that achieved in normotensive individuals (27% risk reduction) only. Combination therapy of the ACE inhibitor and a diuretic decreased the risk of stroke (relative risk reduction, 43%; 95% CI, 30–54). Single‐agent therapy with perindopril was ineffective in reducing risk (5% risk reduction; not significant). Combination treatment also decreased the risk of total major cardiac events by 26% (95% CI, 6–42).

No prospective trials of African Americans with stroke have been performed. However, the high prevalence of stroke and stroke mortality and morbidity in this population and the clear benefit of ACE inhibitors in decreasing cerebrovascular events suggest that these agents (along with a diuretic) are reasonable medications to use.

Acute MI

A number of studies have shown that ACE inhibitors reduce morbidity and mortality when administered early in the course of an acute MI. ³³ , ³⁴ , ³⁵ However, although African Americans are at increased risk for heart failure, acute MI, and stroke, many of the studies were conducted outside of the United States and did not include many black subjects. The Fourth International Study of Infarct Survival (ISIS‐4), ³⁵ involving more than 58,000 patients, showed that treatment with captopril in the first 24 hours after the development of an acute MI produced a 7% (p=0.02) reduction in 5‐week mortality. This survival benefit was maintained with long‐term follow‐up. In the GISSI‐3 (Gruppo Italiano per lo Studio della Sopravvivenz nell'Infarto Miocardico) trial, ³⁴ which was conducted in Italy and included 19,394 patients experiencing an acute MI who presented within 24 hours of symptom onset, subjects were randomized to receive lisinopril or placebo for 6 weeks. Patients receiving the ACE inhibitor had a 12% (95% CI, 1%–21%) reduction in the risk of death and a 10% (95% CI, 2%–16%) reduction in the combined end point of death and severe ventricular dysfunction. Similar results were observed in the Survival of Myocardial Infarction Long‐Term Evaluation (SMILE) study, ³³ which included 1556 Italian patients randomized to zofenopril or placebo within 24 hours of the onset of acute MI symptoms. Treatment with zofenopril produced a significant decrease (34%; 95% CI, 8%–54%) in the risk of death or severe congestive heart failure at 6 weeks. The beneficial effect of ACE inhibitors in the treatment of acute MI was confirmed in a meta‐analysis ³⁶ involving more than 100,000 patients. This analysis showed that patients receiving ACE inhibitors usually in addition to other medications had a 6.5% overall odds reduction for death and an absolute reduction of 4.6 deaths per 1000 patients, ³⁶ compared to subjects on a regimen that did not include an ACE inhibitor.

These data suggest that ACE inhibitors have a role in the acute management of MI as well as in the convalescent phase. The American College of Cardiology/American Heart Association (ACC/AHA) guidelines ³⁷ recommend that, regardless of race or ethnicity, patients should receive ACE inhibitors within the first 24 hours (class I recommendation) if they have suspected acute MI with ST‐segment elevation in 2 anterior precordial leads, clinical heart failure in the absence of hypotension (systolic blood pressure <100 mm Hg), or a known contraindication. The ACC/AHA guidelines also recommend (class IIa recommendation) that all other patients should receive ACE inhibitors within the first 24 hours of a suspected or established acute MI, provided significant hypotension or other clear‐cut contraindications are absent. ³⁷ These recommendations suggest that they should be applied to all patients irrespective of race.

CONCLUSIONS

ACE inhibitor‐based treatment regimens have been shown to reduce morbidity and mortality in patients with a number of high‐risk cardiovascular and renal conditions such as LV dysfunction and heart failure, end‐stage renal disease, stroke, and acute MI. African Americans have an increased risk for many of these conditions and their associated morbidity and mortality. Despite differences in response ratios between African Americans and whites, there are emerging data, particularly for heart failure and renal disease, that ACE inhibitors produce similar benefits in African Americans and whites. Different dosages and appropriate combinations (particularly with diuretics) may be necessary to achieve benefit. Although diuretics remain first‐line therapy for hypertension in African Americans, the clear benefit of treatment with ACE inhibitors to reduce cardiovascular risk suggests that these agents be a part of a regimen regardless of race.