Therapeutic Considerations in the African-American Patient With Hypertension: Considerations With Calcium Channel Blocker Therapy

Authors

  • John M. Flack MD,

    1. From the Wayne State University Health Center, Detroit, MI;1 and the Departments of Medicine and Pharmacology, Section of Clinical Pharmacology and Hypertension, Division of Nephrology, Virginia Commonwealth University, Richmond, VA2
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  • and 1 Domenic A. Sica MD 2

    1. From the Wayne State University Health Center, Detroit, MI;1 and the Departments of Medicine and Pharmacology, Section of Clinical Pharmacology and Hypertension, Division of Nephrology, Virginia Commonwealth University, Richmond, VA2
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John M. Flack, MD, MPH, Wayne State University, University Health Center, 2E, 4201 St. Antoine, Detroit, MI 48201 Email: jflack@intmed.wayne.edu

Abstract

African Americans have a higher prevalence, earlier onset, and more rapid progression of hypertensive end-organ disease, as well as excessive hypertensive mortality compared with other racial/ethnic groups. Most differences in hypertension and pressure-related complications between African Americans and whites appear to be quantitative and not qualitative. Improving the diagnosis, treatment, and control of hypertension in this highly vulnerable population is a major health care goal for the new millennium. In this regard the dietary pattern to be promoted for reduction of hypertension risk in African Americans is one of increased consumption of dairy products, fruit, and vegetables as well as a continued emphasis on decreased Na+ intake. When pharmacologic therapy is considered, multi-drug approaches are generally required, with diuretics, angiotensin-converting enzyme inhibitors (or angiotensin receptor blockers), and calcium channel blocker therapy as oft-selected components of most such treatment regimens.

The excess of hypertension among African Americans has been recognized since the early part of the 20th century and accounts for an important portion of the African American health disadvantage.1 The incidence (especially in women) and the prevalence of hypertension in the African-American population has now reached troubling levels. It has been well documented that African Americans have a higher prevalence, earlier onset, and more rapid progression of hypertensive end-organ disease, as well as excessive hypertensive mortality compared with other racial/ethnic groups.1 Improving the diagnosis, treatment, and control of hypertension in this highly vulnerable population is a major health care goal for the new millennium.

EPIDEMIOLOGY

The United States is an ethnically diverse nation composed of individuals from many cultures. The American Community Survey from 2003 has “black” or “African-American” people currently constituting 12.1% of the American population, which is comparable but less than the 13.9% of Hispanics or Latinos in the United States.2

The prevalence of hypertension is higher in African Americans than in whites, especially at younger ages and in women.3 The age-adjusted prevalence of hypertension in non-Hispanic blacks, whites, and Mexican-American men is 30.9%, 27.7%, and 20.7%, respectively. Among women in these same three groups the age-adjusted prevalences differ more, being 35.8%, 30.2%, and 20.7%, respectively.3 Furthermore, the increase in hypertension prevalence over the last decade has been much larger for women than men.

PATHOPHYSIOLOGY

At the group level, quantitative—not qualitative—differences in the physiologic characteristics of hypertension have been documented between African Americans and whites. Thus, there are no pathophysiologic or hemodynamic factors that are unique to African Americans or any other racial or ethnic group.

That being said, compared with whites, African Americans generally have a more salt-sensitive form of hypertension in association with lower basal and/or stimulated levels of plasma renin activity (PRA).4,5 Suppressed PRA levels are generally associated with plasma volume expansion, a finding that has been noted in several studies (though not all) of African-American hypertensives.5,6 Also, when African Americans are salt-restricted, the rise of PRA is less than in whites, which may at least partly explain the greater fall in blood pressure (BP) in African Americans with a cutback in Na+ intake.6 Intracellular Na+ levels have been consistently higher in African Americans than in whites, and several population-based studies have demonstrated a positive correlation between elevations in intracellular Na+ levels and hypertension prevalence.7 In addition, the age-related drop in PRA occurs at a much earlier age in African Americans than in whites.

The role of intravascular volume expansion as the primary factor leading to a tendency toward suppressed renin in African Americans has been controversial, however, in part because the control of renin synthesis and secretion is very complex and influenced by other factors such as angiotensin II, endothelin, and sympathetic nervous system tone. We recently proposed that suppressed circulating renin, particularly in salt-sensitive individuals, might also be a consequence of centralization of the circulating blood volume in states such as obesity that are characterized by endothelial dysfunction-induced venoconstriction and salt sensitivity.8 We have linked obesity to salt sensitivity in normotensive African Americans,9 and others have linked obesity to resistance to antihypertensive treatment.8,10 We have further postulated that the association of obesity to antihypertensive treatment resistance is mediated significantly through salt sensitivity. The importance of these physiological tendencies is, however, unclear, as they have not been linked to differences in clinical outcomes in specific hypertension end-point trials and have rarely been correlated to BP responses.

Other neurohumoral abnormalities have been observed in African-American hypertensives, though the cause-and-effect relationship between each and the onset and/or progression of hypertension is poorly delineated. For example, immunoreactive endothelin-1 concentrates are considerably higher in African-American hypertensives than in normotensive African Americans or hypertensive whites.11 In addition, transforming growth factor β, a multifunctional cytokine with fibrogenic properties, is hyperexpressed in African-American patients with end-stage renal disease.12 Finally, under conditions of high Na+ intake, salt-sensitive hypertensive African Americans paradoxically decrease atrial natriuretic peptide secretion, which may attenuate natriuresis.13 Additional neurohumoral factors that may influence BP and/or renal salt and water handling include decreased levels of kallikrein-kinin, bradykinin, prostaglandin E2, and dopamine β hydroxylase.14,15 It is, however, unclear if these physiological tendencies are inherited secondary to long-term environmental exposures, or are simply artifacts of contrasting convenience samples of racial groups that were not very comparable to begin with—possibly being at different stages in their natural history of hypertension.

END-ORGAN DISEASE CONSIDERATIONS IN HYPERTENSIVE AFRICAN AMERICANS

There are a number of end-organ disease and treatment considerations in hypertensive African Americans that need to be considered (Table I). Most differences in hypertension and pressure-related complications between African Americans and whites appear to be quantitative rather than qualitative. Heterogeneity in the risk for hypertension, the response to antihypertensive therapy, and the occurrence of pressure-related complications such as stroke and kidney disease have been described within race and ethnic groups when these risks have been stratified either by geography, socioeconomic status, or dietary habits. These within-race differences are typically several-fold larger than previously described interracial differences in these same outcomes.8,16

Table I.  Special Considerations Relative to End-Organ Disease in African Americans With Hypertension
Cerebrovascular accidents-in particular intracerebral hemorrhage-are more common than in whites.
The incidence of end-stage renal disease is several-fold higher than in whites; transforming growth factor β1, a profibrotic substance, is hyperexpressed in African-American hemodialysis patients.
Left ventricular hypertrophy is more prevalent than in whites, which may partially explain the higher rate of sudden cardiac death in African Americans. Exercise favorably impacts left ventricular hypertrophy.
There is a disproportionate rate of coronary heart disease mortality, particularly in women, compared with whites, possibly related to greater clustering of known coronary artery disease risk factors.
Hypertension is a persistent major problem in the development of congestive heart failure.
Obesity, particularly in African-American females, may contribute to the high rates of hypertension and target organ injury.
Nocturnal “nondipping” blood pressure patterns and blood pressure elevations are more common.

TREATMENT CONSIDERATIONS IN HYPERTENSIVE AFRICAN AMERICANS

Nonpharmacologic Therapy

The issue of dietary intervention in the treatment of the African-American hypertensive is of some importance. In fact, it is now evident that the excessive hypertension risk in African Americans may, in substantial part, be due to a specific clustering of multiple dietary factors, the most important of which are a decrease in K+ intake in association with an increase in the Na:K dietary ratio, and/or decrease in calcium intake.17–19

Recent studies employing the Dietary Approaches to Stop Hypertension (DASH)20 diet have shown significant BP-lowering effects. The DASH study was a randomized controlled study of 459 adults with untreated systolic BP <160 mm Hg. Participants fed a normal control diet for 3 weeks were then randomized for 8 weeks to one of three diets: 1) the control diet; 2) a diet rich in fruit and vegetables; or 3) a combination diet rich in fruits, vegetables, low-fat dairy products, and with reduced saturated fat, total fat, and cholesterol (the DASH combination diet).

The DASH combination diet significantly lowered systolic BP in all subgroups and reduced diastolic BP, but to a lesser extent. It is noteworthy that the combination diet lowered systolic BP significantly more in African Americans (6.8 mm Hg) than in whites (3.0 mm Hg).21 Moreover, an even lower intake of Na+ (DASH-Sodium diet study)22 of approximately 60 mmol/d further reduces BP in a broad population of nonhypertensive and hypertensive individuals. In this study, the effects of dietary Na+ reduction tended to be greater in African Americans than whites.

Based on these studies, it is reasonable to conclude that the dietary pattern to be promoted for reduction of hypertension risk in African Americans is one of increased consumption of dairy products, fruit, and vegetables as well as a continued emphasis on decreasing Na+ intake. Those African-American patients who cannot successfully adopt a DASH-like diet should at least increase dietary K+ and calcium, exercise regularly, lose weight, moderate alcohol intake and take steps to reduce stress levels.23

Pharmacologic Therapy

There appears to be no compelling reason to suppose that drug selection for African Americans differs from that for other race or ethnic groups unless dictated by clinical characteristics, which vary at the individual level. Therapeutic recommendations for African Americans have typically been guided by the idea that certain monotherapies— such as thiazide-type diuretics or calcium channel blockers (CCBs)—are more effective in lowering BP than either angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker, or β-blocker monotherapy.

To a certain degree, this therapeutic approach is flawed. In trials where BP was, on average, lowered more by diuretics and CCBs than by other drugs such as ACE inhibitors, the average BP typically remained above goal—accordingly, three to four drugs have typically been needed to reach therapeutic BP targets in high-risk hypertensive patients. Another important issue relating to supposed therapeutic maxims regarding the African-American patient is the blanket extrapolation of group differences to the individual patient. This is particularly the case with the notion that suppressed PRA and/or expanded plasma volume are the norm when, in fact, many African Americans exhibit normal to reduced plasma volume and/or a relative or absolute degree of renin-angiotensin axis activation.

Multi-drug therapy to reach goal BP in the African-American hypertensive is a well appreciated concept; however, important observations concerning CCB as well as ACE-inhibitor use in African Americans have emerged from recently completed clinical trials. These observations can now be merged with available guidelines to develop a best clinical practice to BP control in the hypertensive African American (Table II, Table III).

Table II.  Special Treatment Considerations in African Americans With Hypertension
Hypertension is more common and more severe than in whites.
There is a persistent high rate of undetected, untreated, and uncontrolled hypertension.
Target organ damage is more likely to be present at any given level of blood pressure.
The patient is likely to be younger than his or her white counterpart, presenting potential age-related problems with medication adherence.
Socioeconomic considerations including lack of access to physicians, medications, and other health care resources exist.
Low socioeconomic status, low levels of formal education and exposure to violence lessen the success of antihypertensive therapy.
Uncontrolled severe hypertension is more likely to be seen in current smokers, and smoking, as a marker of poor health behavior, is associated with medication nonadherence.
Responses to individual medications or combinations of drugs may be different in individual patients in this population.
A high need for multi-drug therapy for blood pressure normalization exists.
Will more often encounter factors linked to treatment resistance—obesity, target organ injury, reduced kidney function, proteinuria.
Table III.  Treatment Considerations With Calcium Channel Blocker Therapy
Advantages
Broadly effective blood pressure-lowering efficacy profile (African Americans, diabetics, elderly)
Superior stroke risk reduction
Useful in diastolic dysfunction (rate-lowering)
Metabolically neutral
Minimal erectile dysfunction in males
Blood pressure-lowering effect is robust in setting of high dietary sodium intake
Blood pressure-lowering effect not attenuated by nonsteroidal anti-inflammatory drugs
Disadvantages
Immediately postmyocardial infarction or during unstable angina (short-acting dihydropyridines) may increase coronary heart disease risk
Rate-lowering calcium channel blockers can worsen congestive heart failure and mortality in patients with systolic heart failure
Incident rate for first heart failure episode increased compared with diuretic therapy and blockers of the renin-angiotensin-aldosterone system
Side effect profile varies (verapamil: constipation; dihydropyridines: pedal edema and vasodilatory symptoms)
Rate-limiting calcium channel blocker plus β blockers can result in profound bradycardia and depression of myocardial contractility

Therapeutic Concepts in the Hypertensive African American

Calcium Channel Blockers.

CCBs are particularly effective in reducing BP in African-American patients with hypertension and are an important component of most multi-drug regimens used to reach goal BP values24–26; moreover, unlike most other non-diuretic hypertensives, CCBs appear to manifest a more robust BP-lowering effect in the setting of a high salt intake for salt-sensitive hypertensives (Figure).27 CCBs can significantly reduce BP in severe hypertensives even when administered as monotherapy—and in so doing, effectively regress left ventricular hypertrophy while not adversely affecting pulse rate.28

Figure Figure.

Blood pressure (BP) reduction with the calcium channel blocker isradipine compared with change in BP with enalapril in African-American hypertensives. The final result represents the absolute level of BP attained at the end of each treatment period. In the isradipine group there was no statistical difference in the final result in BP levels between the high-salt and low-salt diets. Reduction of BP with isradipine therapy was, however, significantly greater vs. enalapril during the high-salt diet (p<0.01 for mean arterial pressure difference). Enalapril lowered BP much more effectively during the low sodium diet than during the high sodium diet. SBP=systolic blood pressure; DBP=diastolic blood pressure

ACE Inhibitors.

A number of issues need to be considered to correctly interpret the response to an ACE inhibitor in the African American with hypertension. First, the implicit assumption that African-American hypertensives in clinical trials are similar to white hypertensives is often incorrect. Often there are pre-randomization differences in duration of hypertension, BP levels, smoking status, and/or level of renal function—all of which can influence BP response and therefore potentially confound observed BP response differentials. Racial contrasts in BP response are almost always post hoc comparisons of convenience samples that are outside the usual protections of the randomization process. Thus unadjusted BP response contrasts between racial groups are exceedingly difficult to interpret.

Second, the difference in BP response with ACE inhibitors in African-American hypertensives is most prominent at relatively low doses and either diminishes markedly or disappears altogether with titration of the drug dose into the middle or the upper part of the dosing range.25,29

Third, relatively smaller differences in mean BP responsiveness have overshadowed the much greater heterogeneity of BP response within racial groups.8,16 Investigators have noted that some African-American hypertensives exhibit a significant BP response to drugs such as ACE inhibitors and β blockers.8,16

Application of Guidelines and Clinical Trials to African-American Hypertensives

ALLHAT.

In the recent Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),26 in which 35% of the patients were African American, the diuretic chlorthalidone was associated with greater reductions in BP than the ACE inhibitor lisinopril. Chlorthalidone was also associated with a relative risk reduction in stroke compared with lisinopril. However, the higher stroke risk relative to chlorthalidone in the lisinopril group was experienced only in African-American patients and can plausibly be explained by the lesser BP reduction in the lisinopril treatment group, where systolic BP was on average 4 mm Hg higher. The BP differences were likely even larger between the lisinopril and chlorthalidone treatment groups in preceding study years. The ALLHAT design employed a rather restrictive sequence of treatments scheme, which in no way mimicked accepted clinical practice—particularly as related to African-American hypertensives—in that diuretic therapy was not permitted as add-on therapy in either of the two non-diuretic treatment arms.

In ALLHAT, in a high-risk population (not surveyed for protein excretion) amlodipine was comparable to chlorthalidone and lisinopril for renal event rates as well as for an estimated rate of decline of renal function in an elderly population. This is a pertinent observation, because dihydropyridine CCBs have increasingly been viewed as good antihy-pertensives but ones that do not specifically provide renal protection akin to the achieved BP reduction.26 Also, there was no difference in coronary heart disease event rates in the amlodipine chlorthalidone, or lisinopril groups—despite the fears of some that calcium antagonists, particularly the dihydropyridines, actually increased coronary risk.

African-American Study of Kidney Disease and Hypertension (AASK).

The final results of the AASK trial have shown that the ACE inhibitor ramipril was better than the β blocker metoprolol or the dihydropyridine CCB amlodipine in slowing glomerular-filtration-rate decline in African-American patients with mild-to-moderate renal insufficiency. Of note, there was no difference between the 92 mm Hg or less (lower group) and the 102–107 mm Hg (usual) mean arterial pressure groups as regards the secondary clinical composite end point. The secondary clinical composite end point in this study comprised a threshold drop of at least 50% or 25 mL/min in glomerular filtration rate, death, or reaching end-stage renal disease. The final results from this study would suggest that reduction in BP to levels below those currently advocated for cardiovascular risk reduction, although a clearly attainable goal in this population, does not provide readily identifiable renoprotection benefits to African Americans with hypertensive nephrosclerosis—at least in the short term. However, another factor to consider is that only a third of AASK participants had baseline urinary protein excretion over 300 mg/d. Their low level of urinary protein excretion would also argue against rapid short-term loss of renal function. Importantly, this study provides the basis for the primary use of ACE inhibitors in an African-American population with the characteristics of those studied in AASK. The relative superiority of the ACE inhibitors as initial therapy in African Americans with nondiabetic chronic kidney disease is ironic given the long-held belief that CCBs were preferred antihypertensive agents for African Americans.30,31 The AASK findings were consistent with renal outcomes in other populations with nondiabetic hypertensive nephropathy. In clinical practice, it is very likely that the AASK drugs would be used in combination with each other rather than in opposition to one another.

CONCLUSIONS

The prevalence of hypertension in African Americans is among the highest in the world. Hypertension develops at an earlier age in African Americans than in whites and is associated with more severe complications, including renal failure, stroke, heart failure and cardiovascular disease. While identifying the pathophysiologic and environmental factors that contribute to ethnic disparity in disease is important, steps that can have an important impact on health outcomes of African Americans are presently available. Modifiable factors such as smoking, lack of exercise, and obesity, as well as partial treatment of hypertension by physicians, can be addressed at once. As to the latter, multi-drug approaches are generally required—with diuretics, ACE inhibitors (or angiotensin receptor blockers), and CCB therapy as oft-selected components of such regimens.

Ancillary