From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL;1 and Case Western Reserve University School of Medicine, University Hospitals of Cleveland, Cleveland, OH2
From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL;1 and Case Western Reserve University School of Medicine, University Hospitals of Cleveland, Cleveland, OH2
Suzanne Oparil, MD, Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, University of Alabama at Birmingham, 703 19th Street South, Zeigler Research Building, Room 1034, Birmingham, AL 35294-0007 E-mail: firstname.lastname@example.org
The prevalence, impact, and control of hypertension differ across racial and ethnic subgroups in the United States population. Whether race/ethnicity should be a significant consideration in the choice of individual antihypertensive drugs continues to be a topic of intense interest and debate. This brief review will discuss recent findings that bear on the management of hypertension in these special patient groups.
Race and ethnicity influence the prevalence, impact, and control of hypertension in the United States population (Figure 1). Hypertension is more common, more severe, develops at an earlier age, and leads to more clinical sequelae in blacks than in age-matched, non-Hispanic whites. Overall, non-Hispanic blacks had a higher age-adjusted prevalence of hypertension than the general population in 2000 (33.5% vs. 28.7%). Both non-Hispanic black men (30.9%) and women (35.8%) had a higher prevalence of hypertension compared with non-Hispanic white men (27.7%) and women (30.2%). While treatment rates overall were 63%, a smaller percentage (28.1% vs. 33.4%) of black hypertensives was controlled to <140/90 mm Hg compared with whites. Among black hypertensives, women (29.4%) had higher control rates than men (26.5%). Prevalence rates in Mexican Americans were lower than in blacks and comparable to non-Hispanic whites, but control rates in Mexican Americans and Native Americans were lower than in non-Hispanic whites or blacks.
The prevalence of hypertension and its sequelae also varies by race and region within the United States. Residence in the South is associated with increased incidence of hypertension and stroke in blacks. Data from the Third National Health and Examination Survey (NHANES III) have shown a significant regional difference in hypertension prevalence between Southern and non-Southern non-Hispanic black men aged 40–59 years (44.1% vs. 36.7%) and a trend toward higher rates in Southern vs. non-Southern black women in the same age group (45.6% vs. 39.4%). Regional differences were also reported in the Coronary Artery Development in Young Adults (CARDIA) study, extending the regional disparity to younger black men.
The increased prevalence and severity of hypertension in blacks and other ethnic minority groups have dire consequences in terms of morbid and mortal cardiovascular and renal disease events. Hypertension-related mortality is four to five times higher in the black community, while the risk of left ventricular hypertrophy (LVH), coronary heart disease, congestive heart failure (CHF), and stroke is increased two to four times in blacks compared with whites in the United States. Furthermore, coronary heart disease tends to develop nearly 5 years earlier in blacks compared with whites. Ethnic minorities, especially blacks and Native Americans, have a three- to four-fold higher prevalence of end-stage renal disease (ESRD) vs. whites. In 2002, blacks comprised nearly 29% of the entire ESRD population, a rate 4.4 times higher than for whites. Suboptimal blood pressure (BP) control in blacks and other ethnic minorities may contribute importantly to this alarmingly high incidence of target organ damage.
Many mechanisms have been put forward to account for the earlier onset, greater severity, and increased morbidity of hypertension in blacks (Table I) and other ethnic minorities. No one mechanism is fully explanatory, and it is likely that a combination of many factors is responsible for ethnic differences in hypertension.
Table I. Proposed Mechanisms of Hypertension in Blacks
Low birth weight
Low dietary potassium
Decreased activity of renal vasodilators
Obstructive sleep apnea
Socioeconomic status (SES) has received considerable attention, and many studies have reported that controlling for, or minimizing, differences in SES dramatically reduces racial differences in the epidemiology of hypertension and its target organ damage. For example, among enrollees in the Women's Health Initiative Observational Study (WHI-OS), who tended to be of moderately high SES, black women had higher treatment and control rates than white or Hispanic women (Figure 2). The effect of SES on health outcomes is complex, and gross estimates provided by current markers (e.g., income, education, employment, insurance status, place of residence) probably oversimplify its significance.
Racial differences in renal salt handling have been proposed as a potential explanation for the increased incidence and severity of hypertension in blacks, as well the favorable responses of black hypertensives to diuretic therapy. A blunted renal pressure-natriuresis relationship, resulting in impaired sodium excretion in response to a pressure load, has been suggested by multiple reports of increased salt sensitivity and suppressed plasma renin activity in hypertensive blacks compared with whites. Studies that directly evaluated responses to IV saline loading reported that blacks not only excreted sodium less effectively following a salt load, but also had delayed suppression of renin levels after saline infusion. The prevalence of salt sensitivity assessed by this method was approximately 75% in black hypertensives compared with 50% in white hypertensives. However, a limitation of many studies reporting racial differences in salt sensitivity is failure to control for differences in age, hypertension severity, renal function, and body mass index, as these characteristics may alter salt sensitivity. A recent study in which experimental groups were closely matched for gender, age, renal function, hypertension status, and weight reported no racial difference in prevalence of salt sensitivity; however, the magnitude of BP increase in response to salt loading in this study was greater in black vs. white hypertensives. This racial difference was not seen in normotensive subjects.
A defect in Na+ transport has been proposed to account for altered Na+ metabolism in blacks. Blacks have 10%–20% higher intracellular Na+ than whites, as well as up to a 30% depression in Na+K+ adenosine triphosphatase pump activity. Elevated intracellular Na+ may trigger a cascade of compensatory events that lead to elevated intracellular Ca++, increased vascular reactivity, and eventual hypertension.
Alterations in expression and activity of a variety of neurohumoral factors have been described in blacks and related to their higher incidence and severity of hypertension. Importantly, many studies have reported suppressed activity of the renin-angiotensin-aldosterone system (RAAS) in blacks compared with whites, particularly in response to changes in intra-vascular volume or BP. Thus, hypertension in blacks is usually classified as low renin and is generally associated with a diminished response to antihypertensive drugs that inhibit the RAAS.
Increased levels of the pressor peptide endothelin-1 have been reported in hypertensive blacks. In one study, circulating endothelin-1 levels in black hypertensives were nearly eight-fold higher than in normotensive blacks and nearly four-fold higher than in white hypertensives. Further, increased cardiovascular reactivity and higher circulating levels of endothelin-1 in response to acute physical or mental stress have been reported in adolescent males with family histories of hypertension. In contrast, lower levels of endogenous vasodilators such as kallikrein, atrial natriuretic peptide, prostacyclin, and NO have been reported in hypertensive blacks. Regardless of BP, blacks have been found to excrete less urinary kallikrein than whites. Markedly reduced levels of atrial natriuretic peptide during salt loading have been reported in children of hypertensive compared with normotensive parents, and salt-sensitive blacks have been found to exhibit a paradoxical decrease in atrial natriuretic peptide in response to increased dietary salt intake. Rigorous assessment of the relative roles of these systems in the pathogenesis in hypertension in blacks remains to be carried out.
Epidemiological studies have raised the possibility that low birth weight (LBW) may influence disease later in life, and the increased prevalence of hypertension in blacks has been attributed to a higher incidence of LBW with an associated nephron deficit acquired in utero that is not recovered after birth. The nephron deficit is postulated to lead to glomerular sclerosis, increased salt sensitivity, and subsequent hypertension. The LBW-hypertension hypothesis was supported by a study with almost 5000 persons which reported a statistically significant inverse relationship between systolic BP (SBP) at all ages beyond birth and birth weight. Persons weighing 3180 g or less at birth had a 4–12 mm Hg higher SBP in adulthood than those born weighing over 3860 g. By age 64–71 there was a 5.2 mm Hg increase in SBP for every 1 kg decrease in birth weight. Although the LBW-hypertension hypothesis has been questioned by many and has yet to be rigorously evaluated in black populations, it provides a unifying explanation for the increased salt sensitivity, severity of hypertension, and proclivity to develop ESRD seen in blacks.
The contribution of genetics to hypertension in blacks, as in the general population, is currently a subject of intense investigation. The angiotensinogen (AGT) gene has been linked to hypertension in families of European descent, and a molecular variant of AGT known as T235 has been associated with both higher AGT levels and BP elevation. The frequency of T235 is twice as high in blacks as in nonblacks, but an association with hypertension has only been found with peoples of African origin living in the Caribbean. Other haplotypes of the AGT gene have been associated with serum AGT level, and AGT remains a candidate gene for hypertension in blacks as well as in other racial groups; however, as in other racial/ethnic groups, no major gene or gene family has been identified that makes an important contribution to hypertension in the black population.
As in the general population, lifestyle modification is recommended for all members of ethnic minority groups who have elevated BP. Weight loss is particularly important in the black population due to the greater prevalence of obesity: >60% of non-Hispanic black men and 77% of non-Hispanic black women are overweight (body mass index ≥25 kg/m2). Physical inactivity is also a particular problem in US blacks: approximately half of black adults (44% of men, 55% of women) report no participation in any leisure-time activity. Further, blacks tend to be salt-sensitive due to a combination of prevalent obesity, abnormalities in renal salt handling, and a tendency to eat a high salt/low K+ diet. Therefore, they benefit more than the general population of hypertensives from reductions in dietary salt and improvements in diet quality (i.e., the Dietary Approach to Stop Hypertension [DASH] diet). Recommendations for lifestyle modification in hypertensive and prehypertensive persons are summarized in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and in the Consensus Statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks (Table II).
Table II. Therapeutic Lifestyle Changes for Black Hypertensives
Realistic Personal Plan to Achieve Goal
Normal weight for height
Lose weight gradually by making permanent changes in daily diet for the entire family Set a reasonable weight loss goal (even 5–10 lb [2.2–4.5 kg] can make a difference) Eat fewer fast foods and fried foods, and eat more fruits and vegetables
Eat more grains, fresh fruits, and vegetables
Eat fewer overall fats and use healthier fats, such as olive oil
Eat fewer processed foods and fast foods
Read labels and pay attention to the sodium and fat content of foods
Identify high-sodium foods (e.g., potato chips and hot dogs) that can be comfortably omitted Identify low-sodium, high-potassium snacks (e.g., dried fruits, bananas, orange juice, raw vegetables) Do not salt foods when cooking; instead, taste foods first and add salt at the table, if needed Use vinegar or lemon juice instead of salt for seasoning Do not season foods with smoked meats, such as bacon or ham hocks Become more aware of food sources that are rich in calcium If lactose intolerant, try lactose-free milk or yogurt, or drink calcium-fortified juices or soy milk
Men: no more than two beers, one glass of wine, or one shot of whiskey (or hard liquor) per day Women: no more than one beer or one glass of wine per day (a shot of whiskey exceeds these recommendations)
Increase physical activity as part of the daily routine; e.g., if currently sedentary, get off the bus six blocks from home, or walk in the evening with a spouse or friend Gradually increase time spent at an enjoyable activity to 30—45 minutes at least five times a week
No tobacco use
For nonsmokers, do not start For current smokers, attempt smoking cessation, increase tolerance for failure, and be willing to continue the effort until success is achieved Be aware that smokeless tobacco products (e.g., chewing tobacco) also have associated risks
Derived from Arch Intern Med. 2003;163:525–541.
Guidelines for the pharmacologic treatment of hypertension in ethnic minorities are generally the same as those for the general population of hypertensives. Treatment guidelines are based on the principle that in clinical trials, lowering BP (particularly SBP) prevents the sequelae of hypertension in all racial/ethnic groups. Further, the magnitude of the outcome benefit of antihypertensive treatment is related to the treatment-induced reduction in SBP. However, because there are racial/ethnic differences in BP responses to some classes of antihypertensive drugs, race/ethnicity plays a role in the selection of antihypertensive drugs or drug combinations and drug doses in minority patients. A variety of studies, including the Veteran's Administration study that evaluated BP responsiveness to monotherapy with six antihypertensive agents from different classes, have shown that black patients respond better to diuretics and calcium channel blockers (CCBs) than to other drug classes. In contrast, monotherapy with agents that inhibit components of the RAAS, including angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and β blockers, is less effective in lowering BP in blacks than in whites. This racial difference is eliminated when these agents are combined with diuretics or CCBs, however. The latter observation is particularly important in the light of overwhelming evidence that most hypertensive patients require two or more antihypertensive agents to achieve BP control. Therefore, choice of appropriate doses and combinations is more important than choice of specific first line monotherapy.
In addition to racial/ethnic differences in BP lowering and cardiovascular disease (CVD) outcomes (discussed below), there are also clinically important differences in adverse effects of antihypertensive drugs. For example, blacks and Asians have a three-to four-fold higher risk of angioedema and more cough attributed to ACE inhibitors than whites.
Abundant outcome data from randomized controlled trials have demonstrated the benefit of multi-drug regimens that include a diuretic in black hypertensives. Importantly, the very earliest outcome trials of antihypertensive therapy in the United States enrolled large percentages of black participants. The VA Cooperative trial, conducted more than 35 years ago, enrolled 42% black men who were randomized to a combination of hydrochlorothiazide, reserpine, and hydralazine, compared with placebo. The Hypertension Detection and Follow-Up Program (HDFP), completed 25 years ago, included 44% black participants who were randomized to stepped care with chlorthalidone, reserpine, methyldopa, and hydralazine compared with usual care in the community. Both of these pioneering trials documented the benefit on clinical outcomes of lowering BP in black hypertensives with a thiazide-type diuretic-based regimen. The Systolic Hypertension in the Elderly Program (SHEP) trial, which included 14% blacks with isolated systolic hypertension, extended these findings by demonstrating that active treatment with chlorthalidone and atenolol produced outcome benefits in both blacks and whites compared with placebo.
Results of the Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial (ALLHAT) provide important lessons for the management of hypertension in minority groups. ALLHAT, the largest outcome trial of antihypertensive treatment ever conducted, enrolled the greatest number of minority participants, including 15,094 blacks (36%) and 8342 Hispanics (19%), ever studied in a hypertension trial. ALLHAT was the first outcome study to evaluate the relative benefit of newer classes of antihypertensive agents compared with conventional treatment with a thiazide-like diuretic in black (both African-American and Afro-Caribbean) and Hispanic populations.
ALLHAT confirmed the widely held belief that BP is more difficult to control in blacks than in other racial/ethnic groups, independent of treatment assignment (Figure 3). BP control rates were lower in the southern United States than in other regions of the country, perhaps in part due to overrepresentation of blacks in the South. Further, blacks in ALLHAT were more likely than other groups to be undertreated (less likely to receive multiple drugs), a likely contributor to suboptimal BP control rate. This was true even though the ALLHAT protocol specified dose escalation and addition of second- and third-line drugs for participants with uncontrolled BP. Treatment based on the diuretic chlorthalidone reduced SBP by 4 mm Hg more than treatment based on the ACE inhibitor lisinopril in black ALLHAT participants. In contrast, SBP reductions with the CCB amlodipine vs. the diuretic differed by only 1 mm Hg.
While the primary coronary outcome of ALLHAT did not differ with respect to treatment assignment, there were racial/ethnic differences in major secondary outcomes, including fatal and nonfatal stroke and combined CVD (combined coronary heart disease, stroke, treated angina, CHF [fatal, hospitalized or treated, and non-hospitalized], and peripheral arterial disease), in response to treatment. Interactions between race and treatment were significant for stroke (p=0.01) and combined CVD (p=0.04). Among blacks in ALLHAT, ACE inhibitor treatment assignment was associated with a 40% increase in stroke, a 32% increase in CHF, and a 19% increase in the combined CVD outcome compared with diuretic treatment assignment (Figure 4A, Figure 4B). This contrasts with results for the nonblacks, in whom ACE inhibitor treatment was associated with no increase in stroke, a 15% increase in CHF, and only a 6% increase in combined CVD compared with diuretic therapy (Figure 4C, Figure 4D). Adjustment for follow-up BP as a time-dependent covariate in a Cox proportional hazards regression model produced only slight reductions in risk of stroke and CHF in the black subgroup and did not alter the statistical significance of the results. Thus, only a minor part of these outcome differences could be attributed to racial differences in BP responses to treatment. In addition, as previously observed, the risk of angioedema was increased in blacks assigned to ACE inhibitor treatment.
Taken together, these findings suggest that ACE-inhibitor-based regimens that do not include a diuretic or a CCB (not allowed in the ALLHAT protocol) are not ideal for black patients. Further, results of ALLHAT did not support the use of a blockers or ACE inhibitors in black hypertensives over diuretics or CCBs (in hypertensives unable to take a diuretic) as initial treatment in the absence of chronic kidney disease (CKD) or clinical CHF.
ALLHAT and the other major outcome trials of antihypertensive treatment have excluded patients with CKD, a sequela of hypertension that afflicts blacks disproportionately to other racial groups. The African American Study of Kidney Disease (AASK) addressed this deficiency by testing the hypothesis that lowering BP below the standard goal of 140/90 mm Hg is effective in preventing cardiovascular events and whether choice of antihypertensive regimen (CCB- vs. ACE-inhibitor-vs. β blocker-based) matters in slowing the progression of hypertensive kidney disease. A total of 1094 blacks with hypertension and nondiabetic renal disease (glomerular filtration rate [GFR] 20–65 mL/min/1.73 m2) were randomized to receive either ramipril, amlodipine, or both compared with metoprolol. Participants were also randomized to a usual mean arterial pressure goal of 102–107 mm Hg or a lower goal of ≤92 mm Hg. Mean achieved BPs in the usual and lower goal groups were 141/85 mm Hg and 128/78 mm Hg, respectively. Treatment of study participants to the lower BP did not significantly reduce either the mean rate of GFR decline or the risk of the clinical composite outcome (reduction in GFR by ≥50%, ESRD, or death). In contrast, ACE inhibitor-based treatment was significantly more effective in slowing the progression of kidney disease (mean rate of GFR decline) and in reducing the risk of the clinical composite outcome compared with amlodipine- or metoprolol-based treatment. Thus, the benefit of ACE inhibitor treatment in preventing renal outcomes in black hypertensives with concomitant CKD was demonstrated for the first time. Results of AASK also suggested that the β blocker metoprolol may improve renal outcomes compared with the CCB amlodipine, particularly in participants with higher levels of proteinuria. There were no differences in rates of cardiovascular events or death among treatment groups, although the study was not powered to detect differences in these outcomes.
Results of the Losartan Intervention for Endpoint Reduction (LIFE) study support the general conclusion that drugs that block components of the RAAS are less effective than other drug classes in preventing CVD outcomes in blacks. LIFE randomized 9193 high-risk hypertensive persons with LVH by electrocardiographic criteria, 533 of whom were black, to treatment based on either the ARB losartan or the β blocker atenolol. While overall, the risk of the primary composite end point (cardiovascular death, stroke, and myocardial infarction) was reduced by 13% (p=0.021) in the losartan group, there was a significant interaction between the black and nonblack groups and treatment (p=0.005). The hazard ratio for the primary composite end point favored atenolol in black participants and losartan in nonblacks (Figure 5). Findings were similar for the primary and secondary component end points, and a test for qualitative interaction (that the effect of losartan differed in direction between blacks and nonblacks, not just in magnitude) was statistically significant (p=0.016). Further, the outcome differences between blacks and nonblacks persisted after adjustment for a wide variety of baseline covariates. BP reductions were similar in both treatment groups in black and nonblack participants, and regression of electrocardiographic LVH was greater with losartan than with atenolol in both groups. Thus, BP differences and differential effects on LVH could not account for the outcome.
The LIFE investigators concluded that black persons with hypertension and LVH do not respond as well as nonblacks to ARB-based treatment. The strength of this conclusion is limited by the post hoc nature of the subanalysis on which it is based, the small number of events occurring in black participants in LIFE, and the possibility that observed differences may have been due to confounding factors. The mechanisms responsible for racial differences in outcomes in LIFE, as in other trials, are elusive, underscoring the need for further mechanistic studies in black hypertensives.
JNC 7 recommends that thiazide-type diuretics should be considered as first-line treatment in most hypertensives, regardless of race/ethnicity. Diuretics are particularly effective in lowering BP and preventing cardiovascular events in black hypertensives, who tend to be salt sensitive. CCBs are a reasonable alternative first-line choice in black hypertensives who are unable to take a diuretic. They produce similar lowering of BP and most clinical outcomes but a substantially greater risk of CHF than diuretics. ACE inhibitors and ARBs should be utilized as first-line therapy in all hypertensives—including black hypertensives—with CKD or CHF. Along with the a blockers and all other agents in the antihypertensive armamentarium, ACE inhibitors and ARBs should be used as needed as add-on agents to achieve the BP goal in black hypertensives. Importantly, multiple drug therapy should be considered as initial treatment for all hypertensive persons who are more than 20/10 mm Hg above target BP, and is required to achieve long-term BP control in most patients. This is a particular issue for black hypertensives, who tend to have more severe and treatment-resistant disease.
Blacks develop hypertension at an earlier age and exhibit a higher overall prevalence than whites. Despite similar rates of awareness, black hypertensives not only are more likely to have more severe hypertension, but are also less well controlled once treatment is initiated. The etiology of hypertension in blacks remains unknown. The mechanisms of these racial/ethnic differences are unclear. Treatment should include both lifestyle modifications and pharmacologic intervention, usually with multiple agents. Thiazide-based regimens should be considered as first line in the absence of compelling indications for alternative therapies. Monotherapy with ACE inhibitors, ARBs, or β blockers is less effective in lowering BP in blacks compared with other population groups, but ACE inhibitors or ARBs should be included in antihypertensive regimens prescribed for black hypertensives with CKD or CHF. In the absence of these conditions, ACE inhibitors or ARBs may be added to a regimen containing a thiazide-type diuretic and/or CCB to achieve the desired BP goal. Aggressive treatment of BP to recommended goals, which usually requires use of multiple antihypertensive drugs, has a significant impact on cardiovascular and renal outcomes in racial/ethnic minorities, as in the hypertensive population as a whole.