the impact of ethnicity on response to antihypertensive therapy

The Impact of Ethnicity on Response to Antihypertensive Therapy Kenneth Jamerson, MD, Detroit, Michigan, Vincent DeQuattro, MD, Los Angeles, California

The aim of this review is to assess the prevalence of complications and responses to various antihypertensive drug therapies in ethnic minority groups in the United States. In some instances, these comments are extended to responses of citizens in their countries of origin. The incidence of hypertension, mortality from hypertensive heart disease, stroke, and hypertensive renal disease are higher in African Americans. Although some Hispanic Americans have a lesser risk for hypertension, they have a greater risk for other risk factors such as diabetes and dyslipidemia. There is a similar association between income and mortality for both African Americans and Hispanic Americans. When compared to European Americans and other ethnic minorities, African Americans respond less favorably to p blockers and angiotensin-converting enzyme (ACE) inhibitors. Nevertheless, the observed response in African Americans to ACE inhibitors and p blockers is clinically significant. The available literature indicates that Asian American responses to calcium antagonists seem to be more favorable than responses to ACE inhibitors and equivalent to their responses to diuretic and p blocker therapy. Although there are few published studies of drug efficacy in Hispanic Americans, there appears to be no hierarchy in response to the various antihypertensive drug classes. Ethnic@ is not an accurate criterion for predicting poor response to any class of antihypertensive therapy. Thus, there is little justification to use racial profiling as a criterion for the avoidance of selected drug classes because of presumed lack of efficacy. Observed differences in the incidence of hypertension and its poor outcomes have led some investigators to postulate that the etiology of hypertension in ethnic minority groups is intrinsically different

I- From the Deoartment of Internal Medicine, Division of Hypertension, Uni- versity of Michigan School of Medicine, Detroit, Michigan (K.J.), and the Department of Medicine, Dwlsion of Hypertension, University of Southern California School of Medicine, Los Angeles, California (V.DeQ.1.

Requests for reprints should be addressed to Kenneth Jamerson, MD, Department of Internal Medicine, Division of Hypertension, University of Michigan School of Medicine, 3918 Taubman Center, Ann Arbor, Michl- gan 48109-0356.

3A-22s a1996 by Excerpta Medica, Inc. All rights reserved.

from whites. Awareness of racial differences in hypertension outcomes evolved in the lJnited States within a historical context that does not fully appreciate that race is often a surrogate for many social and economic factors that influence health status and healthcare delivery. Poor outcomes in ethnic minority groups occur in many diseases, not only hypertension. The goal of ethnicity-related research should be to describe the diversity of disease expression in humans and to target at-risk groups folr prevention and early intervention. The use of racial descriptors to explain genetic differences in ethnic groups should take a lesser priority. Am .J Med. 1996;1Ol(suppl3A):22S-32S.

T he medical literature has recorded racial differences in blood pressure as early as 1932, when

Adams reported a 7 mm Hg higher systolic blood pressure in 6,000 black compared with 8,000 white workmen in New Orleans, Louisiana.’ Although the primary analysis of the study was blood pressure, the author went on to conclude that blacks missed twice as many days from work for chronic heart and kidney disease when compared with whites. On the subject of morbidity, he concluded that “‘whites are more susceptible to respiratory diseases and other infections, to gastrointestinal disease, especially appendicitis and gastric ulcers, while colored men were more susceptible to malaria, kidney, heart, and rheumatic disease. Further, the recuperative powers of the colored are less than those of the whites.” The analysis reflected sound observations on racial differences in health, but also had interwoven into it elements of the social climate in which physicians practiced some 60 years ago in the southern United States. In retrospect, physicians enlightened with a better understanding of racial disparity in access to health care are able to discem that race had little to do with the etiology of differences in diseases such as respiratory infections or appendicitis. Instead, race was and still is a surrogate for a multitude of social and physical factors that influence health status, access to care, and healthcare delivery.

Decades after this initial report of racial differences in blood pressure, it remains impassible to un- derstand racial aspects concerning the prevalence or the impact of the treatment of hypertension without considering today’s social climate as it relates to

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SYMPOSIUM ON HYPERTENSION/JAMERSON AND DeQUATTRO

race, health status, and healthcare delivery. Table I demonstrates mortality rates from various causes for African Americans and European Americans. As investigators search for genetic etiologies for observed racial differences in health status, it becomes diffi- cult to postulate that a random assortment of alleles could result in such disparity in health for very different disease states, such as hypertension, diabetes, homicide, and AIDS.

THE BIOLOGIC VERSUS SOCIAL CONCEPT OF RACE

The biologic concept of race attempts to define a subcategory of humans in order to add information about their evolutionary history. In this respect, race becomes a useful concept only if one is concerned with a phenotype difference, which was, in time past, contributory to the origin of races. Important features of the biologic concept of race are the following: the subspecies must consist of a population of actually or potentially interbreeding organisms sharing a common gene pool; the group should be physically distin- guishable from other subspecies; and finally, there must be geographic boundaries between the groups. Thus, the biologic purpose of the concept of race is to give meaning to human variation and the process by which it originated, not merely to point out any particular aspect of that variation. In the United States what are usually referred to as racial groups are in fact ethnic groups that reflect social, political, and cul- tural diversity, not solely biologic variation.

A single trait, such as skin color, is inadequate for characterizing a biologic racial group. Similarly, characterizing individuals based on their spoken lan- guage or their origin from a similar geographic region, such as Asia, represents a convenient descrip- tion but is an inadequate marker of evolutionary variation. The use of racial groups-such as black or white, Hispanic, or Asian Pacific islander-has little biologic value. The study of ethnic groups in the United States has important implications for tar- geting at-risk groups for prevention and intervention but will not likely lead investigators to the underpin- nings of genetic etiologies of hypertension.

It is against a social history of racial disparity and the expectation that ethnic groups are genetically different from whites, in a substantive manner, that we should consider reported racial differences in the prevalence, complications, and treatment of hypertension in the United States. To begin with a naive interpretation of the statistics on the prevalence and on outcomes can often lead to conclusions that con- fer undue importance on presumed intrinsic biologic differences among ethnic groups.

EFFECTS OF ACCESS TO HEALTH CARE IN AFRICAN AMERICANS

The Hypertension Detection and Follow-up Pro- gram (HDFP) is an example of one community-

TABLE I

Age Adjusted Death Rates (per 100,000) by Sekcted Causes and Race: United States. 1990

African European Cause of Death Americans Americans All cause deaths’ 1,000.6 ‘321.0 Homicide* 61.1 8.2 Hypertension’ 33.6 10.9 Diabetes 29.6 15.1 AIDS 19.3 4.6 * Males only. From the Statistrcal Abstracts of the United States, amended by 1991.‘4

based study that analyzed data from some 4,800 Af- rican Americans recruited from a group of 40,000 screened subjects to examine how economic status affects the prevalence, incidence, and outcomes among African Americans with hypertension.’ Level of education was used as a surrogate for socioeconomic status. The overall incidence of hypertension was twofold greater in African American participants. In both black and white subjects there was an inverse relationship between level of education and prevalence of hypertension, yet whites at th’e lowest education levels were less likely to be hypertensive than blacks at the highest education levels. There were two treatment arms in the study: stepped care and referred care. The stepped-care group ‘was diuretic based, but, in addition, patient educaition and free medication were given when necessary. In the stepped-care group the correlation between educational status and mortality was eliminated lby treatment. This was not the case for the referred-care group, which received care from physicians in their community. The implication is that the poor prognosis associated with hypertension in African Amer- icans can, in part, be overcome by the elimination of barriers to appropriate therapy.

Ooi et al” assessed the outcomes of both African and white Americans with hypertension in a New York population where subjects had equal access to health care through their work sites. Africatn Amer- icans, when given equal access to similar treatment, achieved similar reductions in blood pressure and actually experienced a lower incidence of cardiovascular disease than whites. An exception to this ad- vantage was younger African Americans who actually lost more years of life before age 65 (102 vs 64 years/l,000 persons; P t0.025) than did whites.

In addition to educational status, skin tone, ‘J suppressed hostility,” level of social support, 7 and lack of control over one’s environmentX or social mobil- ity” have all been considered as surrogate,s for socioeconomic status. Most cross-sectional studies demonstrate that blacks of lower socioeconomic status have a higher rate of hypertension and cardiovascular risk.lO~‘l However, when level of income

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was used as a measure of socioeconomic status in the National Health Nutrition Examination Survey, there was no consistent relationship between income and elevated blood pressure.”

The educational status of African Americans has progressed over the past 20 years. In 1970 almost 70% of African Americans had less than a high school education compared with 33% in 1990. Al- though the educational status has improved, the rate of uneducated African Americans is 77% higher than the rate for whites in 1990. During the same time period, there has been no improvement in income for African Americans to accompany the improvement in educational status.13 In 1970, 30% of African Americans had an income below the poverty level; the same numbers hold true for 1990.14 The various surrogates for socioeconomic status each measure some aspect of racial disparity; however, no single measure is able to make tangible the impact of the African American experience in the United States.

OUTCOMES TO TREATMENT OF BLOOD PRESSURE IN AFRICAN AMERICANS VERSUS EUROPEAN AMERICANS

In the United States there has been a marked decline in cardiovascular death rates in all strata of socioeconomic status, sex, and race since the mid- 196Os, I5 in part, secondary to the treatment of hypertension. The decline, however, has not been equally great across all strata. The Third National Health and Nutrition Examination Survey (NHANES III) shows that the decline in cardiovascular risk for African American men and women has been blunted when the decade of the 1970s is compared with the decade of the 1980s.‘” This is in contradistinction to the continuous decline in cardiovascular mortality enjoyed by the U.S. population on the whole.16 F’ur- ther, the overall life expectancy for African Ameri- cans is blunted, with special note taken for African American males in inner cities of the United States.17

Morbidity from cerebrovascular disease and hypertensive disease is shown in Tables II and III. These data are adapted from the National Center for Health Statistics.‘” African Americans demonstrate higher death rates from heart disease, stroke, and hypertensive heart disease. Over the past two decades there has been a 39% reduction in mortality from heart disease for white U.S. citizens compared with a 30% reduction for African Americans. The reduction in stroke mortality is the same across races.14

RENAL DISEASE IN AFRICAN AMERICANS

Renal failure secondary to essential hypertension occurs more frequently in African Americans.” The United States Renal Data Registry has provided

TABLE II Age Adjusted Death Rates (per 100,000) for Heart

Disease by Race: United States, 1970-1989

African European Year Americans Americans

1970 307 249 1989 216 151 Percent decline

over 20 years, 1970-1990 30% 40%

From the National Centers for Health StatisticY and the Statistical Ab- stracts of the United States, amended 1991 .I4

TABLE III Age Adjusted Death Rates (per 100,000) for Cardiovascular

Accidents by Race: United States, 1970-1989

African European Year Americans Americans

1970 114.5 61.8 1980 68.5 38.0 1989 49.0 25.9 Percent decline

in stroke over 20 years, 1970-1990 58% 58%

From the National Centers for Health Statistics” and ttle Statistical Ab stracts of the United States, amended 1991.14

sound estimates showing that within the age group 33-45 years there is an B-fold increase in hypertensive renal disease in African Americans when compared with their white counterparts.1s There is evidence from the Multiple Risk Factor Intervention Trial (MRFIT) 19-Z’ that renal function may not im- prove and may even progress despite excellent control of blood pressure.

Rostand et a12’ examined the clinical course of 94 patients with baseline normal creatinine levels treated for essential hypertension for 12-174 months of follow-up. Despite adequate blood pressure control, 16% of all patients had an increase in their serum creatinine. African Americans with excellent blood pressure control were twice as likely as white patients to have an elevation in their serum creatinine. Further, older age, missed office visits, and employment as a laborer were associated with a signif?cant rise in serum creatinine. Any of these additional factors could have influenced the changes in rate of renal impairment rather than biologic differences in susceptibility for the African Americans.

The Medical Diet and Renal Disease Study (MDRD) provides evidence that blacks are at increased risk for end-stage renal disease and that they may benefit from aggressive control of their blood pressure. Of the 585 participants in the study, 53 were African American. The decline in renal function

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as assessed by iothalomate clearance was 18 mL/min for the 3 years of follow-up in blacks versus 11 mL/ min in whites. In subjects who received aggressive control of blood pressure (to a mean arterial blood pressure of 592 mm Hg) , the rate in decline in renal function was cut in half.

The African American Study of Kidney Disease and Hypertension is a clinical trial that will answer two questions. Does tight control of blood pressure, or treatment of blood pressure with antihypertensive agents possessing putative reno-protec- tive properties, halt the progression to renal failure? The study drugs are p blockers, calcium antagonists, and ACE inhibitors. During the feasi- bility study, 92 patients were recruited who under- went renal biopsy prior to randomization into the study to assure that hypertensive nephropathy was being studied. As of May 1996, >500 subjects had been recruited into the full-scale trial. The study is expected to end in 2002.

The excess incidence of end-stage renal disease in African Americans and the rise in prevalence of this disease in the general population threatens the sol- vency of the Medicare system. Past trials have relied on serum creatinine as a marker of renal function. The work from Lewis et al’” suggests that serum creatinine lacks the sensitivity to detect changes in renal function in subjects with normal renal function but is a reasonable marker in subjects with impairment in function. Further, the authors show a benefit for captopril in the treatment of diabetic nephropathy, serum creatinine levels > 1.5 mg/dL, and/or proteinuria of >500 mg protein/day. The renoprotective properties of ACE inhibitors in hypertension have yet to be determined.

LVH AND DIURNAL BLOOD PRESSURE PAlTERN IN AFRICAN AMERICANS

Left ventricular hypertrophy (LVH) has been shown to be a major risk factor for cardiovascular disease and sudden death.““” After adjustment for differences in blood pressure and, to a lesser extent, degree of blood pressure control, LVH is 2-4 times more prevalent among African Americans when compared with whites.2G28

Differences in diurnal blood pressure patterns have been thought by some to influence the excess LVH observed in African Americans. Nighttime blood pressure during ambulatory blood pressure monitoring has been found to correlate with left ventricular mass better than casual office readings.2gm”0 Fumo et al”’ demonstrated that this was particularly true of African Americans. Harshfield et al”” studied blacks in south central Los Angeles and compared them to whites in the more affluent community of Westwood, California. They reported that there was a blunted nocturnal decline in the blood pressure of African Americans, and they hypothesized that the

elevated nighttime blood pressures resulted in extra hours of hypertension, conferring an excess rate of target organ damage. The lack of blood pressure de- crease in blacks could have been due to different environmental stimuli in these two communities instead of intrinsic racial differences. When the investigators reexamined some of these sarne African American subjects with a blunted nocturnal decline in blood pressure in their clinical research center, they found a normal decline in nighttime blood pressure (unpublished personal communication). It is, therefore, likely that the ~20 reports on studies flnd- ing racial differences in diurnal blood pressure that have ensued from this initial report are conceived from an environmental artifact and not on int,rinsic racial differences. Further, an analysis of data on a group of racially diverse young borderline versus normotensive subjects in Ann Arbor, Michigan,“” in- dicated significant nocturnal declines in blood pressure without any racial difference (Jamerson and Johnson, unpublished data). Keys et al”” also found no racial differences in diurnal patterns of blood pressure.

Recently, Lee et a13’ compared the accuracy of standard electrocardiographic criteria to echocardi- ography for the detection of LVH in African Ameri- can and white union members who had equal access to health care. The prevalence of LVH was 2-6 fold higher in African Americans when electrocardiographic criteria were used. In contrast, there was only a marginal increase in the prevalence of LVH in African versus white U.S. citizens by echocardio- graphic criteria (26% vs 20%, P = not, significant). The work provides evidence that previous st.udies using electrocardiographic criteria may .have over- estimated racial differences in the prevalence of LVH. This overestimation may explain in part why reports of the risk associated with LVH in African Americans have not been consistent.

The commonly used electrocardiographic criteria have a low sensitivity in all races; however, in whites, the specificity is 95-100%. In contrast, the specificity of electrocardiographic criteria is as low as 73% in African AmericansZ4 Since the Ielectrocar- diogram is a poor tool for the detection of LVH in African Americans, some caution should .be exerted in the interpretation of electrocardiographically de- rived data on LVH in racially diverse populations.

RACIAL/ETHNIC PATTERNS IN BLOOD PRESSURE RESPONSES: HYPERTENSION IN HISPANICS, ASIANS, AND NATIVE AMERICANS Hispanic Hypertensives: The Demography of Mexican Americans

The Hispanic population is increasing rapidly in the United States. By the year 2000, it is estimated that the Hispanic American, chiefly Mexican Ameri-


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can, population will achieve majority status in the state of California alone. This is occurring at a time when blood pressure control of MexiCan American patients is poorest of all hypertensives. According to NHANES III, only 14% of Mexican American hypertensives have blood pressure control, compared with 25% of black and non-Hispanic white patients over- al1.36 Mexican Americans, accounting for 65% of all Hispanic patients, also have the greatest prevalence of diabetes and obesity compared with black and non-Hispanic white patients in the United States.37”” Faint praise is the fact that Mexican Americans have a lower incidence of hypertension”6 and overall mortality, as compared with the black and non-Hispanic white populations.“” Death rate is related to income status for both Hispanic and non-Hispanic populations. Hispanic males, aged 25-64 years, have a doubling of mortality when family income drops from >$17,00O/year ($8.50/hour) to <$lO,OOO/year ($5.00/hour) .38 Interestingly, the mortality rate of Mexicans in their native country is 40% less than that of Mexican Americans in the United States.“’ Possi- bly, this is related to adversity, including stress of a new life in a foreign land.40 There is strong evidence for worsening of risk factors when indigenous in- habitants of Mexico consumed a typical U.S. junk food diet.“’ HaffnerJ” believes that the prevalence of hypertension is lower in the Mexico City barrio, compared with Mexican Americans in San Antonio, perhaps related to salt or calcium intake or other dietary factors. An important consideration is the lack of any type of medical insurance coverage for >25% of the Mexican American and 22% of the Hispanic populations overall, living in the United States, as compared with < 10% in the non-Hispanic white population.43

Hispanic Hypertensives: The Demography of Puerto Ricans and Cubans

The health status of other Hispanics, e.g., Puerto Rican immigrants and their descendants in the north- eastern United States, is not better than that of Mex- ican Americans. In one survey in the South Bronx, New York, <50% of Puerto Ricans knew that they were hypertensive, and only 22% of those who knew they were hypertensive had blood pressure control.44 In Florida, Cuban patients had greater rates of hypertension than either Puerto Rican or Mexican Americans.45 On average, only 28% of those Cubans who knew they were hypertensive had blood pressure control, similar to the South Bronx Puerto Ri- can experience. On the other hand, there is evidence that the cardiovascular health of those living in Puerto Rico is better than that of Caucasians in Fra- mingham, Massachusetts-apparently related to lower serum cholesterol, lower systolic blood pressures, and perhaps a more relaxed lifestyle.46

However, Puerto Rican immigrants and their descendants residing in New York City account for 50%

of those with diabetic end-stage renal disease and of those with hypertensive end-stage renal disease, although they account for only 12% of the population in that region. 47 The cardiovascular risks of the His- panic American patients are related to the suboptimal control of metabolic risk factors, as well as blood pressure. In a study of 150 Hispanic hypertensives with dyslipidemia over a 2-year period, only 40% were treated, and only 8% reached goad low density lipoprotein cholesterol levels. The rates of obesity, diabetes, and hypertriglyceridemia were also unaffected by therapy or attempts to institute it.48

Hispanic-Native Americans: A Genetic: Bouillabaisse of Hypertension and Syndrome X

Most studies of the various Hispanic populations give evidence of greater prevalence of insulin resistance, diabetes, dyslipidemia, obesity, and syndrome X.3R,39 In a study of 25 Mexican American hypertensives and their 66 offspring, we found higher plasma norepinephrine levels, greater left ventricular mass, and increased carotid wall thickness in these hypertensives compared with those with normal blood pressure. These findings are opposite to those that we described earlier of lower than normal basal levels of plasma norepinephrine and neural tone in Af- rican American patients with hypertension. In Latin0 patients, the norepinephrine levels were related to baseline blood pressures and intimal medial thick- ness4’ Thus, noradrenergi c factors may be important in both the genesis of the hypertension and in the sequelae of these Hispanic patients. In Cauca- sians with congestive heart failure, the level of plasma norepinephrine is related to the magnitude of dysfunction, and is a prognostic marker of morbidity as we115” Recent outcomes of therapy with the p blocker/dilator carvedilol, possibly by shielding the ventricle from the neural onslaught, suggests a 60% reduction in mortality.“’ Thus, antihypertensive therapy with sympatholytic agents, shielding patients from raised neural tone in addition to blood pressure control, may be of special value in Hispanic patients.

Coronary artery disease is rare in Pima Indians, despite the high prevalence of insulin resistance and diabetes.52 On the other hand, the Sioux, descendants of the same ancient Asian ancestors, are more prone to heart disease. Although the ex.act prevalence of hypertension in Native Americans is not known, it seems less than that for Caucasians. Im- portantly, the genetic admixture of the Cherokee and other tribes are associated with lower percentages of diabetes than the Pima. Mexican Americans, who have a 20-40% admixture of the ancient g;enes, have even lower rates of diabetes mellitus.“’ Mexican American diabetics have a higher percentage of clinical proteinuria and micro-albuminuria5” than other ethnic populations or Caucasians. Pima Indians, who

appear to have a mutation of the gene for the & ad- renergic receptor, have a lower glucose utilization rate and earlier onset of non-insulin-dependent diabetes mellitus (NIDDM) .j4 This impaired signaling may lead to obesity, insulin resistance, and NIDDM.X The relationship between insulinemia and insulin resistance and blood pressure is not as strong in Native Americans as in Caucasians.55 The higher prevalence of diabetes in the Native Americans and Mexican Americans is an important ingredient in selections of both drug and lifestyle therapies for hypertensives of these ethnic groups. Insulin resistance increases the risk for ischemic heart disease via NIDDM, with or without hypertension is more prevalent in Pima In- dians, R6 Mexican Americans, 5’.R7 Micronesians,“’ as well as Japanese Americans.5g

Asian Americans and Their Cardiovascular Risk Factors: Comparisons of Native Versus U.S. Born

In a large study of 18,000 patients in California, Filipino women and men had the highest prevalence of hypertension, and Chinese men had the lowest body mass index. Total cholesterol was the highest in Japanese men.60 These ethnic differences in cardiovascular risk factors (including higher smoking tendencies) in Asian American women as compared with men, should be considered in choosing antihypertensive therapy.

In the Pasadena Project, the blood pressure of youth from four ethnic groups was measured in ninth graders: 39% blacks, 30% Hispanics, 21% whites, and 10% Asians. The prevalence of elevated blood pressure for females was 8.1% and 9.3% for systolic and diastolic, respectively, and 16% and 18%, respectively, for males. Asian girls had the highest prevalence of high blood pressure, 13.1% and 14% systolic and diastolic, respectively, compared with 7.1% and 8.8%, respectively, for the other ethnic groups (P tO.OO1). Similar findings were observed for diastolic blood pressure in Asian boys, 23% versus 18% in non-Asian boys (P <0.065) .(j’

The frequency of a deletion in polymorphism in the gene for angiotensin I converting enzyme is associated with raised serum ACE concentration and increased prevalence of hypertension”” and risk for coronary disease in the Japanese,(iB as in the hypertension of African Americans.“” In a study of Japa- nese men in Hawaii and California, no significant effect of migration on blood pressure could be found.“”

Strategies for therapy of hypertension: The coexistence of cigarette smoking greatly increases the risk of hypertension leading to cardiovascular disease. Not only is there a growing epidemic of cigarette smoking in Third World countries, including Asia and especially in China,” but there is a disturb- ing increase in smoking rates among Hispanic youth and women in the United States.“7 This is directly

related to the intensity of media advertising, especially billboards in Hispanic neighborhoods6’

RACIAL DIFFERENCES IN RESPONSE TO ANTIHYPERTENSIVE DRUGS Antihypertensive Therapy in African Americans

One of the earliest references to racial differences in response to hypertensive therapy was in 1968 when Humphreys et a16’ reported on a placebo-controlled crossover trial with propranolol in a largely Jamaican population. Propranolol was reported to be no better than the placebo in controlling blood pressure. The authors concluded that the ‘,‘tranquiI- izing” effect of propranolol was of unlikely benefit in hypertensive Jamaicans. Again, we find social infIu- ences on the interpretation of the drug results. The treatment of hypertension in African Americans has since become the subject of several reviews. Avidly held opinions are that (1) African Americans respond better to diuretics than do whites; (2) African Americans respond equally well to cy blockers, central sympatholytics, and calcium antagonists; and (3) African Americans respond poorly to fi blockers and ACE inhibitors. These opinions have been used to establish race as a significant variable for selecting antihypertensive therapy. A common clinical practice and recommendation is to prefer diuretics and calcium antagonists while avoiding ACE inhibitors and p blockers in African Americans. Mangy of these recommendations have been made utilizing studies with too few African Americans to describ’e the het- erogeneity of the dose-response range in this ethnic group. More amazingly sparse are physiollogic data on which to base race-specific blood-pressure recommendations.

A well accepted notion is that black hypertensives have an expanded plasma volume and subsequently suppressed plasma-renin activity. With this in mind it would follow that blacks should respond better to diuretics and be less responsive to ACE inhibitors. One of the few reports on racial differences in plasma volume is from Chrysant et alio who found that most Af- rican Americans ( >50%) were plasma-volume contracted; only 30% were plasma volume expanded. In white hypertensive subjects 15% were plasma-volume expanded. This work has been interpreted as documenting that blacks are twice as likely to have expanded plasma volume when compared with whites instead of documenting that most blacks and whites have normal or contracted plasma volumes.

Zing et al” reported a recent review of the effect of race on the response to treatment of hypertension with calcium antagonists. Studies that compared Af- rican Americans to whites found no clinically significant racial differences in blood-pressure response to calcium antagonists. Studies that compared the antihypertensive effects of calcium antagonists to

SYMPOSIUM ON HYPERTENSION/JAMERSON AND DeQUAmRO

September 30, 1996 The American Journal of Medicine” Volume 101 (SUPPI 3A) 3A-27s


Reduction in Mean Arterial Blood Pressure in Response to Antihypertfmive Tlwapy in 13 FVospective Trials for Tmatment of

Hyperbmsion in African Americans

Figure 1. Average mean reduction in blood pressure from prospective trials during 1988-1993 involving African Americans.

other agents in African Americans found that calcium antagonists were as effective as diuretics, better than /? blocker+and more effective than ACE inhibitors. The few studies that compared calcium antagonists with other agents in both African Amer- icans and white patients found that African Ameri- cans responded less favorably to p blockers when compared with calcium antagonists, whereas there was no difference in response to ,!? blockers and calcium antagonists in whites.

A review of the Medline data base from 1988 to 1996 was undertaken using the key words “hypertension treatment” and “black/Negroid race” to examine studies subsequent to the report by Zing et al. On the whole, review articles during this time period confirm previous observations on racial differences in response to antihypertensive therapy: lower response rates for African Americans with ,0 blockers and ACE inhibitors, and at least equal efficacy of calcium antagonists, diuretics, and (Y blockers for Afri- can Americans when compared with European Americans.71-xo

An analysis of 13 prospective trials that have examined racial responses to antihypertensive therapy is presented in Figure 1. The intent of the graphic is to emphasize that there is significant, blood-pressure reduction with all drug classes. The few studies that compared response rates across races found equal responses with (Y blockers, calcium antagonists, and diuretics while African Americans showed diminished response to p blockers and ACE inhibitors.R’-R’ There are two studies that examine the blood-pressure-lowering effect of fi blockers on U.S. blacks. The average reduction in mean arterial blood pressure was 11.7 mm Hg for African Americans. Four studies assessed the effect of ACE inhibitors and found an average reduction in mean arterial blood pressure of 10 mm Hg. Thus, whereas Euro- pean Americans may have a greater blood pressure response to p blockers and ACE inhibitors ( 12-13 mm Hg), the response observed in African Ameri- cans in these trials (11.7 and 10 mm Hg for /? block-

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ers and ACE inhibitors, respectively) was significant. Many of these trials do not lend themselves to meta- analysis. With the exception of the work of Saunders et al ” the number of African Americans in each in- dividual study was small. Most subjects were sam- pled from the clinics of tertiary care facilities, and none of the trials report confidence intervals on which a management decision to prefer the tested treatment for future subjects could be made. The p value does not allow this type of manage:ment logic. More importantly, the effect of placebo could not be consistently teased out. The magnitude of reduction is comparable to the 5-6 mm Hg reduction in blood pressure reported in the meta-analysis of the major hypertension treatment trials by Collins et al.” It is therefore reasonable to expect that African Ameri- cans will benefit significantly from the treatment of hypertension with p blockers and ACE inhibitors.

In contrast to the small trials previously reported, the Treatment of Mild Hypertension Study (TOMHS) is a large multicenter study, the design of which is more amenable to comparing the effect of equivalent doses of antihypertensive therapy for the treatment of mild hypertension. Through 48 months of follow- up, the average SBP response in TOMHS to chlorthalidone, acebutolol, and amlodipine was similar in African Americans and whites with stage 1 diastolic hypertension. On the other hand, African Americans responded less favorably to low doses of both enalapril and doxazosin as compared with whites. More- over, among African Americans (most.ly women) higher levels of urinary sodium excretion (345 mmol/8 hours) substantially antagonized the hypotensive effect of all TOMHS drugs except chlorthalidone, with the largest impact in the doxazosin and enalapril treatment groups. Similar proportions of African Americans and whites achieved an amelio- ration of blood pressure over 48 months in the acebutolol and amlodipine groups. However, whites were more likely to achieve an average blood pressure of <130/85 mm Hg in the doxazosin, enalapril, and chlorthalidone treatment groups.

Antihypertensive Therapy in Hispanic: Americans and Asian Americans

The Systolic Hypertension in the Elderly Program (SHEP) participants were classified as either white or black.% This outcome trial was most influential in persuading the Joint National Committee on Detec- tion, Evaluation, and Treatment of High Blood Pres- sure (JNC-V) to recommend diuretics and p blockers as preferred therapy to achieve a 30-35% reduction in stroke and ischemic heart disease morbidity.87 Thus, lacking specific outcome data, the JNC-V asked for further studies to undemtand better the factors influencing the control of hypertension in Hispanic, Asian, and Native American people. In an- other study in elderly patients, the Medical Research


Council (MRC) trial, diuretics and P-blocker therapy with metoprolol were compared. The reduction in strokes was mainly in nonsmokers receiving diuretic therapy. Beta-blocker therapy showed no reduction in events, and diuretics failed in smokers.”

The guidelines for antihypertensive therapy were written for all U.S. citizens with hypertension, re- gardless of ethnic origin, despite the less than adequate representation of ethnic groups and the met- abolically impaired in most of the authoritative outcome trials, including SHEP, MRFIT, HDFP, etc. These trials have shown that diuretic-based therapy in middle-aged and elderly hypertensive patients can reduce the risk of cardiovascular complications. These agents were advocated for diabetics if the dose can be kept low enough, i.e., 525 mg of hydrochlorothiazide per day. As the dose increases, there may be alterations in glucose, lipid metabo- lism, and renal function. There is a residue of con- troversy regarding the cost-benefit ratio of diuretic therapy in diabetics with hypertension. Some say there is no increase in diabetic prevalence”; others say that metabolic abnormalities are caused by diuretics.gOzgl Other findings indicate that diuretics can reduce progression of renal disease, as do ACE inhibitors in type II diabetic patients.” In the HDFP, diabetics comprised only 10% of the population, and thus the trends favoring diuretic reduction of morbidity and mortality were not significant. Findings were similar in SHEP. A mini JNC-V in diabetes/hypertension recommends P-blocker use in diabetics only for those with angina pectoris and myocardial infarctiong” Of course, ACE inhibitors are renoprotective in addition to the benefits of diuretic therapy (including loop diuretics) in diabetics with hyper- tensiong4

Thus, Hispanic patients with or without manifest diabetes may have a greater likelihood of developing insulin resistance, syndrome X, and overt diabetes with dyslipidemia, and if hydrochlorothiazide or a p blocker is selected for therapy, the dose should be the lowest possible.g3

Although there are few published studies of antihypertensive efficacy in Mexican American patients, our own experience at Los Angeles County-the Uni- versity of Southern California Medical Center, and in private practice in the Los Angeles metropolitan area suggests no different hierarchy of responses to the various antihypertensive agents as compared with those of non-Hispanic Caucasians. Formal studies of Mexican patients in Mexico suggest response patterns similar to those of Caucasian patients in the United States. For example, in one study the magnitude of response and the percentage of responders (81%) to a once daily dose of an ACE inhibitor- quinaprilg5 -was similar to the efficacy reported in Hispanic (74%) and Caucasian (70%) patients in the Accupril Study of Clinical, Economic, and Dose Ti-

tration End Points (ASCEND) trial in the United States.%

In a hypertension-control program in New York City, where 35-45% of the clinic population was His- panic, there were no significant differences in blood- pressure control when patients were treated with diuretics and/or p blockers (86Oh of the t!herapies) compared with responses when they received calcium antagonists or ACE inhibitors (90% of the therapies).” They did report that declines in hyperlipi- demia and hyperglycemia were greater in patients begun on ACE inhibitors and calcium antagonists than those initially treated with diuretics and p blockers. The mean fasting blood sugar of patients treated with /? blockers rose minimally over a l-year period.g7 Further, as in the TOMHS trial,‘l doxazosin therapy of Venezuelan hypertensives in a general medical practice controlled blood pressure in 65% of patients (in doses up to 8 mg/day) in a dose-response pattern, ‘* as it did in our own Mexican Amer- ican patients at LAC and the University of Southern California Medical Center.gg There were IS% reductions of cholesterol and triglycerides in the Venezue- lan patients as we11.g8

Blood-Pressure Response in Asian Patients Pasic and Hui”’ at the University of California,

Los Angeles, describe some interesting misconcep- tions held by physicians in their internal medicine clinic practice, relating to the perceived responses of Asian hypertensives to the various agents as compared with those responses in Caucasia&O” In a ret- rospective examination of ethnically related phar- macologic responses to antihypertensive therapy, they compared results in 400 patients divided equally between Asians and Caucasians. Initial meedications were as follows: first and second choices for both groups were a calcium antagonist and ACE: inhibitor, respectively. The third choice was a p blocker for Asians and a diuretic for Caucasians. Medications were changed twice as often in Asian patients (65 vs 33%; P <0.05), with comparable reasons for change. lo1 However, the treating physicians seemed not to be aware of these medication changes. In answer to the query regarding “need to change medications in Asians vs. Caucasians,” they responded as follows: more frequently, 19%; less often, 13%; and equal, 52/o. O loo Side effects were reported more frequently in Asian patients (26 vs 14%; P <O.OOl). However, in answer to the question regarding side effects in Asians versus Caucasians, the treating physicians responded as follows: more frequent, 13%; less, 6%; equal, 64%; and undecided, 13%.100

The responses of Chinese patients in Hong Kong to graded doses of hydrochlorothiazide, 12.5, to 25, to 50 mg/day, showed dose-related hypotensive responses without evidence of reaching a plateau.‘02 Blood pressures in these patients (average age 46 -t

September 30, 1996 The American Journal of Medicine@ Volume 101 (suppl 3A) 3A-29s


2 years, mean SE) were reduced after placebo wash- out period from 151 ? 3/97 t 2 mm Hg by 11 + 2/S -I 1, and 18 2 2112 ? 1, and 23 t 3/14 ? 2 mm Hg, respectively. Plasma potassium was reduced by 0.5 ? 0.1 meq/L, at the two highest dose levels, and plasma urate was increased at the two higher doses by 0.06 2 0.02 and 0.09 I 0.01 mmol/L, respectively. There were no significant effects on blood glucose or cholesterol. There were minimal adverse effects on high-density lipoprotein cholesterol and triglycerides. Thus, for the short term, at least 6 weeks, hydrochlorothiazide therapy appeared to be effective and well tolerated in Chinese patients.‘02 ACE inhibitor therapy was studied in Pusan, China. Among 65 on ACE inhibitor therapy, 40% had a def- inite drug-related cough, using an adverse drug re- action probability scale, compared with none of 45 receiving a non-ACE drug.lo3 The incidence seems much higher than the cough rate due to ACE inhibitors in Asian Americans in Los Angeles.

formly provide the greatest magnitude of blood- pressure reduction in most subpopulations of hypertensive patients. African Americans, when compared with European Americans, respond less favorably to ,f? blockers and ACE inhibitors. However, the results are not strong enough to suggest restriction or to defer usage of ,8 blockers and ACE inhibitors in Af- rican Americans. The available data indicate that there is no hierarchy of response in Hispanic Amer- ican patients in terms of the major antihypertensive drug classes. The literature indicates that Asian American responses to calcium antagonists are favorable and equivalent to their responses to diuretic and P-blocker therapy, and perhaps slightly better than their responses to ACE inhibitors.

In a prospective trial of two ACE inhibitors, imida- pril and enalapril, in 250 outpatients throughout Japan, cough was the most frequent side effect, occurring in 0.9% and 7.0?? of the two groups, respectively. An adequate antihypertensive effect was observed in 71% and 66% of the group, respectively. Blood pressure nor- malization at 12 weeks (149/89) was achieved in 40% of patients treated with both drugs.‘@’

Preference for the use of a specific drug class for the treatment of hypertension in race/ethnic groups should be made only after considering other important factors in the profiling of patients with hypertension, e.g., the nature and extent of target organ sequelae, other cardiovascular risk factors, and other concomitant disease. Therefore, race/ethnicity-oriented research should be generated to target groups of individuals who may be at risk for excess target organ failure for prevention and early intervention.

REFERENCES Finally, in a population of 325 Asian patients

(mean blood pressure 165/103 mm Hg) throughout Southeast Asia, lo5 the response to amlodipine was similar to the 91% response rate described recently in the United States by Kloner and his colleagues.‘M Only 11% had adverse events, possibly related to therapy (only 3 discontinued therapy). The doses were 5 or 10 mg, as required to reach target diastolic blood pressure of <90 mm Hg and a reduction of > 10 mm Hg. The average daily dose was 6.8 mg, with a reduction in blood pressure of 30118 mm Hg.

The available literature indicates that Asian Amer- icans’ responses to calcium antagonists seem to be more favorable than their responses to ACE inhibitors and equivalent to their responses to diuretic and ,8- blocker therapy. Valuable information regarding cardiovascular event reduction, efficacy, and side effects of the various antihypertensive drug therapies in ethnic patients may come from such ongoing outcome trials as ALLHAT, PREDICT, and CONVINCE.‘07

SUMMARY Hypertension is more prevalent in African Ameri-

cans when compared with other ethnic groups in the United States. There is a higher mortality from hypertensive heart and renal disease. Treatment of hypertension has resulted in significant benefits for all ethnic groups. Prospective trials that have assessed the effect of ethnicity on response to antihypertensive therapy suggest that calcium antagonists uni-

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