Cardiovascular Drugs and Therapy 4: 379-382, 1990 ~e Kluwer Academic Publishers, Boston. Printed in U.S.A.

Racial Differences in Antihypertensive Therapy: Evidence and Implications

Myron H. Weinberger Indiana University School of Medicine, Indianapolis, IN, USA

Summary. Blood pressure is controlled by many factors, and thus hypertension is a multifactorial disorder. This etiologic diversity is also reflected in the broad spectrum of different pharmacologic agents known to lower blood pressure. Most carefully controlled studies employing a single antihyperten- sive drug in unselected, uncomplicated mild to moderate hy- periensives demonstrate efficacy in reducing blood pressure in 40-60c~ of the population. If two agents of differing phar- macologic actions are combined, success rates of 70-90q are generally observed. Specific choices of antihypertensive agents have heretofore been based on whimsy, hearsay, or empiricism. More recent studies have identified characteris- tics that may help to predict the efficacy of single drugs. These characteristics have included physiologic factors, such as sodium sensitivity, plasma renin activity, or sympathetic nervous system activity, as well as demographic components, particularly age and race. This review will examine the ef- fects of racial classification on the blood pressure response to antihypertensive agents.

Key Words. blacks, whites, diuretics, ACE inhibitors, beta blockers, alpha blockers, antisympathetics, calcium channel blockers, hypertension

Diuretics have traditionally been the keystone of anti- hypertensive therapy. This is largely the result of the initial Veterans Administration Cooperative Study [1], which used a "stepped-care" treatment algorithm beginning with a diuretic agent and adding other drugs to reduce blood pressure. This was the first, placebo-controlled trial to demonstrate that blood pressure reduction decreased cardiovascular morbid- ity and mortality in hypertensive patients. While con- cern has recently been expressed about the potential adverse effects of diuretic treatment on the risk for sudden death. ]2] and coronary artery disease [3], a continuing role for diuretics in the initial treatment of hypertension has been endorsed by the Joint Na- tional Committee on Detection, Evaluation and Treat- ment of Hypertension in its 1988 report [4]. The re- sponse of blood pressure to diuretics is dependent on initial blood pressure level, duration of treatment, dose, and, perhaps, on the duration of action of the diuretic used. Despite these variables, black hyper- tensives have generally demonstrated impressive re-

ductions of blood pressure with diuretic monotherapy [5-7]. While diuretics also reduce blood pressure in white hypertensives, the magnitude of decrease has generally been greater in blacks [5,8].

The enhanced or more consistent response of black hypertensives to diuretic therapy than whites has been explained by many hypotheses, but definitive proof is lacking. Some have suggested that sodium chloride intake is higher in blacks than whites, but no evidence to confirm this concept has been presented. Alternatively, expanded extracellular fluid volume has also been put forth as an explanation. This too has not been consistently demonstrated. We have ob- served that black subjects, normotensive as well as hypertensive, have a reduced efficiency to excrete a sodium load [9-12]. Indirect evidence in support of relative sodium conservation in blacks has come from repeated observations over the past 20 years of a greater frequency of low renin levels among black hy- pertensives than is found in whites [9,13-2]. Another proposal that may explain the enhanced diuretic re- sponsiveness of black subjects in association with sup- pressed renin levels may be an unexplained decrease in the responsiveness of the renin release mechanism to a reduction of extracellular fluid volume or sodium content. Thus, a sluggish counterregulatory response of renin release to normal stimulation by diuretic ad- ministration could result in a greater fall in blood pres- sure. Whatever the mechanism, diuretics have been found to be economical and effective in the treatment of hypertension in blacks. Nonetheless, recent con- cern has been expressed regarding both the symp- tomatic side effects and the multiple adverse effects on risk factors for cardiovascular disease [3,23,24]. Thus, the Joint National Committee has broadened its recommendations for initial antihypertensive therapy to include consideration of three nondiuretic classes of drugs [4].

Address for correspondence and reprint requests: Myron H. Wein- berger, MD, Professor of Medicine, Director, Hypertension Re- search Center, Indiana University School of Medicine, 541 Clinical D,'ive, Room 409, Indianapolis, IN 46202-5111, USA.

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Beta-adrenergic blocking drugs have long been considered appropriate initial therapeutic agents in the treatment, of hypertension. However, ample evi- dence exists to demonstrate that black hypertensives have a lower response to beta blockers than do whites and that diuretics are more efficacious in lowering blood pressure than are beta blockers in blacks [5,6,25-27]. These studies have utilized cardioselec- t ire [25] as well as nonselective agents [5,271. Even agents with intrinsic sympathomimetie activity ap- pear to be less effective in blacks than in whites [26] or in comparison with diuretics [28]. The combination of alpha-adrenergic blockade with beta blockers in labetalol has been more effective than beta blockers alone in lowering blood pressure in black hyperten- sives [29]. However, one study found that white hy- pertensives were three times more likely to achieve adequate blood pressure control with labetalol alone than were blacks, 76cA of whom required the addition of a diuretic to reach normal blood pressure levels [30]. The beneficial effects of alpha-1 blockade alone in black hypertensives have been confirmed with prazo- sin 131,321.

Centrally acting antisympathetic agents (reser- pine, methyldopa, clonidine, guanabenz, guanfacine) lower blood pressure primarily by decreasing sympa- thetic outflow from central nervous system centers. While these agents have generally been found to have antihypertensive efficacy in blacks when given in ade- quate doses and frequency, the consistent and annoy- ing side effects associated with their administration has decreased their attractiveness as initial therapy. These side effects include drowsiness, lethargy, de- pression, and sexual dysfunction.

Ganglionic blocking drugs such as guanethidine and guanadrel are relatively ineffective as monotherapy, since the closes needed for blood pressure reduction are generally those at which side effects of orthostatic dizziness, diarrhea, and retrogn-ade ejaculation in men are likely. These agents are usually reserved for ad- junctive therapy of severe hypertensives refl'actory to multidrug regimens. There is lttle available data with which to evaluate racial differences in response to these agents.

Direct-acting vasodilators, such as hydralazine or minoxidil, are currently consign~ed to third- or fourth- level therapy in patients in whom blood pressure con- trol cannot be achieved with two or three other drugs. The major disadvantages of these agents are their proclivity to expand extracellular fluid volume and to markedly stimulate the sympathetic nervous system, heart rate, and myocardial function. There is little data examining differential racial responses to mono- therapy with these agents either.

Table I. Rchdil ,e e f.?icttcy qt~lntihPlwrle~sit 'e age~tts i~t bhtcks ~tmt whites

Black > White Black = White White > Black

Diuretics Alpha-adrenerKie Beta-adrenergic blockers blockers

Central antisym- Angiotensin-con- pathics verting

Calcium-channel en- enzyme inhibitm-s try blockers

Angiotensin-converting enzyme (ACE)inhibi tors act as indirect vasodilators by reducing the formation of an~otensin II. When first investigated, these drugs were predicted to be most efficacious in hypertensive patients with increased levels of renin and less likely to have a similar impact on low-renin hypertensives. While this concept has generally been correct, it has not anticipated the broad efficacy of ACE inhibitors, even in those with relative renin suppression. This has given rise to speculation that these agents may lower blood pressure by mechanisms independent of their action to decrease angiotensin II formation. Several studies have reported racial differences in response to monotherapy with ACE inhibitors with blacks, who more fl'equently have renin suppression, demonstrat- ing a smaller decrease in blood pressure than seen in white hypertensives [8,33-37]. However, as described subsequently, combined therapy with diuretics pro- duces equivalent racial responses to ACE inhibition [33-36].

The slow calcium-chmmel entry blockers represent the newest gToup of agents approved for the treat- ment of hypertension. While these agents differ in their specific receptor targets, and in their relative efficacy on different vascular beds and on cardiac con- duction, they lower blood pressure primarily by re- ducing peripheral resistance. In addition to vasodila- tion, calcium-channel entry blockers have also been shown to have a natriuretic effect [38]. This latter effect may explain why these agents have been shown to have similar anithypertensive efficacy in blacks and whites, and to be equipotent with diuretic mono- therapy in black hypertensives [39-431 (Table 1).

In general, without regard to racial differences, antihypertensive therapy with conventional doses of a single agent provides control of blood pressure in 40- 60% of uncomplicated mild to moderate essential hy- pertensives [44]. When a second agent is added, the response rate is found to be 80-90(} if agents of differ- ing pharmacologic actions are chosen. When diuretics are the initial selection, additive antihypertensive efficacy has been seen with virtually all agents in black

Racial D(lfvrences i*~ Hypertenasion Therapy 381

hypertensives. At present, there is some debate con- cerning the additive effect of calcium-channel blockers when combined with diuretics [45-511. However, only one of these studies has specifically examined the re- sponses of black hypertensives [45]. Several studies have demonstrated that the relative lack of efficacy of beta blockers or ACE inhibitors as monotherapy in black hypertensives can be abolished by the addition of a diuretic [8,27,33,34,36] or, in the case of ACE inhibitors, by calcium-channel entry blockers as well [521.

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382 Weinberger

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