Published online before print February 2, 2004, doi: 10.1161/01.HYP.0000118019.28487.9c
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(Hypertension. 2004;43:566.)
© 2004 American Heart Association, Inc.
Scientific Contributions |
Overlap Between Whites and Blacks in Response to Antihypertensive Drugs
From Division of Nephrology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio.
Correspondence to Dr Ashwini R. Sehgal, Division of Nephrology, MetroHealth Medical Center, Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, OH. E-mail axs81{at}cwru.edu
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Abstract |
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On average, whites and blacks differ in their response to specific antihypertensive drugs. These differences are often highlighted in reviews and practice guidelines. However, there is wide variation in drug-associated changes in blood pressure within each race. The goal of this meta-analysis is to quantitate how often whites and blacks have similar responses to specific antihypertensive drugs. Computerized searches of MEDLINE (1983 to March 2003) and manual searches of references listed in identified articles were performed. Studies were included if they provided race-specific changes in blood pressure. Fifteen studies with a total of 9307 white subjects and 2902 black subjects were analyzed. For drug-associated changes in diastolic blood pressure, the mean difference between whites and blacks ranged from 0.6 to 3.0 mm Hg while the standard deviation within each race ranged from 5.0 to 10.1 mm Hg. The percentage of whites and blacks with similar drug-associated changes in diastolic blood pressure was 90% (95% confidence interval: 81 to 99) for diuretics, 90% (95% CI: 83 to 97) for ß-blockers, 95% (95% CI: 92 to 98) for calcium channel blockers, and 81% (95% CI: 76 to 86) for angiotensin converting enzyme inhibitors. The percentage of whites and blacks with similar drug-associated changes in systolic blood pressure ranged from 83% to 93%. In conclusion, the majority of whites and blacks have similar responses to commonly used antihypertensive drugs. Clinical decisions to use a specific drug should be based on other considerations such as efficacy in individual patients, compelling indications, and cost.
Key Words: hypertension • drug therapy • race • meta-analysis
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Introduction |
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On average, whites and blacks differ in their response to many antihypertensive drugs. For example, a large multicenter study found that administration of the angiotensin-converting enzyme inhibitor captopril led to a 10.7 mm Hg reduction in diastolic blood pressure among whites and an 8.0 mm Hg reduction among blacks, resulting in a white–black difference of 2.7 mm Hg (P<0.001).1 In general, whites appear to respond better to ß-blockers and angiotensin-converting enzyme inhibitors whereas blacks appear to respond better to diuretics and calcium channel blockers.2 These average differences are often highlighted in reviews and practice guidelines.2–5 However, there is wide variation in drug-associated changes in blood pressure within each race. In the captopril study mentioned, the standard deviation within each race was 8 to 9 mm Hg, or more than 3-times larger than the white–black difference.1 This variation may mean that many whites and blacks have similar responses to specific drugs (Figure 1). Quantitating the extent of overlap between whites and blacks may guide clinicians as they select antihypertensive drugs for individual patients. The goal of this meta-analysis is to quantify the extent of overlap among all clinical trials in the past 20 years that report race-specific changes in blood pressure for commonly used antihypertensive drugs (ie, among the top 200 most prescribed drugs).6
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Methods |
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Selection of Clinical Trials
Studies were identified through computerized bibliographic searches of MEDLINE (1983 to March 2003) supplemented with manual search of references listed in identified articles. The indexing terms were hypertension (major topic), clinical trial (publication type), human (study group), adult (ages), English (language), and black(s), race, racial, or African-American(s) (text words). Studies were included if they provided race-specific changes in blood pressure (mean and SD) for individual antihypertensive drugs. Studies were excluded if they involved concurrent administration of 2 or more drugs or other interventions (eg, dietary salt modification), used uncommon or experimental drugs, focused exclusively on patients with abnormal cardiac or renal function, or did not include whites and blacks. From the 428 articles identified, 15 studies met all selection criteria. Of the remaining 413 articles, 195 did not quantitate the effect of antihypertensive drugs on blood pressure, 14 focused on patients with abnormal renal or cardiac function, 18 included concurrent interventions, 26 used uncommon or experimental drugs, 5 duplicated other articles, 102 did not include whites and blacks, and 53 did not provide race-specific changes in blood pressure.
Data Extraction
Study characteristics included drug name and daily dose, treatment duration, and number of white and black subjects. Study findings included race-specific changes in systolic and diastolic blood pressure (mean and SD) after drug treatment. Placebo responses were not included in this meta-analysis.
Statistical Analysis
Study findings were pooled separately for each drug category (diuretic, ß-blocker, calcium channel blocker, angiotensin-converting enzyme inhibitor, 
-blocker, central -agonist). Specifically, the mean decrement in systolic blood pressure among white subjects in each study was weighted by the inverse of the variance. These weighted mean differences were then pooled across all studies.7,8 Similar calculations were performed to pool decrements in diastolic blood pressure among whites, decrements in systolic and diastolic blood pressure among blacks, and standard deviations associated with decrements in blood pressure. For studies within each drug category, the Q statistic showed no evidence of heterogeneity while funnel plots showed no evidence of publication bias (not shown).7,8
The pooled results were used to determine how often whites and blacks have similar responses to specific antihypertensive drugs. Because previous studies indicate that changes in blood pressure are normally distributed, the following 5 steps were performed.9,10 First, the pooled mean difference and SDs were used to mathematically describe the normal distributions corresponding to each race (Figure 1). Second, the intersection point of the 2 normal distributions was determined. Third, the area under the leftmost curve to the right of the intersection point was determined. Fourth, the area under the rightmost curve to the left of the intersection point was determined. Fifth, the 2 areas were added and expressed as a percentage of the total area under each curve. A similar procedure was used if the curves intersected at more than one point.
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Results |
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Study Characteristics
The 15 trials analyzed involved a total of 9307 white subjects and 2902 black subjects with a treatment duration that ranged from 4 to 18 weeks (Table 1). All studies were hypertension trials (as opposed to other clinical trials that simply included antihypertensive agents). Most studies were randomized controlled trials and involved blinded administration of antihypertensive drugs. Among trials that reported mean baseline blood pressure separately for each race, blacks generally had a baseline diastolic blood pressure that was 2 to 4 mm Hg higher than whites.
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Study Findings
A statistically significant difference between whites and blacks was found in several of the studies (Table 2
). For example, study 1 found that whites had a 14.7 mm Hg decrement in systolic blood pressure after captopril administration whereas blacks had a 9.1 mm Hg decrement, a white–black difference of 5.6 (95% CI: 2.4 to 8.8). In all s tudies, the magnitude of the white–black difference was smaller than the SD within each race. For example, study 1 found that the SD within each race was approximately 15 mm Hg for change in systolic blood pressure. In addition, the direction of the race difference was not always consistent across studies. For example, whites had a larger response than blacks to diltiazem in study 4 whereas blacks had a larger response in study 5.
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Pooled Decrement in Blood Pressure After Drug Treatment
On average, ß-blockers and angiotensin-converting enzyme inhibitors resulted in larger decrements among whites compared with blacks (indicated by positive white–black difference in Table 3). By contrast, diuretics and calcium channel blockers resulted in larger decrements among blacks (negative white–black difference). However, the white–black differences were small compared with the variation within each race. For example, the white–black difference in systolic blood pressure with angiotensin-converting enzyme inhibitors was 4.6 mm Hg whereas the SD within each race was approximately 12 to 14 mm Hg. In addition, the magnitude of the variation among whites was generally similar to the magnitude of the variation among blacks. For example, the SD for change in systolic blood pressure with diuretics was 11.2 mm Hg (CI: 9.2 to 13.2) among whites and 9.8 mm Hg (CI: 7.8 to 11.7) among blacks.
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Overlap Among Blacks and Whites
The majority of whites and blacks had similar responses to all categories of antihypertensive drugs (Figure 2). For example, 90% (95% CI: 83 to 97) of whites and blacks had similar changes in diastolic blood pressure with ß-blockers.
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Achieving Blood Pressure Goal
The pooled means and SDs in Table 3 may be used to estimate the proportion of subjects achieving a specified decrement in blood pressure. These estimates are presented in Table 4 for ß-blockers and illustrate the impact of baseline blood pressure in determining the proportion of patients reaching a target blood pressure. For example, if whites and blacks are both 6 mm Hg above a target diastolic blood pressure at baseline, then use of this antihypertensive drug will help 77% of whites and 68% of blacks to achieve the target, resulting in a white–black difference of 8% (95% CI: 1 to 15). However, if blacks are 8 mm Hg above the target blood pressure at baseline (while whites are still 6 mm Hg above the target), then drug use will help 77% of whites and 58% of blacks to achieve the target, resulting in a larger white–black difference of 19% (95% CI: 12 to 26). If blacks are 10 mm Hg above the target at baseline, then 77% of whites and 47% of blacks will achieve the target, resulting in an even larger white–black difference of 30% (95% CI: 23 to 37).
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Discussion |
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These results confirm the existence of modest average differences between whites and blacks in response to antihypertensive drugs. Whites generally responded better to ß-blockers and angiotensin-converting enzyme inhibitors whereas blacks generally responded better to diuretics and calcium channel blockers. More importantly, this meta-analysis of 15 clinical trials shows that approximately 80% to 95% of whites and blacks have similar responses to commonly used antihypertensive drugs (ie, even more overlap than that illustrated in Figure 1). The generalizability of these findings is enhanced by the comprehensive literature review, the large sample size of 12 209 patients, and the similarity of results across all drug categories.
It may be argued that achieving a treatment goal (eg, diastolic blood pressure <90 mm Hg) is more clinically relevant than the magnitude of blood pressure reduction. In fact, many previous studies have noted large discrepancies in the proportion of whites and blacks achieving a target blood pressure. For example, 90% of white subjects in one study achieved the treatment goal with an angiotensin-converting enzyme inhibitor whereas only 65% of black subjects did so, resulting in a racial difference of 25%.11 However, black subjects in this study had baseline diastolic blood pressures that were 4 mm Hg higher than white subjects.11 This meta-analysis found that similarly small differences in baseline blood pressure are critical determinants of the likelihood of achieving a treatment goal (Table 3). For example, there was an 8% racial difference with beta-blocker use if whites and blacks were both 6 mm Hg above a treatment goal at baseline. This difference increased to 30% if blacks were 10 mm Hg above a treatment goal at baseline (while blacks were still 6 mm Hg above goal). Most previous studies that reported race-specific baseline blood pressures (Table 1) had a 2- to 4-mm Hg higher baseline diastolic blood pressure among blacks compared with whites.11–16 Thus, these studies may overestimate the difference in the proportion of whites and blacks achieving a target blood pressure after administration of a specific antihypertensive drug. Many other studies did not report baseline blood pressure separately for whites and blacks (Table 1), thereby making if difficult to interpret their results regarding racial differences in achieving a treatment goal.1,17–21
These findings are relevant to recent debate about the role of racial, genetic, and environmental factors in explaining variation across individuals in drug response.5,22,23 Two key questions in this debate are (1) what are the most important genetic and environmental determinants of drug response and (2) is race a good proxy for such genetic and environmental determinants? If race is a good proxy for relevant genetic and/or environmental determinants of drug response, then clinicians should consider race in selecting drugs for individual patients. However, this meta-analysis found that race has little value in predicting antihypertensive drug response, because whites and blacks overlap greatly in their response to all categories of drugs. These findings are consistent with other work demonstrating that most genetic diversity exists within and not between races and that race is a poor predictor of drug-metabolizing enzymes (which in turn influence drug response).24,25
This meta-analysis suggests that clinical decisions to use a specific drug should be based not on race, but rather on other considerations such as efficacy in individual patients, compelling indications, and cost. For example, the most recent report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure highlights the value of using angiotensin-converting enzyme inhibitors for patients with chronic kidney disease.4 This report also points out that modest racial differences in response to individual drugs do exist but can usually be overcome by the addition of another drug.4 In fact, most hypertensive patients need 2 to 4 drugs for adequate blood pressure control.2 Because this systematic review focused on response to individual drugs, recent trials that used multi-drug treatment regimens were not included (eg, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial).10
Several limitations must be considered in interpreting these findings. First, blood pressure changes were assumed to be normally distributed. Although previous work supports this assumption, the individual studies included in this meta-analysis did not specifically describe the distribution of blood pressure change.9,10 Second, subjects received a range of drug doses in most studies (Table 2). For example, subjects in study 3 received an initial enalapril dose of 5 mg per day. This was gradually increased to 40 mg per day, depending on the blood pressure response.17 Although each study included in this meta-analysis applied the same treatment algorithm for white and black subjects, the final drug dosages administered to whites and to blacks were generally not reported separately. Thus, it is possible that some of the observed racial differences may be caused by more aggressive management or dose escalation. Third, data on other factors that may influence blood pressure such as obesity, renal function, and sodium intake were not available. Fourth, it is possible that the study sample is not representative of unpublished studies or non-English language studies.
In conclusion, whites and blacks generally respond similarly to all major categories of antihypertensive drugs. This study’s method of measuring overlap may be helpful in assessing other types of health disparities. Clinicians and researchers should evaluate average differences and overlap between groups when examining health disparities.
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Acknowledgments |
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Supported by grant DK51472 from the National Institute of Diabetes and Digestive and Kidney Diseases.
Received October 21, 2003; first decision November 10, 2003; accepted January 6, 2004.
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References |
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