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(Circulation. 2005;112:3654-3666.)
© 2005 American Heart Association, Inc.

Controversies in Cardiovascular Medicine

Should ethnicity serve as the basis for clinical trial design?

Importance of Race/Ethnicity in Clinical Trials

Lessons From the African-American Heart Failure Trial (A-HeFT), the African-American Study of Kidney Disease and Hypertension (AASK), and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

Anne L. Taylor, MD; Jackson T. Wright, Jr, PhD, MD

	Introduction

Top Introduction The African-American Heart... African-American Study of Kidney... Antihypertensive and Lipid... Establishing the Requirement for... References What Is Ethnicity? Acknowledgments  References

 
The United States has the most affluent and sophisticated medical community in the world, yet large population differences in healthcare outcomes among racial/ethnic populations remain an imposing challenge for the twenty-first century. Although causes of healthcare disparities are many,^1–4 a significant contributor is the absence of research to clearly identify the sources of differences in outcomes in racial/ethnic groups and to distinguish among biological, environmental, or social causes of disease differences.¹ Evaluation of disease differences in subsegments of the population is essential to understand the variety of mechanisms of pathophysiology, as well as to optimally target therapeutic responses. Thus, effective research that would contribute to a reduction in healthcare disparities requires collection of data on health status in racial and ethnic populations and assessment of differences in disease patterns. It also requires clinical trials with the inclusion of adequate numbers of diverse populations to probe for differences in pathophysiology (including environmental or social factors contributing to disease), and responses to treatment. Finally, where differences are observed among population segments, clinical trials focused in these population groups are essential.^1–4

The recently completed African-American Heart Failure Trial (A-HeFT)⁵ and the African-American Study of Kidney Disease and Hypertension (AASK)⁶ are examples of studies focused in ethnic minorities that demonstrate the value of this research approach. In addition, the more than 40 000-participant Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)^7–9 is an example of a clinical trial designed to prospectively assess ethnic differences in response to antihypertensive therapy. Each study has yielded important pathophysiological data with direct impact on the population studied, as well as data that are of great value in the general understanding of disease mechanisms. These studies also represent major advances in the knowledge base for treatment of important diseases and emphasize how the paucity of such studies may actually contribute to racial/ethnic healthcare disparities.

	The African-American Heart Failure Trial

Top Introduction The African-American Heart... African-American Study of Kidney... Antihypertensive and Lipid... Establishing the Requirement for... References What Is Ethnicity? Acknowledgments  References

 
Heart failure is a disease in which there are striking population differences in almost every aspect of the disease.¹⁰ The cause of heart failure is predominantly ischemic disease in nonblacks but is related primarily to hypertension in blacks.¹⁰ Mortality for patients 45 to 64 years of age is significantly higher in blacks, as are rates of hospitalization.¹⁰ A lesser response to angiotensin-converting enzyme inhibitors (ACEIs) and ß-blockers in lowering blood pressure in black versus nonblack hypertensives has been noted.^11,12 Because these drugs have become important for management of heart failure, databases were probed retrospectively to determine the effect of ethnicity on response to these and other agents as heart failure treatments.^13–16 These retrospective analyses reported several important observations: (1) Treatment with isosorbide dinitrate/hydralazine compared with placebo or prazosin conferred a survival advantage for black participants but not for white subjects, and (2) no survival advantage was observed when isosorbide dinitrate/hydralazine was compared with enalapril in black patients, but enalapril was superior to isosorbide dinitrate/hydralazine in white subjects.¹³ Similarly, enalapril compared with placebo reduced hospitalizations for heart failure in whites but did not demonstrate this effectiveness in black patients.^14,15 Trials with the -/ß-blocker carvedilol, when retrospectively reanalyzed by ethnicity, did not reveal differences in benefit between blacks and whites.¹⁶ However, the Beta-Blocker Evaluation of Survival Trial (BEST) trial¹⁷ did find a significant difference in benefit between blacks and whites in response to treatment with bucindolol. In that trial, there was a significant mortality reduction in response to bucindolol only in white subjects. Importantly, BEST was the first heart failure trial designed to prospectively assess response to treatment by ethnicity.

It is notable that the important observations reported in these retrospective analyses occurred 10 to 15 years after the trials were completed, and they were only possible because these studies fortuitously included a sufficient number of black patients to be able to identify differences. Representation of blacks, women, and other minorities in other heart failure trials has been so poor that even meaningful retrospective subgroup analyses have been precluded; thus, the opportunities to define the mechanisms for important population differences may have been missed.

On the basis of the ethnic differences observed in the retrospective analyses of the Veterans Administration Heart Failure Trials (V-HeFT) I and II,¹³ A-HeFT⁵ was designed as the first heart failure trial in an all-black cohort. The rationale was that in this ethnic group, there is a different risk profile for heart failure, including a higher prevalence, morbidity, and mortality from heart failure,¹⁰ and evidence from retrospective analyses that suggested a different response to standard heart failure therapy.¹³ A-HeFT found that the addition of a fixed-dose combination of isosorbide dinitrate/hydralazine to standard neurohormonal blockade resulted in a 43% improvement in survival, a 33% reduction in hospitalizations for heart failure, and significant improvement in quality of life measured with the Minnesota Living With Heart Failure questionnaire⁵ (Figure 1).

View larger version (28K): [in this window] [in a new window]   Figure 1. Improvement in mortality, first hospitalizations for heart failure (HF), and quality of life (QOL) by treatment with isosorbide dinitrate/hydralazine in A-HeFT.

These striking improvements in outcomes occurred in patients well-treated with standard neurohormonal blockade, including ACE inhibition, angiotensin receptor blockade, and ß-blockade. This outcome suggested that alternative or additional mechanisms of progression of heart failure, perhaps related to impaired nitric oxide availability, were present in this population and were treated by this combination. The very rich and unique database of the A-HeFT trial, as well as its genetic substudy, will provide further substantial insights into heart failure–related biomarkers, genetic predictors of response, metabolic markers, and comorbidities in black patients with heart failure. These data have enhanced understanding of the pathophysiology of heart failure in general and presented an opportunity for identification of other populations or disease states that might benefit from this novel therapeutic approach. Even if, after appropriate investigation, no other groups are found who respond to this therapy, the reduction in mortality and hospitalization in a group with greater disease burden would be of significant benefit.

	African-American Study of Kidney Disease and Hypertension

Top Introduction The African-American Heart... African-American Study of Kidney... Antihypertensive and Lipid... Establishing the Requirement for... References What Is Ethnicity? Acknowledgments  References

 
At the time that the AASK trial was initiated, hypertension was the second-leading cause of end-stage renal disease in the United States and the leading cause of end-stage renal disease in blacks.^18,19 Black hypertensives have a 4- to 20-fold higher risk of progression to dialysis-dependent renal disease than do whites with comparable hypertension. Additionally, some have suggested that the pathophysiological mechanisms of hypertension may differ in blacks.^20–22 Despite the observed population differences in hypertensive renal disease, previous studies of renal disease failed to recruit adequate numbers of black participants, and the most promising antihypertensive agents (ACEIs) were known to be less effective in reducing blood pressure in this racial subgroup.^23–25 In fact, the data on renal disease in blacks were so limited that direct measurement of the glomerular filtration rate was required for the AASK trial, because some data suggested that creatinine measurements in blacks did not reflect the same level of renal function as in whites.^26,27 In addition, kidney biopsies were required in the pilot study because of the inadequacy of data regarding whether the renal impairment was related to elevated blood pressure or to undiagnosed, coincident primary renal disease.^28,29

The primary objective of the AASK trial was to determine the optimal choice of antihypertensive regimen and blood pressure level to prevent progression of renal disease attributed to hypertension in a group at high risk for this complication.^6,18 The AASK study more than achieved its original objectives. It clearly demonstrated the benefit of ACEIs in slowing the progression of hypertensive renal disease in black populations (Table). It also showed that once blood pressure is reduced to levels that protect against cardiovascular disease, this level also provides optimal renal protection. An enormous amount of additional data pertinent to blacks was derived from AASK. It confirmed that hypertensive nephrosclerosis in black hypertensives was not due to other occult renal diseases²⁹ and permitted the calibration of creatinine-based renal function measures in this population.^30,31 Because previous studies suggested that black patients were more likely than whites to benefit from lower blood pressure²⁴ and less likely to respond to ACEIs, the findings in AASK may easily be generalized to other population subgroups with hypertensive nephrosclerosis. Finally, the genetic database and ongoing follow-up of this cohort along with another large (3000 participant) multiethnic observational cohort will provide valuable data on the mechanisms related to progression of renal disease in a much wider population.³²

View this table: [in this window] [in a new window]   AASK Clinical End-Point Analysis

	Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

Top Introduction The African-American Heart... African-American Study of Kidney... Antihypertensive and Lipid... Establishing the Requirement for... References What Is Ethnicity? Acknowledgments  References

 
ALLHAT was designed to determine whether antihypertensive regimens initiated with newer agents, ie, ACEIs, calcium channel blockers, or -blockers, were more effective than one initiated with a thiazide-diuretic in preventing cardiovascular events (especially coronary heart disease) in high-risk hypertensives aged 55 years and older. ALLHAT had a goal of recruiting a sufficiently large black cohort to permit the evaluation of drug treatments by race prespecified in the analysis plan.⁷ Cardiovascular disease has become the leading cause of morbidity and mortality worldwide, and elevated blood pressure is a leading contributor to this phenomenon.^11,25 The black hypertensive population has the highest morbidity and mortality from hypertension of any population group in the United States and among the highest in the world.^25,33 Mortality related to hypertension and the risk of end-stage renal disease, coronary heart disease, heart failure, and stroke are increased in the black population compared with the white population in the United States.²² Despite the observed racial differences in prevalence, outcomes, and treatment responses to hypertension, before ALLHAT, there were no studies that evaluated cardiovascular outcomes in black patients either in progress or planned.

ALLHAT recruited more than 15 100 black subjects of African descent (from the United States, Canada, and the Caribbean) and 8000 Hispanic participants.⁹ The most striking findings in the trial were in the black participants in ALLHAT. In the whole cohort and in nonblacks, the thiazide-type diuretics proved to be at least as effective as amlodipine and lisinopril in lowering blood pressure and preventing cardiovascular outcomes (including coronary outcomes). In the black cohort, the difference in outcome between the diuretic and the ACEI was magnified dramatically. Blacks randomized to the ACEI had a 5 mm Hg/2 mm Hg higher average follow-up blood pressure, 40% higher risk of stroke, 30% higher risk of heart failure, 15% higher risk of combined coronary heart disease, and 19% higher risk of combined cardiovascular disease, all significantly higher than those randomized to the diuretic⁸ (Figure 2).

View larger version (29K): [in this window] [in a new window]   Figure 2. Outcomes in black subjects in the ALLHAT trial.8 MI indicates myocardial infarction; CHD, coronary heart disease; and CVD, cardiovascular disease.

The conclusive findings in ALLHAT, along with suggestive findings in the black cohort from the Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial,³⁴ have clearly established the primacy of diuretic-based over ACEI/angiotensin receptor blocker–based therapy in the management of black hypertensives without renal disease or heart failure and have confirmed the lesser benefit of inhibitors of the renin angiotensin system in preventing cardiovascular disease outcomes in black hypertensives. Thus, these trials have also provided a further refinement that guides the use of renin angiotensin system inhibitors for the control of hypertension in situations in which ethnicity impacts the use of these agents in preventing 1 complication of hypertension (ie, renal outcomes) but not another (cardiovascular outcomes). Unfortunately, these findings come more than a quarter century after the introduction of the ACEIs.

	Establishing the Requirement for Trials in Population Subgroups

Top Introduction The African-American Heart... African-American Study of Kidney... Antihypertensive and Lipid... Establishing the Requirement for... References What Is Ethnicity? Acknowledgments  References

 
The A-HeFT, ALLHAT, and AASK trials were benchmark trials focused on ethnic minority populations that illustrate the importance of using differences noted in observational or clinical trial data to probe for important pathophysiological principles and treatment-response differences that may then allow better-targeted therapy. They clearly established the viability of recruiting, retaining, and collecting quality data from black populations. Importantly, they resulted from the observation of population differences in disease patterns, which ultimately yielded focused trials that contributed significant new understanding of the pathophysiology and treatment of diseases. Although the insights gained may have the greatest direct impact on particular population segments, they also provide significant benefit to overall societal health.

Population differences in disease prevalence, pathophysiology, and outcome may be attributed to genetic differences (eg, cystic fibrosis, sickle-cell disease, and breast cancer suppressor gene abnormalities), biomarker differences (eg, estrogen receptor positivity or negativity in breast cancer), environmental differences, lifestyle choices (eg, tobacco use or sedentary lifestyle), social factors, and complex interactions among all these causes. Examples of significant differences in disease prevalence, risk profile, and response to treatment in populations that differ with respect to geographic ancestry are frequent in the literature. Thus, breast cancer risk associated with mutations of the BRCA-1 and -2 genes is higher in women of Ashkenazi Jewish ancestry³⁵ but may be significantly modulated by nongenetic environmental factors. When the response to interferon therapy for hepatitis C was compared among Asian-American, Latino, non-Latino white, and black patients, a significantly lower response to interferon was observed in black patients.^36,37 The hypertension literature is particularly rich in examples of differences between blacks and whites with respect to prevalence, pathophysiology, target-organ damage, and responses to treatment of hypertension.^21,25 In clinical trials, ethnic differences in the antihypertensive responses of ß-blockers and ACEIs as monotherapy have been well-recognized.²⁵ More recently, retrospective analyses of heart failure trials have suggested differences in response to ACEIs,^13,15 to combined isosorbide dinitrate/hydralazine,¹³ and to some but not all ß-blockers.^16,17

Despite the evidence for differences in disease pattern or outcomes, until recently, clinical trials were generally conducted with populations homogenous with respect to age, gender, and/or ethnicity, and the results were then generalized to all populations.³⁸ Although this imposes a limitation in the ability to extrapolate results to all population groups, this model became the standard design for clinical research.^38–40 Population differences with potential pathophysiological and therapeutic implications may be obscured by this clinical trial design. Important mismatches between populations studied as clinical trial subjects and those to whom therapy will be directed often exist.³⁸ Thus, drugs may be studied in young individuals but are most often used by elderly individuals. Therapies studied in adults may have different effects in children, and those studied in men may have different effects in women. Many studies of ACEIs and angiotensin receptor blockers limited the number of blacks enrolled in the studies to evaluate blood pressure lowering and may thereby have influenced the selection of study cohorts for clinical outcome trials. A striking example of the consequences that result from failure to include representative populations are the recommendations that resulted from the large trial that examined the effect of tamoxifen on breast cancer prevention.⁴¹ Although 13 388 women were studied over 5 years, only 220 women were black (a group with a slightly lower breast cancer incidence but higher mortality), and 249 were other unspecified minorities.⁴¹ Despite the extraordinarily low inclusion of minorities, guidelines were subsequently published that suggested that black women be counseled against preventive therapy with tamoxifen at ages 10 years younger than nonblack women.⁴² The potential disservice of such a recommendation in the absence of adequate data in black women is obvious.^43,44 Subsequent studies have shown this therapy to be equally effective in black women.⁴⁵ Such mismatches led the National Institutes of Health in 1994 to mandate the inclusion of women and ethnic minority subjects in clinical trials, which were later followed by Food and Drug Administration mandates to include geriatric and pediatric subjects.^46–48

Current federal guidelines define 5 principal ethnic/racial groups.These groupings roughly correspond to the continent of geographic origin, except for 1 group that is defined by language (ie, Hispanic). This grouping is complicated, especially in the United States, where geographic ancestry may be associated with clustering of genetic characteristics but is also coupled with differences in societal advantage, living environments, physician-patient interactions, accumulation of wealth, and access to quality health services. In spite of these complexities, inclusion of subjects by race/ethnicity in clinical trials is essential to define the reasons for differences in health outcomes, whether environmental or biological.^39,40

Although the A-HeFT, AASK, and ALLHAT studies support the concept of studies focused in specific ethnic groups, there are potent arguments for refinement to this approach. An area of considerable promise currently is the role that genetic characterization may play in understanding population variation in disease patterns. Gene expression patterns are associated with responsiveness to pharmacological treatment.^49,50 Variation in drug response⁵¹ and pathways of drug disposition and response may sort along ethnic divisions.⁵² As more genetic data are acquired, understanding of the role of heritable factors in disease and their interactions with environmental factors will become practical and usable. Although Tang et al⁵³ have reported a close correlation between genetic groupings and racial self-identification, in a thoughtful review, Rotimi⁵⁴ points out the current problems with equating social identity with genetic variation. He accepts the notion that ancestry defined by patterns of genetic variations may roughly correspond to geographic origin but may still not correspond to concepts of "race" and "ethnicity."⁵⁴ Tate and Goldstein⁵⁵ present data summarizing ethnic differences in drug responses related to differences in disease mechanisms but point out that differences in drug response may result from average genetic differences between racial/ethnic groups, from environmental factors, or from environmental factors associated with a particular racial/ethnic group, as well as gene-gene interactions. These authors also summarize the current state of knowledge of genetic associations with diseases in different populations, ie, polymorphisms associated with a specific disease in 1 population may be absent in another population with the same disease.⁵⁵

Although understanding the genetic contributors to disease will make a sizable contribution to optimization of disease management, it will surely not explain all population differences in disease. Genetic-based pathophysiology of disease and intervention will not address population differences that result from environmental/social factors or interactions among causes. Thus, it would be a missed opportunity to not study populations guided by epidemiological and clinical data and to not design studies in which all the variables (eg, biological, genetic, environmental, and social) that might influence health are considered. Despite the complexity of health determinants in populations of differing race/ethnicity/geographic ancestry, the A-HeFT, AASK, and ALLHAT trials have demonstrated the importance of clinical trials focused in population subgroups to further understand disease mechanisms and optimize therapy, especially where substantial population differences have been observed.

In summary, population differences in disease exist that may be attributable to differences in social factors, genetics, environment, lifestyle, comorbidities, and complex interactions among these factors. When population differences are observed, focused studies are warranted to identify the contribution of these factors (including biological, environmental, social, genetic, and lifestyle factors and their interactions) and how best to treat them. Identification and study of population differences may enhance disease treatment in all populations and additionally may provide disparity-reducing benefit for populations with poorer health outcomes.

	Acknowledgments

 
Disclosure

Dr Taylor has received a research grant from NitroMed, Inc, and has served as a consultant to or on the advisory board of NitroMed, Inc, and Bristol-Myers Squibb. Dr Wright has received research grants from Novartis, GlaxoSmithKline, and the National Institutes of Health, has served on the speaker’s bureau of or received honoraria from NitroMed, Inc, Novartis, GlaxoSmithKline, Pfizer, and AstraZeneca, and has served as consultant to or on the advisory board of NitroMed, Inc.

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Top Introduction The African-American Heart... African-American Study of Kidney... Antihypertensive and Lipid... Establishing the Requirement for... References What Is Ethnicity? Acknowledgments  References

 

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Should ethnicity serve as the basis for clinical trial design?

Importance of Race/Ethnicity in Clinical Trials

Diversity and Inclusiveness Should Remain the Guiding Principles for Clinical Trials

Richard S. Cooper, MD; Bruce M. Psaty, MD, PhD

The design of randomized controlled trials relies on theoretical principles that are at the core of clinical science. If performed successfully, randomization is assumed to provide a bias-free comparison of 2 or more groups that have the same prognosis. The difference between what did happen with treatment and what would have happened without it is therefore a rigorous test of efficacy and safety. Because we are almost never interested in interpreting this result within the narrow conditions of the trial, it is further assumed that the results of the trial are generalizable to the broader universe of study-eligible patients.

Most trials must therefore attempt to achieve 2 competing goals. First, the treatment must be submitted to a sufficiently rigorous test to determine whether it actually works. The second competing requirement is the need to determine the value of the intervention in routine practice. The first goal is generally best met by recruiting a narrow spectrum of patients who are most likely to benefit, often defined as the high-risk subset. These patients are selected because their high event rates will increase statistical power, not because their response will be unique or categorically different. The second condition can be addressed most effectively in large, simple studies that have few exclusion criteria and enroll patients from a wide range of settings. To mediate the tension between these opposing aims, it is almost always assumed that although the recruitment of high-risk patients may improve power, the treatment is unlikely to be associated with effect modification, which would undermine the basis for generalizing to a broader group of patients.

Ethnic-specific trials, which in the United States included largely middle-aged white men, were once the norm. This approach did in fact generate concerns that age, sex, or ethnicity might modify the effects of treatment, and the preferred standard is currently to include diverse groups of patients in adequate sample sizes to explicitly test for differential response. The Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial (ALLHAT) is the most prominent example of a trial based on this principle.¹

At this time, ethnic-specific trials would seem to represent a step backwards. At the very least, they need to be supported by a theoretical rationale that can be integrated into the established framework for trials. This rationale could rest on the knowledge that the difference in intrinsic responsiveness is so large that the main effect would be diluted in a trial with a diverse sample of patients. This approach is analogous to the goal of choosing high-risk patients. Typically, a large number of epidemiological studies will have identified high-risk groups. The evidence supporting a differential effect of treatment across ethnic groups, on the other hand, is likely to be meager. A separate rationale for an ethnic approach to restriction would arise if prior clinical trials had shown a response present in only 1 group that could not be explained by known clinical factors or genetic variation. This result implies effect modification and, as suggested, would have complicated the interpretation of the results of the original trial.

Although some overlap therefore exists between the "high-risk" and "ethnic-specific" design, there are also important potential differences. Because ethnicity is a categorical distinction, the basis for generalizing to other groups might be hard to establish. Selection of high-risk patients on the basis of clinical criteria usually supports a generalization to high-risk members of other ethnic groups, and milder cases, or it can provide direction for additional trials. After a positive trial in 1 ethnic group, it would be hard to judge whether the observed response is the same, better, or worse than would be expected in other groups or whether it is categorically different. This result occurs because the criterion for entry (ie, ethnicity) is not defined in clinical terms and does not provide any context for a judgment about generalizability to patients outside that category.

Although the implications of ethnic-specific trials are potentially quite broad, we focus on drug treatment for cardiovascular conditions among European- and African-origin populations in the United States, as reflected in a Food and Drug Administration (FDA) document on collection of ethnicity data and the African-American Heart Failure Trial (A-HeFT), a recently completed vasodilator trial.^2,3 Given its obvious relevance to this debate and its importance as a potential test of the underlying principles, we will address the specific implications of AHeFT at the end of this discussion.

	What Is Ethnicity?

Top Introduction The African-American Heart... African-American Study of Kidney... Antihypertensive and Lipid... Establishing the Requirement for... References What Is Ethnicity? Acknowledgments  References

 
Ethnicity is a catch-all term that describes a set of lifestyle/behavioral/cultural experiences. In racially stratified societies, culture, genes, and environment are strongly confounded.⁴ In practice, the term "ethnicity" often functions as a stand-in for race and refers to both potential genetic factors and acquired effects of environmental exposures. Although the term may remain indifferent about whether genetic and environmental effects are causal, its lack of clarity about which of the explanations is primary often leads to confusion. Because ethnic-specific trials assume that some inherent factor in the patient influences the response, interpretation would be easier if that factor were defined, and the results could be more easily generalized to other subgroups that shared that factor. When possible, therefore, the rationale for an ethnic-specific trial should be supported by arguments that distinguish between genetic or environmental effects. Otherwise, restriction of enrollment using such a "fuzzy" category could be an unreliable tool in clinical trials.

Do Major Cardiovascular Syndromes Vary Qualitatively, Rather Than Quantitatively, by Ethnicity?
The most obvious rationale for testing drugs in a single ethnicity is the idea that the pathophysiology of the disease is special or different in that group. This line of thinking clearly applies to cardiovascular disease in blacks, and an enormous body of literature exists on this subject. Historically, for example, blacks are said to be stroke-prone but relatively protected from coronary heart disease.⁵ More frequent and more severe hypertension is the primary determinant of the black-white contrasts in clinical manifestations of cardiovascular diseases, and an extensive list of putative physiological and biochemical racial differences has been reported.^6,7

Two general conclusions have been advanced about this literature. Some observers are impressed by the nature of the differences and conclude that the manifestations of cardiovascular disease are unique among blacks. Others view these contrasts as epiphenomena that result from differential exposure to cardiovascular risk factors, themselves the consequence of different lifestyle patterns. This controversy cannot be resolved on the basis of current knowledge. We share the view that the clinically relevant racial differences are attributable largely to the degree or intensity of the environmental exposures, an interpretation often supported by epidemiological data. For example, trends over time demonstrate a relative increase in coronary disease among blacks in the last 50 years, and other European populations actually experience more hypertension and associated sequelae than do US blacks.^8,9 Many of the "race-specific" effects, such as an increased prevalence of low-renin hypertension, are also seen in comparisons that stratify by level of risk within ethnicity, eg, age and gender, whereas many others are simply biochemical curiosities, such as differences in ion transport, with no known causal significance.^6,7,10 True pathophysiological differences have thus remained elusive.

Differential responses to cardiovascular drugs between blacks and whites have also received widespread attention and formed part of the rationale for the FDA’s new guidelines regarding data reporting in trials: "Some differences in response to medical products have already been observed in racially and ethnically distinct subgroups of the US population.... For example,...studies have shown that blacks respond poorly to several classes of antihypertensive agents (beta blockers and angiotensin converting enzyme (ACE) inhibitors) (Exner 2001 and Yancy 2001)."² Although the FDA document refers to antihypertensive therapy as the condition of interest, the citations are studies of heart failure. Furthermore, the study by Yancy et al actually found that "(t)he benefit of carvedilol was apparent and of similar magnitude in both black and nonblack patients with heart failure."¹¹ Furthermore, although blood pressure responses for ACE inhibitors do vary modestly among blacks and whites, there is considerable overlap, and race-specific prescribing has not been recommended in the United States.^12,13

Because a rigorous test of the hypothesis about racial differences in fundamental aspects of the physiology of multifactorial diseases is so difficult, the opinions advanced on this topic mainly reflect prior beliefs. Under these circumstances, there is the concern, which we share, that the idea of race can "distort, maximize and exaggerate" the nature of population differences.¹⁴ The appropriate scientific approach is to accept the null hypothesis of no difference until convincing evidence to the contrary is available. In a highly commercialized environment such as drug development and marketing, where strong profit incentives exist, reliance on subjective judgment could have particularly unfortunate consequences.¹⁵

Two conclusions follow from these arguments. First, if after decades of intense study, we cannot resolve the issue of black-white differences in cardiovascular disease, it will be very difficult to determine what clinical syndromes are actually "unique" or "special" in any other pair of racial groups, thereby providing a mechanism for differential drug response. Second, subjective bias will play a large role in determining whether a difference is interpreted as being particularly salient. A clear mechanistic rationale would therefore be required to overcome the primary weakness of nongeneralizability that is inherent in the ethnic-specific design.

What Might Be the Role of Variation in Polymorphisms That Influence Drug Response?
Both adverse and therapeutic drug responses differ among individuals, and some of these differences are likely to be genetic.^16,17 Sequence variations that influence bioavailability, distribution, and metabolism have also been shown to vary by race/ethnicity, although the genotype-phenotype relationships are often complex and within-race heterogeneity is large.^18–21 Accumulating evidence suggests that these genetic variants may in turn have consequences for clinical sequelae.^22,23 It might follow that race-specific drug responses could reflect genetic effects.

This last inference is not well founded, however. Variation at the population level is distributed differently than variation at the individual level, being graded and probabilistic rather than categorical. Furthermore, the vast majority of genetic variation (85% to 90%) is found within, not between, continental populations.^24,25 The hypothesis that sufficiently extreme genetic variation exists between populations for ethnicity to serve as a "diagnostic marker" requires assumptions that are unlikely to be true. For group membership to be a sufficiently precise marker, the variant(s) underlying drug response must both be common and occur at very different frequencies in the 2 populations. However, common mutations tend to be old and, for that reason, widespread among regional populations.^25–27 Between-group variation over the usual range for common drug-metabolizing polymorphisms means that racial identity will have inadequate predictive power.²⁷ For example, in the simplest case, if the prevalence of the minor allele that predicts nonresponse is 20% and 40% in 2 groups, then knowledge of group identity is associated with a boost in the likelihood of response by only 1.7 (Table). Only when the interethnic contrasts in allele prevalences reach levels of 90% versus 10%, which corresponds to likelihood ratios associated with diagnostic tests such as screening mammography, does ethnicity begin to serve as a clinically useful diagnostic predictor of potential drug response. Although possible, such a large difference in allele frequencies will be rare for large continental racial groups. The reliability of ethnicity as a "diagnostic test" would also vary depending on the available alternative treatments, the anticipated benefit, and the potential side effects. With the passage of time, as continental populations intermingle, "race" will continue to lose its predictive value as a marker for unlinked genes altogether, as has already occurred in Brazil.²⁸ Skin color and other observable traits will then be uncorrelated with the alleles that influence drug response.

View this table: [in this window] [in a new window]   Framework for Assessing the Value of Ethnicity in Predicting Drug Response Based on the Presence of a Functional Allele

Furthermore, biological variability in drug response is conditioned by a complex set of processes that involves metabolizing enzymes, receptors, signal transducers, and transporters. Because the clinical response is usually determined by the coordinated action of multiple systems, it becomes even less likely that the pattern of variation in several genes would be race-based.

On the other hand, mutations that are associated with toxic effects tend to be rare, and rare variants are more likely to be group-specific. Numerous examples now exist^29,30; when an adverse event is known to be much more common in one group than another, the choice of a drug or targeted screening for adverse effects could be justified in one population but not others. This distinction between the search for differential group drug response and a differential frequency of adverse drug reactions is important. Variation in low-frequency alleles responsible for adverse events cannot be used to support a general theory that groups, on average, vary in response.

There is substantial irony in the general tendency to view disease syndromes in persons of African descent as unusual or unique by virtue of nonresponse to a common therapy. Because our species evolved in Africa over millions of years, contemporary African populations retain the greatest genetic diversity.³¹ A recent analysis of 1.6 million single nucleotide polymorphisms (SNPs), for example, identified the heterozygous state in 95% of blacks compared with 81% of whites and 74% of Han Chinese.²⁵ If therefore, drug response is predicated on the presence of a specific SNP, it would be least likely for it to be absent from African-origin populations and present in all others.

In many ways, the contradiction between the evidence from genetics and the appeal of race-specific trials reflects one of the most difficult dilemmas that we face in integrating genomics into medical practice. Racial hypotheses evoke considerable skepticism among many geneticists.^32,33 Nonetheless, genomics has provided a new context within which racial hypotheses in medicine appear to make sense, and much of the public attention given to the issue of race-based trials incorrectly assumes that these studies are exploiting the tools of molecular science to find new therapies.^34,35 The concept of race continues to serve as a shortcut, an imagined reality not substantiated by the scientific evidence.¹⁴ Although a proxy measure would clearly be useful, race can almost never serve as a diagnostic test for a medical condition or a common drug response. Instead of being used to reinvigorate an outmoded concept of race, pharmacogenomics should be seen as an opportunity to replace group labels with laboratory-based tests.^16,17

To avoid confusion on this point, we reemphasize the key points. Rare genetic variants tend to be isolated to one population.²⁵ If they are associated with toxic effects, then screening in that group alone is appropriate. However, therapeutic decisions about a class of patients based on ethnicity assume that the functional variants are present at high frequency in one population and not others. This distribution, although possible, is unlikely for common variants and cannot serve as the basis for the design of a trial unless direct genetic evidence is available. If that evidence exists, then the measurement of genetic polymorphisms in individuals, not approximate estimates based on group labels, will improve the design and power of the clinical trials.

Could Ethnicity Be a Marker for the Predominance of Clinical Subtypes?
A clear distinction can be made between the expression of a disease complex that has resulted from inherited predisposition and one that reflects the lifetime accumulation of risk factor exposure. The earlier age of onset and the higher prevalence of hypertension in blacks in the United States are probably responsible for the higher than expected rates of renal failure and stroke. Although some of the contrasts in the epidemiology of cardiovascular sequelae may be an artifact of imprecise measurement of clinical risk factors, ethnicity could be a marker for group differences in the etiology and clinical course, and as a consequence, they may predict outcomes of therapy. This scenario could then justify the focus of a clinical trial on a particular ethnic group, as the equivalent of a focus on a high-risk set of patients, and this approach was incorporated in a recent trial on renal disease among blacks.³⁶ If the hypothesis involves a differential response to drug therapy, an entirely different kind of trial, designed to evaluate effect modification by race, would be in order. As suggested above, the assumptions required for effect modification will usually be harder to justify.

What Is the Experience of Subgroup Comparisons by Ethnicity?
Ironically, the vast majority of trials conducted to date have actually been ethnic-specific. This occurred not by design but because most trials were restricted in recruitment to a single population. The underlying assumption has been that the findings will be generalizable to other populations of whites, blacks, Asians, etc. In practice, the possibility of differential responses has been generally ignored, although recent guidelines stipulate conditions under which "bridging trials" would be required to introduce drugs into new populations in which no experimental data have been collected.³⁷ Dosing and adverse response rates are the most likely factors to vary, and for most classes of cardiovascular drugs, there has been little difficulty extrapolating from one population to another. Other ethnic-specific trials are ongoing, although the scientific justification is not always clear.³⁸ In any case, the conduct of ethnic-specific trials to get physicians’ attention for marketing purposes is not appropriate.

The best source of information on ethnic-specific responses is therefore data from existing trials. Attempts to extract information regarding ethnic subpopulations confront a number of obstacles, however, including the hazards of multiple testing. Undue emphasis can be given to the post hoc interpretation of differential response by race, especially when a large number of secondary end points are examined.^39–41 Because the test of a significant difference between groups is based on a test for interaction, 4 times the sample size of a simple exposed versus unexposed comparison is generally required to achieve similar power.⁴² Rarely do trials have the luxury of 4-fold overrecruiting beyond the primary aims. In the absence of strong statistical evidence of an interaction, the best evidence about a drug effect in a subgroup is the evidence from the trial as a whole. In the absence of prespecified hypotheses about race differences, it is therefore uncommon to be able to make claims about ethnic-specific effects with the same degree of certainty as applied to the main end points. A major exception is ALLHAT, in which tests of ethnic effects were specified in advance.^1,30 Although they confirmed small differences in achieved blood pressure reduction with an ACE inhibitor, ALLHAT investigators concluded that initial therapy for hypertension should be the same for both blacks and whites.³⁰ ALLHAT therefore answered the specific question about the optimal first-line drug for the pharmacological treatment of high blood pressure. This approach, when feasible, is clearly preferable to ethnic-specific studies. We recognize, of course, that trials of this magnitude are very expensive and alternative approaches may be required to move the process of drug evaluation forward.

Having Said That, What About AHeFT?
AHeFT enrolled self-identified African-Americans with New York Heart Association class III and IV heart failure in a trial of the addition of isosorbide dinitrate and hydralazine to standard therapy with ACE inhibitors and ß-blockers.³ The benefit documented in AHeFT was as large as the observed benefit in single-therapy trials of ACE inhibitors and ß-blockers.^3,43 The evidence for a differential response by race before AHeFT was not particularly robust, however. The previous trials with similar agents failed to show a significant interaction by race, and a meta-analysis of ß-blocker and ACE inhibitor trials found identical benefit in blacks and whites, with the exception of Beta-Blocker Evaluation of Survival Trial (BEST).⁴³ In SOLVD (Studies Of Left Ventricular Dysfunction), the only ACE inhibitor heart failure trial with sufficient numbers of blacks and whites, no difference in the primary outcome was noted, and post hoc analyses of secondary end points were inconsistent with regard to differential racial effects.^40,41 In ALLHAT, the relative outcome for heart failure for a diuretic versus an ACE inhibitor in blacks and whites was indistinguishable, before and after control for blood pressure effects.³⁰ Because only blacks were enrolled in AHeFT, it provides no direct evidence on differential efficacy. A similar group of patients from any ethnic background could potentially respond as well. Unfortunately, the hypothesis of a differential response, with which the trial design began, remains untested. The results of AHeFT provide no evidence to justify a change in the basic principles of randomized trials.

Conclusions
The conduct of science creates all sorts of new observations, some exp