Importance of Race/Ethnicity in Clinical Trials
2005; Lippincott Williams & Wilkins; Volume: 112; Issue: 23 Linguagem: Inglês
10.1161/circulationaha.105.540443
ISSN1524-4539
AutoresAnne L. Taylor, Jackson T. Wright,
Tópico(s)Race, Genetics, and Society
ResumoHomeCirculationVol. 112, No. 23Importance of Race/Ethnicity in Clinical Trials Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBImportance of Race/Ethnicity in Clinical TrialsLessons 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 and Jackson T. WrightJr, PhD, MD Anne L. TaylorAnne L. Taylor From the University of Minnesota National Center of Excellence in Women's Health (A.L.T.), University of Minnesota Medical School, Minneapolis, Minn; General Clinical Research Center and Clinical Hypertension Program (J.T.W.), Case Western Reserve University, Cleveland, Ohio; Department of Preventive Medicine and Epidemiology (R.S.C.), Loyola Stritch School of Medicine, Maywood, Ill; and Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle. and Jackson T. WrightJrJackson T. WrightJr From the University of Minnesota National Center of Excellence in Women's Health (A.L.T.), University of Minnesota Medical School, Minneapolis, Minn; General Clinical Research Center and Clinical Hypertension Program (J.T.W.), Case Western Reserve University, Cleveland, Ohio; Department of Preventive Medicine and Epidemiology (R.S.C.), Loyola Stritch School of Medicine, Maywood, Ill; and Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle. Originally published6 Dec 2005https://doi.org/10.1161/CIRCULATIONAHA.105.540443Circulation. 2005;112:3654–3666The 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.1–4The 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 TrialHeart 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 β-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 α-/β-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). Download figureDownload PowerPointFigure 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 β-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 HypertensionAt 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.28,29The 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.32AASK Clinical End-Point AnalysisOutcomeACEI vs Calcium Channel BlockerACEI vs β-Blocker% Risk Reduction*95% CI (P)% Risk Reduction95% CI (P)GFR event indicates ≥50% or 25 mL · min · mol/L−2 decline in glomerular filtration rate; ESRD, end-stage renal disease.*Adjusted for baseline proteinuria, mean arterial pressure, gender, history of congestive heart failure, and age.†179 with declining GFR, 84 with ESRD, and 77 deaths.‡170 with declining GFR, 84 with ESRD.§171 with ESRD, 79 deaths.∥170 events, deaths censored.Source: Wright et al.6GFR event, ESRD, or death†3814 to 55 (P<0.005)221 to 38 (P<0.042)GFR event or ESRD‡4013 to 59 (P<0.007)22−1 to 41 (P<0.066)ESRD or death§4826 to 65 (P<0.004)21−5 to 40 (P<0.11)ESRD alone∥5934 to 74 (P< 0.001)23−10 to 45 (P<0.14)Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack TrialALLHAT was designed to determine whether antihypertensive regimens initiated with newer agents, ie, ACEIs, calcium channel blockers, or α-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). Download figureDownload PowerPointFigure 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 SubgroupsThe 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 β-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 β-blockers.16,17Despite 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.46–48Current 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.39,40Although 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.55Although 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.DisclosureDr 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.FootnotesCorrespondence to Anne L. Taylor, MD, Professor of Medicine/Cardiology, Associate Dean for Faculty Affairs, Co-Director, University of Minnesota National Center of Excellence in Women's Health, University of Minnesota Medical School, Mayo Mail Code 293, 420 Delaware St SE, Minneapolis, MN 55455 (e-mail [email protected]); or Richard S. Cooper, MD, Department of Preventive Medicine and Epidemiology, Loyola Stritch School of Medicine, 2160 S First Ave, Maywood, IL 60153 (e-mail [email protected]). References 1 Gromann R, Ginsberg J, American College of Physicians. Racial and ethnic disparities in health care. Ann Intern Med. 2004; 141: 226–232.CrossrefMedlineGoogle Scholar2 Mayberry R, Boone L. Racial/Ethnic Differences in Cardiac Care: The Weight of the Evidence. Menlo Park, Calif: American College of Cardiology Foundation, Henry J. Kaiser Family Foundation; 2002. Publication No. 6041.Google Scholar3 Smedley BD, Stith AY, Nelson AR. Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care. Washington, DC: National Academies Press; 2003.Google Scholar4 Woolf SH, Johnson RE, Fryer GE Jr, Rust G, Satcher D. The health impact of resolving racial disparities: an analysis of U.S. mortality data. Am J Public Health. 2002; 288: 2421–2431.Google Scholar5 Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino R Jr, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN, for the African-American Heart Failure Trial Investigators. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004; 351: 2049–2057.CrossrefMedlineGoogle Scholar6 Wright JT Jr, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, Cheek D, Douglas-Baltimore JG, Gassman J, Glassock R, Hebert L, Jamerson K, Lewis J, Phillips RA, Toto RD, Middleton JP, Rostland SG, for the African-American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002; 288: 2421–2431.CrossrefMedlineGoogle Scholar7 Davis BR, Cutler JA, Gordon DJ, Forberg CD, Wright JT Jr, Cushman WC, Grimm RH, LaRosa J, Whelton PK, Perry HM, Alderman MH, Ford CE, Oparil S, Francis C, Proschan M, Pressel S, Black HR, Hawkins CM, for the ALLHAT Research Group. Rationale and design for the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Hypertens. 1996; 9: 342–360.CrossrefMedlineGoogle Scholar8 Wright JT, Dunn JK, Cutler JA, Davis BR, Cushman WC, Ford CE, Haywood LJ, Leenen FH, Margolis KL, Papademetriou V, Probstfield JL, Whelton PK, Habib GB, for the ALLHAT Collaborative Research Group. Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA. 2005; 293: 1595–1608.CrossrefMedlineGoogle Scholar9 Grimm RH Jr, Margolis KL, Papademetriou VV, Cushman WC, Ford CE, Bettencourt J, Alderman MH, Basile JN, Black HR, DeQuattro VV, Eckfeldt J, Hawkins CM, Perry HM Jr, Proschan M. Baseline characteristics of participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertension. 2001; 37: 19–27.CrossrefMedlineGoogle Scholar10 Yancy CW. Heart failure in African-Americans: a cardiovascular enigma. J Card Fail. 2000; 6: 183–186.CrossrefMedlineGoogle Scholar11 Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003; 289: 2560–2572.CrossrefMedlineGoogle Scholar12 Johnson ER, Wright JT Jr. Management of hypertension in black populations. In: Weber MA, Oparil S, eds. Hypertension. Philadelphia, Pa: Elsevier; 2005.Google Scholar13 Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. J Card Fail. 1999; 5: 178–187.CrossrefMedlineGoogle Scholar14 Dries DL, Strong MH, Cooper RS, Drazner MH. Efficacy of angiotensin-converting enzyme inhibition in reducing progression from asymptomatic left ventricular dysfunction to symptomatic heart failure in black and white patients [published correction appears in J Am Coll Cardiol. 2002;40:1019]. J Am Coll Cardiol. 2002; 40: 311
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