Correspondence
Race and Responsiveness to Drugs for Heart Failure
N Engl J Med 2001; 345:766-768September 6, 2001
- Article
To the Editor:
As Wood (May 3 issue)1 points out, individual and racial differences in the responses to drugs are increasingly often shown to reflect, at least in part, varying distributions of polymorphisms in drug receptors or drug-metabolizing enzymes among different populations. In several instances, a lesser response was found in nonwhite patients than in white patients to such drugs as the angiotensin-converting–enzyme (ACE) inhibitor enalapril, as reported by Exner et al. (May 3 issue),2 and the beta-blocker bucindolol.3 These findings are valuable for guiding clinical practice.
From another perspective, it would be interesting to examine to what extent the selection processes that take place during the various phases of drug development and that have thus far been conducted in predominantly white American and European populations have led to the selection of drugs that are effective in Western populations but not necessarily in other populations. It is indeed likely that the development of several drugs that would have been effective in other populations has been abandoned because a genetic trait associated with a low response rate or with undesirable side effects is widespread in the predominantly white patients involved in early-stage pharmacologic studies.
A global response is required to tackle worldwide health challenges — particularly the spread of chronic diseases. This response requires the more systematic inclusion of nonwhite populations in clinical and population-based trials.
3 ReferencesPascal Bovet, M.D., M.P.H.
Ministry of Health, Victoria, Seychelles
pascal.bovet@inst. hospvd. ch Fred Paccaud, M.D.
University Institute of Social and Preventive Medicine, 1005 Lausanne, Switzerland1
Wood AJJ . Racial differences in the response to drugs -- pointers to genetic differences. N Engl J Med 2001;344:1393-1396
Full Text | Web of Science2
Exner DV ,Dries DL ,Domanski MJ ,Cohn JN . Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction. N Engl J Med 2001;344:1351-1357
Full Text | Web of Science | Medline3
Ferguson JJ . Highlights of the 72nd Scientific Sessions of the American Heart Association. Circulation 2000;102:E1-E5
Medline
To the Editor:
In his May 3 editorial,1 Dr. Schwartz assumes that comparative studies of different racial or ethnic populations are frivolous and ill founded and that they seek racial distinctions. Most of this work, however, is not anthropological but rather aims to determine the mechanistic basis for clinical observations. Although access to care and other nonmedical issues are important contributors to disparities in clinical outcomes, there are often genetic and physiological components of these problems. An understanding of an objective basis for observed differences would be much easier to integrate quickly into clinical decision making than would the sort of full-scale societal changes that would be necessary to achieve health equality (the ultimate goal).
The use of racial and ethnic populations in studies such as those of Yancy et al.2 and Exner et al. creates a clinical scenario in which it is possible to discover the molecular basis of a clinical phenotype because of the inclusion of variants that have become segregated as a result of the migration of populations or other nongenetic factors. Such studies have been valuable for determining how a pharmacogenetic discovery will translate from one group to other populations3 and for defining the optimal clinical scenario for focused evaluation of the mechanisms of particular agents — that is, what sort of population is likely to help us find the clearest answer.
This type of translational research is not as provocative or sinister as Dr. Schwartz suggests; its goal is actually to eliminate skin pigment as a variable and replace it with an objective molecular end point. The pursuit of this goal needs to be expedited, not stifled, if the genome revolution4 is to lead to real improvements in our ability to select the optimal therapies for individual patients.
4 ReferencesHoward L. McLeod, Pharm.D.
Washington University School of Medicine, St. Louis, MO 63110-1093
hmcleod@im.wustl. edu 1
Schwartz RS . Racial profiling in medical research. N Engl J Med 2001;344:1392-1393
Full Text | Web of Science | Medline2
Yancy CW ,Fowler MB ,Colucci WS , et al. Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure. N Engl J Med 2001;344:1358-1365
Full Text | Web of Science | Medline3
Ameyaw MM ,Regateiro F ,Li T , et al. MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics 2001;11:217-221
CrossRef | Medline4
Holtzman NA ,Marteau TM . Will genetics revolutionize medicine? N Engl J Med 2000;343:141-144
Full Text | Web of Science | Medline
To the Editor:
The editorial by Dr. Schwartz points out a fundamental flaw in the reasoning behind analyses such as that in the report by Exner et al., which describes racial differences in the response to ACE inhibitors as treatments for heart failure. The editorial argues that although race is a useful social construct, it does not hold up as a valid genetic concept.
Unfortunately, this flaw is not widely understood. As consultants for a nationwide effort of the Health Care Financing Administration to improve the care of patients with heart failure,1 we have assisted in developing measures for assessing the quality of care for patients with heart failure. Recently, some physicians objected to the measure for assessing the need to prescribe ACE inhibitors for patients with left ventricular systolic dysfunction. These critics claimed that the indicators should be responsive to the latest data published in the Journal, and thus that black race should constitute an accepted reason for not prescribing ACE inhibitors.
Although we cannot be certain that this belief is common, it is disturbing that it exists at all. This simple-minded interpretation of the study by Exner et al. is not only distasteful, it is dangerous, potentially placing blacks at risk for inappropriate undertreatment. The data presented in the report are provocative but not definitive. They should inspire further research, not change accepted practice. We support the publication of this study and value the debate it generates. We believe, however, that authors — and readers — of such studies should exercise extreme care in interpreting these data given the inherent difficulties in using the construct of race as a predictor of the outcome of treatment.
1 ReferencesFrederick A. Masoudi, M.D., M.S.P.H.
Edward P. Havranek, M.D.
Denver Health Medical Center, Denver, CO 80204
fred.masoudi@uchsc. edu 1
Jencks SF ,Cuerdon T ,Burwen DR , et al. Quality of medical care delivered to Medicare beneficiaries: a profile at state and national levels. JAMA 2000;284:1670-1676
CrossRef | Web of Science | Medline
To the Editor:
We disagree with the conclusion of Exner et al. that it is “appropriate to consider current therapeutic recommendations as applying to white patients but not necessarily to black patients.” The analysis that is presented is not a sufficient basis for withholding ACE inhibitors from black patients with heart failure. Black patients did have responses to enalapril, but these patients were undertreated. The importance of increasing the dose of ACE inhibitors to achieve the maximal therapeutic benefit has been demonstrated in patients with heart failure1 and in those with hypertension.2,3 An alternative interpretation of the study by Exner et al. is that patients with hypertension-induced heart failure have worse outcomes when they receive suboptimal treatment with aspirin, beta-blockade, and ACE inhibition.
3 ReferencesElizabeth Ofili, M.D.
John Flack, M.D.
Gary Gibbons, M.D.
Association of Black Cardiologists, Atlanta, GA 30328
bwainekong@abcardio.org 1
Packer M ,Poole-Wilson PA ,Armstrong PW , et al. Comparative effects of low and high doses of the angiotensin-converting-enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation 1999;100:2312-2318
Web of Science | Medline2
Saunders E ,Weir MR ,Kong BW , et al. A comparison of the efficacy and safety of a beta-blocker, a calcium channel blocker, and a converting enzyme inhibitor in hypertensive blacks. Arch Intern Med 1990;150:1707-1713
CrossRef | Web of Science | Medline3
Weir MR ,Gray M ,Paster R ,Saunders E . Differing mechanisms of action of angiotensin-converting enzyme inhibition in black and white hypertensive patients. Hypertension 1995;26:124-130
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We agree with Wood, Bovet and Paccaud, and McLeod. Differences in therapeutic response probably relate, in part, to polymorphisms in drug receptors, drug-metabolizing enzymes, or other factors. The frequency of polymorphisms in the gene for ACE I differs in whites and blacks,1 and these polymorphisms correlate with the ACE concentration and blood pressure.1,2 Although individual polymorphisms do not fully explain the differences in phenotypic expression, interaction among the polymorphisms appears to be important.2 These and other data refute the assertion of Schwartz that categorizing groups on the basis of self-reported race has “no plausible biologic justification.” Evaluating differences in therapeutic response within subgroups of the population is an important initial step in identifying important polymorphisms.
We are concerned about the assertion of Masoudi and Havranek that some physicians have claimed, on the basis of our findings, that black race should be an accepted reason for not prescribing an ACE inhibitor for heart failure, and we agree with Ofili et al. that our results must be viewed in the proper context. There is substantive evidence that ACE inhibitors reduce morbidity and mortality in patients with a low ejection fraction and heart failure. On the basis of the entirety of the evidence, ACE inhibitors should continue to be prescribed to all patients with this syndrome in whom there is not a contraindication to their use. Our results and other analyses 3 should remind the reader, however, that ACE inhibitors have not been proved effective, on average, in black patients.
Whether different therapeutic agents or higher doses of ACE inhibitors are more effective than the usual doses of ACE inhibitors in this population is not known but warrants further study. The optimal means of addressing these questions — whether through targeted population studies or by means of subgroup analyses in large trials that include patients of both sexes and from many racial and ethnic groups — is open to debate. We echo the concern of Bovet and Paccaud regarding the problems related to the underrepresentation of certain groups in clinical trials and believe that our results highlight this issue.
3 ReferencesDerek V. Exner, M.D., M.P.H.
University of Calgary, Calgary, AB T2N 4N1, Canada
exner@ucalgary.ca Michael J. Domanski, M.D.
National Heart, Lung, and Blood Institute, Bethesda, MD 20892Jay N. Cohn, M.D.
University of Minnesota Medical School, Minneapolis, MN 554551
Borecki IB ,Province MA ,Ludwig EH , et al. Associations of candidate loci angiotensinogen and angiotensin-converting enzyme with severe hypertension: the NHLBI Family Heart Study. Ann Epidemiol 1997;7:13-21
CrossRef | Web of Science | Medline2
Zhu X ,Bouzekri N ,Southam L , et al. Linkage and association analysis of angiotensin I-converting enzyme (ACE)-gene polymorphisms with ACE concentration and blood pressure. Am J Hum Genet 2001;68:1139-1148
CrossRef | Web of Science | Medline3
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
CrossRef | Medline
Author/Editor Response
The editorialist replies:
To the Editor: I agree with McLeod that biomedical research should aim for an “objective molecular end point.” Indeed, that was the main point of my editorial. McLeod suggests that we could “discover the molecular basis of a clinical phenotype” through research on “racial populations.” The problem with his approach is that it entails the vague idea of “racial populations.” The rapidly advancing field of molecular genetics — especially the new methods of genomics and haplotyping — has erased the color line. It is unnecessary in biomedical research to make arbitrary decisions about who is white, black, yellow, or red. The main requirement now is to have a biologically plausible hypothesis.
The letter from Masoudi and Havranek indicates how dangerous the idea of race can be when it is incorporated into medical practice. Physicians who would base clinical decisions on a patient's supposed race ignore not only the extraordinary diversity of humans but also the past 100 years of history.
Robert S. Schwartz, M.D.
- Citing Articles (4)
Citing Articles
1
Chang-Gyu Park, Ho-Joong Youn, Shung-Chull Chae, Joo-Young Yang, Moo-Hyun Kim, Taek-Jong Hong, Cheol Ho Kim, Jae Joong Kim, Bum-Kee Hong, Jin-Won Jeong, Si-Hoon Park, Jun Kwan, Young-Jin Choi, Seung-Yun Cho. (2012) Evaluation of the Dose-Response Relationship of Amlodipine and Losartan Combination in Patients with Essential Hypertension. American Journal Cardiovascular Drugs1
CrossRef2
David S. Jones, Roy H. Perlis. (2006) Pharmacogenetics, Race, and Psychiatry: Prospects and Challenges. Harvard Review of Psychiatry 14:2, 92-108
CrossRef3
Thierry Dervieux, Brian Meshkin, Bruce Neri. (2005) Pharmacogenetic testing: proofs of principle and pharmacoeconomic implications. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 573:1-2, 180-194
CrossRef4
Keith C. Ferdinand, Claudia C. Serrano, Daphne P. Ferdinand. (2002) Contemporary treatment of heart failure: Is there adequate evidence to support a unique strategy for African-Americans? con position. Current Hypertension Reports 4:4, 311-318
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