Correspondence
Coronary Calcium and Events in Four Ethnic Groups
N Engl J Med 2008; 359:202-204July 10, 2008
- Article
To the Editor:
In their report on coronary calcium and coronary events in four ethnic groups, Detrano et al. (March 27 issue)1 grouped persons by ethnicity but did not provide any proof that these persons were ethnically similar or offer an operational definition of ethnicity. An unbiased reader may suspect that multiple populations exist within each of these ethnic groups, and the conclusions of the study do not account for such population stratification. A better approach would be to devise a test that demonstrates that persons are similar on some basis related to ethnic background. One possible approach is to use genetic markers, as some researchers are currently doing to assess population stratification.2,3 These markers could serve as the basis for objective population groups. The use of such markers would generate data that researchers could independently replicate in a consistent manner, instead of assuming that ethnicity has the same meaning in different study populations. Objectively defining populations is a key step toward understanding the effect of risk factors for disease on diverse groups of people and thereby improving their health.
3 ReferencesPerry W. Payne, Jr., M.D., J.D.
George Washington University, Washington, DC 20006
ppayne1@gwu.edu 1
Detrano R ,Guerci AD ,Carr JJ , et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 2008;358:1336-1345
Full Text | Web of Science | Medline2
Choudhry S ,Coyle NE ,Tang H , et al. Population stratification confounds genetic association studies among Latinos. Hum Genet 2006;118:652-664
CrossRef | Web of Science | Medline3
Hoggart CJ ,Parra EJ ,Shriver MD , et al. Control of confounding of genetic associations in stratified populations. Am J Hum Genet 2003;72:1492-1504
CrossRef | Web of Science | Medline
To the Editor:
In the Multi-Ethnic Study of Atherosclerosis (MESA), reported by Detrano et al., participants with elevated coronary calcium scores had a significantly higher adjusted risk of coronary events than participants with no coronary calcium. It is uncertain, however, whether detection of coronary calcium simply predicted or actually contributed to the increased risk. The patients and their physicians were informed of the calcium scores, and as is commonly seen in clinical practice, those with high scores may have undergone unnecessary ischemia testing and interventions. Several studies have indicated that in patients with chronic coronary artery disease, percutaneous coronary intervention (PCI) may increase the risk of myocardial infarction.1-3 It would be important to know how many patients in MESA underwent coronary angiography and PCI after the finding of a high calcium score. Without such data, one cannot rule out the possibility of indirect harm caused by scanning for coronary-artery calcium.
3 ReferencesLaszlo Littmann, M.D.
Carolinas Medical Center, Charlotte, NC 28232
laszlo.littmann@carolinashealthcare. org 1
Henderson RA ,Pocock SJ ,Clayton TC , et al. Seven-year outcome in the RITA-2 trial: coronary angioplasty versus medical therapy. J Am Coll Cardiol 2003;42:1161-1170
CrossRef | Web of Science | Medline2
Bucher HC ,Hengstler P ,Schindler C ,Guyatt GH . Percutaneous transluminal coronary angioplasty versus medical treatment for non-acute coronary heart disease: meta-analysis of randomised controlled trials. BMJ 2000;321:73-77
CrossRef | Web of Science | Medline3
Katritsis DG ,Ioannidis JPA . Percutaneous coronary intervention versus conservative therapy in nonacute coronary artery disease: a meta-analysis. Circulation 2005;111:2906-2912
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To the Editor:
The results of the study by Detrano et al. confirm the importance of coronary calcification as a predictor of cardiovascular events. We are surprised by the lack of reference to renal function as a potential confounding factor to explain the increase in cardiovascular events in the cohort. Renal function is a strong predictor of cardiovascular events in the general population.1 Furthermore, renal function is a strong predictor of the frequency and severity of coronary-artery calcification.2 The authors used the serum creatinine level for evaluation of renal function, but the accuracy of this measurement in estimating renal function is limited. An estimated glomerular filtration rate should have been used for a more accurate analysis.3 We wonder whether the strong effect of coronary calcification in predicting coronary events might not be explained in part by a lower estimated glomerular filtration rate in the patients with coronary-artery calcifications.
3 ReferencesStephane Burtey, M.D., Ph.D.
Bertrand Dussol, M.D., Ph.D.
Philippe Brunet, M.D., Ph.D.
Assistance Publique–Hopitaux de Marseille, 13005 Marseille, France1
Go AS ,Chertow GM ,Fan D ,McCulloch CE ,Hsu C . Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-1305
Full Text | Web of Science | Medline2
Russo D ,Palmiero G ,De Blasio AP ,Balletta MM ,Andreucci VE . Coronary artery calcification in patients with CRF not undergoing dialysis. Am J Kidney Dis 2004;44:1024-1030
CrossRef | Web of Science | Medline3
Levey AS ,Coresh J ,Balk E , et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003;139:137-147[Erratum, Ann Intern Med 2003;139:605.]
Web of Science | Medline
To the Editor:
Detrano et al. conclude that the coronary calcium score is a strong predictor of incident coronary heart disease and provides predictive information beyond that provided by standard risk factors in four major racial and ethnic groups in the United States. MESA was designed with an assumption that there would be approximately 330 coronary heart disease events, defined as death from coronary heart disease or nonfatal myocardial infarction, over a follow-up period of 6 years.1 Power and sample sizes were estimated on the basis of this assumption. According to the report by Detrano et al., only 89 patients either died from coronary heart disease or had nonfatal myocardial infarction. There should have been about 200 major cardiac events, according to the study design, over the median follow-up period of 3.9 years reported in the current study. The very low number of major cardiac events, in contrast to that which was predicted, raises questions about the statistical validity of the study results, which rely on an accurate calculation of power.
1 ReferencesSandeep K. Goyal, M.D.
Sujeeth R. Punnam, M.D.
Michigan State University, East Lansing, MI 48824
sandeep_mamc@rediffmail.com 1
Bild DE ,Bluemke DA ,Burke GL , et al. Multi-ethnic study of atherosclerosis: objectives and design. Am J Epidemiol 2002;156:871-881
CrossRef | Web of Science | Medline
To the Editor:
In their editorial accompanying the report by Detrano et al., Weintraub and Diamond1 downplay the discriminatory power of coronary-artery calcium scores for predicting the risk of coronary heart disease. An increasing coronary-artery calcium burden is associated with a very high relative risk of coronary heart disease events, a desired feature for effective risk discrimination with respect to coronary heart disease. In fact, higher coronary calcium scores are more strongly predictive of hard coronary heart disease events than is diabetes mellitus, which is considered to be a coronary heart disease risk equivalent.2 Furthermore, the absence of coronary-artery calcium, a finding in nearly 50% of adults tested, is associated with an excellent prognosis. In addition, assessment of coronary-artery calcium results in favorable medication use and lifestyle changes,3 a cornerstone of efforts to reduce the risk of coronary heart disease. The editorial also fails to mention a prospective study highlighting the relative cost-effectiveness of coronary-artery calcium incorporated in global risk assessment.4 Given the significant discriminatory ability of coronary-artery calcium assessment, which is additive to the Framingham risk score, the role of coronary-artery calcium in screening for coronary heart disease appears to be extremely promising rather than “unknown.”
Khurram Nasir, M.D., M.P.H.
Massachusetts General Hospital, Boston, MA 02114
knasir@partners.org Matthew J. Budoff, M.D.
Los Angeles Biomedical Research Institute at Harbor–UCLA, Torrance, CA 90502Roger Blumenthal, M.D.
Johns Hopkins University, Baltimore, MD 21287Dr. Budoff reports serving on the speakers' bureau of GE Healthcare. No other potential conflict of interest relevant to this letter was reported.
4 References1
Weintraub WS ,Diamond GA . Predicting cardiovascular events with coronary calcium scoring. N Engl J Med 2008;358:1394-1396
Full Text | Web of Science | Medline2
Becker A ,Leber A ,Becker C ,Knez A . Predictive value of coronary calcifications for future cardiac events in asymptomatic individuals. Am Heart J 2008;155:154-160
CrossRef | Web of Science | Medline3
Orakzai RH ,Nasir K ,Orakzai SH , et al. Effect of patient visualization of coronary calcium by electron beam computed tomography on changes in beneficial lifestyle behaviors. Am J Cardiol 2008;101:999-1002
CrossRef | Web of Science | Medline4
Taylor AJ ,Bindeman J ,Feuerstein I ,Cao F ,Brazaitis M ,O'Malley PG . Coronary calcium independently predicts incident premature coronary heart disease over measured cardiovascular risk factors: mean three-year outcomes in the Prospective Army Coronary Calcium (PACC) project. J Am Coll Cardiol 2005;46:807-814
CrossRef | Web of Science | Medline
Author/Editor Response
Our report presents data indicating that the coronary calcium score is a strong predictor of incident coronary heart disease and provides predictive information beyond that provided by standard risk factors in four major racial and ethnic groups in the United States. Payne questions our use of self-reported ethnicity. Ethnicity is a complicated construct that includes both culture and genetics, each of which may have powerful direct or indirect effects on the risk of disease. In using self-reported ethnicity, we did not intend to focus on genetic influences that might affect the relationship between coronary calcium and coronary events. In any case, whether genes or culture is more important for the interpretation of the current study is moot, since we found no significant ethnic differences to pursue.
Littmann suggests the possibility that detection of coronary calcium may have led to increased use of coronary tests and procedures, leading in turn to an increased risk of iatrogenic coronary events. During the period of follow-up, only three participants had procedure-related nonfatal myocardial infarctions. In all three, angina pectoris had developed before catheterization and revascularization, and the minimum elapsed time from the coronary calcium scan to revascularization was 720 days. Thus, there is no evidence that the results of the coronary calcium scan led to iatrogenic events.
Burtey and colleagues state that renal function may have affected the relationship of coronary calcification to coronary heart disease events and suggest that we allow the estimated glomerular filtration rate to enter our model for predicting coronary events. We have done so, and this resulted in no change in the coefficient for the logarithm of the coronary calcium score. We have previously found that the estimated glomerular filtration rate is unrelated to coronary calcification and thus is unlikely to be a confounder for predicting events.1
Goyal and Punnam state correctly that the number of coronary heart disease events observed was smaller than the number of events expected. However, the preplanned event numbers and the power associated with them are irrelevant to our conclusions, once the outcome is observed. All of our results and conclusions are based on the observed data. Higher event rates would have narrowed the confidence intervals and provided more precise estimates of the hazard ratios but would be unlikely to have resulted in any change in the conclusions of our report.
1 ReferencesAlan D. Guerci, M.D.
St. Francis Hospital, Roslyn, NY 11576Diane E. Bild, M.D., M.P.H.
National Heart, Lung, and Blood Institute, Bethesda, MD 20892Richard A. Kronmal, Ph.D.
University of Washington, Seattle, WA 981951
Ix JH ,Katz R ,Kestenbaum B , et al. Association of mild to moderate kidney dysfunction and coronary calcification. J Am Soc Nephrol 2008;19:579-585
CrossRef | Web of Science | Medline
Author/Editor Response
The key issue is the degree to which coronary-artery calcium provides a clinically important — not just a statistically significant — increment of information to what we already know, and how this can guide therapy. In this regard, Nasir et al. confuse calibration with discrimination. Thus, whereas coronary-artery calcium is well calibrated (the higher the score, the higher the incidence of events), it is not highly discriminatory (having only limited ability to distinguish between patients who will and those who will not have these events, given other risk factors). We do indeed cite the report by Taylor et al. regarding the effectiveness of coronary-artery calcium1 and the report by Shaw et al. regarding its cost-effectiveness2 but note that the Framingham risk score is not necessarily the most appropriate comparator for these assessments.3 Accordingly, although these data can be viewed from alternative perspectives, we continue to hold to our more nuanced belief that the ultimate role of coronary-artery calcium remains unknown.
3 ReferencesWilliam S. Weintraub, M.D.
Christiana Care Health System, Newark, DE 19718George A. Diamond, M.D.
Cedars–Sinai Medical Center, Los Angeles, CA 900481
Taylor AJ ,Bindeman J ,Feuerstein I ,Cao F ,Brazaitis M ,O'Malley PG . Coronary calcium independently predicts incident premature coronary heart disease over measured cardiovascular risk factors: mean three-year outcomes in the Prospective Army Coronary Calcium (PACC) project. J Am Coll Cardiol 2005;46:807-814
CrossRef | Web of Science | Medline2
Shaw LJ ,Taylor AJ ,O'Malley PG . Cost-effectiveness of new tests to diagnose and treat coronary heart disease. Curr Treat Options Cardiovasc Med 2005;7:273-286
CrossRef | Medline3
Diamond GA ,Kaul S . The things to come of SHAPE: cost and effectiveness of cardiovascular prevention. Am J Cardiol 2007;99:1013-1015
CrossRef | Web of Science | Medline
