- Email: [email protected]
Usefulness of Coronary Computed Tomography Angiography to Predict Mortality and Myocardial Infarction Among Caucasian, African and East Asian Ethnicities (from the CONFIRM [Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter] Registry)
Usefulness of Coronary Computed Tomography Angiography to Predict Mortality and Myocardial Infarction Among Caucasian, African and East Asian Ethnicities (from the CONFIRM [Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter] Registry) Edward Hulten, MD, MPHa,*, Todd C. Villines, MDb, Michael K. Cheezum, MDb, Daniel S. Berman, MDc, Allison Dunning, MScd, Stephan Achenbach, MDe, Mouaz Al-Mallah, MDf, Matthew J. Budoff, MDg, Filippo Cademartiri, MD, PhDh,i, Tracy Q. Callister, MDj, Hyuk-Jae Chang, MD, PhDk, Victor Y. Cheng, MDc, Kavitha Chinnaiyan, MDl, Benjamin J.W. Chow, MDm, Ricardo C. Cury, MDn, Augustin Delago, MDo, Gudrun Feuchtner, MDp, Martin Hadamitzky, MDq, Jörg Hausleiter, MDq, Philipp A. Kaufmann, MDr, Ronald P. Karlsberg, MDs, Yong-Jin Kim, MDt, Jonathon Leipsic, MDu, Fay Y. Lin, MDd, Erica Maffei, MDh,i, Fabian Plank, MDp, Gilbert L. Raff, MDl, Troy M. Labounty, MDc, Leslee J. Shaw, PhDv, and James K. Min, MDc, for the CONFIRM Investigators Studies examining coronary computed tomographic angiography (CCTA) have demonstrated increased mortality related to coronary artery disease (CAD) severity but are limited to relatively nondiverse ethnic populations. The aim of this study was to evaluate the prognostic significance of CAD on CCTA according to ethnicity for patients without previous CAD in a prospective international CCTA registry of 11 sites (7 countries) who underwent 64-slice CCTA from 2005 to 2010. CAD was defined as any coronary artery atherosclerosis and obstructive CAD as ‡50% stenosis. All-cause mortality and nonfatal myocardial infarction (MI) were assessed by ethnicity using Kaplan-Meier and Cox proportional hazards, controlling for baseline risk factors, medications, and revascularization. A total of 16,451 patients of mean age 58 years (55% men) were followed over a median of 2.0 years (interquartile range 1.4 to 3.2). Patients were 60.1% Caucasian, 34.4% East Asian, and 5.5% African. Death or MI occurred in 0.5% (38 of 7,109) among patients with no CAD, 1.6% (91 of 5,600) among those with nonobstructive CAD, and 3.8% (142 of 3,742) among those with ‡50% stenosis (p <0.001 among all groups). The annualized incidence of death or MI comparing obstructive to no obstructive CAD among Caucasians was 2.2% versus 0.7% (adjusted hazard ratio [aHR] 2.77, 95% confidence interval [CI] 1.73 to 4.43, p <0.001), among Africans 4.8% versus 1.1% (aHR 6.25, 95% CI 1.12 to 34.97, p [ 0.037), and among East Asians 0.8% versus 0.1% (aHR 4.84, 95% CI 2.24 to 10.9, p <0.001). Compared to other ethnicities, East Asians had fewer than expected events (aHR 0.25, 95% CI 0.16 to 0.38, p <0.001). In conclusion, the presence and severity of CAD visualized by CCTA predict death or MI across 3 large ethnicities, whereas normal results on CCTA identify patients at very low risk. Published by Elsevier Inc. (Am J Cardiol 2013;111:479e485)
a Brigham and Women’s Hospital, Boston, Massachusetts; bWalter Reed National Military Medical Center, Bethesda, Maryland; cCedars-Sinai Medical Center, Los Angeles, California; dWeill Cornell Medical College and New York Presbyterian Hospital, New York, New York; eUniversity of Giessen Hospital, Giessen, Germany; fWayne State University, Henry Ford Hospital, Detroit, Michigan; gHarbor-UCLA Medical Center, Los Angeles, California; hGiovanni XXIII Hospital, Monastier di Treviso, Italy; iErasmus Medical Center, Rotterdam, The Netherlands; jTennessee Heart and Vascular Institute, Hendersonville, Tennessee; kSeverance Cardiovascular Hospital, Seoul, South Korea; lWilliam Beaumont Hospital, Royal Oaks, Michigan; mUniversity of Ottawa Heart Institute, Ottawa, Ontario, Canada; n Baptist Cardiac & Vascular Institute, Miami, Florida; oCapitol Cardiology
0002-9149/12/$ - see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.amjcard.2012.10.028
Associates, Albany, New York; pMedical University of Innsbruck, Innsbruck, Austria; qDeutsches Herzzentrum München, Munich, Germany; r University Hospital, Zurich, Switzerland; sCardiovascular Medical Group, Los Angeles, California; tSeoul National University Hospital, Seoul, South Korea; uUniversity of British Columbia, Vancouver, British Columbia, Canada; and vEmory School of Medicine, Atlanta, Georgia. Manuscript received September 26, 2012; revised manuscript received and accepted October 24, 2012. See page 484 for disclosure information. *Corresponding author: Tel: 857-307-1989; fax: 888-857-3249. E-mail address: [email protected] (E. Hulten).
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Table 1 Baseline characteristics Variable
Caucasian (n ¼ 9,898)
East Asian (n ¼ 5,654)
African (n ¼ 899)
Total (n ¼ 16,451)
p Value
Age (yrs) Men Body mass index (kg/m2) Hypertension* Diabetes mellitus Hyperlipidemia* Family history of premature CAD Smokers Anginal status Asymptomatic Nonanginal Atypical Typical Morise score Baseline statin Baseline aspirin Baseline antihypertensive medication Coronary revascularization†
57.9 12.1 57.2% 27.9 5.4 48.1% 11.2% 53.4% 39.5% 19.2%
58.9 10.7 55.0% 25.0 3.0 51.9% 26.9% 55.3% 9.3% 14.1%
52.4 12.7 39.6% 31.1 6.5 63.5% 18.5% 41.7% 32.9% 16.9%
57.9 11.7 55.5% 27.1 5.1 50.3% 17.0% 53.4% 28.8% 17.4%
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
39.0% 14.5% 36.1% 10.4% 12.9 4.0 30.4% 33.0% 46.7% 7.99%
33.5% 4.7% 46.3% 15.5% 13.5 3.6 42.5% 51.2% 59.4% 6.52%
26.3% 4.9% 58.2% 10.6% 11.5 4.8 29.7% 37.5% 64.4% 2.56%
36.5% 10.7% 40.7% 12.1% 13.0 4.0 36.1% 40.9% 52.7% 7.18%
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
Data are expressed as mean SD or as percentages. * Hypertension and hyperlipidemia were ascertained at the time of CCTA and confirmed, when available, with patient medical records for these diagnoses, medical therapy of such diagnoses, or blood pressure >140/90 mm Hg and total cholesterol >240 mg/dl, respectively. † Performed >90 days after CCTA.
Coronary computed tomographic angiography (CCTA) has emerged as a highly accurate1e3 and prognostically useful4 noninvasive test for the diagnosis or exclusion of coronary artery disease (CAD). Although CCTA has been evaluated in large patient cohorts, there is sparse information about its ability to predict future cardiovascular events across ethnic subgroups. The assessment of CAD using CCTA in patients of different genetic and environmental backgrounds is important because it is proposed that the pathology, epidemiology, and prognosis of CAD may vary across ethnicities.5e9 Given the limited data currently available on coronary computed tomographic angiographic findings and their prognostic implications stratified by ethnicity, we sought to examine the prevalence of cardiovascular risk factors and the prognostic value of CCTA among ethnic subgroups in a large, prospective, multicenter international CCTA registry. Methods The Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter (CONFIRM) registry is an ongoing, prospective, international, multicenter registry designed to evaluate the relation of coronary atherosclerosis and clinical risk factors to adverse outcomes among patients who have undergone at least 64-slice CCTA for clinically referred indications (ClinicalTrials.gov identifier NCT01443637).10 The rationale and design of the CONFIRM registry have been previously reported.11 In brief, the registry uses an identical standardized data collection form and data dictionary at all participating sites to prospectively collect baseline risk factors, symptoms, and medications before CCTA, as well as detailed coronary
computed tomographic angiographic results and clinical outcomes. Patient symptoms were assessed before they underwent CCTA and defined using the criteria of Diamond and Forrester12 according to American College of Cardiology guidelines for chest pain assessment,13 and pretest cardiovascular risk was defined using the Morise score.14 Ethnicity was assessed by investigators at the time of CCTA and coded as Caucasian, African, Hispanic, East Asian, Middle Eastern, South Asian, or other. Patients with known previous CAD (previous myocardial infarction [MI], percutaneous coronary intervention, or coronary artery bypass surgery) were excluded from this analysis. Phase 1 of the CONFIRM registry enrolled 27,125 patients at 12 cluster sites in 6 countries in North America, Europe, and Asia. Phase 2 of the registry enrolled 4,682 patients from 5 sites in 4 countries. The study protocol was approved by all centers’ institutional review boards, and when required, all patients provided written informed consent. CCTA was performed using a single- or dual-source 64-slice computed tomographic scanner according to Society of Cardiovascular Computed Tomography guidelines by highly experienced imagers, as previously described.11,15 Coronary atherosclerotic lesions were graded as normal (no atherosclerosis), mild (1% to 49% stenosis), or obstructive (50% stenosis) in epicardial coronary arteries of 2 mm in diameter. The primary end point was time to all-cause death or nonfatal MI. Patient follow-up was performed as approved at each local participating institution using telephone interviews, available medical records, contact with attending physicians, mailed questionnaires, and, where available, a national death registry. From within the entire CONFIRM registry, only patients with complete information regarding
Coronary Artery Disease/CCTA Prognosis by Ethnicity in CONFIRM
Figure 1. CAD prevalence on CCT according to ethnicity.
ethnicity, severity of CAD on CCTA, and clinical follow-up for the outcomes of all-cause mortality and nonfatal MI after CCTA were included in this analysis. Continuous variables are presented as mean SD or as median (interquartile range), as appropriate. Categorical variables are presented as frequencies with percentages. Means were compared using Student’s t tests or MannWhitney U tests, and intergroup comparisons were assessed using analysis of variance or Kruskal-Wallis tests, as indicated. Proportions were compared using chi-square tests. Ethnicity was evaluated for the prediction of 50% stenosis using logistic regression in univariate analysis and multivariate analysis controlling for baseline cardiovascular risk. All-cause mortality and nonfatal MI were assessed using Kaplan-Meier and Cox proportional hazards to calculate adjusted hazard ratios, controlling for baseline cardiovascular risk factors. Cardiovascular risk factors and symptoms were adjusted in multivariate analysis using a composite Morise score.14 Failure events modeled included a combined major adverse cardiovascular event end point that included all-cause death and nonfatal MI. The same analysis as performed for the entire cohort was conducted stratified by ethnicity. Univariate predictors based on known cardiovascular risk factors were evaluated, including age, gender, diabetes, hypertension, hyperlipidemia, and current smoking. In addition, differences in baseline medication use and the occurrence of coronary revascularization performed <90 days after CCTA (presumably driven by the results of CCTA) were explored and also used to account for potential ethnicity-related differences in patient management. Hazard ratios were first calculated in a Cox proportional-hazards model limited to each ethnicity, and then each ethnicity was compared to all other ethnicities in a multivariate model, adjusted for baseline symptoms and risk factors (Morise score), baseline medications (aspirin, statins, and antihypertensive medications), and coronary revascularization. Model overfitting procedures were carefully considered and postestimation analysis was performed to ensure that the proportional-hazards assumption was met. Excess risk was calculated, after adjusting the hazard ratio for 50% CAD for baseline symptoms and risk factors, within each ethnic subgroup for the prediction of major adverse cardiovascular events. Excess risk was defined
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Figure 2. Survival from death or MI among 16,451 patients according to severity of CAD on CCTA.
as 1 e (ln HRA/ln HRu), where HRu is the unadjusted hazard ratio and HRA is the risk-adjusted hazard ratio (using the Morise score).16 All p values are 2 sided, with significance set at p <0.05. Statistical analysis was conducted using STATA version 11 (StataCorp LP, College Station, Texas) and SPSS version 13.0 (SPSS, Inc., Chicago, Illinois). Results Ethnicity data were coded for 16,451 patients at 11 sites (7 countries). The mean age was 58 12 years (55% men), and patients were followed over a median of 2.0 years (interquartile range 1.4 to 3.2 years). Middle Eastern (n ¼ 67), South Asian (n ¼ 72), Hispanic (n ¼ 534), and other (n ¼ 127) ethnicities were each coded during data collection but were excluded because they were individually underpowered for analysis. Baseline demographics are listed in Table 1. Patients were 60.1% Caucasian, 34.4% East Asian, and 5.5% African. There were significant differences in baseline risk factors, symptoms, and baseline medication use across all ethnic subgroups. Caucasians and East Asians were more likely to be older and male. East Asians had the highest prevalence of diabetes (26.9%) and Morise scores, the highest use of baseline statins and aspirin, but the lowest prevalence of a family history of premature CAD. Coronary revascularization performed <90 days after CCTA was
Table 2 Incidence* of death and nonfatal myocardial infarction Ethnicity
Adverse Event
Caucasian Death (n ¼ 9,898) Nonfatal MI East Asian Death (n ¼ 5,654) Nonfatal MI African Death (n ¼ 899) Nonfatal MI
Coronary Narrowing (Diameter Stenosis) <50%
None
50%
n
%
n
%
n
%
24 3 8 0 2 2
0.64 0.08 0.28 0.00 0.37 0.37
56 26 5 3 7 2
1.49 0.69 0.32 0.19 2.46 0.70
65 50 24 4 4 3
2.75 2.11 1.85 0.31 5.06 3.80
* Unadjusted for follow-up duration or Morise score.
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Figure 3. Annualized event rates among patients with versus without 50% stenosis on CCTA stratified by ethnicity. *Results were significant by the presence of obstructive CAD for death, MI, and death or MI for all 3 ethnicities (p <0.05).
significantly more frequent in Caucasians (7.99%) than East Asians (6.52%) and Africans (2.56%) (p <0.001; Table 1). When restricted to only patients with any obstructive disease on CCTA, these relative differences in coronary revascularization decreased but remained significant: Caucasians (32.4%) versus East Asians (28.5%) versus African (24.7%) (p ¼ 0.033). The unadjusted prevalence of CAD on CCTA according to ethnicity is shown in Figure 1. Caucasians and East Asians had a significantly higher prevalence (24% and 23%, respectively) of obstructive disease (worst stenosis 50%)
compared to Africans (9%) (p <0.0001). The univariate hazards ratios for obstructive disease were 1.20 (95% confidence interval [CI] 1.12 to 1.28) for Caucasians (p <0.001), 0.40 (95% CI 0.33 to 0.49) for Africans (p <0.001), and 0.98 (95% CI 0.91 to 1.06) for East Asians (p ¼ 0.60). Adjusting for baseline Morise score and using Caucasian as the index ethnicity, the adjusted hazard ratios for obstructive disease were 1.0 (95% CI 0.90 to 1.10) for East Asians (p ¼ 0.96) and 0.33 (95% CI 0.25 to 0.44) for Africans (p <0.001). Univariate Kaplan-Meier survival curves for death and nonfatal MI among the entire 16,451-patient cohort are shown
Figure 4. Survival from death or MI according to severity of CAD on CCTA, stratified by ethnicity.
Coronary Artery Disease/CCTA Prognosis by Ethnicity in CONFIRM
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was associated with the coronary computed tomographic angiographic finding of 50% CAD (Figure 5). After adjusting for baseline cardiovascular risk factors, symptoms (Morise score), medications (aspirin, statins, and antihypertensive medications), and early referral patterns for coronary revascularization, patients of East Asian ethnicity had a significantly lower risk for death and nonfatal MI relative to Caucasians (adjusted hazard ratio 0.25, 95% CI 0.16 to 0.35, p <0.001; Supplemental Table 2, available online). Discussion
Figure 5. Hazard ratio (HR) for 50% CAD on CCTA as a predictor of death or MI unadjusted (solid line) and adjusted (dashed line) by baseline risk factors and symptoms. The risk for obstructive CAD persisted within each ethnic subgroup after adjustment for baseline risk factors, symptoms, and revascularization.
in Figure 2. There was significantly decreased event-free survival among patients with nonobstructive and obstructive CAD on CCTA compared to patients with no coronary atherosclerosis. Clinical outcomes including absolute number of all-cause mortality and nonfatal MI events among each ethnicity, unadjusted for baseline Morise score or follow-up duration, are listed in Table 2. The unadjusted annualized incidence rates for death and MI according to ethnicity and presence versus the absence of 50% stenosis on CCTA are shown in Figure 3. Compared to patients without obstructive CAD, the presence of obstructive CAD on CCTA conferred a significantly increased rate of death or nonfatal MI among Caucasians, East Asians, and Africans (p <0.05 for all ethnicities). Patients of African ethnicity had the highest relative increase in the combined rate of death or MI related to the presence of obstructive CAD compared to those without obstructive CAD (3.76%, 95% CI 0.15% to 7.66%) on CCTA (p ¼ 0.007 for comparison to other ethnicities). Unadjusted survival curves for death and nonfatal MI for each ethnic group are shown in Figure 4. Consistent with results from the entire cohort, CAD severity as measured using CCTA demonstrated robust adverse event prediction among Caucasians, East Asians, and Africans. Univariate and multivariate predictors of death and nonfatal MI for cardiovascular risk (Morise score) and 50% stenosis on CCTA are listed in Supplemental Table 1 (available on-line) with adjustment for differences in baseline medication use and coronary revascularization. For Caucasians, Morise score and obstructive CAD on CCTA were predictive of major adverse cardiovascular events in univariate and multivariate analyses. For East Asians and Africans, only obstructive CAD on CCTA was a significant independent predictor of increased hazards for adverse events after multivariate adjustment. Calculation of excess risk (defined previously) to the hazard ratios for 50% CAD in Supplemental Table 1 demonstrated that the excess risk attributable to baseline risk factors and Morise score for Caucasians was 33%, for East Asians 6%, and for Africans 21%. Most of the future clinical event risk in the hazard ratio within each ethnic subgroup
CCTA has emerged as an important diagnostic test for the assessment of CAD with increasingly proved prognostic value, but studies published to date contain minimal information regarding the prognostic value of CCTA among different ethnic subgroups.1,3,4,17e20 Studies using noncontrast computed tomography to detect and quantify calcified atherosclerosis have demonstrated ethnic variations in calcified CAD prevalence and have confirmed the prognostic value of calcium scoring in patients of different ethnicities, but similar data regarding CCTA are currently lacking.7 This is the first large-scale study to validate the prognostic usefulness of CCTA among 3 large ethnic subgroups and furthermore illustrates several important points. First, baseline risk factors for CAD and the riskadjusted prevalence of obstructive CAD diagnosed using modern CCTA differed by ethnicity within the CONFIRM registry. For example, East Asians (26.9%) had a much higher prevalence of baseline diabetes mellitus than Caucasians (11.2%), but Caucasians may have had higher risk genetic profiles, with self-reported family histories of premature CAD at 39.5% compared to 11.3% for East Asians. Patients of African ethnicity had a lower adjusted prevalence of obstructive CAD (50% stenosis) on CCTA compared to Caucasian and East Asian patients. A second finding of this analysis is that, consistent with previous studies involving less diverse ethnic groups,4,18 the presence of nonobstructive and obstructive CAD on CCTA was incrementally and significantly associated with decreased event-free survival compared to normal results on CCTA. Furthermore, within each of the 3 ethnic subgroups analyzed, the presence of obstructive CAD (50% stenosis) on CCTA predicted significantly increased rates of all-cause mortality and nonfatal MI, beyond that provided by symptoms and risk factors alone. Finally, our data suggest that the presence of obstructive CAD in patients of African ethnicity predicted relatively increased likelihood for adverse events compared to other ethnicities. Interestingly, patients with obstructive CAD of African ethnicity were less likely to be referred for coronary revascularization compared to Caucasian patients, but the prognostic value of CCTA remained strongly predicted when adjusted for these early management differences. Conversely, patients of East Asian ethnicity with obstructive CAD on CCTA had comparatively lower rates of all-cause mortality and nonfatal MI events compared to all other ethnicities. These interesting ethnic differences in adverse event rates that are adjusted for symptom status, standard cardiovascular risk factors, baseline medications, post-CCTA revascularization
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rates, and CAD severity on CCTA may reflect differences in lifestyle, socioeconomic status, genetics, and/or CAD management after CCTA, are hypothesis generating, and warrant further study. There are several strengths to this study. First, the CONFIRM data set is the largest presently available CCTA registry, providing the ability to perform the first comparison of the prognostic value of CCTA across ethnicities within the same study cohort. Data regarding the robustness of CCTA in ethnic subgroups are lacking, and our study demonstrates good evidence for prognostic utility among Caucasians, Africans, and East Asians. Unfortunately, ethnic data for other important subgroups were not adequately powered for analysis at this time. Importantly, the absence of CAD predicts extremely low events rates over an intermediate duration of follow-up across all ethnicities studied in this analysis. As with any study, certain design limitations are inherent. First, the registry is observational, so although associations are provocative, conclusions about cause and effect cannot be drawn. Next, as with any registry, there exists the potential for selection and referral biases that may limit the external generalizability of the data. Third, differences in the application of preventative medical therapies and lifestyle habits after CCTA were not assessed and may explain some of the differences in outcomes between ethnicities. Finally, although we controlled for known cardiovascular risk factors, symptoms, baseline medications and ethnic differences in post-CCTA coronary revascularization, there remains a possibility for residual confounding that we cannot exclude. Our study represents the first large prospective cohort evaluation of CCTA and clinical outcomes among 3 varying ethnic subgroups. Within this registry, there were significant ethnic differences in the prevalence of baseline cardiovascular risk factors, symptoms, obstructive CAD prevalence, and the performance of coronary revascularization among those with obstructive CAD. Consistent with previous studies of CCTA, the presence of obstructive CAD was predictive of adverse events across a variety of ethnic subgroups, whereas the absence of CAD on CCTA was associated with an extremely good prognosis over an intermediate-term follow-up duration. Disclosures Dr. Villines has received speaker’s honoraria from Boehringer-Ingelheim, Ingelheim, Germany. Dr. Achenbach has received grant support from Siemens Healthcare, Erlangen, Germany, and Bayer Schering Pharma AG, Berlin, Germany. Dr. Budoff has received speaker’s honoraria from GE Healthcare, Milwaukee, Wisconsin. Dr. Cademartiri has received grant support from GE Healthcare and speaker’s honoraria from Bracco Diagnostics, Milan, Italy. Dr. Callister is on the speaker’s bureau of GE Healthcare. Dr. Chinnaiyan has received grant support from Bayer Pharma AG, Berlin, Germany, and Blue Cross Blue Shield Blue Care Michigan. Dr. Chow has received research support from GE Healthcare; Pfizer, Inc., New York, New York; and AstraZeneca, Wilmington, Delaware. Dr. Chow
has recieved educational support from TeraRecon, Foster City, California. Dr. Hausleiter has received research grant support from Siemens Healthcare. Dr. Kaufmann has received research support from GE Healthcare and grant support from the Swiss National Science Foundation, Bern, Switzerland. Dr. Maffei has received grant support from GE Healthcare and is a consultant for Servier, Neuilly-surSeine, France. Dr. Raff has received grant support from Siemens Healthcare, Blue Cross Blue Shield Blue Care Michigan, and Bayer Pharma AG. Dr. Min has received speaker’s honoraria and research support from and serves on the medical advisory board of GE Healthcare. The views expressed here are those of the investigators only and are not to be construed as those of the United States Department of the Army or Department of Defense. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.amjcard.2012.10.028. 1. Budoff MJ, Dowe D, Jollis JG, Gitter M, Sutherland J, Halamert E, Scherer M, Bellinger R, Martin A, Benton R, Delago A, Min JK. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol 2008;52: 1724e1732. 2. Hamon M, Biondi-Zoccai GG, Malagutti P, Agostoni P, Morello R, Valgimigli M. Diagnostic performance of multislice spiral computed tomography of coronary arteries as compared with conventional invasive coronary angiography: a meta-analysis. J Am Coll Cardiol 2006;48:1896e1910. 3. Schuijf JD, Bax JJ, Shaw LJ, de Roos A, Lamb HJ, van der Wall EE, Wijns W. Meta-analysis of comparative diagnostic performance of magnetic resonance imaging and multislice computed tomography for noninvasive coronary angiography. Am Heart J 2006;151: 404e411. 4. Hulten EA, Carbonaro S, Petrillo SP, Mitchell JD, Villines TC. Prognostic value of cardiac computed tomography angiography: a systematic review and meta-analysis. J Am Coll Cardiol 2011;57: 1237e1247. 5. Budoff MJ, Yang TP, Shavelle RM, Lamont DH, Brundage BH. Ethnic differences in coronary atherosclerosis. J Am Coll Cardiol 2002;39: 408e412. 6. Shaw LJ, Shaw RE, Merz CN, Brindis RG, Klein LW, Nallamothu B, Douglas PS, Krone RJ, McKay CR, Block PC, Hewitt K, Weintraub WS, Peterson ED. Impact of ethnicity and gender differences on angiographic coronary artery disease prevalence and in-hospital mortality in the American College of Cardiology-National Cardiovascular Data Registry. Circulation 2008;117:1787e1801. 7. Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, Folsom AR, Liu K, Shea S, Szklo M, Bluemke DA, O’Leary DH, Tracy R, Watson K, Wong ND, Kronmal RA. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 2008;358: 1336e1345. 8. Ferdinand KC. Coronary artery disease in minority racial and ethnic groups in the United States. Am J Cardiol 2006;97(suppl):12Ae19A. 9. McClelland RL, Chung H, Detrano R, Post W, Kronmal RA. Distribution of coronary artery calcium by race, gender, and age: results from the Multi-Ethnic Study of Atherosclerosis (MESA). Circulation 2006;113:30e37. 10. Min JK. The CONFIRM Registry. Available at: http://clinicaltrials. gov/show/NCT01443637. Accessed November 21, 2012. 11. Min JK, Dunning A, Lin FY, Achenbach S, Al-Mallah MH, Berman DS, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng V, Chinnaiyan KM, Chow B, Delago A, Hadamitzky M, Hausleiter J, Karlsberg
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patients undergoing coronary computed tomographic angiography: results from the multinational Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry (CONFIRM). Circulation 2011;124:2423e2432. 18. Chow BJ, Small G, Yam Y, Chen L, Achenbach S, Al-Mallah M, Berman DS, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng V, Chinnaiyan KM, Delago A, Dunning A, Hadamitzky M, Hausleiter J, Kaufmann P, Lin F, Maffei E, Raff GL, Shaw LJ, Villines TC, Min JK. Incremental prognostic value of cardiac computed tomography in coronary artery disease using CONFIRM: Coronary Computed Tomography Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry. Circ Cardiovasc Imaging 2011;4: 463e472. 19. Min JK, Dunning A, Lin FY, Achenbach S, Al-Mallah M, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng V, Chinnaiyan K, Chow BJ, Delago A, Hadamitzky M, Hausleiter J, Kaufmann P, Maffei E, Raff G, Shaw LJ, Villines T, Berman DS. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the international multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol 2011;58:849e860. 20. Villines TC, Hulten EA, Shaw LJ, Goyal M, Dunning A, Achenbach S, Al-Mallah M, Berman DS, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng VY, Chinnaiyan K, Chow BJ, Delago A, Hadamitzky M, Hausleiter J, Kaufmann P, Lin FY, Maffei E, Raff GL, Min JK. Prevalence and severity of coronary artery disease and adverse events among symptomatic patients with coronary artery calcification scores of zero undergoing coronary computed tomography angiography: results from the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) registry. J Am Coll Cardiol 2011;58:2533e2540.
a Brigham and Women’s Hospital, Boston, Massachusetts; bWalter Reed National Military Medical Center, Bethesda, Maryland; cCedars-Sinai Medical Center, Los Angeles, California; dWeill Cornell Medical College and New York Presbyterian Hospital, New York, New York; eUniversity of Giessen Hospital, Giessen, Germany; fWayne State University, Henry Ford Hospital, Detroit, Michigan; gHarbor-UCLA Medical Center, Los Angeles, California; hGiovanni XXIII Hospital, Monastier di Treviso, Italy; iErasmus Medical Center, Rotterdam, The Netherlands; jTennessee Heart and Vascular Institute, Hendersonville, Tennessee; kSeverance Cardiovascular Hospital, Seoul, South Korea; lWilliam Beaumont Hospital, Royal Oaks, Michigan; mUniversity of Ottawa Heart Institute, Ottawa, Ontario, Canada; n Baptist Cardiac & Vascular Institute, Miami, Florida; oCapitol Cardiology
0002-9149/12/$ - see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.amjcard.2012.10.028
Associates, Albany, New York; pMedical University of Innsbruck, Innsbruck, Austria; qDeutsches Herzzentrum München, Munich, Germany; r University Hospital, Zurich, Switzerland; sCardiovascular Medical Group, Los Angeles, California; tSeoul National University Hospital, Seoul, South Korea; uUniversity of British Columbia, Vancouver, British Columbia, Canada; and vEmory School of Medicine, Atlanta, Georgia. Manuscript received September 26, 2012; revised manuscript received and accepted October 24, 2012. See page 484 for disclosure information. *Corresponding author: Tel: 857-307-1989; fax: 888-857-3249. E-mail address: [email protected] (E. Hulten).
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Table 1 Baseline characteristics Variable
Caucasian (n ¼ 9,898)
East Asian (n ¼ 5,654)
African (n ¼ 899)
Total (n ¼ 16,451)
p Value
Age (yrs) Men Body mass index (kg/m2) Hypertension* Diabetes mellitus Hyperlipidemia* Family history of premature CAD Smokers Anginal status Asymptomatic Nonanginal Atypical Typical Morise score Baseline statin Baseline aspirin Baseline antihypertensive medication Coronary revascularization†
57.9 12.1 57.2% 27.9 5.4 48.1% 11.2% 53.4% 39.5% 19.2%
58.9 10.7 55.0% 25.0 3.0 51.9% 26.9% 55.3% 9.3% 14.1%
52.4 12.7 39.6% 31.1 6.5 63.5% 18.5% 41.7% 32.9% 16.9%
57.9 11.7 55.5% 27.1 5.1 50.3% 17.0% 53.4% 28.8% 17.4%
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
39.0% 14.5% 36.1% 10.4% 12.9 4.0 30.4% 33.0% 46.7% 7.99%
33.5% 4.7% 46.3% 15.5% 13.5 3.6 42.5% 51.2% 59.4% 6.52%
26.3% 4.9% 58.2% 10.6% 11.5 4.8 29.7% 37.5% 64.4% 2.56%
36.5% 10.7% 40.7% 12.1% 13.0 4.0 36.1% 40.9% 52.7% 7.18%
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
Data are expressed as mean SD or as percentages. * Hypertension and hyperlipidemia were ascertained at the time of CCTA and confirmed, when available, with patient medical records for these diagnoses, medical therapy of such diagnoses, or blood pressure >140/90 mm Hg and total cholesterol >240 mg/dl, respectively. † Performed >90 days after CCTA.
Coronary computed tomographic angiography (CCTA) has emerged as a highly accurate1e3 and prognostically useful4 noninvasive test for the diagnosis or exclusion of coronary artery disease (CAD). Although CCTA has been evaluated in large patient cohorts, there is sparse information about its ability to predict future cardiovascular events across ethnic subgroups. The assessment of CAD using CCTA in patients of different genetic and environmental backgrounds is important because it is proposed that the pathology, epidemiology, and prognosis of CAD may vary across ethnicities.5e9 Given the limited data currently available on coronary computed tomographic angiographic findings and their prognostic implications stratified by ethnicity, we sought to examine the prevalence of cardiovascular risk factors and the prognostic value of CCTA among ethnic subgroups in a large, prospective, multicenter international CCTA registry. Methods The Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter (CONFIRM) registry is an ongoing, prospective, international, multicenter registry designed to evaluate the relation of coronary atherosclerosis and clinical risk factors to adverse outcomes among patients who have undergone at least 64-slice CCTA for clinically referred indications (ClinicalTrials.gov identifier NCT01443637).10 The rationale and design of the CONFIRM registry have been previously reported.11 In brief, the registry uses an identical standardized data collection form and data dictionary at all participating sites to prospectively collect baseline risk factors, symptoms, and medications before CCTA, as well as detailed coronary
computed tomographic angiographic results and clinical outcomes. Patient symptoms were assessed before they underwent CCTA and defined using the criteria of Diamond and Forrester12 according to American College of Cardiology guidelines for chest pain assessment,13 and pretest cardiovascular risk was defined using the Morise score.14 Ethnicity was assessed by investigators at the time of CCTA and coded as Caucasian, African, Hispanic, East Asian, Middle Eastern, South Asian, or other. Patients with known previous CAD (previous myocardial infarction [MI], percutaneous coronary intervention, or coronary artery bypass surgery) were excluded from this analysis. Phase 1 of the CONFIRM registry enrolled 27,125 patients at 12 cluster sites in 6 countries in North America, Europe, and Asia. Phase 2 of the registry enrolled 4,682 patients from 5 sites in 4 countries. The study protocol was approved by all centers’ institutional review boards, and when required, all patients provided written informed consent. CCTA was performed using a single- or dual-source 64-slice computed tomographic scanner according to Society of Cardiovascular Computed Tomography guidelines by highly experienced imagers, as previously described.11,15 Coronary atherosclerotic lesions were graded as normal (no atherosclerosis), mild (1% to 49% stenosis), or obstructive (50% stenosis) in epicardial coronary arteries of 2 mm in diameter. The primary end point was time to all-cause death or nonfatal MI. Patient follow-up was performed as approved at each local participating institution using telephone interviews, available medical records, contact with attending physicians, mailed questionnaires, and, where available, a national death registry. From within the entire CONFIRM registry, only patients with complete information regarding
Coronary Artery Disease/CCTA Prognosis by Ethnicity in CONFIRM
Figure 1. CAD prevalence on CCT according to ethnicity.
ethnicity, severity of CAD on CCTA, and clinical follow-up for the outcomes of all-cause mortality and nonfatal MI after CCTA were included in this analysis. Continuous variables are presented as mean SD or as median (interquartile range), as appropriate. Categorical variables are presented as frequencies with percentages. Means were compared using Student’s t tests or MannWhitney U tests, and intergroup comparisons were assessed using analysis of variance or Kruskal-Wallis tests, as indicated. Proportions were compared using chi-square tests. Ethnicity was evaluated for the prediction of 50% stenosis using logistic regression in univariate analysis and multivariate analysis controlling for baseline cardiovascular risk. All-cause mortality and nonfatal MI were assessed using Kaplan-Meier and Cox proportional hazards to calculate adjusted hazard ratios, controlling for baseline cardiovascular risk factors. Cardiovascular risk factors and symptoms were adjusted in multivariate analysis using a composite Morise score.14 Failure events modeled included a combined major adverse cardiovascular event end point that included all-cause death and nonfatal MI. The same analysis as performed for the entire cohort was conducted stratified by ethnicity. Univariate predictors based on known cardiovascular risk factors were evaluated, including age, gender, diabetes, hypertension, hyperlipidemia, and current smoking. In addition, differences in baseline medication use and the occurrence of coronary revascularization performed <90 days after CCTA (presumably driven by the results of CCTA) were explored and also used to account for potential ethnicity-related differences in patient management. Hazard ratios were first calculated in a Cox proportional-hazards model limited to each ethnicity, and then each ethnicity was compared to all other ethnicities in a multivariate model, adjusted for baseline symptoms and risk factors (Morise score), baseline medications (aspirin, statins, and antihypertensive medications), and coronary revascularization. Model overfitting procedures were carefully considered and postestimation analysis was performed to ensure that the proportional-hazards assumption was met. Excess risk was calculated, after adjusting the hazard ratio for 50% CAD for baseline symptoms and risk factors, within each ethnic subgroup for the prediction of major adverse cardiovascular events. Excess risk was defined
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Figure 2. Survival from death or MI among 16,451 patients according to severity of CAD on CCTA.
as 1 e (ln HRA/ln HRu), where HRu is the unadjusted hazard ratio and HRA is the risk-adjusted hazard ratio (using the Morise score).16 All p values are 2 sided, with significance set at p <0.05. Statistical analysis was conducted using STATA version 11 (StataCorp LP, College Station, Texas) and SPSS version 13.0 (SPSS, Inc., Chicago, Illinois). Results Ethnicity data were coded for 16,451 patients at 11 sites (7 countries). The mean age was 58 12 years (55% men), and patients were followed over a median of 2.0 years (interquartile range 1.4 to 3.2 years). Middle Eastern (n ¼ 67), South Asian (n ¼ 72), Hispanic (n ¼ 534), and other (n ¼ 127) ethnicities were each coded during data collection but were excluded because they were individually underpowered for analysis. Baseline demographics are listed in Table 1. Patients were 60.1% Caucasian, 34.4% East Asian, and 5.5% African. There were significant differences in baseline risk factors, symptoms, and baseline medication use across all ethnic subgroups. Caucasians and East Asians were more likely to be older and male. East Asians had the highest prevalence of diabetes (26.9%) and Morise scores, the highest use of baseline statins and aspirin, but the lowest prevalence of a family history of premature CAD. Coronary revascularization performed <90 days after CCTA was
Table 2 Incidence* of death and nonfatal myocardial infarction Ethnicity
Adverse Event
Caucasian Death (n ¼ 9,898) Nonfatal MI East Asian Death (n ¼ 5,654) Nonfatal MI African Death (n ¼ 899) Nonfatal MI
Coronary Narrowing (Diameter Stenosis) <50%
None
50%
n
%
n
%
n
%
24 3 8 0 2 2
0.64 0.08 0.28 0.00 0.37 0.37
56 26 5 3 7 2
1.49 0.69 0.32 0.19 2.46 0.70
65 50 24 4 4 3
2.75 2.11 1.85 0.31 5.06 3.80
* Unadjusted for follow-up duration or Morise score.
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Figure 3. Annualized event rates among patients with versus without 50% stenosis on CCTA stratified by ethnicity. *Results were significant by the presence of obstructive CAD for death, MI, and death or MI for all 3 ethnicities (p <0.05).
significantly more frequent in Caucasians (7.99%) than East Asians (6.52%) and Africans (2.56%) (p <0.001; Table 1). When restricted to only patients with any obstructive disease on CCTA, these relative differences in coronary revascularization decreased but remained significant: Caucasians (32.4%) versus East Asians (28.5%) versus African (24.7%) (p ¼ 0.033). The unadjusted prevalence of CAD on CCTA according to ethnicity is shown in Figure 1. Caucasians and East Asians had a significantly higher prevalence (24% and 23%, respectively) of obstructive disease (worst stenosis 50%)
compared to Africans (9%) (p <0.0001). The univariate hazards ratios for obstructive disease were 1.20 (95% confidence interval [CI] 1.12 to 1.28) for Caucasians (p <0.001), 0.40 (95% CI 0.33 to 0.49) for Africans (p <0.001), and 0.98 (95% CI 0.91 to 1.06) for East Asians (p ¼ 0.60). Adjusting for baseline Morise score and using Caucasian as the index ethnicity, the adjusted hazard ratios for obstructive disease were 1.0 (95% CI 0.90 to 1.10) for East Asians (p ¼ 0.96) and 0.33 (95% CI 0.25 to 0.44) for Africans (p <0.001). Univariate Kaplan-Meier survival curves for death and nonfatal MI among the entire 16,451-patient cohort are shown
Figure 4. Survival from death or MI according to severity of CAD on CCTA, stratified by ethnicity.
Coronary Artery Disease/CCTA Prognosis by Ethnicity in CONFIRM
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was associated with the coronary computed tomographic angiographic finding of 50% CAD (Figure 5). After adjusting for baseline cardiovascular risk factors, symptoms (Morise score), medications (aspirin, statins, and antihypertensive medications), and early referral patterns for coronary revascularization, patients of East Asian ethnicity had a significantly lower risk for death and nonfatal MI relative to Caucasians (adjusted hazard ratio 0.25, 95% CI 0.16 to 0.35, p <0.001; Supplemental Table 2, available online). Discussion
Figure 5. Hazard ratio (HR) for 50% CAD on CCTA as a predictor of death or MI unadjusted (solid line) and adjusted (dashed line) by baseline risk factors and symptoms. The risk for obstructive CAD persisted within each ethnic subgroup after adjustment for baseline risk factors, symptoms, and revascularization.
in Figure 2. There was significantly decreased event-free survival among patients with nonobstructive and obstructive CAD on CCTA compared to patients with no coronary atherosclerosis. Clinical outcomes including absolute number of all-cause mortality and nonfatal MI events among each ethnicity, unadjusted for baseline Morise score or follow-up duration, are listed in Table 2. The unadjusted annualized incidence rates for death and MI according to ethnicity and presence versus the absence of 50% stenosis on CCTA are shown in Figure 3. Compared to patients without obstructive CAD, the presence of obstructive CAD on CCTA conferred a significantly increased rate of death or nonfatal MI among Caucasians, East Asians, and Africans (p <0.05 for all ethnicities). Patients of African ethnicity had the highest relative increase in the combined rate of death or MI related to the presence of obstructive CAD compared to those without obstructive CAD (3.76%, 95% CI 0.15% to 7.66%) on CCTA (p ¼ 0.007 for comparison to other ethnicities). Unadjusted survival curves for death and nonfatal MI for each ethnic group are shown in Figure 4. Consistent with results from the entire cohort, CAD severity as measured using CCTA demonstrated robust adverse event prediction among Caucasians, East Asians, and Africans. Univariate and multivariate predictors of death and nonfatal MI for cardiovascular risk (Morise score) and 50% stenosis on CCTA are listed in Supplemental Table 1 (available on-line) with adjustment for differences in baseline medication use and coronary revascularization. For Caucasians, Morise score and obstructive CAD on CCTA were predictive of major adverse cardiovascular events in univariate and multivariate analyses. For East Asians and Africans, only obstructive CAD on CCTA was a significant independent predictor of increased hazards for adverse events after multivariate adjustment. Calculation of excess risk (defined previously) to the hazard ratios for 50% CAD in Supplemental Table 1 demonstrated that the excess risk attributable to baseline risk factors and Morise score for Caucasians was 33%, for East Asians 6%, and for Africans 21%. Most of the future clinical event risk in the hazard ratio within each ethnic subgroup
CCTA has emerged as an important diagnostic test for the assessment of CAD with increasingly proved prognostic value, but studies published to date contain minimal information regarding the prognostic value of CCTA among different ethnic subgroups.1,3,4,17e20 Studies using noncontrast computed tomography to detect and quantify calcified atherosclerosis have demonstrated ethnic variations in calcified CAD prevalence and have confirmed the prognostic value of calcium scoring in patients of different ethnicities, but similar data regarding CCTA are currently lacking.7 This is the first large-scale study to validate the prognostic usefulness of CCTA among 3 large ethnic subgroups and furthermore illustrates several important points. First, baseline risk factors for CAD and the riskadjusted prevalence of obstructive CAD diagnosed using modern CCTA differed by ethnicity within the CONFIRM registry. For example, East Asians (26.9%) had a much higher prevalence of baseline diabetes mellitus than Caucasians (11.2%), but Caucasians may have had higher risk genetic profiles, with self-reported family histories of premature CAD at 39.5% compared to 11.3% for East Asians. Patients of African ethnicity had a lower adjusted prevalence of obstructive CAD (50% stenosis) on CCTA compared to Caucasian and East Asian patients. A second finding of this analysis is that, consistent with previous studies involving less diverse ethnic groups,4,18 the presence of nonobstructive and obstructive CAD on CCTA was incrementally and significantly associated with decreased event-free survival compared to normal results on CCTA. Furthermore, within each of the 3 ethnic subgroups analyzed, the presence of obstructive CAD (50% stenosis) on CCTA predicted significantly increased rates of all-cause mortality and nonfatal MI, beyond that provided by symptoms and risk factors alone. Finally, our data suggest that the presence of obstructive CAD in patients of African ethnicity predicted relatively increased likelihood for adverse events compared to other ethnicities. Interestingly, patients with obstructive CAD of African ethnicity were less likely to be referred for coronary revascularization compared to Caucasian patients, but the prognostic value of CCTA remained strongly predicted when adjusted for these early management differences. Conversely, patients of East Asian ethnicity with obstructive CAD on CCTA had comparatively lower rates of all-cause mortality and nonfatal MI events compared to all other ethnicities. These interesting ethnic differences in adverse event rates that are adjusted for symptom status, standard cardiovascular risk factors, baseline medications, post-CCTA revascularization
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rates, and CAD severity on CCTA may reflect differences in lifestyle, socioeconomic status, genetics, and/or CAD management after CCTA, are hypothesis generating, and warrant further study. There are several strengths to this study. First, the CONFIRM data set is the largest presently available CCTA registry, providing the ability to perform the first comparison of the prognostic value of CCTA across ethnicities within the same study cohort. Data regarding the robustness of CCTA in ethnic subgroups are lacking, and our study demonstrates good evidence for prognostic utility among Caucasians, Africans, and East Asians. Unfortunately, ethnic data for other important subgroups were not adequately powered for analysis at this time. Importantly, the absence of CAD predicts extremely low events rates over an intermediate duration of follow-up across all ethnicities studied in this analysis. As with any study, certain design limitations are inherent. First, the registry is observational, so although associations are provocative, conclusions about cause and effect cannot be drawn. Next, as with any registry, there exists the potential for selection and referral biases that may limit the external generalizability of the data. Third, differences in the application of preventative medical therapies and lifestyle habits after CCTA were not assessed and may explain some of the differences in outcomes between ethnicities. Finally, although we controlled for known cardiovascular risk factors, symptoms, baseline medications and ethnic differences in post-CCTA coronary revascularization, there remains a possibility for residual confounding that we cannot exclude. Our study represents the first large prospective cohort evaluation of CCTA and clinical outcomes among 3 varying ethnic subgroups. Within this registry, there were significant ethnic differences in the prevalence of baseline cardiovascular risk factors, symptoms, obstructive CAD prevalence, and the performance of coronary revascularization among those with obstructive CAD. Consistent with previous studies of CCTA, the presence of obstructive CAD was predictive of adverse events across a variety of ethnic subgroups, whereas the absence of CAD on CCTA was associated with an extremely good prognosis over an intermediate-term follow-up duration. Disclosures Dr. Villines has received speaker’s honoraria from Boehringer-Ingelheim, Ingelheim, Germany. Dr. Achenbach has received grant support from Siemens Healthcare, Erlangen, Germany, and Bayer Schering Pharma AG, Berlin, Germany. Dr. Budoff has received speaker’s honoraria from GE Healthcare, Milwaukee, Wisconsin. Dr. Cademartiri has received grant support from GE Healthcare and speaker’s honoraria from Bracco Diagnostics, Milan, Italy. Dr. Callister is on the speaker’s bureau of GE Healthcare. Dr. Chinnaiyan has received grant support from Bayer Pharma AG, Berlin, Germany, and Blue Cross Blue Shield Blue Care Michigan. Dr. Chow has received research support from GE Healthcare; Pfizer, Inc., New York, New York; and AstraZeneca, Wilmington, Delaware. Dr. Chow
has recieved educational support from TeraRecon, Foster City, California. Dr. Hausleiter has received research grant support from Siemens Healthcare. Dr. Kaufmann has received research support from GE Healthcare and grant support from the Swiss National Science Foundation, Bern, Switzerland. Dr. Maffei has received grant support from GE Healthcare and is a consultant for Servier, Neuilly-surSeine, France. Dr. Raff has received grant support from Siemens Healthcare, Blue Cross Blue Shield Blue Care Michigan, and Bayer Pharma AG. Dr. Min has received speaker’s honoraria and research support from and serves on the medical advisory board of GE Healthcare. The views expressed here are those of the investigators only and are not to be construed as those of the United States Department of the Army or Department of Defense. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.amjcard.2012.10.028. 1. Budoff MJ, Dowe D, Jollis JG, Gitter M, Sutherland J, Halamert E, Scherer M, Bellinger R, Martin A, Benton R, Delago A, Min JK. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol 2008;52: 1724e1732. 2. Hamon M, Biondi-Zoccai GG, Malagutti P, Agostoni P, Morello R, Valgimigli M. Diagnostic performance of multislice spiral computed tomography of coronary arteries as compared with conventional invasive coronary angiography: a meta-analysis. J Am Coll Cardiol 2006;48:1896e1910. 3. Schuijf JD, Bax JJ, Shaw LJ, de Roos A, Lamb HJ, van der Wall EE, Wijns W. Meta-analysis of comparative diagnostic performance of magnetic resonance imaging and multislice computed tomography for noninvasive coronary angiography. Am Heart J 2006;151: 404e411. 4. Hulten EA, Carbonaro S, Petrillo SP, Mitchell JD, Villines TC. Prognostic value of cardiac computed tomography angiography: a systematic review and meta-analysis. J Am Coll Cardiol 2011;57: 1237e1247. 5. Budoff MJ, Yang TP, Shavelle RM, Lamont DH, Brundage BH. Ethnic differences in coronary atherosclerosis. J Am Coll Cardiol 2002;39: 408e412. 6. Shaw LJ, Shaw RE, Merz CN, Brindis RG, Klein LW, Nallamothu B, Douglas PS, Krone RJ, McKay CR, Block PC, Hewitt K, Weintraub WS, Peterson ED. Impact of ethnicity and gender differences on angiographic coronary artery disease prevalence and in-hospital mortality in the American College of Cardiology-National Cardiovascular Data Registry. Circulation 2008;117:1787e1801. 7. Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, Folsom AR, Liu K, Shea S, Szklo M, Bluemke DA, O’Leary DH, Tracy R, Watson K, Wong ND, Kronmal RA. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 2008;358: 1336e1345. 8. Ferdinand KC. Coronary artery disease in minority racial and ethnic groups in the United States. Am J Cardiol 2006;97(suppl):12Ae19A. 9. McClelland RL, Chung H, Detrano R, Post W, Kronmal RA. Distribution of coronary artery calcium by race, gender, and age: results from the Multi-Ethnic Study of Atherosclerosis (MESA). Circulation 2006;113:30e37. 10. Min JK. The CONFIRM Registry. Available at: http://clinicaltrials. gov/show/NCT01443637. Accessed November 21, 2012. 11. Min JK, Dunning A, Lin FY, Achenbach S, Al-Mallah MH, Berman DS, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng V, Chinnaiyan KM, Chow B, Delago A, Hadamitzky M, Hausleiter J, Karlsberg
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RP, Kaufmann P, Maffei E, Nasir K, Pencina MJ, Raff GL, Shaw LJ, Villines TC. Rationale and design of the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) registry. J Cardiovasc Comput Tomogr 2011;5:84e92. Diamond GA, Forrester JS. Analysis of probability as an aid in the clinical diagnosis of coronary-artery disease. N Engl J Med 1979;300: 1350e1358. Gibbons RJ, Chatterjee K, Daley J, Douglas JS, Fihn SD, Gardin JM, Grunwald MA, Levy D, Lytle BW, O’Rourke RA, Schafer WP, Williams SV. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Chronic Stable Angina). Circulation 1999;99:2829e2848. Morise AP, Haddad WJ, Beckner D. Development and validation of a clinical score to estimate the probability of coronary artery disease in men and women presenting with suspected coronary disease. Am J Med 1997;102:350e356. Abbara S, Arbab-Zadeh A, Callister TQ, Desai MY, Mamuya W, Thomson L, Weigold WG. SCCT guidelines for performance of coronary computed tomographic angiography: a report of the Society of Cardiovascular Computed Tomography Guidelines Committee. J Cardiovasc Comput Tomogr 2009;3:190e204. Brotman DJ. Mediators of the association between mortality risk and socioeconomic status. JAMA 2006;296:763e764. Cheng VY, Berman DS, Rozanski A, Dunning AM, Achenbach S, Al-Mallah M, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Chinnaiyan K, Chow BJ, Delago A, Gomez M, Hadamitzky M, Hausleiter J, Karlsberg RP, Kaufmann P, Lin FY, Maffei E, Raff GL, Villines TC, Shaw LJ, Min JK. Performance of the traditional age, sex, and angina typicality-based approach for estimating pretest probability of angiographically significant coronary artery disease in
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patients undergoing coronary computed tomographic angiography: results from the multinational Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry (CONFIRM). Circulation 2011;124:2423e2432. 18. Chow BJ, Small G, Yam Y, Chen L, Achenbach S, Al-Mallah M, Berman DS, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng V, Chinnaiyan KM, Delago A, Dunning A, Hadamitzky M, Hausleiter J, Kaufmann P, Lin F, Maffei E, Raff GL, Shaw LJ, Villines TC, Min JK. Incremental prognostic value of cardiac computed tomography in coronary artery disease using CONFIRM: Coronary Computed Tomography Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry. Circ Cardiovasc Imaging 2011;4: 463e472. 19. Min JK, Dunning A, Lin FY, Achenbach S, Al-Mallah M, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng V, Chinnaiyan K, Chow BJ, Delago A, Hadamitzky M, Hausleiter J, Kaufmann P, Maffei E, Raff G, Shaw LJ, Villines T, Berman DS. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the international multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol 2011;58:849e860. 20. Villines TC, Hulten EA, Shaw LJ, Goyal M, Dunning A, Achenbach S, Al-Mallah M, Berman DS, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng VY, Chinnaiyan K, Chow BJ, Delago A, Hadamitzky M, Hausleiter J, Kaufmann P, Lin FY, Maffei E, Raff GL, Min JK. Prevalence and severity of coronary artery disease and adverse events among symptomatic patients with coronary artery calcification scores of zero undergoing coronary computed tomography angiography: results from the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) registry. J Am Coll Cardiol 2011;58:2533e2540.