Ethnic variation in adverse cardiovascular outcomes and bleeding complications in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study

Ethnic variation in adverse cardiovascular outcomes and bleeding complications in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study Koon-Hou Mak, MD, a Deepak L. Bhatt, MD, b Mingyuan Shao, MS, c Graeme J. Hankey, MD, d J. Donald Easton, MD, e Keith A.A. Fox, MB, ChB, f and Eric J. Topol, MD g Singapore, Singapore; Boston, MA; Cleveland, OH; Perth, Australia; Providence, RI; Edinburgh, UK; and La Jolla, CA

Background Atherothrombosis is a common condition affecting individuals worldwide. Its impact on different ethnic groups receiving evidence-based therapy is unclear. We aimed to determine if ethnicity is an independent predictor for cardiovascular events and bleeding complications in a contemporary clinical trial on antiplatelet therapy. Methods

This was a prospective observational study of 15,603 patients enrolled in the CHARISMA trial followed up every 6 months for a median of 28 months. The primary efficacy end point was the first occurrence of cardiovascular death, myocardial infarction, or stroke. The primary safety end point was bleeding.

Results The cohort comprised 12,502 (80.1%) white, 486 (3.1%) black, 775 (5.0%) Asian, and 1,613 (10.3%) Hispanic patients. There was no difference in the occurrence of the primary composite end point among the 4 ethnic groups. Compared with Asians, cardiovascular and all-cause mortality occurred more frequently among black (adjusted hazard 2.19 and 2.04) and Hispanic (adjusted hazard, 1.83 and 1.69) patients. Although the occurrence of severe bleeding was similarly low among the 4 ethnic groups, Asian (adjusted hazard, 2.21) and black (adjusted hazard, 3.06) patients were more likely to have moderate bleeding complications than Hispanic patients. Conclusion

In this trial of individuals at risk of vascular events, ethnicity was not a significant, independent predictor of the primary composite cardiovascular event. However, ethnicity was a significant, independent predictor of the secondary outcomes, cardiovascular and all-cause mortality (blacks and Hispanics), and moderate bleeding complications (blacks and Asians). (Am Heart J 2009;157:658-65.)

Atherothrombosis, consisting of coronary artery, cerebrovascular, and peripheral vascular diseases, is a major cause of morbidity and mortality worldwide. Several medical advances have improved the outcomes of these patients. However, there are marked differences in the rate, natural history, and outcomes of cardiovascular disease among individuals from various ethnic groups.1 Even in a small closely knitted society with freely

From the aGleneagles Medical Centre, Singapore, Singapore, bVA Boston Healthcare System and Brigham and Women's Hospital, Boston, MA, cCleveland Clinic, Cleveland, OH, dDepartment of Neurology, Royal Perth Hospital and School of Medicine and Pharmacology, University of Western Australia, Perth, Australia, eDepartment of Neurology, Rhode Island Hospital and Brown University, Providence, RI, fUniversity and Royal Infirmary of Edinburgh, Edinburgh, UK, and gScripps Translational Research Institute, La Jolla, CA. The CHARISMA trial is registered with ClinicalTrials.gov, NCT00050817. Submitted April 13, 2008; accepted August 20, 2008. Reprint requests: Koon-Hou Mak, MD, Gleneagles Medical Centre, 6 Napier Road #0813, Singapore 258499. E-mail: [email protected] 0002-8703/$ - see front matter © 2009, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2008.08.031

accessible health care such as Singapore, the incidence, and short- and long-term case fatality of acute coronary events varied considerably among different ethnic groups.2 Although variations in risk factors and cultural background3 may account for these differences, others have attributed these variations to access to health care facilities, availability of resources, care-seeking behavior, religious beliefs, socioeconomic factors, and adherence to evidence-based therapies. Indeed, clinical management and adverse event rates vary among different geographical regions and ethnic groups.4,5 However, most of this information was derived from international registries that did not provide specific guidance on how patients were to be treated. Importantly, physician and patient beliefs, practices, and preferences also might have contributed to these differences. The CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial randomly assigned 15,603 patients with established atherothrombotic disease or multiple cardiovascular risk factors to either clopidogrel plus aspirin or placebo plus aspirin.6 After

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Table I. Baseline characteristics Ethnic group Number Age⁎ (y) Female BMI⁎ (kg/m2) Current smoker Hypertension Diabetes mellitus Hypercholesterolemia Previous history CCF Previous MI TIA Stroke AF Diabetic nephropathy Revascularization PCI CABG Peripheral vascular Carotid artery Prior antiplatelet therapy Prior aspirin use Dose ≤162 mg Dose N162 mg Prior ticlodipine§ Prior clopidogrel# Prior dipyridamole GP IIb/IIIa inhibitor§ Prior diuretics Prior nitrates§ Prior CCB Prior β-blockers Prior ARB§ Prior ACE inhibitors Prior ramipril Other antihypertensives Prior statins Prior atorvastatin Prior simvastatin Other lipid-lowering agents Prior fibric acids⁎⁎ Prior binding resins Prior nicotinic acids Prior antidiabetics Prior insulin Prior thiazolidinediones Other oral hypoglycemics Duration of follow-up (d)

Whites 12 502 65 (58, 72) 3597 (28.8) 28.0 (25.2, 31.4) 2621 (21.0) 9078 (72.6) 4854 (38.8) 9419 (75.3) 772 (6.2) 4559 (36.5) 1583 (12.7) 2909 (23.3) 513 (4.1) 1382 (11.1) 6218 (49.7) 2973 (23.8) 2656 (21.2) 1545 (12.4) 731 (5.8) 11 823 (94.6) 11 725 (93.8) 8726 (74.4) 2999 (25.6) 77 (0.6) 407 (3.3) 90 (0.7) 11 (0.1) 4244 (33.9) 2055 (16.4) 3324 (26.6) 5936 (47.5) 2047 (16.4) 6272 (50.2) 1752 (14.0) 981 (7.8) 8426 (67.4) 3507 (28.1) 3244 (25.9) 1035 (8.3) 715 (5.7) 101 (0.8) 263 (2.1) 4389 (35.1) 1599 (12.8) 647 (5.2) 3412 (27.3) 857 (713 938)

Blacks

Asians

Hispanics

486 61 (55, 69) 225 (46.3) 30.0 (26.1, 34.4) 109 (22.4) 448 (92.2) 287 (59.1) 361 (74.3)

775 62 (55, 69) 199 (25.7) 25.7 (23.4, 28.3) 112 (14.5) 597 (77.0) 440 (56.8) 548 (70.7)

1613 64 (57, 72) 543 (33.7) 27.6 (25.0, 30.8) 267 (16.6) 1185 (73.5) 830 (51.5) 1045 (64.8)

40 (8.2) 135 (27.8) 25 (5.1) 154 (31.7) 11 (2.3) 84 (17.3) 174 (35.8) 87 (17.9) 80 (16.5) 45 (9.3) 15 (3.1) 438 (90.1) 432 (88.9) 239 (55.3) 193 (44.7) 2 (0.4) 18 (3.7) 10 (2.1) 1 (0.2) 265 (54.5) 90 (18.5) 192 (39.5) 229 (47.1) 95 (19.5) 277 (57.0) 31 (6.4) 64 (13.2) 298 (61.3) 123 (25.3) 120 (24.7) 30 (6.2) 13 (2.7) 12 (2.5) 6 (1.2) 274 (56.4) 109 (22.4) 47 (9.7) 198 (40.7) 814 (713 928)

44 (5.7) 204 (26.3) 68 (8.8) 301 (38.8) 19 (2.5) 183 (23.6) 262 (33.8) 179 (23.1) 81 (10.5) 18 (2.3) 11 (1.4) 728 (93.9) 713 (92.0) 665 (93.3) 48 (6.7) 6 (0.8) 41 (5.3) 21 (2.7) 0 159 (20.5) 119 (15.4) 267 (34.5) 351 (45.3) 146 (18.8) 349 (45.0) 94 (12.1) 57 (7.4) 482 (62.2) 165 (21.3) 219 (28.3) 47 (6.1) 42 (5.4) 3 (0.4) 2 (0.3) 411 (53.0) 132 (17.0) 37 (4.8) 347 (44.8) 731 (679 887)

54 (3.3) 435 (27.0) 171 (10.6) 426 (26.4) 35 (2.2) 295 (18.3) 563 (34.0) 278 (17.2) 225 (13.9) 113 (7.0) 67 (4.2) 1426 (88.4) 1394 (86.4) 1040 (74.6) 354 (25.4) 7 (0.4) 69 (4.3) 6 (0.4) 1 (0.1) 429 (26.6) 246 (15.3) 397 (24.6) 627 (38.9) 272 (16.9) 766 (47.5) 111 (6.9) 83 (5.1) 787 (48.8) 303 (18.8) 236 (14.6) 127 (7.9) 110 (6.8) 10 (0.6) 8 (0.5) 763 (47.3) 226 (14.0) 53 (3.3) 608 (37.7) 839 (706 935)

CCF, Congestive cardiac failure; TIA, transient ischemic attack; AF, atrial fibrillation; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; GP, glycoprotein; CCB, calcium channel blockers; ARB, angiotensin receptor blockers; ACE, angiotensin converting enzyme. Data are expressed as number with percentage inside parentheses unless otherwise stated. For overall comparison among the 4 ethnic groups, P b .001 except for §P N .05; #P = .006; ⁎⁎P = .007. ⁎Median with interquartile range inside parentheses.

a median follow-up period of 28 months, there was no significant difference in the first occurrence of the primary efficacy end point, consisting of cardiovascular death, myocardial infarction (MI), or stroke in the overall population of stable patients studied, although the subgroup of higher-risk secondary prevention patients seemed to benefit. Unlike registries in which

medical therapy is left to the discretion of physicians, in CHARISMA, investigators were specifically instructed to optimize blood pressure (BP), lipid, and glycemic control to achieve current therapeutic targets. Furthermore, patients were enrolled from 32 countries in 6 continents7 and, therefore, provided a unique opportunity to explore ethnic differences in

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Table II. Univariable analysis for clinical efficacy outcomes and bleeding complications Ethnic group n CV death/ MI/ stroke HR (95% CI) P† CV death HR (95% CI) P† Nonfatal MI HR (95% CI) P† Nonfatal stroke HR (95% CI) P† All-cause mortality HR (95% CI) P† CV death/MI/stroke/hosp HR (95% CI) P† Hospitalization HR (95% CI) P† Severe bleeding HR (95% CI) P† Moderate bleeding HR (95% CI) P†

Asians 775 48 (6.2) Referent NA 15 (1.9) Referent NA 11 (1.4) 1.39 (0.65-2.94) .393 22 (2.8) 1.47 (0.86-2.54) .161 24 (3.1) referent NA 100 (12.9) Referent NA 57 (7.4) 1 NA 12 (1.5) 1.31 (0.49-3.50) .587 19 (2.5) 2.21 (1.17-4.19) .012

Blacks

Whites

486 42 (8.6) 1.32 (0.87-1.99) .195 22 (4.5) 2.19 (1.13-4.22) .017 10 (2.1) 1.89 (0.87-4.09) .101 10 (2.1) 1.04 (0.51-2.12) .906 33 (6.8) 2.04 (1.20, 3.45) .007 91 (18.7) 1.41 (1.06-1.88) .017 55 (11.3) 1.54 (1.06-2.23) 0.021 6 (1.2) Referent NA 17 (3.5) 3.06 (1.59-5.89) b.001

12,502 892 (7.1) 1.07 (0.80-1.43) .665 364 (2.9) 1.37 (0.82-2.30) .226 257 (2.1) 1.82 (1.13-2.94) .013 271 (2.2) 1.08 (0.75-1.55) .695 585 (4.7) 1.36 (0.91, 2.05) .136 2242 (17.9) 1.32 (1.08-1.62) .006 1551 (12.4) 1.62 (1.24-2.11) b0.001 185 (1.5) 1.16 (0.51-2.61) .721 207 (1.7) 1.39 (0.87-2.22) .170

Hispanics 1613 110 (6.8) 1.04 (0.74-1.46) .817 60 (3.7) 1.83 (1.04-3.22) .034 18 (1.1) Referent NA 32 (2.0) referent NA 91 (5.6) 1.69 (1.08, 2.66) .020 229 (14.2) 1.05 (0.83-1.32) .713 137 (8.5) 1.11 (0.82-1.52) 0.504 29 (1.8) 1.44 (0.60-3.47) .411 19 (1.2) Referent NA

P⁎

.518

.021

.073

.440

.012

b.001

b.001

.687

b.001

CV, Cardiovascular; NA, not applicable; hosp, hospitalization. ⁎ P values were based on log-rank test across the ethnic groups. † P values were based on log-rank test with the referent ethnic group.

cardiovascular events and bleeding complications among patients with atherothrombosis globally.

Methods The study design8 and major findings6,9 of the CHARISMA trial have been published previously. Briefly, patients with documented coronary artery disease, cerebrovascular disease, or peripheral arterial disease, or with multiple risk factors for atherothrombosis were enrolled and randomly assigned to clopidogrel plus aspirin or placebo plus aspirin in a double-blind fashion. Patients were excluded if they had indications or contraindications for open-label clopidogrel use or were at high risk of bleeding. Participants were followed up prospectively every 6 months for a median of 28 months. All patients will be followed up according to the study flowchart from randomization until the study end date or death, with the last patient followed for at least 3 months (90 days), regardless of whether they discontinued study drug prematurely or not. For patients considered lost to follow-up, the case report form must be completed up to the last visit performed. The completeness of follow-up for the trial was 99.5%. Baseline data were obtained through patient interviews by research nurses. Ethnic identification was self-reported and entered prospectively for each participant. Based on prespecific ethnic groups in the case report forms, patients were categorized into white, Hispanic, black, and Asian patients. Most

of the Asian patients were enrolled from Hong Kong, Malaysia, Singapore, and Taiwan. The primary efficacy end point was the first occurrence of cardiovascular death (including hemorrhagic death), MI, or stroke (from any cause). The primary safety end point was severe bleeding as defined by the GUSTO (Global Utilization of Streptokinase and Tissue-plasminogen activator for Occluded coronary arteries) criteria, which included fatal bleeding, primary intracranial hemorrhage, or bleeding causing hemodynamic compromise and requiring blood or fluid replacement, inotropic support, or surgical intervention.10 These events were validated by the Cleveland Clinic Clinical Events Adjudication Committee. The secondary efficacy end points included death from any causes, death from cardiovascular causes, nonfatal MI, nonfatal stroke, hospitalization, and the primary efficacy end point or hospitalization. Moderate bleeding as determined by the GUSTO criteria was the secondary safety end point; this end point captures bleeding that leads to transfusion but that does not lead to hemodynamic compromise requiring intervention.

Statistical analysis Baseline demographics, medical history, and prior medications for the enrolled patients were compared among the 4 ethnic groups. Ethnic differences for the efficacy end points and safety end points were assessed using a 2-sided log-rank test and were plotted using cumulative Kaplan-Meier estimates of the event rates. Hazard ratios (HRs) of the ethnic groups and their associated 95% CIs were estimated using Cox proportional

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Figure 1

Cumulative hazard curves for the primary composite end point. The primary composite end point was the first occurrence of cardiovascular death, MI, or stroke. Cumulative hazard curves are truncated to 30 months because the estimated percentages beyond this time point become subject to large random error.

hazards model. No adjustments for multiple comparisons were made. For those study end points that showed some significant association with ethnicity, multivariable time-to-event analyses were performed to examine the effect of ethnicity after adjusting for treatment, age, gender, body mass index (BMI), geographical region (US vs non-US), other baseline demographics, and baseline medication. For each model, the ethnic group with the lowest event rate was used as the referent group. Multivariable subgroup analysis was conducted to further investigate the differences between the highest incidence ethnic group and the lowest incidence ethnic group. Concomitant medications were not included in the multivariable analyses because there was no record of corresponding dates of initiation and discontinuation of administration. All P values are 2-sided and were considered statistically significant when P is b.05. All analyses were performed using SAS software version 9.1.3 (SAS Institute Inc, Cary, NC). The CHARISMA study was funded by Sanofi-Aventis (Paris, France) and Bristol-Myers Squibb (Princeton, NJ).

Results There were small but statistically significant differences in baseline characteristics among the 4 ethnic groups (Table I). White patients were older; more likely to have had hypercholesterolemia, previous MI, transient

ischemic attacks, atrial fibrillation; and more likely to have undergone various revascularization procedures. Black patients had the highest BMI and proportion of female, were most likely to be smokers, and had hypertension, diabetes mellitus, and congestive heart failure (CHF). Asian patients were more likely to have had stroke and diabetic nephropathy. Regarding the use of evidence-based medicines, Hispanic patients were least likely to receive antiplatelet therapy (Table I). White, Asian, and Hispanic patients were least likely to receive angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and statins, respectively. The proportion of patients with diabetes treated with insulin was highest among the black patients.

Primary end points The first occurrence of cardiovascular death, MI, or stroke ranged from 6.2% (Asian patients) to 8.6% (black patients) (Table II). There was no significant event rate difference among the ethnic groups for the primary efficacy end point (Table II and Figure 1). Although there was no difference in the occurrence of severe bleeding among the ethnic groups (Table II), Hispanic patients were more likely to have intracranial hemorrhage compared with white patients (P = .004).

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Figure 2

Kaplan-Meier estimates of the cumulative incidence of all-cause mortality (A) and cardiovascular mortality (B). The P values were calculated with the log-rank test. Kaplan-Meier curves are truncated to 30 months because the estimated percentages beyond this time point become subject to large random error.

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Table III. Multivariable analysis for clinical efficacy outcomes and bleeding complications Ethnic group CV death Adjusted HR (95% CI) P All-cause mortality Adjusted HR (95% CI) P Nonfatal MI Adjusted HR (95% CI) P CV death/MI/stroke/hosp Adjusted HR (95% CI) P Hospitalization Adjusted HR (95% CI) P Moderate bleeding Adjusted HR (95% CI) P

Asians

Blacks

Whites

Hispanics

Referent NA

2.56 (1.29-5.07) .007

1.33 (0.79-2.25) .285

1.67 (0.94-2.95) .079

Referent NA

1.90 (1.12-3.22) .018

1.19 (0.79-1.80) .406

1.51 (0.96-2.37) .077

1.35 (0.64-2.86) .436

1.90 (0.88-4.13) .104

1.64 (1.02-2.65) .043

Referent NA

Referent NA

1.35 (1.01-1.80) .041

1.24 (1.01-1.52) .038

1.09 (0.86-1.38) .491

Referent NA

1.40 (0.97-2.03) .076

1.39 (1.07-1.82) .015

1.12 (0.82-1.53) .462

3.78 (1.35, 10.60) .012

1.46 (0.63, 3.36) .377

Referent NA

3.15 (1.09, 9.11) .034

CV, Cardiovascular; NA, not applicable.

Secondary end points Compared with Asian patients, cardiovascular and allcause mortality occurred significantly higher among black and Hispanic patients (Table II) (Figure 2). However, the difference was maintained only for black patients in a multivariable model for both cardiovascular (after adjusting for smoking, female gender, US patients, age, systolic BP, history of CHF, MI, stroke, diabetic nephropathy, coronary angioplasty, carotid endarterectomy, peripheral vascular revascularization procedures, and baseline use of antiplatelet or antidiabetic agents, diuretics, nitrates, and statins) and total mortality (after adjusting for smoking, female gender, age, systolic BP, history of CHF, MI, diabetic nephropathy, cerebrovascular accident, coronary angioplasty, peripheral vascular revascularization procedure, and baseline use of diuretics, anti-diabetic agents, nitrates, calcium antagonists, and statins) (Table III). The occurrence of MI for white patients was significantly higher than for Hispanic patients in both univariable (Table II) and multivariable (after adjusting for age, female gender, smoking, history of CHF, MI, stroke, coronary, peripheral or carotid revascularization procedures, and baseline use of antithrombotic, agents, statins, nitrates, calcium antagonists, and insulin) (Table III) analyses. Hospitalization rates occurred more frequently among black and white patients compared with Asian patients (Table II), and this relationship was maintained only for white patients in a multivariable model (after adjusting for age, female gender, smoking, history of CHF, MI, stroke, coronary angioplasty, peripheral vascular revascularization procedure, and baseline use of nitrates, calcium antagonists, statins, insulin, antiplatelet and antithrombotic agents) (Table III).

Moderate bleeding complications occurred least frequently among Hispanic patients (Table II), and it remained higher among black and Asian patients in a multivariable model (after adjusting for age, BMI, US patients, diastolic BP, hypercholesterolemia, history of CHF, MI, transient ischemic attack, diabetic nephropathy and baseline use of BP lowering agents) (Table III). Among the various end points, there was no difference between those treated with clopidogrel plus aspirin or placebo plus aspirin except for moderate bleeding (P value for interaction product terms for ethnicity and treatment was b.001). This event rate was lower for black patients when treated with clopidogrel plus aspirin than did Hispanic patients, with an adjusted HR of 0.24 (95% CI 0.06-0.95, P = .043).

Discussion The occurrence of the primary composite end point was similar among the 4 ethnic groups. However, there were important differences in the individual components of the composite end points. Compared with Asian patients, all-cause and cardiovascular mortality rates were substantially 2.56 and 1.90 times, respectively, higher for black patients, even after adjusting for differences in baseline characteristics. White patients were 1.64 times more likely than Hispanic patients to have MI. Although the rates of severe bleeding complications were similar among the 4 ethnic groups, Asian and black patients were 3.15 and 3.78 times, respectively, more likely to have moderate bleeding complications than white patients. Although most of the risk for MI is accounted for by traditional risk factors among individuals in different ethnic groups,11 outcome after an atherothrombotic

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event may vary in each ethnic group, even after adjusting for these risk factors. Indeed, difference in all-cause mortality was also observed in a large cohort of patients of dissimilar ethnic origins.12 In a prospective cohort of 14,812 patients without symptomatic or established coronary disease who were referred for coronary calcium scoring by their primary care physicians, they were followed for a mean period of 6.8 years. Long-term allcause mortality was highest for black individuals compared with white, Hispanic, and Asian patients. After adjusting for age, gender, hypertension, hyperlipidemia, diabetes mellitus, family history of premature coronary disease and coronary calcium score, black patients were 3 times (95% CI 1.9-4.7) more likely to die than persons of the other 3 ethnic groups. Interestingly, this mortality trend was also observed among patients with out-ofhospital cardiac arrest.13 The age-adjusted odds for survival for black patients was only 0.4 (95% CI 0.2-0.7) as compared with white patients. Demographic factors, prior functional status, initial cardiac rhythm, and characteristics of the event explained about 41% of the higher age-adjusted mortality among black patients in a multivariable model. Importantly, delay in emergency medical service response or difference in the likelihood of receipt of cardiopulmonary resuscitation, which were previously thought to account for adverse outcome among black patients, were determined not to have contributed substantially to ethnic disparities in survival in this study. Similarly, we found that cardiovascular and allcause mortality were significantly higher in black than in white patients in the CHARISMA trial, even after adjusting for differences in baseline characteristics. The reasons for these findings remained uncertain, and the impact of the burden of coronary atherosclerosis may also differ among various ethnic groups. Coronary calcium score, a surrogate marker for coronary atherosclerosis, has been shown to be an independent predictor for all-cause mortality and possibly superior to traditional risk factors.14 Compared with other ethnic groups in a population-based study, a raised coronary calcium score conferred the highest mortality risk among black patients.12 In this trial, investigators were instructed to treat patients with angiotensin-converting enzyme inhibitors, where appropriate, and keep glycemic control, BP, and lipid levels at recommended current guidelines. As such, traditional factors that account for ethnic variations such as access to health care, patient, and physician preferences were less likely to have influenced the difference in outcomes. Indeed, by improving the quality of health care delivery, racial disparities in clinical performance have been shown to have diminished in Medicaremanaged care.15 However, we did not have specific performance indicators in our study to determine the adherence of evidence-based therapies. Nonetheless, the high rates of utilization of these medicines at baseline suggested that our investigators did attempt to optimize

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medical treatment for our patients. Unfortunately, individual response to drug may vary16 and could have partly accounted for the difference in outcome. Adverse drug effects have also been shown to vary among different ethnic groups.17,18 However, we did not find significant differences in severe bleeding among the 4 ethnic groups in our study. However, intracranial hemorrhage occurred more frequently among Hispanic patients. Before enrolment, they were less likely to have received, and hence were less exposed, to antiplatelet agents. Being naive to antithrombotic agents, Hispanic patients may be more likely to experience this complication. Differences in the rate of intracranial hemorrhage among different ethnic groups have been observed in general population and clinical trials of pharmacologic reperfusion among patients with ST– segment-elevation MI. Whereas both Hispanic and black patients were more likely to have intracranial hemorrhage in the general population,19,20 Hispanic patients have been shown not to be more likely to have this complication after fibrinolytic therapy.21 Instead, black patients were at greater risk for intracranial hemorrhage compared with non-black patients when treated with fibrinolytic agents (rate ratio 1.5, 95% CI 1.2-1.9)18 and may be related to increased sensitivity to tissue plasminogen activator.22 Moderate bleeding occurred more frequently among black and Asian patients than white patients in our study. Similarly, in the GUSTO-1 study, black patients were at increased risk of moderate or severe bleeding after fibrinolytic treatment (adjusted odds ratio 1.9, 1.6-2.3).10 Approximately 17% of black patients experienced moderate to severe bleeding compared with 11% of nonblack patients. In our study, after adjusting for differences in baseline characteristics, the association of increased bleeding complications was observed for Asian and black patients compared with Hispanic patients. We found that geographical region has a strong influence on this adverse outcome and may suggest variation in patient management and practices. However, the number of events in each ethnic group is small, and these findings have to be interpreted with caution. The strength of our study is the global reach in a rigorously conducted clinical trial and the completeness of follow-up. However, there are several other limitations in this analysis. Because this is a post hoc analysis, the findings are only hypothesis generating. Furthermore, most of the patients were whites, and the number of individuals in the Asian and black groups was small and might not have had sufficient statistical power to detect differences. Although Asians should include any individual from Asia, participants in CHARISMA were recruited from only 4 relatively close geographically countries in Southeast Asia. Therefore, the sample of Asians is not representative of several other regions such as South Asia and the Middle East.

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Nonetheless, our study was conducted in an environment where physicians were instructed and reminded to optimize medical therapy, making geographical variation in disease management less likely. Another limitation of our study was that there is genetic diversity among those in the same race, although ethnicity may indicate people arising from the same ancestry and with similar cultural and social backgrounds. This issue is being addressed by the genomic substudy of CHARISMA. Despite the imperfections of ethnicity as a biological marker, we found that there were important differences in cardiovascular outcomes and bleeding complications among various ethnic groups in the CHARISMA Trial. Further studies are required to clarify these findings and determine the underlying causes for this variation.

Acknowledgements The executive committee would like to acknowledge the efforts of Bernard Job, MD, and Christophe Gaudin, MD, from Sanofi-Aventis and Mel Blumenthal, MD, and Ravi Saini, MD, from Bristol-Myers Squibb on behalf of the CHARISMA trial.

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