new england journal of medicine The established in 1812 april 12, 2007 vol. 356 no. 15 Optimal Medical Therapy with or without PCI for Stable Coronary Disease William E. Boden, M.D., Robert A. O'Rourke, M.D., Koon K. Teo, M.B., B.Ch., Ph.D., Pamela M. Hartigan, Ph.D., David J. Maron, M.D., William J. Kostuk, M.D., Merril Knudtson, M.D., Marcin Dada, M.D., Paul Casperson, Ph.D., Crystal L. Harris, Pharm.D., Bernard R. Chaitman, M.D., Leslee Shaw, Ph.D., Gilbert Gosselin, M.D., Shah Nawaz, M.D., Lawrence M. Title, M.D., Gerald Gau, M.D., Alvin S. Blaustein, M.D., David C. Booth, M.D., Eric R. Bates, M.D., John A. Spertus, M.D., M.P.H., Daniel S. Berman, M.D., G.B. John Mancini, M.D., and William S. Weintraub, M.D., for the COURAGE Trial Research Group* A BS T R AC T Background In patients with stable coronary artery disease, it remains unclear whether an initial management strategy of percutaneous coronary intervention (PCI) with intensive pharmacologic therapy and lifestyle intervention (optimal medical therapy) is superior to optimal medical therapy alone in reducing the risk of cardiovascular events. Methods Affiliations for all authors are listed in the Appendix. Address reprint requests to Dr. Boden at the Division of Cardiology, Buf- falo General Hospital, 100 High St., Buffalo, NY 14203, or at wboden@kaleidahealth. org. *Members of the Clinical Outcomes Uti- lizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial are list- ed in the Appendix and in the Supplemen- tary Appendix, available with the full text of this article at www.nejm.org. This article (10.1056/NEJMoa070829) was published at www.nejm.org on March 26, 2007. N Engl J Med 2007;356:1503-16. Copyright (C) 2007 Massachusetts Medical Society. We conducted a randomized trial involving 2287 patients who had objective evidence of myocardial ischemia and significant coronary artery disease at 50 U.S. and Canadian centers. Between 1999 and 2004, we assigned 1149 patients to undergo PCI with optimal medical therapy (PCI group) and 1138 to receive optimal medical therapy alone (medical-therapy group). The primary outcome was death from any cause and nonfatal myocardial infarction during a follow-up period of 2.5 to 7.0 years (median, 4.6). Results There were 211 primary events in the PCI group and 202 events in the medicaltherapy group. The 4.6-year cumulative primary-event rates were 19.0% in the PCI group and 18.5% in the medical-therapy group (hazard ratio for the PCI group, 1.05; 95% confidence interval [CI], 0.87 to 1.27; P = 0.62). There were no significant differences between the PCI group and the medical-therapy group in the composite of death, myocardial infarction, and stroke (20.0% vs. 19.5%; hazard ratio, 1.05; 95% CI, 0.87 to 1.27; P = 0.62); hospitalization for acute coronary syndrome (12.4% vs. 11.8%; hazard ratio, 1.07; 95% CI, 0.84 to 1.37; P = 0.56); or myocardial infarction (13.2% vs. 12.3%; hazard ratio, 1.13; 95% CI, 0.89 to 1.43; P = 0.33). Conclusions As an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events when added to optimal medical therapy. (ClinicalTrials.gov number, NCT00007657.) n engl j med 356;15 www.nejm.org april 12, 2007 1503 The New England Journal of Medicine Downloaded from nejm.org on December 20, 2011. For personal use only. No other uses without permission. Copyright (C) 2007 Massachusetts Medical Society. All rights reserved. The n e w e ng l a n d j o u r na l of m e dic i n e D uring the past 30 years, the use of percutaneous coronary intervention (PCI) has become common in the initial management strategy for patients with stable coronary artery disease in North America, even though treatment guidelines advocate an initial approach with intensive medical therapy, a reduction of risk factors, and lifestyle intervention (known as optimal medical therapy).1,2 In 2004, more than 1 million coronary stent procedures were performed in the United States,3 and recent registry data indicate that approximately 85% of all PCI procedures are undertaken electively in patients with stable coronary artery disease.4 PCI reduces the incidence of death and myocardial infarction in patients who present with acute coronary syndromes,5-10 but similar benefit has not been shown in patients with stable coronary artery disease.11-15 This issue has been studied in fewer than 3000 patients,16 many of whom were treated before the widespread use of intracoronary stents and current standards of medical management.17-28 Although successful PCI of flow-limiting stenoses might be expected to reduce the rate of death, myocardial infarction, and hospitalization for acute coronary syndromes, previous studies have shown only that PCI decreases the frequency of angina and improves short-term exercise performance.11,12,15 Thus, the long-term prognostic effect of PCI on cardiovascular events in patients with stable coronary artery disease remains uncertain. Our study, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, was designed to determine whether PCI coupled with optimal medical therapy reduces the risk of death and nonfatal myocardial infarction in patients with stable coronary artery disease, as compared with optimal medical therapy alone. support from the pharmaceutical industry consisted of unrestricted research grants payable to the Department of Veterans Affairs. The study protocol was approved by the human rights committee at the coordinating center and by the local institutional review board at each participating center. An independent data and safety monitoring board oversaw the conduct, safety, and efficacy of the trial. Data management and statistical analyses were performed solely by the data coordinating center with oversight by the trial executive committee, whose members, after unblinding, had full access to the data and vouch for the accuracy and completeness of the data and the analyses. The companies that provided financial support, products, or both had no role in the design, analysis, or interpretation of the study. Study Population Patients with stable coronary artery disease and those in whom initial Canadian Cardiovascular Society (CCS) class IV angina subsequently stabilized medically were included in the study. Entry criteria included stenosis of at least 70% in at least one proximal epicardial coronary artery and objective evidence of myocardial ischemia (substantial changes in ST-segment depression or T-wave inversion on the resting electrocardiogram or inducible ischemia with either exercise or pharmacologic vasodilator stress) or at least one coronary stenosis of at least 80% and classic angina without provocative testing. Exclusion criteria included persistent CCS class IV angina, a markedly positive stress test (substantial ST-segment depression or hypotensive response during stage 1 of the Bruce protocol), refractory heart failure or cardiogenic shock, an ejection fraction of less than 30%, revascularization within the previous 6 months, and coronary anatomy not suitable for PCI. A detailed description of the inclusion and exclusion criteria is included in the Supplementary AppenMe thods dix (available with the full text of this article at Study Design www.nejm.org). Patients who were eligible for the The methods we used in the trial have been de- study underwent randomization after providing scribed previously.29,30 Sponsorship and oversight written informed consent. of the trial were provided by the Department of Veterans Affairs Cooperative Studies Program. Treatment Additional funding was provided by the Canadian Patients were randomly assigned to undergo PCI Institutes of Health Research. Supplemental cor- and optimal medical therapy (PCI group) or optiporate support from several pharmaceutical com- mal medical therapy alone (medical-therapy group). panies included funding and in-kind support. All A permuted-block design was used to generate 1504 n engl j med 356;15 www.nejm.org april 12, 2007 The New England Journal of Medicine Downloaded from nejm.org on December 20, 2011. For personal use only. No other uses without permission. Copyright (C) 2007 Massachusetts Medical Society. All rights reserved. Optimal Medical Ther apy with or without PCI for Stable Coronary Disease random assignments within each study site along with previous coronary-artery bypass grafting (CABG) as a stratifying variable. All patients received antiplatelet therapy with aspirin at a dose of 81 to 325 mg per day or 75 mg of clopidogrel per day, if aspirin intolerance was present. Patients undergoing PCI received aspirin and clopidogrel, in accordance with accepted treatment guidelines and established practice standards. Medical antiischemic therapy in both groups included longacting metoprolol, amlodipine, and isosorbide mononitrate, alone or in combination, along with either lisinopril or losartan as standard secondary prevention. All patients received aggressive therapy to lower low-density lipoprotein (LDL) cholesterol levels (simvastatin alone or in combination with ezetimibe) with a target level of 60 to 85 mg per deciliter (1.55 to 2.20 mmol per liter). After the LDL cholesterol target was achieved, an attempt was made to raise the level of high-density lipoprotein (HDL) cholesterol to a level above 40 mg per deciliter (1.03 mmol per liter) and lower triglyceride to a level below 150 mg per deciliter (1.69 mmol per liter) with exercise, extended-release niacin, or fibrates, alone or in combination. In patients undergoing PCI, target-lesion revascularization was always attempted, and complete revascularization was performed as clinically appropriate. Success after PCI as seen on angiography was defined as normal coronary-artery flow and less than 50% stenosis in the luminal diameter after balloon angioplasty and less than 20% after coronary stent implantation, as assessed by visual estimation of the angiograms before and after the procedure. Clinical success was defined as angiographic success plus the absence of inhospital myocardial infarction, emergency CABG, or death. Drug-eluting stents were not approved for clinical use until the final 6 months of the study, so few patients received these intracoronary devices. Clinical Outcome gina status of patients was assessed according to the CCS classification during each visit. Further analyses of other secondary outcomes -- including quality of life, the use of resources, and costeffectiveness -- are being conducted but have not yet been completed. The prespecified definition of myocardial infarction (whether periprocedural or spontaneous) required a clinical presentation consistent with an acute coronary syndrome and either new abnormal Q waves in two or more electrocardiographic leads or positive results in cardiac biomarkers. Silent myocardial infarction, as detected by abnormal Q waves, was confirmed by a core laboratory and was also included as an outcome of myocardial infarction. Statistical Analysis Clinical outcome was adjudicated by an independent committee whose members were unaware of treatment assignments. The primary outcome measure was a composite of death from any cause and nonfatal myocardial infarction. Secondary outcomes included a composite of death, myocardial infarction, and stroke and hospitalization for unstable angina with negative biomarkers. The an- We projected composite 3-year event rates of 21.0% in the medical-therapy group and 16.4% in the PCI group (relative difference, 22%) during a followup period of 2.5 to 7.0 years. We also incorporated assumptions about crossover between study groups and loss to follow-up.31 We estimated that the enrollment of 2270 patients would provide a power of 85% to detect the anticipated difference in the primary outcome at the 5% two-sided level of significance. A detailed description of the sample-size calculation is included in the Supplementary Appendix. Estimates of the cumulative event rate were calculated by the Kaplan-Meier method,32 and the primary efficacy of PCI, as compared with optimal medical therapy, was assessed by the stratified log-rank statistic.33 The treatment effect, as measured by the hazard ratio and its associated 95% confidence interval (CI), was estimated with the use of the Cox proportional-hazards model.34 Data for patients who were lost to follow-up were censored at the time of the last contact. Analyses were performed according to the intention-to-treat principle. Categorical variables were compared by use of the chi-square test or the Wilcoxon rank-sum test, and continuous variables were compared by use of the Student t-test. Adjusted analysis of the primary outcome was performed with the use of a Cox proportionalhazards regression model with eight preidentified covariates of interest -- age, sex, race, previous myocardial infarction, extent or distribution of angiographic coronary artery disease, ejection frac- n engl j med 356;15 www.nejm.org april 12, 2007 1505 The New England Journal of Medicine Downloaded from nejm.org on December 20, 2011. For personal use only. No other uses without permission. Copyright (C) 2007 Massachusetts Medical Society. All rights reserved. The n e w e ng l a n d j o u r na l of m e dic i n e tion, presence or absence of diabetes, and health care system (Veterans Affairs or non-Veterans Affairs facility in the United States, or a Canadian facility) -- as well as the stratifying variable of previous CABG. All other comparisons were unadjusted. A level of significance of less than 0.01 was used for all subgroup analyses and interactions. After PCI, successful treatment as seen on angiography was achieved in 1576 of 1688 lesions (93%), and clinical success (i.e., all lesions successfully dilated and no in-hospital complications) was achieved in 958 of 1077 patients (89%). Medication and Treatment Targets R e sult s Baseline Characteristics and Angiographic Data Between June 1999 and January 2004, a total of 2287 patients were enrolled in the trial at 50 U.S. and Canadian centers (Fig. 1). Of these patients, 1149 were randomly assigned to the PCI group and 1138 to the medical-therapy group. The baseline characteristics of the patients were recently published35 and were similar in the two groups (Table 1). The median time from the first episode of angina before randomization was 5 months (median, three episodes per week, with exertion or at rest), and 58% of patients had CCS class II or III angina. A total of 2168 patients (95%) had objective evidence of myocardial ischemia, whereas the remaining 119 patients with classic angina (CCS class III) and severe coronary stenoses did not undergo ischemia testing (56 in the PCI group and 63 in the medical-therapy group). Among patients who underwent myocardial perfusion imaging at baseline, 90% had either single (23%) or multiple (67%) reversible defects for inducible ischemia. Two thirds of the patients had multivessel coronary artery disease. Of the 1149 patients in the PCI group, 46 never underwent a procedure because the patient either declined treatment or had coronary anatomy unsuitable for PCI, as determined on clinical reassessment. In 27 patients (2%), the operator was unable to cross any lesions. PCI was attempted for 1688 lesions in 1077 patients, of whom 1006 (94%) received at least one stent. In the stent group, 590 patients (59%) received one stent and 416 (41%) more than one stent. Drug-eluting stents were used in 31 patients. On average, stenosis in the luminal diameter, as evaluated on visual assessment of angiograms, was reduced from a mean (?SD) of 83?14% to 31?34% in the 244 lesions not treated with stents and from 82?12% to 1.9?8% in the 1444 lesions treated with stents. Patients had a high rate of receiving multiple, evidence-based therapies after randomization and during follow-up, with similar rates in both study groups (Table 2). At the 5-year follow-up visit, 70% of subjects had an LDL cholesterol level of less than 85 mg per deciliter (2.20 mmol per liter) (median, 71?1.3 mg per deciliter [1.84?0.03 mmol per liter]); 65% and 94% had systolic and diastolic blood pressure targets of less than 130 mm Hg and 85 mm Hg, respectively; and 45% of patients with diabetes had a glycated hemoglobin level of no more than 7.0% (Table 2). Patients had high rates of adherence to the regimen of diet, regular exercise, and smoking cessation as recommended by clinical practice guidelines,1,2 although the mean body-mass index did not decrease. Follow-up Period The median follow-up period was 4.6 years (interquartile range, 3.3 to 5.7) and was similar in the two study groups, with a total of 120,895 patientmonths at risk. Only 9% of patients were lost to follow-up in the two groups (107 in the PCI group and 97 in the medical-therapy group, P = 0.51) before the occurrence of a primary outcome or the end of follow-up. Vital status was not ascertained in 194 patients (99 in the PCI group and 95 in the medical-therapy group, P = 0.81). Primary Outcome The primary outcome (a composite of death from any cause and nonfatal myocardial infarction) occurred in 211 patients in the PCI group and 202 patients in the medical-therapy group (Table 3). The estimated 4.6-year cumulative primary event rates were 19.0% in the PCI group and 18.5% in the medical-therapy group (unadjusted hazard ratio for the PCI group, 1.05; 95% CI, 0.87 to 1.27; P = 0.62) (Fig. 2). Secondary Outcomes For the prespecified composite outcome of death, nonfatal myocardial infarction, and stroke, the event rate was 20.0% in the PCI group and 19.5% 1506 n engl j med 356;15 www.nejm.org april 12, 2007 The New England Journal of Medicine Downloaded from nejm.org on December 20, 2011. For personal use only. No other uses without permission. Copyright (C) 2007 Massachusetts Medical Society. All rights reserved. Optimal Medical Ther apy with or without PCI for Stable Coronary Disease 35,539 Patients underwent assessment 32,468 Were excluded 8677 Did not meet inclusion criteria 5155 Had undocumented ischemia 3961 Did not meet protocol for vessels 6554 Were excluded for logistic reasons 18,360 Had one or more exclusions 4513 Had undergone recent (<6 mo) revascularization 4939 Had an inadequate ejection fraction 2987 Had a contraindication to PCI 2542 Had a serious coexisting illness 1285 Had concomitant valvular disease 1203 Had class IV angina 1071 Had a failure of medical therapy 947 Had left main coronary artery stenosis >50% 722 Had only PCI restenosis (no new lesions) 528 Had complications after myocardial infarction 3071 Met eligibility criteria 784 Did not provide consent 450 Did not receive physician's approval 237 Declined to give permission 97 Had an unknown reason 2287 Consented to participate (74% of patients with protocol eligibility) 1149 Were assigned to PCI group 46 Did not undergo PCI 27 Had a lesion that could not be dilated 1006 Received at least one stent 1138 Were assigned to medical-therapy group 107 Were lost to follow-up 97 Were lost to follow-up 1149 Were included in the primary analysis 1138 Were included in the primary analysis Figure 1. Enrollment and Outcomes. Of 35,539 patients who were assessed for eligibility in the trial, 32,468 were excluded for a variety of reasons (patients could have more than one reason for exclusion). A Bodenof 3071 patients RETAKE inclusion criteria. Of these, 2287 met all 1st AUTHOR: total ICM 2nd (74%) consented to participate in the study (932 in of 3 Canada, 968 in U.S. Veterans Affairs facilities, and 387 in U.S. REG F FIGURE: 1 3rd facilities other than Veterans Affairs hospitals). Of these patients, 1149 were randomly assigned to the PCI group CASE Revised and 1138 to the medical-therapy group. The median follow-up was 4.6 years for both study groups. Line 4-C EMail Enon ARTIST: ts H/T Combo H/T SIZE 33p9 AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset. Please check carefully. JOB: 35615med 356;15 n engl j www.nejm.org ISSUE: 04-12-07 april 12, 2007 1507 The New England Journal of Medicine Downloaded from nejm.org on December 20, 2011. For personal use only. No other uses without permission. Copyright (C) 2007 Massachusetts Medical Society. All rights reserved. The n e w e ng l a n d j o u r na l of m e dic i n e Table 1. Baseline Clinical and Angiographic Characteristics.* Characteristic Demographic Age -- yr Sex -- no. (%) Male Female Race or ethnic group -- no. (%)+ White Black Hispanic Other Clinical Angina (CCS class) -- no. (%) 0 I II III Missing data Duration of angina -- mo Median Interquartile range Episodes/wk with exertion or at rest within last mo Median Interquartile range History -- no. (%) Diabetes Hypertension Congestive heart failure Cerebrovascular disease Myocardial infarction Previous PCI CABG Stress test? Total patients -- no. (%) Treadmill test -- no. (%) Duration of treadmill test -- min Pharmacologic stress -- no. (%) Echocardiography -- no. (%) Nuclear imaging -- no. (%) Single reversible defect? Multiple reversible defects? 972 (85) 555 (57) 7.0?2.7 417 (43) 63 (6) 685 (70) 154 (22) 444 (65) 977 (86) 553 (57) 6.9?2.3 424 (43) 54 (6) 708 (72) 161 (23) 483 (68) 0.59 0.09 0.09 0.43 0.84 367 (32) 757 (66) 57 (5) 100 (9) 437 (38) 174 (15) 124 (11) 399 (35) 764 (67) 51 (4) 102 (9) 439 (39) 185 (16) 124 (11) 0.12 0.53 0.59 0.83 0.80 0.49 0.94 3 1-6 3 1-6 5 1-15 5 1-15 0.83 135 (12) 340 (30) 409 (36) 261 (23) 3 (<1) 148 (13) 341 (30) 425 (37) 221 (19) 2 (<1) 0.53 0.24 988 (86) 57 (5) 68 (6) 35 (3) 975 (86) 57 (5) 58 (5) 47 (4) 979 (85) 169 (15) 968 (85) 169 (15) 0.64 61.5?10.1 61.8?9.7 0.54 0.95 PCI Group (N = 1149) Medical-Therapy Group (N = 1138) P Value 1508 n engl j med 356;15 www.nejm.org april 12, 2007 The New England Journal of Medicine Downloaded from nejm.org on December 20, 2011. For personal use only. No other uses without permission. Copyright (C) 2007 Massachusetts Medical Society. All rights reserved. Optimal Medical Ther apy with or without PCI for Stable Coronary Disease Table 1. (Continued.) Characteristic Angiographic Vessels with disease -- no. (%) 1 2 3 Disease in graft? Proximal LAD disease Ejection fraction 361 (31) 446 (39) 341 (30) 77 (62) 360 (31) 60.8?11.2 343 (30) 439 (39) 355 (31) 85 (69) 417 (37) 60.9?10.3 0.36 0.01 0.86 0.72 PCI Group (N = 1149) Medical-Therapy Group (N = 1138) P Value * Plus-minus values are means ?SD. Baseline data were missing for one patient in each study group. CCS denotes Canadian Cardiovascular Society, CABG coronary-artery bypass grafting, and LAD left anterior descending artery. + Race or ethnicity was reported by the patient at enrollment. ? Nuclear imaging could have been performed after either an exercise treadmill test or pharmacologic stress. ? The percentage in this category is the proportion of patients who underwent imaging. ? The percentage in this category is the proportion of patients who had undergone previous CABG. in the medical-therapy group (hazard ratio, 1.05; 95% CI, 0.87 to 1.27; P = 0.62) (Table 3 and Fig. 2). The rates of hospitalization for acute coronary syndromes were 12.4% in the PCI group and 11.8% in the medical-therapy group (hazard ratio, 1.07; 95% CI, 0.84 to 1.37; P = 0.56), and adjudicated rates of myocardial infarction were 13.2% and 12.3%, respectively (hazard ratio, 1.13; 95% CI, 0.89 to 1.43; P = 0.33). For death alone, the rates were 7.6% and 8.3%, respectively (hazard ratio, 0.87; 95% CI, 0.65 to 1.16); the mortality curves for the two groups were virtually identical during the initial 4.6 years of the study. For stroke alone, the rate was 2.1% in the PCI group and 1.8% in the medical-therapy group (hazard ratio, 1.56; 95% CI, 0.80 to 3.04; P = 0.19). When the primary end point was calculated with the exclusion of periprocedural myocardial infarction, the event rates were 16.2% and 17.9% (hazard ratio, 0.90; 95% CI, 0.73 to 1.10; P = 0.29). At a median follow-up of 4.6 years, 21.1% of patients in the PCI group had additional revascularization, as compared with 32.6% of those in the medical-therapy group (hazard ratio, 0.60; 95% CI, 0.51 to 0.71; P<0.001). In the PCI group, 77 patients subsequently underwent CABG, as compared with 81 patients in the medical-therapy group. Revascularization was performed for angina that was unresponsive to maximal medical therapy or when there was objective evidence of worsening ischemia on noninvasive testing, at the discretion of the patient's physician. The median time to subsequent revascularization was 10.0 months (interquartile range, 4.5 to 28.0) in the PCI group and 10.8 months (interquartile range, 3.2 to 30.7) in the medical-therapy group. There was a substantial reduction in the prevalence of angina in both groups during follow-up. There was a statistically significant difference in the rates of freedom from angina throughout most of the follow-up period, in favor of the PCI group (Table 2). At 5 years, 74% of patients in the PCI group and 72% of those in the medicaltherapy group were free of angina (P = 0.35). Subgroup Analyses There was no significant interaction (P<0.01) between treatment effect and any predefined subgroup variable (Fig. 3). Of note, among patients with multivessel coronary artery disease, previous myocardial infarction, and diabetes, the rate of the primary end point was similar for both groups. When subgroup variables were included in a multivariate analysis, the hazard ratio for treatment was essentially unchanged (1.09; 95% CI, 0.90 to 1.33; P = 0.77). Dis cus sion As an initial management strategy, PCI added to optimal medical therapy did not reduce the primary composite end point of death and nonfatal n engl j med 356;15 www.nejm.org april 12, 2007 1509 The New England Journal of Medicine Downloaded from nejm.org on December 20, 2011. For personal use only. No other uses without permission. Copyright (C) 2007 Massachusetts Medical Society. All rights reserved. The n e w e ng l a n d j o u r na l of m e dic i n e Table 2. Clinical Status, Risk and Lifestyle Factors, and Use of Medication.* Variable Baseline Clinical status No. evaluated Blood pressure -- mm Hg Systolic Diastolic Cholesterol -- mg/dl Total HDL LDL Triglycerides -- mg/dl Body-mass index Angina-free -- no. (%)+ Risk or lifestyle factor Current smoker -- no. (%) AHA Step 2 diet -- no. (%) Moderate activity -- no. (%)? Glycated hemoglobin in patients with diabetes No. evaluated Level -- % Medication No. evaluated ACE inhibitor -- no. (%) ARB -- no. (%) Statin -- no. (%) Other antilipid -- no. (%) Aspirin -- no. (%) Beta-blocker -- no. (%) Calcium-channel blocker -- no. (%)? Nitrates -- no. (%)? 1147 669 (58) 48 (4) 992 (86) 89 (8) 1097 (96) 975 (85) 459 (40) 714 (62) 1044 668 (64) 93 (9) 972 (93) 236 (23) 995 (95) 887 (85) 415 (40) 553 (53) 837 536 (64) 104 (12) 780 (93) 324 (39) 792 (95) 705 (84) 360 (43) 396 (47) 428 284 (66) 49 (11) 398 (93) 211 (49) 408 (95) 363 (85) 180 (42) 173 (40) 1138 680 (60) 54 (5) 1014 (89) 94 (8) 1077 (95) 1008 (89) 488 (43) 825 (72) 1028 633 (62) 99 (10) 972 (95) 253 (25) 977 (95) 916 (89) 501 (49) 690 (67) 838 522 (62) 108 (13) 769 (92) 321 (38) 796 (95) 724 (86) 418 (50) 511 (61) 417 260 (62) 67 (16) 386 (93) 224 (54) 391 (94) 357 (86) 217 (52) 237 (57) 319 6.9?0.1 239 7.1?0.1 197 7.1?0.1 97 7.1?0.1 336 7.1?0.1 286 7.0?0.1 233 7.1?0.1 123 7.1?0.1 260 (23) 626 (55) 290 (25) 206 (20) 803 (78) 473 (46) 156 (19) 631 (77) 351 (42) 74 (17) 326 (77) 179 (42) 259 (23) 613 (54) 279 (25) 206 (20) 800 (79) 433 (43) 160 (19) 660 (80) 330 (40) 80 (20) 312 (77) 146 (36) 172?1.37 39?0.39 100?1.17 143?2.96 28.7?0.18 135 (12) 156?1.17 42?0.39 84?0.97 129?2.74 28.5?0.19 680 (66) 148?1.13 43?0.47 76?0.85 124?2.79 29.0?0.21 602 (72) 143?1.74 41?0.67 71?1.33 123?4.13 29.0?0.34 316 (74) 177?1.41 39?0.37 102?1.22 149?3.03 28.9?0.17 148 (13) 150?1.10 41?0.42 81?0.86 133?2.90 29.0?0.19 595 (58) 145?1.30 42?0.49 74?0.92 126?2.84 29.3?0.21 558 (67) 140?1.64 41?0.75 72?1.21 131?4.70 29.5?0.31 296 (72) 131?0.77 74?0.33 126?0.64 72?0.35 125?0.68 70?0.52 124?0.81 70?0.81 130?0.66 74?0.33 124?0.73 70?0.43 123?0.78 70?0.52 122?0.92 70?0.65 1148 1031 820 423 1137 1010 824 406 PCI Group (N = 1149) 1 Yr 3 Yr 5 Yr median ?SE Medical-Therapy Group (N = 1138) Baseline 1 Yr 3 Yr 5 Yr * Plus-minus values are medians ?SE, with the SE calculated with the use of the interquartile range. To convert cholesterol values to milli- moles per liter, multiply by 0.02586. To convert triglyceride values to millimoles per liter, multiply by 0.01129. ACE denotes angiotensin- converting enzyme, and ARB angiotensin-receptor blocker. + The comparison between the PCI group and the medical-therapy group was significant at 1 year (P<0.001) and 3 years (P = 0.02) but not at baseline or at 5 years. ? This category includes at least 30 to 45 minutes of moderate activity five times per week or vigorous activity three times per week. ? The comparison between the PCI group and the medical-therapy group was significant at 1 year (P<0.001), 3 years (P = 0.005), and 5 years (P = 0.003). ? The comparison between the PCI group and the medical-therapy group was significant at all time points (P<0.001). 1510 n engl j med 356;15 www.nejm.org april 12, 2007 The New England Journal of Medicine Downloaded from nejm.org on December 20, 2011. For personal use only. No other uses without permission. Copyright (C) 2007 Massachusetts Medical Society. All rights reserved. Optimal Medical Ther apy with or without PCI for Stable Coronary Disease Table 3. Primary and Secondary Outcomes.* Outcome Number of Events Medical-Therapy PCI Group Group Death and nonfatal myocardial infarction? Death? Periprocedural myocardial infarction Spontaneous myocardial infarction Death, myocardial infarction, and stroke Hospitalization for ACS Death? Cardiac Other Unknown Total nonfatal myocardial infarction Periprocedural myocardial infarction Spontaneous myocardial infarction Death, myocardial infarction, and ACS Stroke Revascularization (PCI or CABG)? 211 68 35 108 222 135 85 23 45 17 143 35 108 294 22 228 202 74 9 119 213 125 95 25 51 19 128 9 119 288 14 348 1.05 (0.90-1.24) 1.56 (0.80-3.04) 0.60 (0.51-0.71) 0.52 0.19 <0.001 27.6 2.1 21.1 27.0 1.8 32.6 1.13 (0.89-1.43) 0.33 13.2 12.3 1.05 (0.87-1.27) 1.07 (0.84-1.37) 0.87 (0.65-1.16) 0.62 0.56 0.38 20.0 12.4 7.6 19.5 11.8 8.3 1.05 (0.87-1.27) 0.62 Hazard Ratio (95% CI)+ P Value+ Cumulative Rate at 4.6 Years PCI Group 19.0 Medical-Therapy Group % 18.5 * ACS denotes acute coronary syndrome, PCI percutaneous coronary intervention, and CABG coronary-artery bypass grafting. + The hazard ratio is for the PCI group as compared with the medical-therapy group, and P values were calculated by the log-rank test and are unadjusted for multiple variables. ? The definition of myocardial infarction was the finding of new Q waves at any time; a spontaneous creatine kinase MB fraction of at least 1.5 times the upper limit of normal or a troponin T or I level of at least 2.0 times the upper limit of normal; during a PCI procedure, a cre- atine kinase MB fraction of at least 3 times the upper limit of normal or a troponin T or I level of at least 5.0 times the upper limit of nor- mal, associated with new ischemic symptoms; and after CABG, a creatine kinase MB fraction or a troponin T or I level of at least 10.0 times the upper limit of normal. If periprocedural myocardial infarction is excluded from the primary outcome, the hazard ratio is 0.90 (95% CI, 0.73 to 1.10; P = 0.29). ? Some patients had a nonfatal myocardial infarction before their subsequent death so that the number of deaths overall is greater than the number of deaths in the primary outcome analysis, which includes the time until the first event. ? Values exclude the initial PCI procedure in patients who were originally assigned to the PCI group. myocardial infarction or reduce major cardiovascular events, as compared with optimal medical therapy alone, during follow-up of 2.5 to 7.0 years, despite a high baseline prevalence of clinical coexisting illnesses, objective evidence of ischemia, and extensive coronary artery disease as seen on angiography. Although the degree of angina relief was significantly higher in the PCI group than in the medical-therapy group, there was also substantial improvement in the medical-therapy group. All secondary outcomes and individual components of the primary outcome showed no significant differences between the study groups, nor was there a significant interaction between treatment effect and any prespecified subgroup variable. For the primary outcome, the 95% CI excludes a relative benefit of more than 13% in the PCI group. Thus, it is highly unlikely that we missed a prognostically important treatment benefit in favor of the initial PCI strategy. n engl j med 356;15 www.nejm.org april 12, 2007 1511 The New England Journal of Medicine Downloaded from nejm.org on December 20, 2011. For personal use only. No other uses without permission. Copyright (C) 2007 Massachusetts Medical Society. All rights reserved. The n e w e ng l a n d j o u r na l of m e dic i n e A Survival Free of Death from Any Cause and Myocardial Infarction 1.0 0.9 0.8 0.7 0.6 0.5 0 0 B PCI Medical therapy 1.0 0.9 PCI Medical therapy Overall Survival 0.8 0.7 0.6 0.5 Hazard ratio, 1.05; 95% CI (0.87-1.27); P=0.62 Hazard ratio, 0.87; 95% CI (0.65-1.16); P=0.38 1 2 3 4 5 6 7 0 0 1 2 3 4 5 6 7 Years No. at Risk Medical therapy 1138 PCI 1149 1017 1013 959 952 834 833 638 637 408 417 192 200 30 35 Years No. at Risk Medical therapy 1138 PCI 1149 1073 1094 1029 1051 917 929 717 733 468 488 302 312 38 44 C 1.0 Medical therapy PCI D 1.0 Survival Free of Myocardial Infarction Survival Free of ACS 0.9 0.8 0.7 0.6 0.5 0 0 0.9 0.8 0.7 0.6 0.5 0 0 Medical therapy PCI Hazard ratio, 1.07; 95% CI (0.84-1.37); P=0.56 Hazard ratio, 1.13; 95% CI (0.89-1.43); P=0.33 1 2 3 4 5 6 7 1 2 3 4 5 6 7 Years No. at Risk Medical therapy 1138 PCI 1149 1025 1027 956 957 833 835 662 667 418 431 236 246 127 134 Years No. at Risk Medical therapy 1138 PCI 1149 1019 1015 962 954 834 833 638 637 409 418 192 200 120 134 Figure 2. Kaplan-Meier Survival Curves. In Panel A, the estimated 4.6-year rate of the composite primary outcome of death from any cause and nonfatal myocardial infarction was 19.0% in the PCI group and 18.5% in the medical-therapy group. In Panel B, the estimated 4.6-year rate of death from any cause was 7.6% in the PCI group and 8.3% in the medical-therapy group. In Panel C, the RETAKE estimated 1st 4.6-year rate of hospitalization for acute AUTHOR: Boden ICM coronary syndrome (ACS) was 12.4% in the PCI group and 11.8% in the medical-therapy group. In Panel D, the estimated 4.6-year rate 2nd REG F FIGURE: 2 of 3 of acute myocardial infarction was 13.2% in the PCI group and 12.3% in the medical-therapy 3rd group. CASE Enon EMail ARTIST: ts Our findings may be explained, in part, by dif- more smooth-muscle cells, fewer macrophages, AUTHOR, PLEASE NOTE: ferences in atherosclerotic plaque been redrawn andand has beenmore collagen and are ultimately associated Figure has morphology type and reset. Please check carefully. vascular remodeling associated with acute coro- with inward (constrictive) remodeling that narnary syndromes, as compared with stable coronary rows the coronary lumen. These lesions produce JOB: 35615 ISSUE: 04-12-07 artery disease. Vulnerable plaques (precursors of ischemia and anginal symptoms and are easily acute coronary syndromes) tend to have thin detected by coronary angiography but are less likefibrous caps, large lipid cores, fewer smooth- ly to result in an acute coronary syndrome.37,38 muscle cells, more macrophages, and less collaThus, unstable coronary lesions that lead to gen, as compared with stable plaques, and are myocardial infarction are not necessarily severely associated with outward (expansive) remodeling stenotic, and severely stenotic lesions are not necof the coronary-artery wall, causing less stenosis essarily unstable. Focal management of even of the coronary lumen.36 As a result, vulnerable severely stenotic coronary lesions with PCI in our plaques do not usually cause significant stenosis study did not reduce the rate of death and myobefore rupture and the precipitation of an acute cardial infarction, presumably because the treated coronary syndrome.36 By contrast, stable plaques stenoses were not likely to trigger an acute corotend to have thick fibrous caps, small lipid cores, nary event. Furthermore, our lower-than-projected 1512 n engl j med 356;15 www.nejm.org april 12, 2007 Line H/T Combo 4-C H/T Revised SIZE 39p6 The New England Journal of Medicine Downloaded from nejm.org on December 20, 2011. For personal use only. No other uses without permission. Copyright (C) 2007 Massachusetts Medical Society. All rights reserved. Optimal Medical Ther apy with or without PCI for Stable Coronary Disease Baseline Characteristics Overall Sex Male Female Myocardial infarction Yes No Extent of CAD Multivessel disease Single-vessel disease Smoking Current Not current Diabetes Yes No CCS angina class 0 or I II or III Ejection fraction <=50% >50% Age >65 yr <=65 yr Previous CABG No Yes Race White Nonwhite Health care system Canadian U.S. non-VA U.S. VA No. of Patients 2287 1947 338 876 1371 1581 700 653 1631 766 1468 964 1371 406 1848 904 1381 2039 248 1963 322 932 387 968 Hazard Ratio (95% CI) 1.05 (0.87-1.27) 1.15 (0.93-1.42) 0.65 (0.40-1.06) 0.91 (0.69-1.21) 1.22 (0.93-1.60) 1.04 (0.84-1.30) 1.17 (0.76-1.80) 1.00 (0.71-1.41) 1.08 (0.86-1.36) 0.99 (0.73-1.32) 1.20 (0.92-1.56) 1.01 (0.75-1.38) 1.09 (0.85-1.40) 1.14 (0.77-1.70) 1.05 (0.84-1.32) 1.10 (0.83-1.46) 1.00 (0.77-1.32) 1.04 (0.84-1.29) 0.98 (0.52-1.82) 1.08 (0.87-1.34) 0.87 (0.54-1.42) 1.27 (0.90-1.78) 0.71 (0.44-1.14) 1.06 (0.80-1.38) 0.25 0.50 1.00 1.50 1.75 2.00 Event Rate for the Primary Outcome PCI Medical Therapy 0.19 0.19 0.18 0.23 0.17 0.21 0.15 0.20 0.19 0.25 0.17 0.17 0.20 0.28 0.17 0.24 0.16 0.17 0.34 0.19 0.19 0.17 0.15 0.22 0.19 P Value 0.03 0.18 0.26 0.15 0.25 0.14 0.65 0.21 0.12 0.71 0.21 0.18 0.33 0.24 0.15 0.73 0.20 0.18 0.72 0.26 0.16 0.62 0.22 0.16 0.81 0.17 0.29 0.43 0.18 0.24 0.17 0.14 0.21 0.22 PCI Better Medical Therapy Better Figure 3. Subgroup Analyses. The chart shows hazard ratios (black squares, sized in proportion to the number of subjects in a group), 95% CIs (horizontal lines), cumu- RETAKE 1st AUTHOR: Boden ICM lative 4.6-year event rates for the composite primary outcome (death from any cause and nonfatal2nd myocardial infarction) for the PCI group FIGURE: 3 of 3 REG versus the medical-therapy group for the specified F subgroups, and P values for the interaction between the treatment effects and sub- 3rd CASE Revised group variables. P values were calculated with the use of the Wald statistic. There was no significant interaction between treatment and Line 4-C EMail SIZE subgroup variables as defined according to the prespecified value for interaction (P<0.01), although there was a trend for interaction with ARTIST: ts H/T H/T 39p6 Enon respect to sex (P = 0.03). PCI denotes percutaneous coronary intervention, CAD coronary artery disease, CCS Canadian Cardiovascular Combo Society, CABG coronary-artery bypass grafting, and VA Veterans Affairs. AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset. Please check carefully. event rate in the medical-therapy group may be JOB: 35615 explained by systemic therapy that reduced plaque vulnerability through aggressive intervention for multiple risk factors and evidence-based use of medication. Rates of angina were consistently lower in the PCI group than in the medical-therapy group durn engl j med 356;15 ing follow-up, and rates of subsequent revascuISSUE: lower. larization were likewise 04-12-07 However, there was a substantial increase in freedom from angina in patients in the medical-therapy group as well, most of which had taken place at 1 year but with a further improvement at 5 years. To what extent this finding reflects a benefit of specific april 12, 2007 www.nejm.org 1513 The New England Journal of Medicine Downloaded from nejm.org on December 20, 2011. For personal use only. No other uses without permission. Copyright (C) 2007 Massachusetts Medical Society. All rights reserved. The n e w e ng l a n d j o u r na l of m e dic i n e antianginal medications (e.g., nitrates and betablockers) or a favorable effect of therapies such as statins on endothelial function and atherosclerosis is unclear. Our findings parallel those reported in recent trials,39,40 in which observed clinical-event rates that were associated with optimal medical therapy were lower than projected in the trial design. These results are also concordant with a metaanalysis of all previous trials involving PCI versus medical management.16 In the aggregate, these studies, including our own, include outcome data on more than 5000 patients and show that PCI has no effect in reducing major cardiovascular events. The preponderance of male patients (85%) is a limitation of our study, as is the lack of ethnic diversity (14% of the patients were nonwhite). We used bare-metal stents, since drug-eluting stents were not available until late during accrual. Although the latter factor may be perceived as a limitation, published data indicate no benefit (either short-term or long-term) with respect to death and myocardial infarction in patients with stable coronary artery disease who receive drugeluting stents, as compared with those who receive bare-metal stents.41-46 Our findings reinforce existing clinical practice guidelines, which state that PCI can be safely deferred in patients with stable coronary artery disease, even in those with extensive, multivessel involvement and inducible ischemia, provided that intensive, multifaceted medical therapy is instituted and maintained.1,2 As an initial management approach, optimal medical therapy without routine PCI can be implemented safely in the majority of patients with stable coronary artery disease. However, approximately one third of these patients may subsequently require revascularization for symptom control or for subsequent development of an acute coronary syndrome. In summary, our trial compared optimal medical therapy alone or in combination with PCI as an initial management strategy in patients with stable coronary artery disease. Although the addition of PCI to optimal medical therapy reduced the prevalence of angina, it did not reduce longterm rates of death, nonfatal myocardial infarction, and hospitalization for acute coronary syndromes. Supported by the Cooperative Studies Program of the U.S. Department of Veterans Affairs Office of Research and Development, in collaboration with the Canadian Institutes of Health Research; and by unrestricted research grants from Merck, Pfizer, BristolMyers Squibb, Fujisawa, Kos Pharmaceuticals, Datascope, AstraZeneca, Key Pharmaceutical, Sanofi-Aventis, First Horizon, and GE Healthcare. All industrial funding in support of the trial was directed through the U.S. Department of Veterans Affairs. Dr. Boden reports receiving consulting fees and lecture fees from Kos Pharmaceuticals, PDL BioPharma, Pfizer, CV Therapeutics, and Sanofi-Aventis, and grant support from Merck and Abbott Laboratories; Dr. O'Rourke, consulting fees from King Pharmaceuticals, Lilly, and CV Therapeutics; Dr. Teo, grant support from Boehringer Ingelheim; Dr. Knudtson, lecture fees from Medtronic and Lilly; Dr. Harris, having equity ownership in Amgen; Dr. Chaitman, receiving consulting fees from CV Therapeutics, Merck, and Bayer, lecture fees from Pfizer, AstraZeneca, and CV Therapeutics, and grant support from Pfizer, CV Therapeutics, and Sanofi-Aventis; Dr. Shaw, grant support from BristolMyers Squibb and Astellas Healthcare; Dr. Booth, grant support from Actelion; Dr. Bates, consulting fees from Sanofi-Aventis and AstraZeneca and lecture fees from Sanofi-Aventis; Dr. Spertus, consulting fees from Amgen and United Healthcare and grant support from Amgen, Roche Diagnostics, and Lilly (and in the past, consulting fees and grant support from CV Therapeutics and owning the copyright for the Seattle Angina Questionnaire, the Peripheral Artery Questionnaire, and the Kansas City Cardiomyopathy Questionnaire); Dr. Berman, consulting fees and lecture fees from Bristol-Myers Squibb, Astellas, Tyco, and Siemens and grant support from Bristol-Myers Squibb and Astellas; Dr. Mancini, consulting and lecture fees from Pfizer, Abbott, and GlaxoSmithKline, lecture fees from Merck and Sanofi-Aventis, and grant support from Cordis and GlaxoSmithKline; and Dr. Weintraub, consulting fees from Sanofi-Aventis and Bristol-Myers Squibb and grant support from Sanofi-Aventis. No other potential conflict of interest relevant to this article was reported. Appendix The authors' affiliations are as follows: Western New York Veterans Affairs (VA) Healthcare Network and Buffalo General Hospital- SUNY, Buffalo, NY (W.E.B.); South Texas Veterans Health Care System-Audie Murphy Campus, San Antonio, TX (R.A.O., P.C.); McMaster University Medical Center, Hamilton, ON, Canada (K.K.T.); VA Cooperative Studies Program Coordinating Center, VA Connecticut Healthcare System, West Haven, CT (P.M.H); Vanderbilt University Medical Center, Nashville (D.J.M); London Health Sciences Centre, London, ON, Canada (W.J.K.); Foothills Hospital, Calgary, AB, Canada (M.K.); Hartford Hospital, Hartford, CT (M.D.); VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, NM (C.L.H.); Saint Louis University, St. Louis (B.R.C.); Cedars-Sinai Medical Center, Los Angeles (L.S., D.S.B.); Montreal Heart Institute, Montreal (G. Gosselin); Sudbury Regional Hospital, Sudbury, ON, Canada (S.N.); Queen Elizabeth Health Sciences Centre, Halifax, NS, Canada (L.M.T.); Mayo Clinic, Rochester, MN (G. Gau); Houston VA Medical Center, Houston (A.S.B.); Lexington VA Medical Center, Lexington, KY (D.C.B.); University of Michigan Medical Center, Ann Arbor (E.R.B.); Mid America Heart Institute, Kansas City, MO (J.A.S.); Vancouver Hospital and Health Sciences Centre, Vancouver, BC, Canada (G.B.J.M.); and Christiana Care Health System, Newark, DE (W.S.W.). The members of the COURAGE trial were as follows: Writing Committee: W. Boden (study cochair), R. O'Rourke (study cochair) K. Teo (study cochair), P. Hartigan. W. Weintraub, D. Maron, J. Mancini; Executive Committee: W. Weintraub (chair), W. Boden, R. O'Rourke, K. Teo, P. Hartigan, M. Knudtson, D. Maron, E. Bates, A. Blaustein, D. Booth, R. Carere, S. Ellis, G. Gosselin, G. Gau, A. Jacobs, 1514 n engl j med 356;15 www.nejm.org april 12, 2007 The New England Journal of Medicine Downloaded from nejm.org on December 20, 2011. For personal use only. No other uses without permission. Copyright (C) 2007 Massachusetts Medical Society. All rights reserved. Optimal Medical Ther apy with or without PCI for Stable Coronary Disease S. King, III, W. Kostuk, C. Harris, J. Spertus; P. Peduzzi (ex officio); Data and Safety Monitoring Board: T. Ryan (chair), B. Turnbull, T. Feldman, R. Bonow, W. Haskell, P. Diehr, P. Lachenbruch, D. Waters, D. Johnstone; Adjudication Committee: L. Cohen (chair), B. Cantin, W. Hager, F. Samaha, J. Januzzi, J. Arrighi, B. Chaitman; Economics Committee: W. Weintraub (chair), P. Hartigan, R. O'Rourke, W. Boden, P. Barnett, J. Spertus, R. Goeree; Optimal Medical Therapy Committee: D. Maron (chair), W. Boden, R. O'Rourke, K. Teo, W. Weintraub. The following members assisted in coordination of the study: VA Cooperative Studies Program Coordinating Center, VA Connecticut Healthcare System, West Haven, CT -- P. Peduzzi (director); M. Antonelli, (associate director of operations); J. Smith (project manager); R. Kilstrom, B. Hunter (coordinators); L. Durant (quality assurance officer); S. O'Neil (end points coordinator); T. Economou, J. Nabors (programmers); A. Kossack (data clerk); VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, NM -- M. Sather (director), C. Harris (assistant director), W. Gagne (project manager), C. Fye (pharmacist); VA Cooperative Studies Human Rights Committee, West Haven, CT -- R. Marottoli (chair), H. Allore, D. Beckwith, W. Farrell, R. Feldman, R. Mehta, J. Neiderman, E. Perry, S. Kasl, M. Zeman; VA Office of Research and Development, Clinical Science Research and Development, Washington, DC -- T. O'Leary (acting director), G. Huang (deputy director, Cooperative Studies Program); Study Chairs Offices -- Western New York VA Healthcare Network and Buffalo General Hospital-SUNY, Buffalo, NY -- W. Boden (study cochair), M. Dada, K. Potter (national coordinators), T. Rivera (program assistant); South Texas Veterans Health Care System, San Antonio, TX -- R. O'Rourke (study cochair), P. Casperson (national coordinator), A. O'Shea (program assistant); McMaster University Medical Center, Hamilton, ON, Canada -- K. Teo (study cochair), G. Woodcock (coordinator); Laboratories: Christiana Care Center for Outcomes Research, Newark, DE, and Emory University, Atlanta -- W. Weintraub; Health Economics Research Center, Menlo Park, CA -- P. Barnett; Program for Assessment of Technology in Health, Hamilton, ON, Canada -- R. Goeree, B. O'Brien; Vancouver Hospital, Cardiovascular Imaging Research Core Laboratory, Vancouver, BC, Canada -- G.B.J. Mancini, E. Yeoh; Washington University Central Lipid Core Laboratory, St. Louis -- J. Ladenson, V. Thompson; Saint Louis University ECG Core Laboratory, St. Louis -- B. Chaitman, T. Bertran; Cedars-Sinai Medical Center Nuclear Core Laboratory, Los Angeles -- D. Berman, J. Gerlach, R. Littman, L. Shaw; San Diego State University PACE Program, San Diego, CA -- K. Calfas, J. Sallis. The following investigators are listed according to their clinical study sites: VA: South Texas Veterans Health Care System, San Antonio, TX -- R. O'Rourke, P. Baker, J. Bolton; VA Medical Center, Houston -- A. Blaustein, C. Rowe; VA Medical Center, Durham, NC -- K. Morris, S. Hoffman; VA Health Care System, New York -- S. Sedlis, M. Keary; VA Health Care System, Ann Arbor, MI -- C. Duvernoy, C. Majors; VA Medical Center, Lexington, KY -- Booth, M. Shockey; James A. Haley Veterans Hospital, Tampa, FL -- R. Zoble, I. Fernandez; VA Health Care System, Puget Sound, WA -- K. Lehmann, A. Sorley, M. Abel; VA Health Care System, Albuquerque, NM -- M. Sheldon, K. Wagoner; Portland VA Medical Center, Portland, OR -- E. Murphy, K. Avalos; Iowa City VA Medical Center, Iowa City -- J. Rossen, K. Schneider; Central Arkansas Veterans Health Care System, Little Rock, AR -- B. Molavi, L. Garza, P. Barton; VA Medical Center, Atlanta -- K. Mavromatis, Z. Forghani; Tennessee Valley Health Care System, Nashville -- R. Smith, C. Mitchell; VA Medical Center, Memphis, TN -- K. Ramanathan, T. Touchstone. Canada: London Health Sciences Centre, London, ON -- W. Kostuk, K. Sridhar, S. Carr, D. Wiseman; Sudbury Regional Hospital, Sudbury, ON -- S. Nawaz, C. Dion; Montreal Heart Institute, Montreal -- G. Gosselin, J. Theberge, M. Cuso; Queen Elizabeth II Health Care Center, Halifax, NS -- L. Title, P. Simon, L. Carroll, K. Courtney-Cox; Sunnybrook Health Care Centre, Toronto -- E. Cohen, E. Hsu; University Health Network-Toronto Hospital, Toronto -- V. Dzavik, J. Lan; Foothills Hospital, Calgary, AB -- M. Knudtson, D. Lundberg; Hamilton General Hospital-McMaster Clinic, Hamilton, ON -- M. Natarajan, G. Cappelli; St. Michael's Hospital, Toronto -- M. Kutryk, A. DiMarco, B. Strauss; Vancouver Hospital, Vancouver, BC -- A. Fung, J. Chow; Saint John Regional Hospital, Saint John, NB -- D. Marr, F. Fitzgerald; St. Paul's Hospital, Vancouver, BC -- R. Carere, T. Nacario; University of Alberta Hospital, Edmonton -- W. Tymchak, L. Harris; Trillium Health Care, Newmarket, ON -- C. Lazzam, A. Carter; H?pital du Sacre Coeur de Montreal, Montreal -- D. Palisaitis, C. Mercure. U.S. Non-VA: Mayo Clinic, Rochester, MN -- M. Bell, M. Peterson; MIMA Century Research Associates, Melbourne, FL -- R. Vicari, M. Carroll; University of Michigan Medical Center, Ann Arbor -- E. Bates, A. Luciano; Southern California Kaiser Permanente Medical Group, CA -- P. Mahrer; S. Reyes; University of Oklahoma, Oklahoma City -- J. Saucedo, D. vanWieren; Mid America Heart Institute, St. Louis -- J. O'Keefe, P. Kennedy; Boston Medical Center, Boston -- A. Jacobs. C. Berger, S. Mayo; Emory University Hospital, Atlanta -- J. Miller, T. Arnold; Hartford Hospital, Hartford, CT -- F. Kiernan, D. Murphy; Henry Ford Health System, Detroit -- A. Kugelmass, R. Pangilinan; University of Rochester Medical Center, Rochester, NY -- R. Schwartz, L. Caufield; Vanderbilt University Hospital, Nashville -- D. Hansen, C. Mitchell; SUNY University Hospital, Syracuse, NY -- R. Carhart, A. Pennella; Cleveland Clinic, Cleveland -- S. Ellis, C. Stevenson; Barnes-Jewish Hospital, St. Louis -- R. Krone, J. Humphrey; Mayo Clinic, Scottsdale, AZ -- C. Appleton, J. Wisbey; Christiana Care Health Systems, Wilmington, DE -- M. Stillabower, A. DiSabatino; Rush-Presbyterian-St. Luke's Medical Center, Chicago -- M. Davidson, J. Mathien. References 1. Gibbons RJ, Abrams J, Chatterjee K, et al. 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