COURAGE: Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation

1. COURAGE: Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation Purpose To compare the efficacy of optimal medical therapy (OMT) alone versus percutaneous coronary intervention (PCI) and OMT in reducing cardiovascular risk in patients with stable coronary artery disease. Reference Boden WE, O’Rourke RA, Teo KK, et al. for the COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease.N Engl J Med 2008;358:1887–1898.

2. COURAGE: Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation- TRIAL DESIGN - Design Multicenter, prospective, randomized trial. Patients 2287 patients who had either stable coronary artery disease (CAD) or Canadian Cardiovascular Society (CCS) class IV angina that had subsequently stabilized. Exclusion criteria included persistent CCS class IV angina, refractory heart failure or cardiogenic shock, classic angina, ejection fraction of <30%, revascularization within the previous 6 months, and coronary anatomy not suitable for PCI. Primary and secondary endpoints The primary endpoint was a composite of all-cause mortality and non-fatal myocardial infarction (MI) during a follow-up period of 2.5–7.0 years. Secondary endpoints included non-fatal MI, hospitalization for acute coronary syndrome, and a composite of death, MI and stroke.

3. COURAGE: Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation- TRIAL DESIGN continued - Treatment For OMT, all patients received aspirin (81–325 mg/day) or clopidogrel (75 mg/day). All patients received simvastatin alone or in combination with ezetimibe to reduce LDL-cholesterol levels (target of 1.55–2.220 mmol/L). Exercise, fibrates and/or extended release niacin were used to raise HDL-cholesterol levels (target 1.03 mmol/L) and to reduce triglyceride levels (target of 1.69 mmol/L). PCI + OMT In addition to OMT, complete revascularization was performed as necessary, and target-lesion revascularization was attempted when appropriate. Patients undergoing PCI received aspirin or clopidogrel in accordance with the guidelines. Other therapeutic considerations Both groups received anti-ischemic therapy (metoprolol, amlodipine and/or isosorbide mononitrate) with lisinopril or losartan.

4. COURAGE: Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation - TRIAL DESIGN continued - Baseline characteristics OMT OMT + PCI (n=1138) (n=1149) Mean age - years 61.5 61.8 Male - number (%) 979 (85) 968 (85) Angina – CCS class (%) 0 135 (12) 148 (13) I 340 (30) 341 (30) II 409 (36) 425 (37) 261 (23) III 221 (19) History – number (%) Hypertension 757 (66) 764 (67) 367 (32) Diabetes 399 (35) Congestive heart failure 57 (5) 51 (4) 100 (9) Cerebrovascular disease 102 (9) Myocardial infarction 437 (38) 439 (39) 174 (15) Previous PCI 185 (16) Vessels with disease (%) 361 (31) 343 (30) One 446 (39) Two 439 (39) Three 341 (30) 355 (31) Proximal LAD disease (%) 360 (31) 417 (37) 60.8 60.9 Ejection fraction Boden et al. N Eng J Med 2007;356:1–14.

5. COURAGE: Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation - RESULTS - Primary endpoint and follow-up At 4.6 years, the estimated cumulative primary event rates were 19.0% in the PCI + OMT group, and 18.5% in the OMT group (unadjusted hazard ratio [HR] in PCI group, 1.05; 95% confidence interval [CI], 0.87–1.27; p=0.62). Secondary endpoints There were no significant differences between the PCI + OMT group and the OMT group in terms of the following: • Composite of death, myocardial infarction and stroke (20% vs. 19.5%, respectively; HR, 1.05; 95% CI, 0.87–1.27; p=0.62) • Hospitalization for acute coronary syndromes (12.4% vs. 11.8%, respectively; HR, 1.07; 95% CI 0.84–1.37; p=0.56) • Myocardial infarction (13.2% vs. 12.3%, respectively; HR, 1.13; 95% CI, 0.89–1.43; p=0.33) Subgroup analysis The primary endpoint was similar across both groups in patients with multivessel CAD, previous MI and diabetes.

6. 1.0 1.0 0.9 0.9 Survivalfree ofdeathfrom anycause and myocardialinfarction 0.8 0.8 Overallsurvival 0.7 0.7 0.6 0.6 0.5 0.5 HR, 1.05; 95% CI, 0.87–1.27; p=0.62 HR, 0.87; 95% CI, 0.65–1.16; p=0.38 0 0 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 Years Years COURAGE: Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation - RESULTS continued - Kaplan-Meier survival curves PCI Medical therapy No. at risk Medical therapy PCI 1138 1138 1073 1017 959 1029 917 834 717 638 408 468 302 192 30 38 1149 1149 1013 1094 1051 952 833 929 733 637 488 417 312 200 44 35 Boden et al. N Eng J Med 2007;356:1–14.

7. COURAGE: Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation - RESULTS continued - Secondary endpoints PCI + OMTn=1149 OMTn=1149 Hazard ratio(95% CI) p value Hospitalization for acutecoronary syndromes HR, 1.07(95% CI, 0.84–1.37) 12.4 11.8 0.56 HR, 0.87(95% CI, 0.65–1.16) Death alone 0.38 7.6 8.3 HR, 1.56(95% CI, 0.80–3.04) Stroke alone 0.19 2.1 1.8 HR, 1.13(95% CI, 0.89–1.43) Total non-fatal MI 0.33 13.2 12.3 HR, 0.60(95% CI, 0.51–0.71) Revascularization (PCI or CABG) 21.1 32.6 <0.001 Patients free from angina at5 years follow-up 74 72 0.35 Data indicate percentages of patients. Boden et al. N Eng J Med 2007;356:1–14.

8. COURAGE: Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation - SUMMARY - Compared with OMT alone, PCI + OMT did not reduce the primary composite endpoints of all-cause mortality and non-fatal MI, and it did not reduce the incidence of major cardiovascular events. In terms of secondary endpoints, there was no significant difference between the groups. However, PCI + OMT did reduce the occurrence of angina in comparison with OMT alone. The results of this study are in agreement with the guidelines stating that PCI can be safely conducted in patients with stable coronary artery disease, provided that aggressive medical therapy is also maintained.