1. The Truth and Consequences of Objective Ischemia: The COURAGE Trial Nuclear Substudy Dean J. Kereiakes, M.D. Medical Director, The Christ Hospital Heart and Vascular Center and the Lindner Research Center Chairman,Executive Committee, The Ohio Heart and Vascular Center, Cincinnati, Ohio Professor of Medicine, Ohio State University

2. Objectives Identify pivotal observation(s) from the COURAGE trial nuclear substudy Is this observation(s) novel? Is the obsevation realistic and applicable to clinical practice? What are the limitations & caveats regarding COURAGE observations? Summary and Conclusions 3. Nuclear Substudy (n=314 / 2,287) Hypothesis: Reduction in ischemia will be greater for patients Randomized to PCI+OMT than for those randomized to OMT Serial rest/stress myocardial perfusion SPECT (MPS) To compare patient management strategy for ischemia reduction Documented Pre-Rx Ischemia PCI + OMT OMT (n=159) (n=155) Repeat MPS* Repeat MPS* at 6-18m at 6-18 m *Timing chosen to occur beyond window of in- stent restenosis and delayed to allow effects of medical Rx to be observed Pre-Rx = off meds Post-Rx = on meds Source: Shaw et al. J Nucl Cardiol 2006;13:685 4. MPS Ischemia Based on Total Perfusion Defect (TPD) TPD: Quantitative measure of defect extent and severity % Ischemic myocardium = (Stress TPD-Rest TPD) < 5%: Minimal (no ischemia) 5.0%-9.9%: Mild 10%: Moderate to severe Significant reduction in ischemia 5% reduction in ischemic myocardium* Source: Simoka et al. J Nucl Cardiol 2005;12:66 *Threshold exceeds test repeatability TPD Defect Extent Lower NI Limit Defect Severity 5. Pre-Treatment Clinical Characteristics and MPS Results PCI + OMT N=159 OMT N=155 P value Angina CCS* Class I-II 74% 73% 0.99 Angiographic 2-3 vessel CAD 73% 77% 0.38 Rest gated LVEF 57%11% 58%9% 0.97 % Ischemic myocardium 8.2% 8.6% 0.63 (95% CI) (7.2-9.3%) (7.5-9.8%) Moderate to Severe Ischemia** 34% 33% 0.81 *CCS=Canadian Cardiovascular Society ** 10% ischemic myocardium Compared to main trial, substudy patients more often CCS* class I-II angina (p=0.013) & less multivessel CAD (p=0.05); with similar % of MPS ischemia (p=0.55) 6. 33.3 19.8 0 10 20 30 40 50 PCI + OMT (n=159) OMT (n=155) IschemiaReduction5% Primary Endpoint: % with Ischemia Reduction 5% Myocardium (n=314) P=0.004 7. 31.4 17.8 0 10 20 30 40 50 PCI + OMT (n=53) OMT (n=29) %withLowRisk*MPS Ischemia Normalization* on Follow-Up MPS In Patients with Significant Ischemia Resolution P=0.007 *1% ischemic myocardium 8. 13.4 24.7 0 10 20 30 40 50 Ischemia Reduction n=82 No Ischemia Reduction n=232 DeathorMIrate(%) Rates of Death or MI by Ischemia Reduction P=0.037 RR=0.47 (95% CI=0.23-0.95) 5%* *primary endpoint 9. 16.2 32.4 0 10 20 30 40 50 Ischemia Reduction n=68 No Ischemia Reduction n=37 DeathorMIrate(%) Rates of Death or MI by Ischemia Reduction in Subset of 105 Patients with Moderate to Severe Pre-Rx Ischemia* P=0.001 5% *50% reduction 10. 0.0 15.6 22.3 39.3 0 10 20 30 40 50 0% (n=23) 1 - 4.9% (n=141) 5 -9.9% (n=88) 10% (n=62) DeathorMIrate(%) Rates of Death or MI by Residual Ischemia on 6-18m MPS P=0.002 P=0.023 P=0.063 11. Conclusions PCI added to OMT was more effective in reducing ischemia and improving angina than OMT alone, particularly in patients with moderate to severe pre-RX ischemia Is this Observation Novel? 12. 0.3 0.8 2.3 2.9 0.5 2.7 2.9 4.2 0 1 2 3 4 5 Myocardial Infarction Cardiac Death Hachamovitch, Diamond et al. Circ 1998;97:535 Cardiac Death or Myocardial Infarction Rate/Year Stratified by SPECT Quantitative Ischemia EventRate% * Statistically significant increase as function of scan result ** Increased rate of MI vs cardiac death within scan stratum ** * * Normal Mildly Normal Moderately Abnormal Severely Abnormal N = 2946 884 455 898 13. 0.7 1.0 2.9 4.8 6.7 6.3 1.8 3.7 3.3 2.0 0 2 4 6 8 10 7110 16 1331 56 718 109 545 243 252 267 Medical RX Revasc Hachamovitch et al. Circ 2003;107:2900 Cardiac Death Rate Stratified by Spect Quantification of Ischemia and Treatment Modality CardiacDeathRate(%) 0% 1-5% 5-10% 11-20% >20% *p < 0.0001 % Total Myocardium Ischemic * 14. Hachamovitch et al. Circ 2003;107:2900 Mortality Hazard by Treatment Modality and % Ischemic Myocardium logHazardRatio(Mortality) 0 1 2 3 4 5 6 0 12.5% 25% 32.5% 50% *p