1. PCI - A prospective, randomized, double- blind substudy of patients undergoing PCI in the CURE trial

2. PCI - Background and Hypothesis  Despite pretreatment and long term use of ASA in patients undergoing PCI, there remains a significant risk of major CV events following PCI  Hypothesis: in patients undergoing PCI receiving ASA, pretreatment with clopidogrel, in addition to ASA, followed by long term therapy is superior to a strategy of treating for only 4 weeks after PCI

3. PCI -Objectives  To determine whether: 1. Clopidogrel pretreatment, in addition to aspirin, is superior to placebo in preventing major ischemic events 30 days after PCI 2. Long term therapy with clopidogrel, in addition to aspirin, for up to 1 year after PCI, is superior to placebo

4. PCI - PCI-CURE: Study Design R PCIPCI PLACEBO + ASA + ASA CLOPIDOGREL + ASA 30 d. post PCI* Follow-up (to 12 m after rand.) Follow-up (to 12 m after rand.) Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N=2,658 patients undergoing PCI N = 1345 N = 1313 CUREPCI-CURE *1 o Outcome: CV Death, MI, Urg Revasc. Mehta SR et al. Lancet 2001:358:527-33

5. PCI -Statistics Primary Outcome: CV death, MI, urgent revascularization 30 days after PCI Other Outcomes: CV death, MI from PCI to end of long term followup Primary Analysis: Intention to treat Follow-up: 100%

6. PCI - Procedural Characteristics PlaceboN=1345ClopidogrelN=1313 Median Day of PCI 1010 During initial Hosp During initial Hosp66 After initial Hosp After initial Hosp4949 Stent81.3%82.4% Open label thienopyridine Before PCI 24.7%26.4% Overall84.1%82.9%

7. PCI -43.2%42.4% ST depression 12.0%13.0% Prior CABG 13.4%13.8% Prior PCI 27.3%26.0% Previous MI 19.0%19.0% Diabetes 30.3%30.1% Sex (%F) 61.661.4 Age (yrs) Clopidogreln=1313PlaceboN=1345 Baseline Characteristics Mehta SR et al. Lancet 2001:358:527-33

8. PCI - Primary Endpoint: CV Death, MI, Urgent Revascularization Mehta SR et al. Lancet 2001:358:527-33

9. PCI -EventsPlaceboN=1345Clopid.N=1313RR 95% CI P CV death, MI, urg. revasc.* 6.4%4.5%0.700.50-0.970.03 CV death, MI 4.4%2.9%0.660.44-0.990.04 CV death CV death1.0%1.1%1.100.52-2.35 MI MI3.8%2.1%0.560.35-0.89 Q wave MI Q wave MI2.4%0.8%0.350.18-0.70 Urg Rev. Urg Rev.2.8%1.9%0.670.41-1.11 *Primary outcome Major Outcomes: From PCI to 30 days Mehta SR et al. Lancet 2001:358:527-33

10. PCI - Events Prevented Within 30 Days of PCI No. Days After PCI PlacClopidARRRR 95% CI  2 2 2 23.02.4-0.60.800.50-1.27  7 7 7 74.43.0-1.40.690.46-1.03  14 5.43.7-1.70.670.47-0.96  30 6.44.5-1.90.700.50-0.97 CV Death, MI, Urgent Revascularization Mehta SR et al. Lancet 2001:358:527-33

11. PCI - CV Death, MI: From PCI to End of Followup Mehta SR et al. Lancet 2001:358:527-33

12. PCI - Long Term Outcomes EventsPlacebo N =1345 Clopid N =1313 RR95% CIP PCI to End CV Death, MI8.0%6.0%0.750.56-1.000.047 MI6.4%4.5%0.710.51-0.99 >30 days to End CV Death, MI, Rehosp. 28.9%25.3%0.860.74-1.000.046 CV Death or MI 3.9%3.1%0.790.53-1.20 Mehta SR et al. Lancet 2001:358:527-33

13. PCI - Overall Results: CV Death or MI Mehta SR et al. Lancet 2001:358:527-33

14. PCI - CV Death or MI at Various Intervals RRR 31% 32% 34% 21% * *P=0.002 Mehta SR et al. Lancet 2001:358:527-33

15. PCI - Other Outcomes Placebo N = 1345 Clopidogrel N=1313 RRRP Value GP IIb/IIIa Inhibitor Use 26.6%20.9%21%0.001 Need for second revascularization 17.1%14.2%18%0.049 Mehta SR et al. Lancet 2001:358:527-33

16. PCI - Bleeding Outcomes Placebo N=1362 Clopidogrel N=1362 RRP From PCI to 30 days Major1.4%1.6%1.130.69 Life threatening0.7% 0.920.86 Minor0.7%1.0%1.330.49 From PCI to follow-up Major 2.5%2.7%1.120.64 Life threatening1.3%1.2%0.910.78 Minor2.1%3.5%1.680.03 Mehta SR et al. Lancet 2001:358:527-33

17. PCI - Bleeding and GP IIb/IIIa Antagonists PlaceboClopidogrelRRP At 30 Days Major2.2%2.2%0.980.97 Life threatening 1.1%1.1%0.980.98 Mehta SR et al. Lancet 2001:358:527-33

18. PCI - CV Death or MI from Randomization to End 7.911.91854 Male 13.416.91042 Age >65 5.99.81616 Age  65 9.416.2486 No Stent 8.711.72172 Stent 8.812.6 Overall ClopidPlac2N 11.014.1804 Female 0.2 1.21.00.80.60.4 Relative Risk Clopidogrel better Placebo better 2658 Mehta SR et al. Lancet 2001:358:527-33

19. PCI -7.911.72154 No Diabetes 12.916.5504Diabetes 13.5 12.0 8.912.32114 PCI > 72 h Rand 8.5544 PCI  72 h Rand 8.31730 PCI in 1st Hosp. 13.89.8928 PCI After 1 st Hosp. 21.79.6332 H/O CABG 11.28.72326 No H/O CABG Clopid Plac 2N Clopidogrel better Placebo better 0.2 1.21.00.80.60.4 Relative Risk CV Death or MI from Randomization to End Mehta SR et al. Lancet 2001:358:527-33

20. PCI - PCI-CURE – Conclusions In patients with non-ST elevation ACS undergoing PCI: Pretreatment with Clopidogrel followed by long term therapy for up to 1 year after PCI demonstrated a significant reduction in major CV events, compared with placebo (overall death/MI P=0.002) Pretreatment with Clopidogrel followed by long term therapy for up to 1 year after PCI demonstrated a significant reduction in major CV events, compared with placebo (overall death/MI P=0.002) There were consistent reductions in events in the mutually exclusive time periods before PCI, 4 weeks after PCI and in the months thereafter up to one year There were consistent reductions in events in the mutually exclusive time periods before PCI, 4 weeks after PCI and in the months thereafter up to one year There was consistent benefit regardless of whether PCI was performed during the initial hospital admission (including very early PCI <72 hrs) or more electively after discharge There was consistent benefit regardless of whether PCI was performed during the initial hospital admission (including very early PCI <72 hrs) or more electively after discharge

21. PCI - PCI CURE Implications  All patients with non-ST elevation ACS should be routinely pretreated with clopidogrel before PCI with therapy continued long term after PCI  The results of and together suggest that clopidogrel should be initiated as early as possible and continued long term in all appropriate non- ST elevation ACS patients regardless of management strategy PCI -