1. Keith A A Fox Royal Infirmary & University of Edinburgh CURE and PCI-CURE

2. Total outcomes: admission to 6 months Largest multinational registry covering the full spectrum of ACS ESC 2001

3. Randomized, double-blind trial: clopidogrel vs placebo in patients with ACS All patients receive ASA (75-325 mg) International trial (28 countries), 12,562 patients Central randomization Primary outcome: -CV death, MI, strokes Study DesignCURE

4. CURE Study 3 months > double-blind treatment < 12 months Aspirin 75-325mg Clopidogrel 75mg o.d. (~6,250 patients) Placebo 1 tab o.d. (~6,250 patients) Aspirin 75-325mg Day 1 6 m. Visit9 m. Visit 12 m. or Final Visit 300mg loading dose 3 m. Visit1 m. Visit Patients with Acute Coronary Syndrome (UA or MI Without ST elevation) R loading doseCURE

5. CV Death: Excludes clear non-CV deaths MI: Two of three standard criteria: (Chest Pain, ECG, enzyme changes) Stroke: Neurological deficit  24 hrs (CT/MRI) Outcome DefinitionsCURE Refractory Ischemia: Inhosp*: recurrent ischemia on max med Rx + ECG changes + intervention  1 day After discharge: Rehosp for UA with ECG changes Severe Ischemia*: Changes similar to RFA, but no intervention Recurrent Angina*: All other ischemic CP in hospital

6. Cumulative Hazard Rates for CV Death/MI/Stroke Clopidogrel Placebo Cumulative Hazard Rates Months of Follow-up 036912 6203 6259 5778 5864 4660 4780 3599 3640 2378 2414 Plac Clop No of Pts 6303 6259 P = 0.00005CURE

7. Cumulative Hazard Rates for CV Death/MI/Stroke up to 30 Days P=0.003 Clopidogrel Placebo Cumulative Hazard Rates Days of Follow-up 0102030 6303 6259 6097 6093 5994 6027 5954 5981 No. Plac No. ClopCURE

8. Very Early Events Placebo vs Clopidogrel Day 1Day 2Day 3 CVD, MI, Stroke (RR) 48 v 38 (0.80) 80 v 65 (0.82) 102 v 86 (0.85) Above + RFA (RR) 86 v 65 (0.76) 140 v 104 (0.75)* 178 v 142 (0.80)* Severe (RR) 103 v 65 (0.63)** 174 v 114 (0.66)*** 211 v 153** (0.73) Primary + Severe (RR) 149 v 100 (0.67)*** 247 v 173 (0.70)*** 302 v 228 (0.75)*** *p<0.05 **<0.01 *** <0.002CURE

9. Events During Initial Hospitalization PlacClopRR (95% CI)P % Refract Ang2.11.40.69 (0.53-0.91)0.008 Other Severe Ischemia 3.72.80.74 (0.61-0.90)0.0028 Other Recurrent Angina 22.921.00.92 (0.86-0.98)0.01 Heart Failure4.43.70.83 (0.70-0.98)0.029 CURE

10. CURE: Who Benefits and When? Similar benefits across all major treatment groups On or off lipid lowering treatment, beta-blockers, heparin, ACE inhibitors Irrespective of revascularization or not RR 0.81 with and RR 0.78 without, both significant Higher and lower risk groups show similar risk reduction Curves separate early and remain separated Primary outcome at 24hrs: 143 vs 93 clopidogrel (RR 0.65 CI 0.50 – 0.85)

11. Life Threatening Bleed PlacClop # Patients63036259 Percent Life Threatening1.82.2 Fatal0.2 5 g/L Drop Hemoglobin0.9 Hypotension-inotropes0.5 Surgery Required0.7 Hemorrhagic Stroke0.1 4+ Blood Units1.01.2 CURE

12. Bleeds With CABG PlaceboClopidogrel %RRCI # Patients10611011 All Major6.68.31.260.93-1.71 Life Threatening5.06.41.290.90-0.83 Other Major1.61.91.170.61-2.24 TIMI Major3.12.60.830.50-1.37 GUSTO Severe/LT3.64.51.240.81-1.90 CURE

13. CURE: Magnitude of Benefit Primary Outcome: MI, stroke or CV death: 11.4% placebo, 9.2%** clopidogrel (22 per 1000 absolute difference) (Non-CV death 0.7 vs 0.7%) Treating 1000 patients for 9 months: prevents 28 vascular events with 6 individuals requiring transfusion TIMI bleeding criteria: 68 clopidogrel,73 placebo RR 0.94 (CI 0.68-1.30) GUSTO criteria: 78 clopidogrel, 70 placebo RR 1.11 (CI 0.81-1.55)

14. Study Design Randomize PCIPCI PLACEBO + ASA + ASAPLACEBO CLOPIDOGREL + ASA CLOPIDOGREL 30 d. post PCI End of follow-up: 12 months End of follow-up: 12 months Open-label thienopyridine Pretreatment N=2,658 patients undergoing PCI N = 1345 N = 1313 CURE PCI-CURE PCI - Open-label thienopyridine

15. Baseline Characteristics 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% Diabetes 30.3%30.1%Sex (%F) 61.661.4Age (yrs) Clopidogrel n=1254 Placebo n=1272 PCI -

16. 0.0 0.05 0.10 0.15 04010020030040010100200300400 A B Days following PCI Cumulative Hazard Rate P=0.002 Clopidogrel Placebo A=median time to PCI B=30 days after PCI Overall Results: CV Death or MI Lancet 2001: 358:527-33 PCI -

17. Events Before PCI Placebo N=1345 Clop. N=1313 RR95% CIP MI or Refract. Ischemia 15.3%12.1%0.760.62-0.930.008 MI5.1%3.6%0.680.47-0.990.04 PCI - Lancet 2001: 358:527-33

18. EventsPlacebo N=1345 Clopid. N=1313 RR95% CIP CV death, MI, urg. revasc.* 6.4%4.5%0.700.50-0.970.03 CV death, MI4.4%2.9%0.660.44-0.990.04 CV death1.0%1.1%1.100.52-2.35 MI3.8%2.1%0.560.35-0.89 Q wave MI2.4%0.8%0.350.18-0.70 Urg Rev.2.8%1.9%0.670.41-1.11 Major Outcomes: From PCI to 30 days PCI - Lancet 2001: 358:527-33 *Primary endpoint

19. Other Outcomes PCI - Placebo + ASA* N = 1345 Clopidogrel + ASA* N=1313 RRRP Value GP IIb/IIIa Inhibitior 26.6%20.9%81%0.001 Need for second revascularization 17.1%14.2%18%0.049 Mehta SR et. al. Lancet 2001: 358:527-33

20. EventsPlacebo N = 1345 Clopid N = 1313 RRR95% CIP From PCI to End of Followup CV death, MI, any revasc 21.7%18.3%17%0.56-0.990.03 CV Death or MI8.1%6.0%26%0.56-1.000.047 From >30 after PCI to end of follow-up CV death, MI, any rehosp 28.9%25.3%14%0.74-1.000.05 CV Death or MI3.9%3.1%21%0.53-1.20 Before and After PCI CV death or MI12.6%8.8%32%0.54-0.870.002 Major Outcomes: Long Term Treatment PCI - Lancet 2001: 358:527-33

21. Clinical Suspicion of ACS: Physical examination, ECG Blood samples No persistent STelevation Aspirin  -blocker “heparin” clopidogrel Persistent ST elevation Thrombolysis or Primary PCI Stress Test Pre- or post- discharge GP IIb/IIIa coronary angio High Risk recurrent ischaemia elevated troponin haemodynamic instability arrhythmia with ischaemia early post-MI unstable angina Low Risk stable normal troponin