1. CURE CURE (OASIS-4) Clopidogrel in Unstable Angina to prevent Recurrent ischemic Events

2. CURE Atherothrombosis: a Generalized and Progressive Process Normal Fatty streak Fibrous plaque Athero- sclerotic plaque Plaque rupture/ fissure & thrombosis MI Ischemicstroke/TIA Critical leg ischemia Clinically silent Cardiovascular death Increasing age Stable angina Intermittent claudication Unstableangina } ACS ACS, acute coronary syndrome; TIA, transient ischemic attack

3. CURE Based on data from the Atherosclerotic Risk in Communities study (ARIC) of the National Heart, Lung, and Blood Institute, 1987–94. Includes Americans hospitalized with definite or probable MI or fatal CHD, not including silent MIs. American Heart Association, 2001, Heart and Stroke Statistical Update Epidemiology of MI and Angina in the USA Single largest cause of death –459 000 deaths in the USA in 1998 –1 in every 5 deaths Incidence –1 100 000 Americans will have a new or recurrent coronary attack each year. Over 40% of people who experience a coronary attack in a given year will die of it in the same year –400 000 new cases of stable angina and about 150 000 new cases of unstable angina per year Prevalence –12 400 000 with a history of MI, angina, or both

4. CURE Hospitalizations in the USA Due to ACS Acute Coronary Syndromes 1.5 million hospital admissions per year Unstable angina Myocardial infarction (Q-wave and non-Q-wave) Cairns J et al Can J Cardiol 1996;12:1279–1292 750 000 admissions

5. CURE Théroux P et al Circulation 1998; 97:1195–1206 The Role of Antiplatelet Therapy in Unstable Angina and Non-Q-wave MI Atherothrombosis is a generalized disease affecting the coronary, cerebral and peripheral circulations Unstable angina/non-Q-wave MI is one of the classic examples of the progression of atherothrombotic disease Platelets play a key role in thrombus formation associated with rupture of an unstable atherosclerotic plaque Angioscopic findings show that unstable angina is due to the formation of a platelet-rich thrombus Consequently, antiplatelet therapy is recognized as the foundation of long-term management

6. CURE Efficacy of Antiplatelet Therapy: Antiplatelet Trialists’ Collaboration Antiplatelet Trialists’ Collaboration BMJ 1994;308:81–106 Prior MI111331/96771693/991425% (4) Acute MI9992/93881348/938529% (4) Prior stroke/181076/58371301/587022% (4) TIA Unstable angina 7182/1991285/2027 Category of trial No. of trials with data Anti- platelet Adjusted controls Odds ratio and confidence interval (Antiplatelet: control) % odds reduction (SD) MI, stroke, or vascular death 00.51.01.52.0 Antiplatelet therapy better Antiplatelet therapy worse TIA, transient ischemic attack

7. CURE UA: CV Death or MI - ASA vs Placebo % of Patients with Event Cairns et al NEJM 1985;313:1369-1375 Efficacy: Cardiac Death or Non-Fatal MI At Risk ASA (263) No ASA (274) (174) (180) (137) (144) (107) (115) (73) (80) Time

8. CURE The Role of an ADP Receptor Antagonist Clopidogrel is an advanced ADP receptor antagonist and inhibits platelet aggregation by antagonizing the effects of ADP Clopidogrel is indicated for the reduction of atherothrombotic events in patients with a history of stroke, MI or peripheral arterial disease. Clopidogrel is at least as safe as ASA Combining clopidogrel with ASA may potentially lead to greater benefit Jarvis B et al Drugs 2000;60:347–377 Antiplatelet Trialists’ Collaboration BMJ 1999;308:81–106 CAPRIE Steering Committee Lancet 1996:348:1329–1339

9. CURE Complementary Mode of Action between Clopidogrel and ASA COX, cyclooxygenase; ADP, adenosine diphosphate; TxA 2, thromboxane A 2 Schafer AI Am J Med 1996;101:199–209

10. CURE Trials of ADP-receptor Antagonists vs Placebo in Patients with Atherosclerosis Trial, YearSettingPrimary OutcomeOdds Ratio95% CI DefinitionThieno- pyridine (n/N) Comparator (n/N) Thienopyridine versus Placebo or Control CATS 1989 (Ticlopidine vs Placebo Recent Stroke Death, MI, Stroke 106/525134/5280.740.56-0.99 Balsano 1990 (Ticlopidine vs Control) Unstable Angina Death, MI23/31446/3380.520.31-0.85 STIMS 1990 (Ticlopidine vs Placebo) Intermittent Claudication Death, MI, Stroke 89/34699/3410.850.61-1.18 TOTAL218/1185279/12070.730.60-0.90 CURE Study Investigators Eur Heart J 2000; 21: 2033-41.

11. CURE Trials of ADP-receptor Antagonists vs ASA in Patients with Atherosclerosis Trial, YearSettingPrimary OutcomeOdds Ratio95% CI DefinitionThieno- pyridine (n/N) Comparator (n/N) Thienopyridine versus ASA TASS, 1989 (Ticlopidine vs ASA) Cerebral Ischemia Death, Stroke 306/1529349/15400.850.82-0.97 CAPRIE, 1996 (Clopidogrel vs ASA) Recent Stroke, Previous MI or PVD Death, MI, Stroke 939/95991021/95860.910.83-1.00 TOTAL1245/111281370/111260.900.83-0.97 CURE Study Investigators Eur Heart J 2000; 21: 2033-41.

12. CUREStudy HALL, 1996 STARS, 1998* TOTAL 0.11.010.0 Odds Ratio 95% CI 0.170.01-0.72 0.250.10-0.63 0.230.11-0.49 P=0.0001 Test for heterogeneity P=0.66 ASA + Ticlopidine versus ASA after Coronary Artery Stenting Page 30 of 30 Death or MI CURE Study Investigators Eur Heart J 2000; 21:2033-41 Combination Better ASA Alone Better

13. Study ISAR, 1996 MATTIS, 1998 TOTAL 0.11.010.0 Odds Ratio 95% CI 0.310.11-0.91 0.61 0.26-1.43 0.510.33-0.78 P=0.002 Test for heterogeneity P=0.51 ASA + Ticlopidine vs ASA + Oral Anticoagulation after Stenting FANTASTIC, 1998 0.660.33-1.30 STARS, 1998 0.320.11-0.91 Death or MI Combination Better ASA Alone Better CURE Study Investigators Eur Heart J 2000; 21:2033-41CURE

14. CURE Effect of Clopidogrel Alone or in Combination with ASA on Thrombus Formation: Animal Model -100 -80 -60 -40 -20 0 05101520253035404550 Time (min) Clopidogrel + ASA (10 + 10 mg/kg) Clopidogrel (10 mg/kg) ASA (10 mg/kg) Placebo Herbert JM et al Thromb Haemost 1998;80:512–518 Blood flow (% decrease)

15. CURE Rapid and Synergistic Effect of Clopidogrel on top of ASA (Healthy Volunteers) Mean reduction of platelet deposition compared with ASA alone Cadroy Y et al Circulation 2000;101:2823–2828 C75+ASA vs ASA alone C300+ASA vs ASA alone -10 0 10 20 30 40 50 60 70 80 Day 1 1.5 hrs Day 1 6 hrs Day 10 6 hrs Mean reduction (%) p=0.03 vs ASA p<0.001 vs ASA p=0.04 vs ASA p<0.001 vs ASA p=0.03 p=0.01 p=NS n=18 for all comparisons

16. CURE Randomized, double-blind, parallel group, clinical trial of clopidogrel vs placebo in patients with ACS All patients receive ASA (75-325 mg) International trial (28 countries) 12,562 patients (482 Hospitals) Central randomization 3-12 month Rx and follow-up Main outcomes: -CV death/MI, stroke -Above + refractory ischemia Study Design

17. CURE Study Objectives To evaluate if clopidogrel is superior to placebo in preventing a)CV death, MI, stroke (Primary at  0.045) b)Above and refractory ischemia (Co-primary at  0.01)

18. CURE Inclusion Criteria Ischemic symptoms, suspected to represent UA or MI without ST segment elevation Randomized within 24 hours of onset of CP and ECG evidence of ischemia at inclusion or already elevated cardiac enzymes or Troponin I or T to at least 2 x ULN* *Prior to June 1999, pts > 60 yrs with normal ECG allowed Revised July, 1999

19. CURE Outcome Definitions (1/2) CV Death: Excludes clear non-CV deaths MI: Two of three usual criteria (CP, ECG or enzyme changes) Stroke: Neurological deficit  24 hrs (CT/MRI encouraged) 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 in hospital Refractory Ischema, but no intervention Recurrent Angina*: All other ischemic CP in hospital

20. CURE Outcome Definitions (2/2) Major Bleeds: Significantly disabling, intraocular (vision loss), or transfusion of  2 units Classified as Life Threatening if: Hb  > 5g/dl, hypotension needing IV inotropes, surgery to stop bleeding, symptomatic ICH or transfusion or  4 units of blood

21. CURE Patient Schedule 3 months  double-blind treatment  12 months Aspirin 75-325mg Clopidogrel (~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 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (UA or MI Without ST elevation) R loading dose 300 mg loading + 75 mg o.d. dose

22. CURE Sample Size (12,500) and Power Calculations Main EndpointsControl Event Rate 80% Power 90% Power CV Death/MI/Stroke10%14.7%16.9%  =0.045 (two-sided) 12%13.3%15.3% Above + Refractory ischemia 14%14.6%16.4%  =0.01 (two-sided) 16%13.6%15.3%

23. 2463 1110 831 5036 3122 CURE: 12,562 from 482 centres in 28 countries

24. CURE Baseline Characteristics (1) PlaceboClopidogrel N=6303 % N=6259 % Male61.761.3 Female38.338.7 Unstable Angina74.9 MI w/o ST Elevation25.1 Abnormal ECG93.993.7 Elevated enzymes/marker25.3

25. CURE Baseline Characteristics (2) PlaceboClopidogrel N=6303 Mean (SD) N=6259 Mean (SD) Age64.2 (11.3) Heart rate73.0 (14.6)73.2 (14.8) Systolic BP134.1 (22.0)134.4 (22.5) Symptom onset to randomization (hrs) 14.1 (7.1)14.2 (7.2)

26. CURE Medications After Randomization in Hospital PlaceboClopidogrel % IV Heparin46.946.0 LMW Heparin56.056.1 Beta-blocker78.478.7 Any CCB36.0 ACE-I49.950.9 Lipid-lowering47.046.3

27. CURE Temporary Interruptions by Procedure Any Procedure (PTCA + CABG + Other Surgery) PlacClop With procedure No. pts24302359 % interruptions(84%) Without procedure No. pts38733900 % interruptions(21%)(23%)

28. CURE ASA at Each Visit Placebo N = 6303 Clopidogrel N = 6259 % on ASAMedian Dose% on ASAMedian Dose Pre-Rand65.615066.6150 Since-Rand99.815099.8150 1-Month94.115094.0150 3-Month96.215096.0150 6-Month95.812595.4125 9-Month94.710094.6100

29. CURE Outcomes 1 /2 PlacClop %RRCIp # Patients63036259 1 st Co-Primary11.419.300.800.72-0.90< 0.001 CV Death5.475.080.930.79-1.08 MI6.655.180.770.67-0.89 Stroke1.381.200.860.63-1.18 Non CV death0.710.660.910.60-1.39

30. CURE Cumulative Hazard Rates for CV Death/MI/Stroke P < 0.001 Clopidogrel Placebo Cumulative Hazard Rates Months of Follow-up 036912 6303 6259 5780 5866 4664 4779 3600 3644 2388 2418 Plac Clop No of Pts

31. CURE 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 6108 6103 5998 6035 5957 5984 No. Plac No. Clop

32. CURE Outcomes 2/2 PlacClop %RRCIp # Patients63036259 2nd Co-Primary18.8316.540.860.79-0.94< 0.001 Refract.Ischemia9.318.690.930.82-1.04 In hospital2.001.360.680.52-0.90 After Discharge7.597.570.990.87-1.13 Severe Ischemia5.033.800.750.63-0.89< 0.001

33. CURE Cumulative Hazard Rates for CV Death/MI/Stroke/RFA P < 0.001 Clopidogrel Placebo Cumulative Hazard Rates Months of Follow-up 036912 6303 6259 5441 5542 4322 4438 3295 3346 2159 2201 Plac Clop No of Pts

34. CURE Events During Initial Hospitalization PlacClopRR (95% CI)P % Refract Isch2.01.40.68 (0.52-0.90)< 0.007 Other Severe Ischemia 3.82.80.74 (0.61-0.90)< 0.003 Other Recurrent Angina 22.920.90.91 (0.85-0.98)< 0.01 Heart Failure4.43.70.82 (0.69-0.98)< 0.027

35. CURE CV Death/MI/Stroke in Subgroups: (1) Subgroup 2NPlacebo % Clopidogrel % RRCI Major ST Dev627514.311.50.790.69-0.91 Others62878.67.00.810.68-0.97 With Enzyme Elevation317613.010.70.810.66-0.99 Without Enzyme Elevation938610.98.80.800.70-0.91

36. CURE CV Death/MI/Stroke by Revascularization : (2) Subgroup 2NPlac % Clop % RRCI H/O Revasc224614.48.40.560.43-0.72 Others1031610.79.50.880.78-0.99 Post Rand Revasc +457713.911.50.820.69-0.96 Post Rand Revasc -798510.08.10.800.69-0.92

37. CURE Thrombolytic & GP IIb/IIIa Inhib use after Randomization Plac N=6303 Clop N=6259 RRCIp (%) Thrombolytics2.01.10.570.43-0.76<0.001 IV GP IIb/IIIa Inhib7.25.90.820.72-0.930.003

38. CURE Bleeding Complications PlaceboClopidogrelRR95% CIp # Patients63036259 Major2.7%3.7%1.381.13-1.670.001 Life Threatening 1.8%2.2%1.210.95-1.560.13 Other Major0.9%1.5%1.701.22-2.35< 0.002 Minor2.4%5.1%2.121.75-2.56< 0.001 Transfusion (2+Units) 2.2%2.8%1.301.04-1.620.02

39. CURE TIMI Major Bleeding / GUSTO Severe- Life-Threatening Bleeding Criteria PlacClopRR (95% CI) P # Patients63036259 TIMI Criteria73 (1.2%) 68 (1.1%) 0.940.70 GUSTO Criteria70 (1.1%) 78 (1.2%) 1.120.48

40. CURE Major/Life-Threatening Bleeds within 7 Days of CABG Surgery PlacClopRRp Stopped < 5 days prior to CABG N = 476N = 436 Pts with Maj/LT Bleeds6.3%9.6%1.530.06 Stopped > 5 days prior to CABG N = 454N = 456 Pts with Maj/LT Bleeds5.3%4.4%0.830.53

41. CURE Thrombocytopenia and Neutropenia PlacClop # Rand63036259 Thrombocytopenia28 (0.44%)26 (0.42%) Neutropenia5 (0.1%)8 (0.13%)

42. CURE Conclusions Clopidogrel significantly reduces the risk of: a)CV Death, MI, Stroke by about one-fifth (p < 0.001) b)CV Death, MI, Stroke, and Refractory Ischemia by about one-sixth (p < 0.001) c)Early revascularization, severe and recurrent ischemia and heart failure by about one-fifth to one- quarter in hospital There is a small (absolute 1%) significant excess of major, but not life threatening, bleeds

43. CURE Clinical Implications Clopidogrel is beneficial both early and long term in patients with ACS, with a small excess in bleeds. The benefits are consistently observed in various subgroups examined and in addition to other established therapies. Treating 1000 patients for 9 months prevents about 27 major events in 23 patients at a cost of 4 life threatening bleeds (+ 2 other transfusions).

44. CURE Public Health Implications USA: 1.5 million MI per year  0.5 mill non-fatal non-Q MI 1.5 million UA pts per year Potential eligible for clopidogrel is about 2 million Major vascular events (CV death/MI/Stroke) reduced from about 250,000 to 200,000 (i.e. 12.5% to 10%) at one year. If patients are treated longer (e.g. 3 yrs) 500,000 reduced to 400,000 (i.e. 25% to 20%) Therefore 50,000 to 100,000 individuals will avoid a major vascular event in the USA per year Global impact: if one-fifth of eligible pts receive clopidogrel, 250,000–500,000 individuals could benefit