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CURE (OASIS-4)

CURE. CURE (OASIS-4). C lopidogrel in U nstable Angina to prevent R ecurrent ischemic E vents. Atherothrombosis: a Generalized and Progressive Process. Unstable angina. Plaque rupture/ fissure & thrombosis. } ACS. Athero- sclerotic plaque. Fatty streak. Fibrous plaque. MI. Normal.

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CURE (OASIS-4)

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

  2. Atherothrombosis: a Generalized and Progressive Process Unstable angina Plaquerupture/fissure &thrombosis }ACS Athero-scleroticplaque Fattystreak Fibrousplaque MI Normal Ischemic stroke/TIA Critical leg ischemia Clinically silent Stable angina Intermittent claudication Cardiovasculardeath Increasing age ACS, acute coronary syndrome; TIA, transient ischemic attack

  3. 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 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 andStroke Statistical Update

  4. 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) 750 000 admissions 750 000 admissions Cairns J et al Can J Cardiol 1996;12:1279–1292

  5. 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 Théroux P et al Circulation 1998; 97:1195–1206

  6. Efficacy of Antiplatelet Therapy:Antiplatelet Trialists’ Collaboration MI, stroke, orvascular death Odds ratio andconfidence interval(Antiplatelet:control) No. oftrialswithdata % oddsreduction(SD) Anti-platelet Adjustedcontrols Categoryof trial Prior MI 11 1331/9677 1693/9914 25% (4) Acute MI 9 992/9388 1348/9385 29% (4) Prior stroke/ 18 1076/5837 1301/5870 22% (4)TIA Unstable angina 7 182/1991 285/2027 0 0.5 1.0 1.5 2.0 Antiplatelettherapybetter Antiplatelettherapyworse TIA, transient ischemic attack Antiplatelet Trialists’ Collaboration BMJ 1994;308:81–106

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

  8. 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. Complementary Mode of Action between Clopidogrel and ASA COX, cyclooxygenase; ADP, adenosine diphosphate; TxA2, thromboxane A2 Schafer AI Am J Med 1996;101:199–209

  10. Trials of ADP-receptor Antagonists vs Placebo in Patients with Atherosclerosis CURE Study Investigators Eur Heart J 2000; 21: 2033-41.

  11. Trials of ADP-receptor Antagonists vs ASA in Patients with Atherosclerosis CURE Study Investigators Eur Heart J 2000; 21: 2033-41.

  12. ASA + Ticlopidine versus ASA after Coronary Artery Stenting Death or MI Study Odds Ratio 95% CI 0.17 0.01-0.72 HALL, 1996 0.25 0.10-0.63 STARS, 1998* TOTAL 0.23 0.11-0.49 P=0.0001 Test for heterogeneity P=0.66 0.1 1.0 10.0 Combination Better ASA Alone Better CURE Study Investigators Eur Heart J 2000; 21:2033-41 Page 30 of 30

  13. CURE ASA + Ticlopidine vs ASA + Oral Anticoagulation after Stenting Death or MI Study Odds Ratio 95% CI ISAR, 1996 0.31 0.11-0.91 0.32 0.11-0.91 STARS, 1998 0.61 0.26-1.43 MATTIS, 1998 0.66 0.33-1.30 FANTASTIC, 1998 0.51 0.33-0.78 TOTAL P=0.002 Test for heterogeneity P=0.51 0.1 1.0 10.0 Combination Better ASA Alone Better CURE Study Investigators Eur Heart J 2000; 21:2033-41

  14. Effect of Clopidogrel Alone or in Combinationwith ASA on Thrombus Formation: Animal Model Blood flow(% decrease) Clopidogrel (10 mg/kg) Clopidogrel + ASA (10 + 10 mg/kg) ASA (10 mg/kg) Placebo 0 -20 -40 -60 -80 -100 0 5 10 15 20 25 30 35 40 45 50 Time (min) Herbert JMet al Thromb Haemost 1998;80:512–518

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

  16. Study Design • 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

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

  18. 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. 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. 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. Patient Schedule 300 mg loading + 75 mg o.d. dose Clopidogrel(~6,250 patients) Patients with Acute CoronarySyndrome Aspirin 75-325mg R 3 months £double-blind treatment£ 12 months (UA or MI Without STelevation) Aspirin 75-325mg Placebo 1 tab o.d.(~6,250 patients) Day 1 1 m. Visit 3 m. Visit 6 m. Visit 9 m. Visit Discharge Visit 12 m.or Final Visit loading dose

  22. Sample Size (12,500) and Power Calculations

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

  24. Baseline Characteristics (1)

  25. Baseline Characteristics (2)

  26. Medications After Randomization in Hospital

  27. Temporary Interruptions by Procedure

  28. ASA at Each Visit

  29. Outcomes 1 /2

  30. Placebo Cumulative Hazard Rates Clopidogrel P < 0.001 0 3 6 9 12 No of Pts Months of Follow-up Plac Clop 6303 6259 5780 5866 4664 4779 3600 3644 2388 2418 Cumulative Hazard Rates for CV Death/MI/Stroke

  31. Cumulative Hazard Rates for CV Death/MI/Stroke up to 30 Days Placebo Cumulative Hazard Rates Clopidogrel P = 0.003 0 10 20 30 Days of Follow-up No. Plac No. Clop 6303 6259 6108 6103 5998 6035 5957 5984

  32. Outcomes 2/2

  33. Placebo Clopidogrel Cumulative Hazard Rates P < 0.001 0 3 6 9 12 No of Pts Months of Follow-up Plac Clop 6303 6259 5441 5542 3295 3346 2159 2201 4322 4438 Cumulative Hazard Rates for CV Death/MI/Stroke/RFA

  34. Events During Initial Hospitalization

  35. CV Death/MI/Stroke in Subgroups: (1)

  36. CV Death/MI/Stroke by Revascularization: (2)

  37. Thrombolytic & GP IIb/IIIa Inhib use after Randomization

  38. Bleeding Complications

  39. TIMI Major Bleeding / GUSTO Severe-Life-Threatening Bleeding Criteria

  40. Major/Life-Threatening Bleeds within 7 Days of CABG Surgery

  41. Thrombocytopenia and Neutropenia

  42. Conclusions • Clopidogrel significantly reduces the risk of: • CV Death, MI, Stroke by about one-fifth (p < 0.001) • CV Death, MI, Stroke, and Refractory Ischemia by about one-sixth (p < 0.001) • 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. 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. 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

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