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Keith A A Fox

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

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

  3. CURE Study Design • 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

  4. CURE CURE Study 300mg loadingdose Clopidogrel75mg o.d.(~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 loading dose 1 m. Visit 3 m. Visit 6 m. Visit 9 m. Visit 12 m.or Final Visit

  5. CURE Outcome Definitions 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) 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. CURE Placebo Cumulative Hazard Rates Clopidogrel 0 3 6 9 12 No of Pts Months of Follow-up Plac Clop 6203 6259 5778 5864 4660 4780 3599 3640 2378 2414 Cumulative Hazard Rates for CV Death/MI/Stroke P = 0.00005 6303 6259

  7. CURE 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 6097 6093 5994 6027 5954 5981

  8. CURE Very Early Events *p<0.05 **<0.01 *** <0.002

  9. CURE Events During Initial Hospitalization

  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. CURE Life Threatening Bleed

  12. CURE Bleeds With CABG

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

  15. PCI- Baseline Characteristics Placebo n=1272 Clopidogrel n=1254 Age (yrs) 61.4 61.6 Sex (%F) 30.1% 30.3% Diabetes 19.0% 19.0% Previous MI 26.0% 27.3% Prior PCI 13.8% 13.4% Prior CABG 13.0% 12.0% ST depression 43.2% 42.4%

  16. PCI- Overall Results: CV Death or MI 0.15 Placebo 0.10 Clopidogrel Cumulative Hazard Rate 0.05 P=0.002 0.0 0 10 40 100 100 200 200 300 300 400 400 A=median time to PCI B=30 days after PCI B Days following PCI A Lancet 2001: 358:527-33

  17. PCI- Events Before PCI Lancet 2001: 358:527-33

  18. PCI- Major Outcomes: From PCI to 30 days *Primary endpoint Lancet 2001: 358:527-33

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

  20. PCI- Major Outcomes: Long Term Treatment Lancet 2001: 358:527-33

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