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  • How does CLARITY-TIMI 28 fit into the overall study of clopidogrel in acute MI? This slide depicts the four trials that address the MI population. There has been one trial published, the CAPRIE study, that included a large group of patients who were post MI and looked at long-term secondary prevention. In that case, they studied clopidogrel alone for patients who had an MI within 35 days in addition to stroke or PAD and treatment, and the primary endpoint went up to 3 years with a mean of 1.6 years. The recently initiated CHARISMA trial will look at patients with any prior MI or any other high-risk vascular disease and will study the combination of aspirin plus clopidogrel as compared with aspirin alone, with treatment and follow-up up through 3.5 years. With regard to acute STEMI, there are two trials: CLARITY-TIMI 28 and the Second Chinese Cardiac Study, CCS-2, also n as COMMIT. These two trials will be very complimentary. CLARITY-TIMI 28 will enroll patients within 6 hours of STEMI and have treatment duration and primary endpoint up to approximately day 3 to 4, that is through the time of angiography, which can be between day 2 and day 8. In contrast, CCS-2 is a very large, 40,000-patient trial of patients with STEMI within 24 hours, some of whom will get fibrinolytic therapy and others not. The primary endpoint would be a clinical one, out to 30 days.

    1. 1. CLARITY-TIMI 28 and COMMIT/CCS 2: Trials of clopidogrel in STEMI Christopher P Cannon MD Senior Investigator, TIMI Study Group Associate Professor of Medicine Harvard Medical School Cardiovascular Division Brigham and Women's Hospital Boston, MA
    2. 2. Background <ul><li>Fibrinolytic treatment for STEMI limited by inadequate reperfusion and/or reocclusion in ~25% of patients. </li></ul><ul><li>An occluded infarct-related artery is associated with a doubling of long-term mortality. </li></ul>0 8 16 24 32 40 48 0 5 10 15 20 Occluded Patent Weeks Mortality (%) Dalen JE, Gore JM, Braunwald E, et al. Am J Cardiol. 1988; 62:179-185 Evidence for the open artery hypothesis: TIMI 1
    3. 3. Study design Fibrinolytic, ASA, heparin Clopidogrel 300 mg + 75 mg qd Coronary angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI flow grade 0/1) or D/MI by time of angiogram Randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 years with STEMI < 12 hours Study drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Sabatine MS. N Engl J Med 2005;352(12):1179
    4. 4. Primary endpoint: Occluded artery (or D/MI through angio/HD) Placebo Clopidogrel p=0.00000036 Odds ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds reduction Sabatine MS. N Engl J Med 2005;352(12):1179
    5. 5. CV death, MI, RI  urgent revascularization Days Percentage with endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds ratio 0.80 (95% CI 0.65-0.97) p=0.026 20% Sabatine MS. N Engl J Med 2005;352(12):1179
    6. 6. Bleeding Sabatine MS. N Engl J Med 2005;352(12):1179 NS 7.2 7.5 In those undergoing CABG NS 7.9 9.1 CABG within 5 d of study med 0.9 1.7 0.7 0.5 1.1 Placebo (%) NS NS NS NS NS p value 1.9 TIMI major 1.6 0.5 1.0 1.3 Clopidogrel (%) TIMI minor (Hgb  3-5 g/dL) Intracranial hemorrhage Through 30 days TIMI minor TIMI major (Hgb  >5 g/dL or ICH) Through angiography Outcome
    7. 7. Summary <ul><li>In patients with STEMI  75 years receiving a standard fibrinolytic regimen, a loading dose of 300 mg of clopidogrel followed by 75 mg daily resulted in: </li></ul><ul><li>36% reduction in the odds of an occluded infarct-related artery, or death/MI by time of angiogram (NNT = 16). </li></ul><ul><li>Highly consistent benefit across all major subgroups. </li></ul><ul><li>20% reduction in CV death, MI, or recurrent ischemia leading to urgent revascularization through 30 days (NNT = 36). </li></ul><ul><li>No excess in TIMI major or minor bleeding (including in those undergoing CABG) or in ICH. </li></ul>Sabatine MS. N Engl J Med 2005;352(12):1179
    8. 8. Evolution of pharmacologic reperfusion TPA SK TIMI 1 ASA + clopidogrel ASA NEJM 1985;312:932 APRICOT Placebo ASA Circ 1993;87:1524 36%  p<0.001 90 mins 3 mos 3.5 d 47%  p<0.001 22%  p=0.26 Sabatine MS. N Engl J Med 2005;352(12):1179
    9. 9. <ul><li>Conclusion </li></ul><ul><li>Clopidogrel offers an effective, simple, inexpensive, and safe means by which to improve infarct-related artery patency and reduce ischemic complications. </li></ul>M A R C H 9, 2 0 0 5 Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH and Braunwald E for the CLARITY-TIMI 28 Investigators. N Engl J Med. 2005;352:1179-1189 ACC 2005 LBCT Slide Set available at
    10. 10. <ul><li>TREATMENT: Clopidogrel 75 mg daily vs placebo </li></ul><ul><li>(aspirin 162 mg daily in both groups) </li></ul><ul><li>INCLUSION: Suspected acute MI (ST change or LBBB) within 24 hours of symptom onset </li></ul><ul><li>EXCLUSION: Primary PCI or high-risk of bleeding </li></ul><ul><li>1  OUTCOMES: Death, and death, re-MI, or stroke up to 4 weeks in hospital (or prior discharge) </li></ul><ul><li>Mean treatment and follow-up: 16 days </li></ul>COMMIT: Study design Chen ZM. Presented ACC 2005
    11. 11. COMMIT: Effects of clopidogrel on death, re-MI or stroke Days since randomization (up to 28 days) Event (%) 9% (SE3) relative risk reduction (2P=0.002) Placebo: 2311 events (10.1%) Clopidogrel: 2125 events (9.3%) Chen ZM. Presented ACC 2005
    12. 12. COMMIT: Effect of clopidogrel on death in hospital Dead (%) Days since randomization (up to 28 days) Placebo: 1846 deaths (8.1%) Clopidogrel: 1728 deaths (7.5%) 7% (SE3) relative risk reduction (2P=0.03) Chen ZM. Presented ACC 2005
    13. 13. <ul><li>Type Clopidogrel Placebo (n=22 958) (n=22 891) </li></ul><ul><li>Cerebral </li></ul><ul><li>Fatal 39 40 </li></ul><ul><li>Non-fatal 16 15 </li></ul><ul><li>Non-cerebral </li></ul><ul><li>Fatal 36 37 </li></ul><ul><li>Non-fatal 46 36 </li></ul><ul><li>Any major bleed 134 124 </li></ul><ul><li> (0.58%) (0.54%) </li></ul>COMMIT: Major bleed in hospital Chen ZM. Presented ACC 2005
    14. 14. COMMIT/CCS-2: Conclusions <ul><li>Adding 75 mg daily clopidogrel to aspirin in acute MI prevents ~10 major vascular events per 1000 treated. </li></ul><ul><li>No excess of cerebral, fatal, or transfused bleeds (even with fibrinolytic therapy and in older people). </li></ul><ul><li>Each million MI patients treated for ~2 weeks would avoid 5000 deaths and 5000 non-fatal events . </li></ul>Chen ZM. Presented ACC 2005
    15. 15. Milestones in the evolution of thrombolysis in myocardial infarction <ul><li> Mortality </li></ul><ul><li>1988 ISIS-2 SK 25% ↓ </li></ul><ul><li> ASA 23% ↓ </li></ul><ul><li>1993 GUSTO-1 tPA 14%↓ </li></ul><ul><li>2005 COMMIT/ Clopidogrel 7% ↓ CCS-2 </li></ul>Chen ZM. Presented ACC 2005
    16. 16. Drugs that failed to show mortality reduction in STEMI in the past decade <ul><li>Double-bolus t-PA </li></ul><ul><li>TNK </li></ul><ul><li>rPA </li></ul><ul><li>nPA </li></ul><ul><li>GP IIb/IIIa inhibitor + lytic </li></ul><ul><li>Oral GP IIb/IIIa </li></ul><ul><li>Bivalirudin </li></ul><ul><li>Hirudin </li></ul><ul><li>Pexelizumab </li></ul><ul><li>Magnesium </li></ul><ul><li>Adenosine </li></ul><ul><li>PSGL </li></ul><ul><li>GIK </li></ul><ul><li>etc…. </li></ul>Chen ZM. Presented ACC 2005
    17. 17. Clopidogrel in STEMI <ul><li>Evidence from two large trials in ~50 000 patients </li></ul><ul><li>Benefit in opening infarct-related artery and in reducing mortality and morbidity </li></ul><ul><li>No excess in major bleeding </li></ul><ul><li>Low cost </li></ul><ul><ul><li>A new addition to treatment of STEMI </li></ul></ul>Chen ZM. Presented ACC 2005
    18. 18. Clopidogrel trials – ACS/CAD COMMIT (CCS-2) CAPRIE Lancet 1996 MI / stroke PAD Vasc dis/risk Up to 3.5 years STEMI Acute STEMI Long-term 2 o (1 o ) prevention UA/NSTEMI PCI PCI UA/ NSTEMI + Benefit + Benefit 1 year 1 year + Benefit 1-3 years 30 days + Benefit
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