1. Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated with a doubling of long-term mortality. 0816243240 48 0 5 10 15 20 Occluded Patent Weeks Mortality (%) Dalen, Gore, Braunwald et al. Am J Cardiol 1988;62:179. Evidence for the open artery hypothesis: TIMI 1

2. Clopidogrel Oral antiplatelet medication that blocks ADP receptor and works synergistically with aspirin Modified from Schafer. Am J Med 1996;101:199-209.

3. Study Design of CLARITY Trial Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 years with STEMI < 12 hours 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 angio randomize Placebo Study drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups As presented by Dr Marc Sabatine to ACC 2005 Sabatine et al. N Engl J Med 2005;352:1179-1189.

4. Initial Therapy CharacteristicClopidogrelPlacebo Fibrin-specific lytic69% Non-fibrin specific lytic31% Initial aspirin99% UFH46% LMWH30%29% Both5% Neither19%20% Beta-blockers89% Statins80%81% ACEI or ARB73%72% Sabatine et al. N Engl J Med 2005;352:1179-1189.

5. Interventions ParameterClopidogrelPlacebo Sx onset to fibrinolytic2.7 hrs2.6 hrs Fibrinolytic to study drug10 mins Median # doses of study med44 Angiography93.9%94.2% Study drug to angiography3.5 days Coronary revascularization62.8%62.4% PCI57.2%56.6% CABG5.9%6.0% Sabatine et al. N Engl J Med 2005;352:1179-1189.

6. Primary Endpoint: Occluded Artery (or D/MI thru Angio/HD) PlaceboClopidogrel P=0.00000036 Odds ratio 0.64 (95% CI 0.53-0.76) 1.00.40.60.81.21.6 Clopidogrel better Placebo better n=1752n=1739 36% Odds reduction 36% Odds reduction Sabatine et al. N Engl J Med 2005;352:1179-1189.

7. Subgroups – Primary Endpoint 1.00.40.60.81.21.6 Clopidogrel betterPlacebo better CharacteristicOdds ratio (95% CI) All interactions non-significant OddsEvent rates (%) reduction ClopidogrelPlacebo OVERALL36%15.021.7 Age <65 yr42%13.221.0  65 yr22%19.023.1 Gender Male35%14.520.8 Female38%16.924.7 Infarct location Anterior33%15.020.7 Non-anterior38%15.022.2 Fibrinolytic Fibrin-specific31%14.720.1 Non-fibrin specific44%15.724.9 Predominant heparin Low-molecular-weight31%11.415.7 Unfractionated42%17.827.1 None26%17.121.9 Sabatine et al. N Engl J Med 2005;352:1179-1189.

8. Primary & Angiographic Outcomes (median 3.5 days) OutcomeClopidogrelPlacebo Odds ratio P value Primary Endpoint 15.0%21.7%0.64<0.001 TIMI Flow Grade 0/111.7%18.4%0.59<0.001 MI2.5%3.6%0.700.08 Death2.6%2.2%1.170.49 Angiographic Outcome TIMI Flow Grade 367.8%60.8%1.36<0.001 TIMI Myocardial Perfusion 3 55.8%51.2%1.210.008 Thrombus43.0%50.8%0.73<0.001 Sabatine et al. N Engl J Med 2005;352:1179-1189.

9. Need for Urgent or Additional Treatment Early Angio (< 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI 21%  P=0.01 21%  P=0.005 16%  P=0.07 Sabatine et al. N Engl J Med 2005;352:1179-1189.

10. CV Death, MI, RI  Urg Revasc Days Percent with endpoint 0 5 10 15 051015202530 Placebo Clopidogrel Odds ratio 0.80 (95% CI 0.65-0.97) P=0.026 20% Sabatine et al. N Engl J Med 2005;352:1179-1189.

11. Odds reduction Clopidogrel better Placebo better Odds ratio (95% CI) 1.00.40.60.81.21.6 Event rates (%) ClopidogrelPlacebo CV death or MI17%8.49.9 Stroke46%0.91.7 Recurrent ischemia leading to urgent revasc 24%3.54.5 CV death, MI, or stroke18%9.110.9 CV death, MI, stroke, or RI  urgent revasc 21%12.315.0 Clinical Endpoints Through 30 Days Sabatine et al. N Engl J Med 2005;352:1179-1189.

12. Bleeding Outcome Clopidogrel (%) Placebo (%) P value Through angiography TIMI major (Hgb  >5 g/dL or ICH) 1.31.1NS TIMI minor (Hgb  3-5 g/dL) 1.00.5NS Intracranial hemorrhage 0.50.7NS Through 30 days TIMI major 1.91.7NS In those undergoing CABG 7.57.2NS CABG w/in 5 d of study med 9.17.9NS TIMI minor 1.60.9NS Sabatine et al. N Engl J Med 2005;352:1179-1189.

13. Summary 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: 36% reduction in the odds of an occluded infarct- related artery or death / MI by time of angio (NNT = 16) Highly consistent benefit across all major subgroups 20% reduction in CV death, MI, or recurrent ischemia leading to urgent revasc through 30 days (NNT = 36) No excess of TIMI major or minor bleeding (including in those undergoing CABG) or of ICH Sabatine et al. N Engl J Med 2005;352:1179-1189.

14. TPASK Evolution of Pharmacologic Reperfusion TIMI 1 ASA + Clopidogrel ASA N Engl J Med 1985;312:932 APRICOT PlaceboASA Circulation 1993;87:1524 36%  P<0.001 36%  P<0.001 47%  P<0.001 47%  P<0.001 22%  P=0.26 22%  P=0.26 90 mins3 mos3.5 d

15. Clopidogrel offers an effective, simple, inexpensive, and safe means by which to improve infarct-related artery patency and reduce ischemic complications in STEMI patients receiving aspirin and standard fibrinolytic therapy. Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH, Braunwald E for the CLARITY- TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352(12):1179-1189. ACC 2005 LBCT Slide Set available at www.timi.org. Conclusion M A R C H 9, 2 0 0 5

16. To determine whether, following admission for acute MI, the addition of clopidogrel to aspirin (& early metoprolol) can produce a further reduction in either  the composite endpoint of in-hospital death, MI, or stroke; or  mortality alone COMMIT / CCS-2 (ClopidOgrel and Metoprolol in Myocardial Infarction Trial) As presented by Dr Zhengming Chen to ACC 2005

17. COMMIT: Study Design TreatmentClopidogrel 75 mg daily vs placebo (aspirin 162 mg daily in both groups) InclusionSuspected acute MI (ST change or LBBB) within 24 h of symptom onset ExclusionPrimary PCI or high risk of bleeding 1  OutcomesDeath & death, re-MI, or stroke up to 4 weeks in hospital (or prior discharge) Mean treatment + follow-up = 16 days As presented by Dr Zhengming Chen to ACC 2005

18. Characteristic Clopidogrel Placebo (n=22,960) (n=22,891) Age 70+ years 26.0%26.0% Female27.7%27.9% Time delay <6 h 33.8%33.7% STEMI / LBBB93.1%93.1% Killip class II/III24.1%24.0% Fibrinolytic: All patients 49.7%49.8% STEMI <12h 67.8%67.7% COMMIT: Baseline Characteristics As presented by Dr Zhengming Chen to ACC 2005

19. Therapy ClopidogrelPlacebo (n=22,958) (n=22,891) Anticoagulants74.1%75.0% ACE inhibitors68.2%68.3% Anti-arrhythmics22.4%22.2% Nitrates94.1%94.3% Diuretics23.3%23.3% Calcium antagonists11.8%11.8% COMMIT: Concomitant Therapy As presented by Dr Zhengming Chen to ACC 2005

20. 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 + ASA: 2311 events (10.1%) Clopidogrel + ASA: 2125 events (9.3%) As presented by Dr Zhengming Chen to ACC 2005

21. COMMIT: Effect of Clopidogrel on Death in Hospital Dead (%) Placebo + ASA: 1846 deaths (8.1%) Clopidogrel + ASA: 1728 deaths (7.5%) 7% (SE3) relative risk reduction (2P=0.03) Days since randomization (up to 28 days) As presented by Dr Zhengming Chen to ACC 2005

22. COMMIT: Effects of CLOPIDOGREL on Death, Re-MI, or Stroke by Day of Event ClopidogrelPlaceboOdds ratio & 95% CI Clopid. betterPlacebo better Day of event (22,958) (22,891) 0463523(2.0%)(2.3%) 1486527(2.1%)(2.3%) 2-3449451(2.0%) 4-7432463(1.9%)(2.0%) 8-28295347(1.3%)(1.5%) ALL21252311(9.3%)(10.1%) 9% SE 3 (2P = 0.002) 0.40.60.81.01.21.41.6 As presented by Dr Zhengming Chen to ACC 2005

23. Clopidogrel Placebo Type (n=22,958) (n=22,891) Cerebral Fatal3940 Non-fatal1615 Non-cerebral Fatal3637 Non-fatal4636 Any major bleed134 124 (0.58%) (0.54%) COMMIT: Major Bleed in Hospital As presented by Dr Zhengming Chen to ACC 2005

24. COMMIT / CCS-2: Conclusions  Adding 75 mg daily clopidogrel to aspirin in acute MI prevents ~10 major vascular events per 1000 treated  No excess of cerebral, fatal, or transfused bleeds (even with fibrinolytic therapy and in older people)  Treating each million MI patients for ~2 weeks would avoid 5000 deaths and 5000 non-fatal events As presented by Dr Zhengming Chen to ACC 2005

25. Milestones in the Evolution of Thrombolysis in Myocardial Infarction YearTrialAgentMortality 1988ISIS-2SK25%  ASA23%  1993GUSTO-1TPA14%  2005COMMIT / CCS-2 Clopidogrel7% 

26. Double-bolus TPABivalirudin TNKHirudin rPAPexulizamab nPAMagnesium GP IIb/IIIa inhibition + lyticAdenosine Oral GP IIb/IIIa inhibitorsPSGL GIK etc… Drugs that Have Failed to Show Mortality Reduction in STEMI in Past Decade

27. ST-Elevation MI: Clopidogrel Trials COMMIT / CCS-2 46,000 patients Mortality, D / MI / CVA AMI < 24 hrs Age up to 100 ~ 50% lytic No loading dose China Non-invasive strategy 3,500 Patients Infarct artery patency AMI < 12 hrs Age < 75 100% fibrinolytic Loading dose Europe / N. America Invasive strategy

28. Special Considerations for Clinical Use Bolus vs no bolus  Benefit on clinical endpoints emerged in first 24 hrs in both trials  CLARITY-TIMI 28: 20% benefit  COMMIT / CCS-2: 9% benefit (~13% in patients <12 hrs) Elderly: evidence for benefit in COMMIT  In patients > 75 years: no loading dose  In patients < 75 years: 300 mg loading dose Worldwide public health benefit: 1 month ~$100 vs TPA $2,200 No excess major bleeding in CABG

29. Clopidogrel in STEMI  Evidence from 2 large trials in ~50,000 patients  Benefit in opening infarct-related artery and in reducing mortality and morbidity  No excess of major bleeding  Low cost A new addition to the treatment of STEMI

30. www.theheart.org Accessed 3/20/2005