1. CLopidogrel as Adjunctive ReperfusIon TherapY – Thrombolysis In Myocardial Infarction (TIMI) 28

2. Background Fibrinolytic Rx for STEMI 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

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

4. Hypothesis The addition of clopidogrel to standard fibrinolytic regimens that include aspirin would: Improve infarct-related artery patency Decrease ischemic complications

5. 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 angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups

6. Major Exclusion Criteria Clopidogrel within 7 days or planned Rx with clopidogrel or GP IIb/IIIa before angiography Contraindications to lysis (stroke, ICH, brain tumor) Cardiogenic shock Intention of angiography within 48 hours in absence of a new clinical indication 4000 U bolus UFH or > 67 kg & > 5000 U bolus UFH

7. Trial Organization TIMI Study GroupEugene Braunwald, MD Brigham and Women’s Hospital Christopher P. Cannon, MD Harvard Medical School Marc S. Sabatine, MD, MPH Amy C. McCagg, MBA TIMI Angio Core LabC. Michael Gibson, MD, MS Data Coordinating CenterAllan M. Skene, PhD Nottingham Clinical Research Karen A. Hill, BS Sponsors: Sanofi-AventisBernard Job, MD Christophe Gaudin, MD & Bristol-Myers SquibbRavinder Saini, MD Leigh Townes, BS, RN

8. Top Enrolling Countries SpainJ. Lopez-Sendon364 FranceG. Montalescot265 CanadaP. Theroux261 BelgiumM. Claeys242 RussiaM. Ruda237 GermanyU. Zeymer211 UKA. Gershlick & R. Wilcox205 IsraelB. Lewis198

9. Top Enrolling Centers PrincipalResearch HospitalInvestigatorCoordinator AZ Klina, BelgiumF. CoolsS. Vanhagendoren Canisius-Wih. Ziek., NLD.P. HertzbergerA. Schut Hosp. de Cabueñes, SpainA. Batalla Centre Hosp., FranceA. BonneauL. Soulat Scarborough Card. Res., CAKassam/HalperinP. Parsons Celso da Puccamp, Brazil J.F. Kerr Saraiva C. Travaini Garcia Centre Hospitalier, FranceY. LambertJ. M. Caussanel Szpital Miejski, PolandJ. GesselL. Pawlowicz St. Petersburg Med Acad, RUS. Boldueva Royal Victoria Hospital, UKJ. AdgeyT. McAllister

10. Baseline Characteristics Characteristic Clopidogrel (n=1752) Placebo (n=1739) Age (yrs  SD) 57  10 Male (%) 8081 Hypertension (%) 4344 Hyperlipidemia (%) 3233 Current smoker (%) 5150 Diabetes (%) 1716 Prior MI (%) 99 Anterior MI (%) 4140

11. Initial Therapy Characteristic Clopidogrel (%) Placebo (%) Fibrin-specific lytic 6969 Non-fibrin specific lytic 3131 Initial Aspirin 9999 UFH4646 LMWH3029 Both55 Neither1920 Beta-blockers8989 Statins8081 ACEI or ARB 7372

12. Interventions ParameterClopidogrelPlacebo Sx onset to fibrinolytic 2.7 hrs 2.6 hrs Fibrinolytic to study drug 10 mins Median # doses of study med 44 Angiography93.9%94.2% Study drug to angiography 3.5 days Coronary revascularization 62.8%62.4% PCI57.2%56.6% CABG5.9%6.0%

13. Primary Endpoint: Occluded Artery (or D/MI thru Angio/HD) PlaceboClopidogrel P=0.00000036P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.00.40.60.81.21.6 Clopidogrelbetter Placebobetter n=1752n=1739 36% Odds Reduction 36% Odds Reduction

14. ClopidogrelPlacebo OVERALL3615.021.7 Age <65 yr4213.221.0  65 yr2219.023.1 Gender Male3514.520.8 Female3816.924.7 Infarct location Anterior3315.020.7 Non-anterior3815.022.2 Fibrinolytic Fibrin-specific3114.720.1 Non-fibrin specific4415.724.9 Predominant heparin Low-molecular-weight3111.415.7 Unfractionated4217.827.1 None2617.121.9 Subgroups – Primary Endpoint OddsEvent Rates (%) Reduction 1.00.40.60.81.21.6 Clopidogrel better Placebo better CharacteristicOdds Ratio (95% CI) All interactions non-significant

15. Angiographic (%) TIMI Flow Grade 3 67.860.81.36<0.001 TIMI Myocardial Perfusion 3 55.851.21.210.008 Thrombus43.050.80.73<0.001 Primary & Angiographic Outcomes (median 3.5 days) OutcomeClopidogrelPlacebo Odds Ratio P value Primary End Point (%) 15.021.70.64<0.001 TIMI Flow Grade 0/1 11.718.40.59<0.001 MI2.53.60.700.08 Death2.62.21.170.49

16. Need for Urgent or Additional Treatment 21%  P=0.01 21%  P=0.005 16%  P=0.07 Early Angio (w/in 48 hrs) Urgent Revasc (index hosp) GP IIb/IIIa if PCI

17. CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) 0 5 10 15 051015202530 Placebo Clopidogrel Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 20%20%

18. CV Death or MI 178.49.9 Stroke460.91.7 Recurrent ischemia leading to urgent revasc 243.54.5 CV Death, MI, or Stroke 189.110.9 CV Death, MI, Stroke, or RI  Urg Revasc 2112.315.0 Clinical Endpoints through 30d OddsReduction Clopidogrel better Placebobetter Odds Ratio (95% CI) 1.00.40.60.81.21.6 Event Rates (%) ClopidogrelPlacebo

19. 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

20. Summary In patients with STEMI  75 yrs, 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 angio (NNT = 16)36% reduction in the odds of an occluded infarct- related artery, or death/MI by angio (NNT = 16) Highly consistent benefit across all major subgroupsHighly consistent benefit across all major subgroups 20% reduction in CV death, MI, or recurrent ischemia leading to urgent revasc through 30 days (NNT = 36)20% reduction in CV death, MI, or recurrent ischemia leading to urgent revasc through 30 days (NNT = 36) No excess in TIMI major or minor bleeding (including in those undergoing CABG) or in ICHNo excess in TIMI major or minor bleeding (including in those undergoing CABG) or in ICH

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

22. Clopidogrel offers an effective, simple, inexpensive, and safe means by which to improve infarct-related artery patency and reduce ischemic complications. Conclusion