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

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 Occluded Patent Weeks Mortality (%) Dalen, Gore, Braunwald et al. Am J Cardiol 1988; 62:179. Evidence for the open artery hypothesis: TIMI 1

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

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

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 yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups

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

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

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

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

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

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

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%

Primary Endpoint: Occluded Artery (or D/MI thru Angio/HD) PlaceboClopidogrel P= P= Odds Ratio 0.64 (95% CI ) Clopidogrelbetter Placebobetter n=1752n= % Odds Reduction 36% Odds Reduction

ClopidogrelPlacebo OVERALL Age <65 yr  65 yr Gender Male Female Infarct location Anterior Non-anterior Fibrinolytic Fibrin-specific Non-fibrin specific Predominant heparin Low-molecular-weight Unfractionated None Subgroups – Primary Endpoint OddsEvent Rates (%) Reduction Clopidogrel better Placebo better CharacteristicOdds Ratio (95% CI) All interactions non-significant

Angiographic (%) TIMI Flow Grade <0.001 TIMI Myocardial Perfusion Thrombus <0.001 Primary & Angiographic Outcomes (median 3.5 days) OutcomeClopidogrelPlacebo Odds Ratio P value Primary End Point (%) <0.001 TIMI Flow Grade 0/ <0.001 MI Death

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

CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) Placebo Clopidogrel Odds Ratio 0.80 (95% CI ) P= %20%

CV Death or MI Stroke Recurrent ischemia leading to urgent revasc CV Death, MI, or Stroke CV Death, MI, Stroke, or RI  Urg Revasc Clinical Endpoints through 30d OddsReduction Clopidogrel better Placebobetter Odds Ratio (95% CI) Event Rates (%) ClopidogrelPlacebo

Bleeding Outcome Clopidogrel (%) Placebo (%) P value Through angiography TIMI major (Hgb  >5 g/dL or ICH) NS TIMI minor (Hgb  3-5 g/dL) NS Intracranial hemorrhage NS Through 30 days TIMI major NS In those undergoing CABG NS CABG w/in 5 d of study med NS TIMI minor NS

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

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

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