Disclosures

1. Early Glycoprotein IIb/IIIa Inhibition in Non-ST-segment Elevation Acute Coronary Syndrome: A Randomized, Double-blind, Placebo-Controlled Trial Evaluating the Clinical Benefits of Early Front-loaded Eptifibatide in the Treatment of Patients with Non-ST-segment Elevation Acute Coronary Syndromes

2. Disclosures • Funded by Millennium Pharmaceuticals and Schering Plough • Individual disclosures • Armstrong • Braunwald • Califf • Gibson • Giugliano • Harrington • Montalescot • Newby • Strony • Van de Werf

3. Study Structure—figure with the below components • Exec Comm • Steering Committee • Sponsor • Coordinating Centers—DCRI, TIMI, CVC • DSMB • Sites • CEC

4. Primary Objective To demonstrate the superiority of a strategy of early, routine eptifibatide begun shortly after presentation compared with a strategy of delayed, provisional use of eptifibatide pre-PCI in reducing the composite of death, MI, recurrent ischemia, and thrombotic bail-out within 96 hours in patients with high-risk NSTE ACS managed with an invasive strategy

5. Study Design 2 of 3 high-risk criteria: 1. Age > 60 years 2. + CKMB or TnT/I 3. ST  or transient ST  (Or age 50-59, h/o CVD and + CKMB or TnT/I) High-risk NSTE ACS n = 10,500 (9500) Early, routine eptifibatide (180/2/180) Placebo / provisional eptifibatide pre-PCI Randomize within 12 hours of presentation Invasive strategy: 12 to 96 hours after randomization 1 Endpoint: 96-hr Death/MI/Urgent Revasc/Thrombotic bailout 2 Endpoint: 30-d Death/MI Fade in safety endpoints at 120 hours (bleeding (GUSTO and TIMI scales), transfusions, stroke, non-hemorrhagic SAEs

6. Key Exclusion Criteria • Increased bleeding risk • active bleeding or recent bleed • Recent surgery or trauma • Prior ICH or recent ischemic stroke • Serious concomitant illness or pregnancy • ESRD with dialysis < 30 days • Recent or planned use of direct thrombin inhibitor, fXa inhibitor, abciximab/tirofiban • amendment 1: bivalirudin at PCI • amendment 2: acute fondaparinux or bivalirudin

7. Blinded Study Drug Administration • Double bolus and infusion regimen • 180 ug/Kg IV eptifibatide (or matching placebo) bolus as soon as possible after randomization • Immediate initiation of 2 ug/Kg/min eptifibatide (or matching placebo) infusion (1 ug/Kg/min if CrCl <50 cc/min) • Second 180 ug/Kg IV eptifibatide (or matching placebo) bolus 10 minutes after initial bolus • Provisional, blinded transition to open label eptifibatide at time of PCI using blinded bolus kit • PCI active if transition before wire crossed lesion • PCI bailout if after wire crossed the lesion

8. Statistical Methods • Power = 85% to detect a 22.5% reduction in the primary quadruple composite assuming an event rate of 5.8% with placebo at alpha 0.048 after single interim efficacy analysis • Power = 85% for the key secondary efficacy endpoint of death or MI at 30 days (15% RRR, placebo rate 12.7%); also at alpha 0.048, using step down testing procedure where formally tested only if primary endpoint significant • Power after sample size reduction to 9500 patients • 98% for 96-hour primary composite endpoint • 81% for 30-day key secondary endpoint of death or MI • Prespecified subgroups • Proper: Age, baseline troponin, hospital type, diabetes, early clopidogrel, UFH vs enoxaparin, TIMI Risk Score • Post-randomization (improper): By management strategy (PCI, CABG, medical)

9. Enrollment • Use map of world with enrollment by country on the map • Recognize top 20 (?30) enrollers worldwide—could be a “build” on top of the map

10. Study Conduct Patients randomized 9492 Patients excluded for site conduct 64 Patients without informed consent 22 Intent-to-treat population 9406 Patients who received no study drug 77 As-treated safety population 9329 Lost to follow-up 11

11. Baseline Characteristics ERE (n=4722) DPE (n=4684) Age (years) 67 (60, 75) 68 (60, 75) Female (%) 32.0 31.2 Region (%) Most of World 69.2 69.4 North America 30.8 30.6 Diabetes mellitus (%) 30.1 30.7 Hypertension (%) 70.5 71.9 Dyslipidemia (%) 57.9 57.8 Prior MI (%) 27.0 28.2 Prior PCI (%) 24.3 25.0 Prior CABG (%) 13.1 14.2 Creatinine Clearance (cc/min) 75 (56, 96) 74 (56, 96) Troponin or CKMB positive (%) 85.9 87.0 ST-segment shifts (%) 61.6 62.0 Presentation to rand (hours) 5.4 (3.3, 8.8) 5.7 (3.4,8.8)

12. In-hospital Management ERE (n=4722) DPE (n=4684) Cardiac Catheterization (%) 97.5 97.6 Randomization to cath (hours) 21.4 (16.9, 34.2) 21.4 (16.7, 31.0) PCI (%) 58.5 59.7 Active provisional (%) 24.9 26.8 Bailout (%) 11.3 12.0 CABG (%) 13.2 12.9 Medically Treated only (%) 30.3 31.4 Use of Evidence-based Rx (%) ASA 97.5 97.3 UFH or enoxaparin 94.3 94.2 Beta-blocker 87.7 87.7 Statin 86.4 86.9 ACEI / ARB 78.4 78.5 Clopidogrel (intended early) 74.8 75.2 Clopidogrel (any) 90.4 90.6

13. 96-Hour Primary Efficacy Results ERE DPE OR P (n=4722) (n=4684) (95% CI) Death, MI, RIUR, TBO 9.3 10.0 0.92 0.23 (0.80-1.06) Death 0.8 0.9 0.96 0.87 (0.62-1.50) Death / MI 7.5 8.3 0.89 0.13 (0.77-1.04) Death / MI / RIUR 8.4 9.4 0.89 0.11 (0.77-1.03 )

14. 15 N # Events Hours to Event Delayed provisional eptifibatide 4684 469 25.9 (18.7, 48.4) Early routine eptifibatide 4722 439 31.1 (18.8, 62.2) 10.0% 10 9.3% Delayed provisional eptifibatide Death, MI, RIUR or TBO (%) P = 0.23 (stratified for intended early clopidogrel use) 5 Early routine eptifibatide 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 Time Since Randomization (Hours) Kaplan-Meier Curves for Primary Endpoint

15. 30-Day Secondary Efficacy Results ERE DPE OR P (n=4722) (n=4684) (95% CI) Death or MI 11.2 12.3 0.89 0.079 (0.79-1.01) Death 2.8 2.6 1.10 0.46 (0.86-1.41) Death, MI, RIUR 12.5 13.8 0.89 0.065 (0.79-1.01)

16. 15 12.4% Delayed provisional eptifibatide 11.2% 10 P = 0.079 Death or MI (%) Early routine eptifibatide (stratified for intended early clopidogrel use) 5 N # Events Days to Event Delayed provisional eptifibatide 4684 578 2.1 (1.0, 5.8) Early routine eptifibatide 4722 528 2.7 (1.0, 4.9) 0 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 0 1 2 3 4 5 Time Since Randomization (Days) Kaplan-Meier Curves for 30-day Death or MI

17. Delayed Odds Ratio for Upstream Early Routine Provisional Eptifibatide (95% CI) Eptifibatide, % Eptifibatide, % Baseline Characteristic Overall 9.3 10.0 Men 9.1 9.8 Women 9.7 10.4 8.6 9.5 Age < 75 yr 11.4 11.4 Age > 75 yr 9.5 10.6 Troponin positive 7.7 6.8 Troponin negative Diabetes 8.9 10.6 9.5 9.8 No Diabetes 8.8 9.5 Upfront clopidogrel intended 10.8 11.5 No upfront clopidogrel intended Randomized 8.9 10.5 < 4 hours 9.5 9.8 Randomized > 4 hours High TIMI Risk Score (5 - 7) 10.4 10.8 Intermediate TIMI Risk Score (3 - 4) 9.4 10.1 Low TIMI Risk Score (0 - 2) 6.8 8.0 9.1 11.0 Unfractionated heparin only Low molecular weight heparin only 9.9 9.9 Primary Care Hospital 9.0 9.7 Tertiary Care Hospital 9.4 10.1 North America 10.3 10.6 Western Europe 7.3 8.6 Eastern Europe 11.2 11.2 Middle East, Africa and Asia 10.9 11.5 0.50 0.60 0.70 0.80 0.90 1.00 2.00 Early Eptifibatide Better Delayed Provisional Eptifibatide Better 96-hour Primary Efficacy ResultsBy Prespecified Subgroups

18. Delayed Odds Ratio for Upstream Early Routine Provisional Baseline Characteristic Eptifibatide (95% CI) Eptifibatide, % Eptifibatide, % Overall 11.2 12.3 Men 11.4 12.0 Women 10.7 13.0 Age < 75 yr 10.2 11.6 Age > 75 yr 14.0 14.6 Troponin positive 11.6 13.0 Troponin negative 8.1 8.4 Diabetes 11.7 13.8 No Diabetes 10.9 11.7 Upfront clopidogrel intended 10.3 12.0 No upfront clopidogrel intended 13.7 13.4 Randomized < 4 hours 11.1 12.8 Randomized > 4 hours 11.2 12.1 High TIMI Risk Score (5 - 7) 13.2 13.3 Intermediate TIMI Risk Score (3 - 4) 10.9 12.8 Low TIMI Risk Score (0 - 2) 8.1 9.1 Unfractionated heparin only 11.3 13.0 Low molecular weight heparin only 11.3 12.8 Primary Care Hospital 10.7 12.3 Tertiary Care Hospital 11.3 12.4 North America 13.2 14.5 Western Europe 10.2 8.8 Eastern Europe 14.5 15.2 Middle East, Africa and Asia 11.0 11.6 0.50 0.60 0.70 0.80 0.90 1.00 2.00 Early Eptifibatide Better Delayed Provisional Eptifibatide Better 30-day Death or MI By Prespecified Subgroups

19. Safety Results (through 120 hours) ERE DPE OR(95%CI) P (n=4686) (n=4643) Bleeding (overall) TIMI Major 2.6 1.8 1.42 (1.07-1.89) 0.015 TIMI major or minor 5.8 3.4 1.75 (1.43-2.14) <0.001 GUSTO Severe 0.8 0.9 0.99 (0.64-1.55) 0.97 GUSTO Moderate or Severe 7.6 5.1 1.52 (1.28-1.80) <0.001 PRBC transfusion 8.6 6.7 1.31 (1.12-1.53) 0.001 Bleeding (CABG) Re-operation for bleeding 6.0 8.4 0.70 (0.39-1.27) 0.24 Chest tube output (mL/24 H) 720 770 -- 0.41 Thrombocytopenia (nadir <100K) 3.3 2.8 Stroke 0.6 0.8 0.79 (0.48-1.30) 0.36

20. Conclusions • Among high-risk NSTE ACS patients, a strategy of early, routine eptifibatide compared with delayed provisional eptifibatide at PCI • did not significantly reduce the primary composite of D/MI/RIUR/TBO at 96h (9.3% vs. 10.0%, OR 0.92; 0.80-1.06; p = 0.234) • resulted in a trend toward reduction in death or MI at 30 days (11.2% vs. 12.3%; OR 0.89; 0.79-1.03; p = 0.079), but no difference in 30-day mortality (x.x% vs. y.y%; OR 0.xx; 0.yy-0.zz; p = 0.aa) • resulted in significantly higher rates of non-life-threatening bleeding and transfusions

21. Implications • The results of EARLY ACS do not support a strategy of early, routine eptifibatide use among NSTE ACS patients managed with an invasive strategy • It may be reasonable to consider early eptifibatide use in selected high-risk subsets of ACS patients with low risk of bleeding who are scheduled to undergo PCI • In selected high-risk NSTE ACS patients who are also at increased bleeding risk, a delayed provisional eptifibatide strategy pre-PCI would be reasonable

22. Primary and Key Secondary Efficacy ResultsBy Clopidogrel Strata at Randomization ERE DPE OR (95% CI) 96-hr Death, MI, RIUR, TBO Clopidogrel intended 8.8 9.5 0.92 (0.78-1.08) No Clopidogrel intended 10.8 11.5 0.93 (0.72-1.20) 30-day Death / MI Clopidogrel intended 10.3 12.0 0.85 (0.73-0.91) No Clopidogrel intended 13.7 13.4 1.03 (0.81-1.31)