1. A Safety and Efficacy Study of Integrilin Facilitated PCI versus Primary PCI in ST Elevation Myocardial Infarction Principal Investigator: Michel Le May, MD ClinicalTrials.gov Identifier: NCT00251823

2. Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial RelationshipCompany Grant/Research Support Grant/Research SupportInvestigator initiated trial with financial support from Schering- Plough of Canada Inc., & Medtronic of Canada Ltd. Consulting Fees/Honoraria Major Stock Shareholder/Equity Royalty Income Ownership/Founder Intellectual Property Rights Other Financial Benefit

3. Investigators Michel R. Le May MD, George A. Wells, PhD, Chris A. Glover, Derek Y. So, MD, MD, Michael P. Froeschl, MD, Jean-François Marquis, MD, Edward R. O'Brien, MD, Michele Turek, MD, Marino Labinaz, MD Research Nurses/Staff Allyson Thomas, Tanya. Abarbanel, Julie Finnigan Adjudication Committee Cathy McLellan (chair), Waytak. Kong, Paul Malik Data Safety Monitoring Jean-Claude Tardif (chair), Philippe L'Allier Participating Hospitals University of Ottawa Heart Institute (on-site cath lab) Ottawa Hospital (Alta Vista campus) Ottawa Hospital (Civic campus)

4. Background n Randomized trials have shown that abciximab is a useful adjunct in pts referred for primary PCI. n Observational studies have shown that eptifibatide yields similar results to abciximab. n No study has examined clinical outcomes by directly comparing eptifibatide to a control group in primary PCI. n Studies with high clopidogrel loading dose are limited in primary PCI.

5. Trial Design Primary endpoint Death, Reinfarction, Recurrent Severe Ischemia at 30 Days. Death, Reinfarction, Recurrent Severe Ischemia at 30 Days. Primary endpoint Death, Reinfarction, Recurrent Severe Ischemia at 30 Days. Death, Reinfarction, Recurrent Severe Ischemia at 30 Days.

6. Reinfarction Recurrent ischemic symptoms at rest lasting at least 30 min and accompanied by n New or recurrent ST-segment elevation of ≥1 mm (0.1 mV) in any contiguous leads or n New left bundle branch block or n Re-elevation in serum CK level > twice the upper limit of normal and at least 50% above the lowest level measured post-infarction.

7. Recurrent Severe Ischemia Recurrent symptoms of ischemia at rest associated with any one of the following New ST-segment deviation (elevation at least 0.1 mV or depression > 0.05 mV measured 80 ms after the J-point in at least 2 contiguous leads). An episode of acute pulmonary edema, sustained ventricular arrhythmias or hemodynamic instability. The need for urgent revascularization. Recurrent myocardial infarction.

8. Exclusion Criteria n Active bleeding n Stroke within 90 days or intracranial bleeding at any time n Major surgery or trauma within six weeks n Systolic blood pressure > 200 mm Hg n Diastolic blood pressure > 110 mm Hg n Prolonged CPR (>10 min) n PCI within 30 days n Fibrinolytic or GP 2b/3a within 7 days n Coagulation disorder / warfarin therapy

9. Exclusion Criteria (2) n Known severe renal impairment (creatinine > 200  mol/L) n Contrast allergy n LMWH within 12 hrs n Cardiogenic shock n Intolerance to aspirin or clopidogrel n Medical condition likely to result in death within 12 months n Participation in another study n Pregnancy

10. Sample Size n Estimated the incidence of the primary endpoint at 30 days in pts assigned to PCI with heparin alone at 15% and in pts assigned to PCI with heparin plus eptifibatide at 5%. n  -level: 0.05 (two-sided);  -error: 0.10 n Anticipated a loss to follow-up rate of 5%. n The number of pts required was 200 per group.

11. Timeline n Open label study design 400 pts were randomly assigned: 201 to PCI with heparin plus eptifibatide 199 to PCI with heparin alone n Enrollment started August 2005 n Enrollment completed March 2008 n Final 6-month follow-up September 2008

12. Baseline Characteristics Heparin plus Eptifibatide Heparin Alone (n = 201)(n = 199) Age, yr60.4 ± 12.160.6 ± 11.8 Age ≥ 75, %15.412.6 Male sex, %80.671.9 Hypertension, %45.849.8 Diabetes mellitus, %14.418.1 Current smoker, %44.838.2 History of hyperlipidimia, %33.338.7 Prior myocardial infarction, %10.513.6 Prior angioplasty, %8.0

13. Baseline Characteristics (2) Heparin plus Eptifibatide Heparin Alone (n = 201)(n = 199) Prior bypass surgery, %5.04.0 Anterior MI, %36.337.7 Heart rate, beats/min74 ± 1676 ± 18 Systolic blood pressure, mm Hg130 ± 23134 ± 24 Diastolic blood pressure, mm Hg77 ± 1480 ± 15 Killip class 1, %90.686.4 Body mass index, kg/m 2 28 ± 5 Creatinine clearance, ml/min93 ± 3587 ± 31 Peak CK, units/L2009 ± 18792047 ± 1627

14. Initial Medications Heparin plus Eptifibatide Heparin Alone (n = 201)(n = 199) Aspirin, %100 Clopidogrel, %100 Eptifibatide, %100*3.0 Abciximab, %0.54.5 * Duration of eptifibatide infusion > 16 hrs in 82% pts; 94% received eptifibatide before cardiac catheterization.

15. Median Time Intervals (min) Heparin plus Eptifibatide Heparin Alone (n = 201)(n = 199) Symptoms to hospital arrival9088 Hospital arrival to randomization4631 Randomization to balloon inflation4850 Hospital arrival to balloon inflation9695 Clopidogrel to balloon inflation75 Eptifibatide to balloon inflation43- Symptoms to eptifibatide144- Symptoms to balloon inflation196194

16. Angiographic Results Heparin plus Eptifibatide Heparin Alone (n = 201)(n = 199) Coronary angiography, %100 Diseased coronary arteries Left main, %0.5 One vessel, %48.846.2 Two vessel, %30.828.6 Three vessel, %19.424.6 No significant disease, %0.50.0

17. Infarct-Related Artery Heparin plus Eptifibatide Heparin Alone (n = 201)(n = 199) Left main, %0.5 Left anterior descending, %3637 Left circumflex, %1412 Right coronary, %4648 Bypass graft, %31 Unknown, %02

18. PCI Procedure Heparin plus Eptifibatide Heparin Alone (n = 201)(n = 199) PCI, %9592 Stent Insertion, %9392 Stents per patient, %1.4 ± 0.91.5 ± 0.9 Drug eluting stent, %1916 Aspiration catheters, %107 Final balloon size, mm3.2 ± 0.5 Maximum balloon pressure, atm17 ± 3 Maximal ACT achieved, sec193213 Intra-aortic balloon, %22

19. Infarct-Related Artery TIMI Flow Rates TIMI 0-1TIMI 3TIMI 2 % Heparin plus eptifibatide Heparin alone Prior to PCIAfter PCI Heparin plus eptifibatide Heparin alone % p = 0.16p = 0.43

20. Events Within 30 Days p = 0.54p = 0.62p = 0.76p = 0.69 % pts

21. Kaplan-Meier Estimates 30 days Log-Rank p = 0.70 6.5% 5.5%

22. Clinical Events at 30 Days Heparin plus Eptifibatide Heparin Alone p valueR R (95% CI) (n = 201)(n = 199) Death, %3.52.00.541.76 (0.51, 6.11) Reinfarction, %1.50.50.623.00 (0.31, 29.1) Death or ReMI, %5.02.50.492.03 (0.68, 6.05) Severe Rec. Ischemia, %3.03.50.760.84 (0.28, 2.56) Primary Outcome, %6.55.50.691.18 (0.52, 2.70) C H F, %7.511.00.220.65 (0.33, 1.29) Cardiogenic Shock, %4.03.00.601.33 (0.45, 3.92) Stroke, %00.50.50 Hemorrhagic00.5

23. Events Within Six Months p = 0.54p = 0.62p = 0.97p = 0.75 % pts

24. Kaplan-Meier Estimates 180 days Log-Rank p = 0.76 8.0% 7.1%

25. Clinical Events at Six Months Heparin plus Eptifibatide Heparin Alone p valueR R (95% CI) (n = 201)(n = 199) Death,%4.53.00. 451.49 (0.52, 4.27) Reinfarction,%2.01.00.681.98 (0.36, 10.9) Death or ReMI,%6.53.60.181.88 (0.73, 4.81) Severe Rec. Ischemia,%4.54.60.970.98 (0.38, 2.52) Primary Outcome,%8.07.10.891.13 (0.54, 2.38) C H F,%7.512.20.110.58 (0.30, 1.14) Cardiogenic Shock,%4.04.60.770.87 (0.33, 2.29) Stroke,%02.00.06 Hemorrhagic01.0

26. Primary Outcome Subgroup Analysis

27. TIMI Bleeding Events During Initial Hospitalization p = 0.14p = 0. 21p = 0.04 % pts

28. Revascularization Initial Hospitalization Heparin plus Eptifibatide Heparin Alone p valueR R (95% CI) (n = 201)(n = 199) Non-protocol PCI, %17.418.10.860.95 (0.6, 1.6) PCI IRA, %2.01.00.692.00 (0.4, 11.1) Repeat TVR, %3.52.00.541.76 (0.5, 6.1) Bypass Surgery, %4.53.00.451.50 (0.5, 4.3) Any Revascularization, %21.920.60.751.08 (0.7, 1.7)

29. Revascularization 30 Days and Six Months Heparin plus Eptifibatide Heparin Alone p valueR R (95% CI) 30 Days Non-protocol PCI, %19.418.60.841.05 (0.6, 1.7) Repeat TVR, %4.02.00.381.76 (0.5, 6.1) Bypass Surgery, %5.03.00.321.68 (0.6, 4.7) Any Revascularization, %23.921.10.511.17 (0.7, 1.9) Six Months Non-protocol PCI, %19.919.10.841.05 (0.6, 1.7) Repeat TVR, %4.03.00.601.33 (0.5, 3.9) Bypass Surgery, %5.04.00.651.25 (0.5, 3.2) Any Revascularization, %24.422.60.681.10 (0.7, 1.8)

30. Limitations n Relatively small sample size. n Study was performed after the establishment of an integrated city-wide rapid response STEMI system that resulted in relatively short ischemic time intervals. n Relatively high percentage of PCI to a non–infarct- related artery performed later during the initial hospitalization may have contributed to the low event rates.

31. Conclusions In pts with acute STEMI pre-treated with high dose clopidogrel, as compared with PCI with heparin alone, PCI with eptifibatide initiated before catheterization 1) does not improve clinical outcomes and 2) is associated with more bleeding.