1. 1 PCI in Patients Receiving Enoxaparin or UFH Following Fibrinolytic Therapy for STEMI: PCI ExTRACT-TIMI 25 C. Michael Gibson, Sabina A. Murphy, David A. Morrow, Carolyn H. McCabe, Dietrich C. Gulba, Gilles Montalescot, Servet Cetin, Oscar H. Kracoff, Basil S. Lewis, Nathan Roguin, Elliott M. Antman, Eugene Braunwald, for the ExTRACT-TIMI 25 Investigators

2. 2 Disclosure Accumetrics, Inc. Amgen, Inc. AstraZeneca Pharmaceuticals LP Baxter Bayer Healthcare LLC Beckman Coulter, Inc. Biosite Incorporated Bristol-Myers Squibb CardioKinetix CV Therapeutics, Inc. Eli Lilly and Company FoldRxGlaxoSmithKline INO Therapeutics LLC Inotek Pharmaceuticals Corporation Integrated Therapeutics Corporation KAI Pharmaceuticals Merck & Co., Inc. Millennium Pharmaceuticals, Inc. Novartis Pharmaceuticals Nuvelo, Inc. Ortho-Clinical Diagnostics, Inc. Pfizer, Inc. Roche Diagnostics Corporation Roche Diagnostics GmbH Sanofi-Aventis Sanofi-Synthelabo Recherche Schering-Plough Research Institute St Jude Medical The National Institutes of Health The TIMI Study Group has received research / grant support in the past 2 yrs through the Brigham & Women’s Hospital with funding from (in alphabetical order):

3. 3 Background: Main Results ExTRACT-TIMI 25 Primary Endpoint: Death or non-fatal re-MI by 30 days Primary Endpoint: Death or non-fatal re-MI by 30 days Main Secondary Endpoint: Death, non-fatal re-MI, urgent revascularization by 30 days Main Secondary Endpoint: Death, non-fatal re-MI, urgent revascularization by 30 days N Engl J Med 2006;354:1477-88. 12.0 9.9 UFH ENOX 14.5 11.7 Days % % RR = 0.83 p = 0.000003 RR = 0.81 p = 0.000001

4. 4 Objective To determine whether ENOX is superior to UFH as adjunctive therapy for patients undergoing PCI for STEMI who initially received fibrinolytic therapy.

5. 5 10,256 Assigned ENOX 10,256 Assigned ENOX 20,479 Patients Randomized into ExTRACT-TIMI 25 2,272 Underwent 2,272 Underwent PCI by 30 days 22.8% 10,223 Assigned UFH 10,223 Assigned UFH 2,404 Underwent 2,404 Underwent PCI by 30 days 24.2% Study Profile

6. 6 Anticoagulation for PCI 8 h since SC dose 8 h since SC dose Additional Enox/Plac NO 0.3 mg/kg IV Additional UFH/Plac GP IIb/IIIa ACT 200 s* ACT 200 s* No GP IIb/IIIa ACT 250 s* ACT 250 s* *ACT TESTING ONLY BY UNBLINDED MEDICAL PROFESSIONAL Sheath Removal Closure DeviceEnd of PCI No Closure Device Wait 6 hours after last sc/IV dose After PCI STUDY MEDICATION SHOULD NOT BE + Groin Hemostasis STARTED UNLESS CLINICALLY INDICATED ONLY blinded study drug to be used All Pts receive BOTH blinded Enox/Plac AND UFH/Plac

7. 7 Baseline Characteristics PCI Cohort N = 4,676 Baseline Characteristics PCI Cohort N = 4,676 41 11 16 51 23 37 82 57 Prior MI (%) Hypertension (%) Hyperlipidemia (%) Current smoker (%) Diabetes (%) Anterior MI (%) Male (%) Age (yrs)-median ALL P = NS for ENOX vs UFH 27 92 0.7 20 87 > 3 (%) LMWH within 7 d (%) Killip Class I (%) TIMI Risk Score (STEMI) UFH within 3 h (%) CrCl (ml/min)-median

8. 8 Medications During Hospitalization PCI Cohort N = 4,676 Medications During Hospitalization PCI Cohort N = 4,67680 86 98 79 21 ACEI / ARB (%) Fibrin-specific (%) ASA (%) Beta Blocker (%) SK (%) Fibrinolytic 85 Statin (%) 68 Clopidogrel (%)

9. 9 PCI Cohort: Primary Endpoint Death or Nonfatal MI by 30 days ENOX Days 13.8% 0 5 10 15 051015202530 Death or MI (%) UFH 10.7% RR 0.77 p=0.001

10. 10 PCI Cohort: Safety EventENOXUFHRRP-Value n=2,238 n=2,377 TIMI Major Bleed1.4%1.6%0.87 (0.55-1.39)0.56 TIMI Minor Bleed3.3%2.4%1.34 (0.95-1.88)0.09 TIMI Major or 4.6%4.0%1.15 (0.88-1.51)0.31 Minor Bleed ICH 0.2%0.4%0.42 (0.13-1.35)0.18 Stroke0.3%0.9%0.30 (0.12-0.75)0.006

11. 11 PCI Cohort: Death or Nonfatal reMI - Major Subgroups ENOX BetterOdds Ratio UFH Better

12. 12 PCI Cohort: Nonfatal Recurrent MI by 30 days UFH ENOX 0 5 10 15 051015202530 Non-Fatal MI (%) 7.8% 10.9% Days RR 0.72 p<0.001

13. 13 Incidence and Relative Timing of PCI ENOX UFH Days 22.8% 24.2% 0 5 10 15 20 25 051015202530 PCI (%) p=0.027 Median time to PCI: UFH (n=2,404) : 109 hours Enox (n=2,272) : 122 hours Incidence of PCI: p=0.006

14. 14 n=1885 Relative Timing of PCI: Urgent vs Non-Urgent PCI UFH ENOX Hours All PCI p=0.006 p=0.31 Urgent PCI Non- Urgent PCI n=1,885 n=1,829n=278n=442 p=0.08 n=2,404 n=2,272

15. 15 Outcomes by 30 Days in Patients Undergoing PCI on Blinded Study Drug UFH (n=1,075) ENOX (n=1,103) % Events Death or Nonfatal reMI Major Bleed RR 0.77 P=0.002 RR 0.75 P=0.33

16. 16 PCI Performed on Blinded Study Drug Two scenarios in which a patient underwent PCI on study drug: 1) Blinded study drug never discontinued and PCI performed on blinded study drug 2) Blinded study drug discontinued prior to PCI and then resumed at time of PCI

17. 17 0 5 10 15 20 051015202530 Days UFH ENOX 14.2% 18.9% Death or MI (%) Death or Nonfatal MI by 30 days Among PCI Patients in Whom Study Drug Was Not Discontinued (n=1501) RR 0.75 p=0.018

18. 18 Death or Nonfatal MI by 30 days Among PCI Patients in Whom Study Drug Was Discontinued and Resumed For PCI (n=677) 0 5 10 15 20 051015202530 Days UFH ENOX 5.9% 14.4% Death or MI (%) RR 0.41 p=0.004

19. Conclusion When compared to UFH as adjunctive therapy among patients undergoing PCI, ENOX: When compared to UFH as adjunctive therapy among patients undergoing PCI, ENOX: Reduced death or MI Reduced death or MI Reduced stroke Reduced stroke No difference in bleeding No difference in bleeding

20. 20 ENOX was associated with ↓ risk of death or reMI both among patients in whom antithrombin was continued as well as discontinued prior to PCI. ENOX associated with both delayed onset and ↓ occurrence of reMI, both of which may expand window of opportunity to perform PCI following fibrinolytic administration.ENOX associated with both delayed onset and ↓ occurrence of reMI, both of which may expand window of opportunity to perform PCI following fibrinolytic administration. Conclusion (cont.)

21. 21 Clinical Implications Among STEMI pts treated with lytic, ENOX can be administered as the sole antithrombin therapy before and during PCI without the need for additional antithrombin inhibition. Among STEMI pts treated with lytic, ENOX can be administered as the sole antithrombin therapy before and during PCI without the need for additional antithrombin inhibition. Periprocedural ENOX is preferable to UFH in the management of these patients. Periprocedural ENOX is preferable to UFH in the management of these patients.

22. 22 Back Up Slides

23. 23 Death at 30 days by PCI and randomization group 0 5 10 15 051015202530 Days ENOX/PCIENOX/no PCI UFH/PCIUFH/no PCI p=0.07 for ENOX vs UFH in no PCI cohort p=0.93 for ENOX vs UFH in PCI cohort Death (%)