1. 1 Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction ExTRACT- TIMI 25 ACC 2006 Atlanta, GA Disclosure Statement: Dr. Antman received research grant support via the Brigham and Women’s Hospital from sanofi-aventis

2. 2Background Advantages of ENOX over UFH Greater anti Xa:anti IIa activity Reliable A/C without monitoring Convenient sc administration Prior trials suggest ENOX may be superior to UFH Pharmacologic reperfusion remains the most common treatment for STEMI Definitive evaluation of ENOX vs UFH needed

3. 3 Primary Hypothesis Compared to UFH, adjunctive antithrombin therapy with ENOX reduces the composite end point of all-cause mortality or non-fatal re-MI within 30 days in patients with STEMI who are eligible to receive fibrinolytic therapy.

4. 4 Trial Organization TIMI Study Group Eugene Braunwald Elliott M. Antman David A. Morrow Carolyn H. McCabe Sabina Murphy Susan McHale Sponsor: sanofi-aventis Frank JiangChristophe Gaudin Paul ChewSylvie Fontecave Lu CuiKim Giordano Data Safety Monitoring Board Frans Van de Werf (Chair) David DeMets Desmond Julian Jean Rouleau J. Ward Kennedy Jeffrey Anderson

5. 5 STEMI < 6 h Lytic eligible Lytic choice by MD (TNK, tPA, rPA, SK) ENOX < 75 y: 30 mg IV bolus SC 1.0 mg / kg q 12 h (Hosp DC) ≥ 75 y: No bolus SC 0.75 mg / kg q 12 h (Hosp DC ) CrCl < 30: 1.0 mg / kg q 24 h Double-blind, double-dummy ASA Day 30 1° Efficacy Endpoint: Death or Nonfatal MI 1° Safety Endpoint: TIMI Major Hemorrhage Protocol Design UFH 60 U / kg bolus (4000 U) Inf 12 U / kg / h (1000 U / h) Duration: at least 48 h Cont’d at MD discretion

6. 6 Enrollment: Oct 2002 - Oct 2005 N = 20,479 (ITT) 48 Countries674 Sites 48 Countries674 Sites ArgentinaFinlandLatviaSingapore AustraliaFranceLebanonSlovakia AustriaGermanyLithuania South Africa BelarusGreeceMalaysiaSpain Belgium Hong Kong MexicoSweden BrazilHungaryNetherlandsSwitzerland BulgariaIndia New Zealand Thailand CanadaIrelandNorwayTurkey ChileIsraelPolandUkraine ChinaItalyPortugal United Kingdom CroatiaJordanRomania United States Estonia Republic of Korea Russian Federation Uruguay

7. 7 Baseline Characteristics ITT N = 20,479 Baseline Characteristics ITT N = 20,479 44 13 15 47 18 44 77 59 Prior MI (%) Hypertension (%) Hyperlipidemia (%) Current smoker (%) Diabetes (%) Anterior MI (%) Male (%) Age (yrs)-median ALL P = NS 36 64 89 0.5 16 82 > 3 (%) LMWH within 7 d (%) Killip Class I (%) TIMI Risk Score (STEMI) < 3 (%) UFH within 3 h (%) CrCl (ml/min)-median

8. 8 Medications ITT N = 20,479 Medications ITT N = 20,479 80 86 95 80 20 ACEI / ARB (%) Fibrin-specific (%) ASA (%) Beta Blocker (%) SK (%) Fibrinolytic 70 Statin (%) ALL P = NS

9. 9 Primary End Point (ITT) Death or Nonfatal MI Primary End Point (%) Primary End Point (%) ENOX UFH Relative Risk 0.83 (0.77 to 0.90) P<0.0001 Days 9.9% 12.0% Lost to follow up = 3 17% RRR

10. 10 Treatment Benefit over Time (ITT) Death or Nonfatal MI Primary End Point (%) Primary End Point (%) ENOX UFH Days 9.9% (1017) 12.0% (1223) 4.7% 5.2% RR 0.90 (0.80 to 1.01) P=0.08 48 h UFH ENOX 206 events

11. 11 Major Secondary End Point Death or Nonfatal MI or Urgent Revascularization (ITT) Secondary End Point (%) Secondary End Point (%) Days ENOX UFH 11.7% (1199) 14.5% (1479) 5.3% 6.1% RR 0.88 (0.79 to 0.98) P=0.02 48 h UFH ENOX 280 events 19% RRR RR 0.81 (0.75 to 0.87) P<0.0001 12% RRR

12. 12 Outcomes at 30 Days (ITT) RR P value 0.92 0.11 0.67 <0.0001 0.74 0.0008 % 8% 33% 26%UFH ENOX

13. Death or Nonfatal MI - Day 30 Major Subgroups B B B > Median < Median Fibrin-specific Streptokinase Prior MI No Prior MI DM No DM Other Anterior 0.512 PRIOR MI OVERALL DIABETES FIBRINOLYTIC INFARCT LOCATION ENOX BetterUFH Better Relative Risk TIME TO Rx 20,479 11 23 17 21 17 20 13 18 23 12 17 Reduction In Risk (%) >= 75 < 75 AGE (y) 20 6 Female Male SEX 18 16 All Interaction Tests P = NS P < 0.0001

14. 14 Death or Nonfatal MI - Day 30 Medical Rx vs Any PCI 0.00040.001 % Events Medical Rx N = 15,223 (75%) Any PCI N = 4,676 (23%) ENOX UFH P Value 9.7 RRR 16% 11.4 13.8 10.7 RRR 23%

15. 15 Death or Nonfatal MI - Day 30 Clopidogrel Use 0.0005 0.0006 0.0006 % Events No Clopidogrel N = 14,752 (78%) Clopidogrel Used* N = 5,727 (28%) ENOX UFH P Value 10.4 RRR 15% 12.2 11.4 8.7 RRR 24% * 2546 clopidogrel treated patients did not undergo PCI

16. 16 Bleeding Endpoints (TIMI) 30 Days Bleeding Endpoints (TIMI) 30 Days UFH ENOX % Events Major Bleed (fatal + nonfatal) ICH ARD 0.7% RR 1.53 P<0.0001 ARD 0.1% RR 1.27 P = 0.14 Nonfatal Major Bleed ARD 0.4% RR 1.39 P = 0.014

17. 17 Net Clinical Benefit at 30 Days 11.250.90.8 Death or Nonfatal MI or Nonfatal ICH Death or Nonfatal MI or Nonfatal Major Bleed Death or Nonfatal MI or Nonfatal Disabl. Stroke ENOX Better UFH Better RR UFH (%)ENOX (%)RRR (%) 12.3 10.118 12.8 11.014 12.2 10.117 Prespecified Definitions P <0.0001

18. 18 For Every 1000 Pts Treated with Enoxaparin Events / 1000 Pts Nonfatal reMI Urgent Revasc. Death Nonfatal TIMI Major Bleed (No increase in nonfatal ICH) +

19. 19 Clinical Implication A strategy of ENOX is clearly preferable to the current standard of UFH as the antithrombin to support fibrinolysis, the most common form of reperfusion for STEMI used worldwide. A strategy of ENOX is clearly preferable to the current standard of UFH as the antithrombin to support fibrinolysis, the most common form of reperfusion for STEMI used worldwide.

20. Publication of Primary Results Slides and Full Listing of Trial Participants at www.TIMI.org www.NEJM.org www.NEJM.org

21. 21

22. 22 Trial Results In Perspective: Major Bleeding Rates % Pts with Major Bleed Keeley Lancet 2003 Eikelboom Circ. 2005 Major Bleed (Total) Lytic Arms UFH LMWH UFH UFH ENOX UFH ENOX Nonfatal Major Bleed Major Bleeds in Prior Trials Pooled Data

23. 23 Trial Results In Perspective: PCI vs Lysis for STEMI % Events (30-42 Days) Reinfarction Lytic Arms (UFH) PCI Arms ENOX Overview of 23 RCTs Keeley Lancet 2003 The significant advance in adjunctive therapy with enoxaparin has narrowed the gap between PCI and Lysis as reperfusion for STEMI.