1. Presenters’ Disclosure Information: Relationships Related to this Presentation Research Grants and/or Consultant fees: Mahaffey: l Aventis, AstraZeneca, Berlex, Lilly, Daiichi, Millennium, Merck, Schering-Plough, The Medicines Company Ferguson: l Aventis, AstraZeneca, Bristol Myers Squibb, Guidant, Merck, Sanofi, Schering-Plough, The Medicines Company

2. Kenneth W. Mahaffey, M.D. James J. Ferguson, M.D. On behalf of the SYNERGY Investigators The SYNERGY Trial

3. S uperior Y ield of the N ew strategy of E noxaparin, R evascularization & G l Y coprotein IIb/IIIa Inhibitors The SYNERGY Trial

4. Key Prior Trials l ESSENCE / TIMI 11b: l Superiority of enoxaparin vs UFH in conservative management strategy l NICE Registries: l Comparable safety and efficacy to historical controls in PCI l ACUTE 2 / INTERACT / AtoZ l Contemporary trials in higher risk patients

5. Key Questions l What is the role of enoxaparin in high- risk NSTEMI ACS patients managed with an early invasive treatment strategy ? l Can we safely bring patients on enoxaparin rapidly forward to the catheterization laboratory ?

6. Study Design At least 2 of 3 required: Age  60 Age  60 ST  (transient) or  ST  (transient) or  (+) CK-MB or Troponin (+) CK-MB or Troponin EnoxaparinIV Heparin Primary endpoint: Death or MI at 30 days High-Risk ACS Patients Randomize (n = 10,000) Early invasive strategy Other therapy per AHA/ACC Guidelines (ASA,  -blocker, ACE, clopidogrel, GP IIb/IIIa) 60 U/kg  12 U/kg/hr (aPTT 50-70 sec) 1 mg/kg SC Q12H

7. Statistical Assumptions l Control group 15% death/MI l 17% reduction primary endpoint l Type I error of 5% (2-sided) l 90% power l Sample size ~10,000 patients Sample size: 8000  10,000 pts For crossover and interim event rate Sample size: 8000  10,000 pts For crossover and interim event rate 1.1 zone of noninferiority

8. Europe: 5163 Australia: 253 New Zealand: 160 Brazil: 289 Argentina: 192 Canada: 1616 USA: 5702 Belgium355 Germany456 Italy72 Poland381 Spain412 Turkey139 12 Countries. 467 Sites. 10,027 Patients.

9. Inclusion Criteria Age (+) ECG (+) Biomarkers 20% 16% 20% 44%

10. EnoxaparinUFH (n = 4993)(n = 4985) Median age (years)6868 Female sex (%)3434 Hypertension (%)6868 Diabetes (%)2930 Hypercholesterolemia (%)5859 Family history of CAD (%)4645 Myocardial infarction (%)2928 CHF (%)99 Stroke (%)55 PVD (%)1010 CABG (%)1617 PCI (%)2119 Baseline Characteristics

11. Concomitant Medications EnoxaparinUFH (n = 4993)(n = 4985) Aspirin (%)9595 Beta blocker (%)8686 Ace inhibitor (%)6462 Statin (%)6970 Clopidogrel (%)6263 GP IIb-IIIa inhibitor (%)5658

12. Pre-randomization Therapy EnoxaparinUFHAll Patients (n = 4993)(n = 4985)(n = 9978) Received pre-randomization (%): No antithrombin24 2524 UFH only29 3029 Enoxaparin only42 4243 UFH and enoxaparin 3 3 3 No antithrombin24 2524 UFH only29 3029 Enoxaparin only42 4243 UFH and enoxaparin 3 3 3

13. EnoxaparinUFH (n = 4993)(n = 4985) Cath during baseline hosp (%)9292 Time to cath*2221 (hours) (6, 44)(6, 43) Percutaneous intervention4647 Time to PCI*2322 (hours) (6, 49)(6, 48) CABG (%)1918 Time to CABG* 9189 (hours)(44, 167)(45, 166) Days hospitalized*54 (3, 8)(3, 8) In-hospital Procedures *Median (25th,75th)

14. Kenneth W. Mahaffey, M.D. James J. Ferguson, M.D. On behalf of the SYNERGY Investigators The SYNERGY Trial

15. Primary Results (30 Days) EnoxaparinUFH Unadjusted (n = 4993)(n = 4985) P-value Death and MI (%) 14.014.5 0.396 Death (%)3.23.1 0.705 MI (%)11.712.7 0.135

16. Death and MI at 30 Days 051015202530 0.8 0.85 0.9 0.95 1.0 Freedom from Death / MI Days from Randomization UFH Enoxaparin HR 0.96 (0.87-1.06) 1.1

17. In-hospital Cardiac Events EnoxaparinUFH (n = 4993)(n = 4985) CHF (%)8.07.9 Cardiogenic shock (%)2.02.3 Cardiac arrest (%)2.02.2 Ventricular tachycardia/fib (%)4.84.9 Atrial fib / flutter (%)8.67.7 2nd or 3rd degree heart block (%)1.01.1 Acute mitral regurgitation (%)0.30.3 Pulmonary edema (%)0.20.2 Deep vein thrombosis (%)0.20.2 Ventricular septal defect (%)0.1< 0.1

18. Bleeding Events EnoxaparinUFH (n = 4993)(n = 4985) P-value GUSTO severe2.92.40.106 TIMI major - clinical: 9.17.60.008 CABG-related6.85.90.081 Non-CABG-related2.41.80.025 H/H drop - algorithm15.212.50.001 Any RBC transfusion17.016.00.155 ICH< 0.1< 0.1NS

19. PCI Patients: Thrombotic Complications EnoxaparinUFH (n = 2321)(n = 2364) Any unsuccessful PCI3.63.4 Any threatened abrupt closure1.11.0 Any abrupt closure1.31.7 Emergency CABG0.30.3

20. No prior UFH Enox Both Pre-randomization

21. No prior UFH Enox Both Pre-randomizationRandomization

22. Prior Antithrombin Therapy: Efficacy and Safety Enox UFH (%) (%) 30-DAY DEATH / MI BLEEDING GUSTO Severe TIMI Major BLEEDING GUSTO Severe TIMI Major Enox UFH (%) (%) 2.92.4 Total (n = 9978) 14.014.5 9.17.6 3.11.8 No Prior Rx (n = 2440) 12.614.8 9.76.9 3.12.2 Consistent Therapy (n = 6138) 13.315.9 9.37.9

23. No prior UFH Enox Both Pre-randomizationRandomization

24. No prior UFH Enox Both Pre-randomizationRandomizationCrossover

25. Crossovers: Relation to Bleeding TIMI MajorGUSTO Severe (n = 9978) (n = 9180) (n =798) (n = 9978) (n = 9180) (n =798) Enoxaparin UFH

26. Crossovers: Relation to Outcome Enoxaparin UFH Consistent Rx Death / MI Total Population Death / MI (n = 9978) (n = 9180) (n =798) (n = 6130) (n = 5637) (n =493)

27. Systematic Overview: 30-Day Death/MI and In-hospital Transfusions 30-DAY DEATH / MI IN-HOSPITAL TRANSFUSIONS EnoxUFH 2.6%3.3% 0.7%0.6% 2.5%4.3% 1.0%0.8% 17.0%16.0% 0.8%0.9% ESSENCE INTERACT TIMI 11B ACUTE 2 AtoZ SYNERGY EnoxUFH 5.0%9.0% 7.4%8.3% 7.9%8.1% 7.4%7.9% 14.0%14.5% 6.2%7.7%

28. Systematic Overview: Death/MI and Bleeding 10.1%11.0% EnoxUFH 8.2%7.8% 4.8%4.1% (n = 21,946) (n = 22,104) AtoZ did not include CABG data.

29. Systematic Overview—No Pre-rando Therapy: Death/MI and Bleeding 8.1%9.5% EnoxUFH 5.6%5.5% 3.5%2.7% (n = 9835) (n = 8627) AtoZ did not include CABG data.

30. Summary l l High-risk population treated with an early invasive management strategy The study

31. Summary l l Efficacy — not superior but at least as effective as UFH in the overall population The results v v met criteria for non-inferiority l l High-risk population treated with an early invasive management strategy

32. Summary l l Efficacy — not superior but at least as effective as UFH in the overall population l l Bleeding — more frequent with enoxaparin The results UFH Enoxaparin 7.6 % 9.1 % 2.4 % 2.9 % 16.0 % 17.0 % TIMI Major GUSTO Severe Transfusion l l High-risk population treated with an early invasive management strategy p = 0.007 p = 0.106 p = 0.155

33. Summary l l Prior antithrombotic therapy l l Post-randomization management l l Bleeding definitions l l Age, renal function l l Prior antithrombotic therapy l l Post-randomization management l l Bleeding definitions l l Age, renal function Issues to consider

34. Summary l l An overview of all recent RCTs comparing enoxaparin and UFH shows a consistent effect across the management spectrum The study in context l l Prior antithrombotic therapy l l Post-randomization management l l Bleeding definitions l l Age, renal function l l Prior antithrombotic therapy l l Post-randomization management l l Bleeding definitions l l Age, renal function

35. Summary l l Current role — enoxaparin is an effective and safe alternative to UFH for the early invasive management of high risk ACS patients. The message