MICHELANGELO: Organization to Assess Strategies in Ischemic Syndromes (OASIS) 6 Trial

1. MICHELANGELO: Organization to Assess Strategies in Ischemic Syndromes (OASIS) 6 Trial Disclosure Funded by Organon, Sanofi-Aventis & GSK Mehta & Yusuf have rec’d grants and honoraria from above companies plus several others.

2. Fondaparinux A Synthetic Factor Xa Inhibitor • Fondaparinux is an effective factor Xa inhibitor that is given in a once daily fixed dose (2.5 mg) without monitoring • For prevention of VTE it is twice as effective as enoxaparin • In UA/NSTEMI it halves the risk of severe and fatal bleeds compared to enoxaparin, resulting in lower mortality, MI and strokes over long term follow-up • The role of current antithrombotics in STEMI is unclear and there are concerns about increased bleeding and ICH This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

3. Study Design: Randomized, Double Blind, Double Dummy 12,000 Patients with STEMI < 12 h of symptom onset Inclusion: ST   2 mm prec leads or  1 mm limb leads Exclusion: Contra-ind. for anticoagulant, INR>1.8, pregnancy, ICH<12 mo. Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (eg. late) Stratification UFH not indicated UFH indicated Randomization Randomization Fondaparinux 2.5 mg Placebo Fondaparinux 2.5 mg UFH This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

4. Objectives Primary To determine whether fondaparinux is superior to usual care (UFH/placebo) in patients with STEMI: Primary Efficacy Outcome: Death or MI at 30 days Primary Safety Outcome: Severe bleeding (TIMI Major) Balance of Efficacy and Safety: Death, MI, severe bleeds Secondary Same outcomes and individual components at 9 days and at the end of follow-up (90-180) days. This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

5. Data Management and Follow-up • 12,092 patients from 447 centers in 41 countries recruited from Sept 2003 to Sept 2005. • Data were managed independently by the Population Health Research Institute, McMaster University, Hamilton, Canada • Trial was designed and overseen by an international steering committee • Final follow-up in Jan 2006. • Complete follow-up in 99.9% • Clean data in 99.99% This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

6. Baseline Characteristics and Medications in Hospital This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

7. OASIS 6 Results

8. Primary Efficacy OutcomeDeath/MI at 30 Days This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

9. Primary Efficacy OutcomeDeath/MI at 30 Days 0.12 UFH/Placebo 0.10 Fondaparinux 0.08 0.06 Cumulative Hazard HR 0.86 95% CI 0.77-0.96 P=0.008 0.04 0.02 0.0 0 3 6 9 12 15 18 21 24 27 30 Days This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

10. Death/MI at 9 Days (end of treatment) This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

11. Death/MI at Study End(3 or 6 months) This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

12. Death at Study End (3 or 6 months) 0.12 UFH/Placebo 0.10 Fondaparinux 0.08 0.06 Cumulative Hazard HR 0.88 95% CI 0.79-0.99 P=0.029 0.04 0.02 0.0 0 18 36 54 72 90 108 126 144 162 180 Days This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

13. Efficacy of Fondaparinux by Strataon Death/MI at Study End Interaction P=0.88 This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

14. Death/ReMI in Stratum II at Study EndPrimary PCI vs. no Primary PCI This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

15. Bleeding Outcomes Severe Hemorrhage at 9 Days This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

16. Severe Hemorrhage by type of reperfusion therapy at 180 Days This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

17. Death/MI/Severe Hemorrhage at Day 30 0.12 UFH/Placebo 0.10 Fondaparinux 0.08 HR 0.86 95% CI 0.77-0.95 P=0.005 0.06 Cumulative Hazard 0.04 0.02 0.0 0 3 6 9 12 15 18 21 24 27 30 Days This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

18. Pre-Specified Subgroup Analyses Death or MI at 30 days Interaction P value N UFH/Placebo Fonda Overall 12092 11.2% 9.7% Initial Reperfusion Rx 0.04 None 2867 15.1 12.2 Thrombolytic 5436 13.6 10.9 Primary PCI 3789 4.9 6.0 GRACE Risk Score 0.03 < 112 5958 4.3 4.6 >=112 6134 18.0 14.5 0.5 0.7 0.8 1.0 1.2 1.4 1.6 2.0 Fonda better UFH/Plac better This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource. Hazard Ratio

19. Death and Net Clinical Benefit at Study End This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

20. OASIS 6 Conclusions: • Fondaparinux significantly reduces mortality and re-MI in STEMI without increasing bleeding compared to placebo or UFH. • Benefits emerge at 9 days and are sustained to 180 days. • 3. In primary PCI, there was no benefit with fondaparinux. • The benefits are marked in those receiving no reperfusion therapy and those receiving thrombolytics (21% RRR at 30 days), with lower severe bleeding. • 5. Mortality is significantly reduced This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

21. Number of Events Prevented by Treating 1000 patients with Fondaparinux vs Usual Care This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

22. OASIS 5 (NSTE ACS)Mortality Day 30 Enoxaparin 0.03 Fondaparinux 0.02 Cumulative Hazard HR 0.83 95% CI 0.71-0.97 P=0.022 0.01 Published on-line in N Engl J Med March 14, 2006 0.0 0 3 6 9 12 15 18 21 24 27 30 Days This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

23. OASIS-6: Committees/Project Office Operations Committee: J.P Bassand, A. Budaj, S. Chrolavicius (Proj Manager), K.A.A. Fox (Co-Chair), C. Granger, C. Joyner (Chair, Adj Comm), S.R. Mehta (Proj Director), R.J. Peters, L. Wallentin, S. Yusuf (Chair & PI) Steering Committee: National Coordinators + Sponsors Sponsors: I. Bobbink, T.Lensing (Organon) A. Moryusef, R. Cariou, A. Denys (Sanofi-Aventis) S. Laing, L.Macartney S. Okada, N. Zariffa (GSK) Statisticians: R. Afzal, J. Pogue Project Office: N. Barr, S. Boccalon, K. Chrysler*, B. Cracknell, A. Djuric*, C. Easton, T. Gracie, C. Horsman*, T. Hoskin, B. Jedrzejowski, M. Lawrence, B. Meeks, R. Napoleoni*, M. Smiley, C. Stevens, J. Willcox* * former This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

25. OASIS-6 slides are available at www.phri.ca/oasis6

26. OASIS 6 For Discussion

27. OASIS-6 Study Drug RegimenStratum I and II (no Primary PCI) For Primary PCI, doses of fondaparinux and UFH were adjusted for use of GP IIb/IIIa antagonists and pre-randomization UFH For PCI after the index event, UFH was used for PCI This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

28. Effect of Using UFH Prior to PCI on Catheter Thrombus, Death/MI and Bleeding Only ONE case of catheter thrombus was associated a clinical event *includes rescue PCI, routine PCI, and PCI for recurrent ischemia This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

29. Primary PCI Results:Death/MI in 1-3 days and 4-9 days HR 1.30 95% CI 0.87-1.96 HR 0.68 95% CI 0.41-1.13 This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.

30. 0.06 Enoxaparin 0.04 HR 0.53 95% CI 0.45-0.62 P<<0.00001 0.05 0.03 0.04 Cumulative Hazard 0.03 Cumulative Hazard 0.02 HR 1.01 95% CI 0.90-1.13 0.02 Fondaparinux 0.01 0.01 Enoxaparin Fondaparinux 0.0 0.0 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 Days Days OASIS 5: Efficacy and Major Bleeding at Day 9 Death/MI/Ref Ischemia Major Bleeding This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology. Content Distributed by Cardiosource.