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.

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.

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. 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. UFH not indicated Study Design: Randomized, Double Blind, Double Dummy Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (eg. late) StratificationStratification UFH indicated 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.

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.

Data Management and Follow-up 12,092 patients from 447 centers in 41 countries recruited from Sept 2003 to Sept 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 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.

Baseline Characteristics and Medications in Hospital Baseline Characteristics and Medications in Hospital Control (%) n = 6056 Fonda (%) n = 6036 Age Hrs from pain to entry (median )4.8 No reperfusion therapy Thrombolytic therapy Primary PCI ASA Clopidogrel/Ticlopidine ACE-Inhibitor/ARB Beta Blockers Lipid Lowering Agents 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.

OASIS 6 Results

Primary Efficacy Outcome Death/MI at 30 Days No. of Events (%) ControlFondaHR95% CIP No. of Patients Death or Re-MI Death Reinfarction 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.

Primary Efficacy Outcome Death/MI at 30 Days Days Cumulative Hazard UFH/Placebo Fondaparinux HR % CI P=0.008 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.

Death/MI at 9 Days (end of treatment) No. of Events (%) ControlFondaHR95% CIP No. of Patients Death or Re-MI Death Reinfarction 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.

Death/MI at Study End (3 or 6 months) No. of Events (%) ControlFondaHR95% CIP No. of Patients Death or Re-MI Death Reinfarction 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.

Death at Study End (3 or 6 months) Days Cumulative Hazard UFH/Placebo Fondaparinux HR % CI P=0.029 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.

Efficacy of Fondaparinux by Strata on Death/MI at Study End No. of Events (%) ControlFondaHR95% CI Stratum I (n = 5658) (Fonda vs. Placebo) Stratum II (n = 6434) (Fonda vs. UFH) 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.

Death/ReMI in Stratum II at Study End Primary PCI vs. no Primary PCI No. of Events (%) UFHFondaHR95% CIPInteract n Death or Reinfarction No 1 o PCI (n = 2666) o PCI (n = 3772) Death No 1 o PCI o PCI Reinfarction No 1 o PCI o 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.

Bleeding Outcomes Severe Hemorrhage at 9 Days No. of Events ControlFondaHR95% CIP Severe Hemorrhage Fatal ICH Retroperitoneal Cardiac Tamponade Hg drop ≥ 5 g/dL 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.

Severe Hemorrhage by type of reperfusion therapy at 180 Days No. of Events ControlFondaHR95% CIP None1.8%1.6% Thrombolytics2.3%1.6% Primary PCI1.0%1.2% 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.

Days Cumulative Hazard UFH/Placebo Fondaparinux Death/MI/Severe Hemorrhage at Day 30 HR % CI P=0.005 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.

OASIS-6: Strokes at 9 Days Number of EventsControlFondaparinux Overall5543 Ischemic Strokes3826 Hemorrhagic or uncertain strokes 17 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.

Pre-Specified Subgroup Analyses UFH/Plac better Hazard Ratio Overall None Thrombolytic Primary PCI < 112 >= % % Initial Reperfusion Rx GRACE Risk Score NUFH/Placebo Death or MI at 30 days Fonda Interaction P value Fonda 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.

Death and Net Clinical Benefit at Study End DeathDeath/MI/Stroke/ Severe Hemorrhage HR (95% CI) PHR (95% CI) P No Reperfusion 0.84 ( ) ( ) Thrombolytic0.85 ( ) ( ) o PCI1.09 ( ) ( ) 0.29 Overall0.88 ( ) ( ) 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.

OASIS 6 Conclusions: 1.Fondaparinux significantly reduces mortality and re-MI in STEMI without increasing bleeding compared to placebo or UFH. 2.Benefits emerge at 9 days and are sustained to 180 days. 3.In primary PCI, there was no benefit with fondaparinux. 4.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.

Number of Events Prevented by Treating 1000 patients with Fondaparinux vs Usual Care Type of EventOverallNo reperfusion therapy Thrombolytic therapy Death MI8179 Strokes261 Death/MI/Strokes Severe bleeds327 Death/MI/Strokes/ Severe Bleeds 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.

OASIS 5 (NSTE ACS) Mortality Day 30 Days Cumulative Hazard HR % CI P=0.022 Enoxaparin Fondaparinux Published on-line in N Engl J Med March 14, 2006 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.

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.

OASIS-6 slides are available at

OASIS 6 For Discussion

OASIS-6 Study Drug Regimen Stratum I and II (no Primary PCI) Indication for UFH Fondaparinux Regimen Control Regimen NO (Stratum I) 2.5 mg sc od x 8 days (1 st dose IV) Placebo sc od x 8 days (1 st dose IV) YES (Stratum II) 2.5 mg sc od x 8 days (1 st dose IV) UFH bolus 60 IU/kg (max 4000 IU) + IV Infusion 12 IU/kg/hr x 48 hrs 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.

Effect of Using UFH Prior to PCI on Catheter Thrombus, Death/MI and Bleeding Primary PCIPCI After Rand* No UFH PriorUFH PriorUFH by Protocol # of EventsUFH N=1652 Fonda N=1641 UFH N=251 Fonda N=245 UFH N=226 Fonda N=231 Catheter Thrombus (1)** Death/MI 30 d Major Bleed *includes rescue PCI, routine PCI, and PCI for recurrent ischemia Only ONE case of catheter thrombus was associated a clinical event 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.

Primary PCI Results: Death/MI in 1-3 days and 4-9 days HR % CI HR % CI 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.

Days Cumulative Hazard Enoxaparin Fondaparinux HR % CI Days Cumulative Hazard HR % CI P<< Enoxaparin Fondaparinux OASIS 5: Efficacy and Major Bleeding at Day 9 Death/MI/Ref IschemiaMajor 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.