1. VBWG OASIS-6 The Sixth Organization to Assess Strategies in Acute Ischemic Syndromes trial

2. VBWG OASIS-6: Background and hypothesis There is a clear need for safe and effective antithrombotic agents for STEMI patients In clinical trials, unfractionated heparin, direct thrombin inhibitors, and enoxaparin have failed to demonstrate significant mortality reductions and lower bleeding rates in STEMI patients Compared to standard antithrombotic therapies, does fondaparinux prevent CV events, revascularization, and mortality when initiated early in a broad range of STEMI patients? OASIS-6 Trial Group. JAMA. 2006;295:1519-30.

3. VBWG OASIS-6 Trial Group. JAMA. 2006;295:1519-30. OASIS-6: Study design Stratum I: UFH not indicated (receiving thrombolytics) (n = 5658) Stratum II: UFH indicated (receiving tPA or scheduled PCI) (n = 6434) Patients with STEMI randomized <12 h of symptom onset N = 12,092 Primary outcome: Composite of death or reinfarction at 30 days Main safety outcome: Severe bleeding Placebo* (n = 2835) Fondaparinux 2.5 mg qd* (n = 2823) UFH 60 IU/kg IV bolus/ 12 IU/kg 24–48 h infusion + placebo* (n = 3221) Fondaparinux 2.5 mg qd + placebo* (n = 3213) *Up to 8 days (or earlier discharge)

4. VBWG OASIS-6: Baseline characteristics Fondaparinux (n = 6036) Placebo/UFH (n = 6056) Age (years)61.661.5 Male (%)72.871.9 Time from pain onset (hours)4.8 Heart rate (bpm)76.376.0 Systolic BP (mm Hg)134.0134.3 OASIS-6 Trial Group. JAMA. 2006;295:1519-30. Strata 1 and 2 combined

5. VBWG OASIS-6: Medical history Fondaparinux (n = 6036) Placebo/UFH (n = 6056) Current/former smoker58.857.2 Hypertension54.354.6 Diabetes18.017.6 Heart failure14.013.9 MI12.812.3 Stroke6.96.4 PCI/CABG3.9 % OASIS-6 Trial Group. JAMA. 2006;295:1519-30. Strata 1 and 2 combined

6. VBWG OASIS-6: Concomitant in-hospital medications following randomization OASIS-6 Trial Group. JAMA. 2006;295:1519-30. Fondaparinux (n = 6036) Placebo/UFH (n = 6056) ASA96.896.4 Clopidogrel/ticlopidine57.758.5 GP IIb/IIIa receptor antagonist15.815.5 UFH10.811.2 Low-molecular-weight heparin5.36.3 β-Blocker84.483.8 ACEI/ARB79.480.0 Lipid-lowering agents74.574.8 Calcium channel blockers10.610.3 % Other medications <1% each Strata 1 and 2 combined

7. VBWG OASIS-6: Treatment effect on primary efficacy outcome at 30 days Composite of death, MI OASIS-6 Trial Group. JAMA. 2006;295:1519-30. Cumulative event rate UFH or placeboFondaparinux Days 0.14 0.12 0.10 0.08 0.06 0.04 0.02 0 036912161821242730 HR 0.86 (0.77–0.96) P = 0.008

8. VBWG OASIS-6: Severe bleeding at 30 days OASIS-6 Trial Group. JAMA. 2006;295:1519-30. 0.016 0.014 0.010 0.008 0.006 0.004 0.002 0 Cumulative event rate UFH or placeboFondaparinux 0.012 036912161821242730 Modified TIMI criterion Days HR 0.79 (0.58–1.09) P = 0.15

9. VBWG OASIS-6: Net clinical benefit 9.3 11.6 14.7 7.7 10.0 12.9 9 days 30 days 6 months Death, MI, severe bleeding Fondaparinux UFH or placebo Hazard ratio (95% CI) Favors fondaparinux Favors UFH or placebo OASIS-6 Trial Group. JAMA. 2006;295:1519-30. % 0.81.01.2 0.003 0.005 P

10. VBWG OASIS-6: Treatment effect on primary outcome at 30 days–Subgroup analyses 11.2 8.3 12.2 10.9 6.0 14.0 8.7 15.1 13.6 4.9 Stratum UFH not indicated UFH indicated Initial reperfusion therapy None Thrombolytic Primary PCI Composite of death, MI at 30 days Fondaparinux UFH or placebo Characteristic Hazard ratio (95% CI) Favors fondaparinux Favors UFH or placebo 0.512.0 OASIS-6 Trial Group. JAMA. 2006;295:1519-30. %

11. VBWG OASIS-6: Reduction in death and MI at study end OASIS-6 Trial Group. JAMA. 2006;295:1519-30. Cumulative event rate 030 0 0.02 0.04 0.10 0.08 0.06 0.12 0.14 0.16 6090120150 Days 180030 0 0.02 0.04 0.10 0.08 0.06 0.12 0.14 0.16 6090120150 Days 180 HR 0.81 (0.67–0.97) P = 0.03 HR 0.88 (0.79–0.99) P = 0.03 UFH or placeboFondaparinux DeathMI All patients followed for 3 months; n = 6976 followed for 6 months

12. VBWG OASIS-6: Conclusion Primary efficacy outcome at 30 days Fondaparinux significantly reduced death and reinfarction vs UFH/placebo Main safety outcome Trend to lower rate of severe bleeding Overall, results occurred early (9 days) and remained consistent through study end Significant reduction in death (12%, P = 0.03) and MI (19%, P = 0.03) Benefit/risk balance Rate of combined death, MI, and severe bleeding was significantly lower for fondaparinux vs UFH/placebo Subgroup analysis Benefit shown in 5436 patients who received thrombolytic therapy Little benefit in 3789 patients who underwent primary PCI OASIS-6 Trial Group. JAMA. 2006;295:1519-30.

13. VBWG OASIS-6: Summary Fondaparinux demonstrated a moderate reduction in mortality and reinfarction vs UFH/placebo Unlike other antithrombotic agents (eg, LMW heparin, direct thrombin inhibitors, intravenous antiplatelet agents), fondaparinux reduced deaths and reinfarction without increased bleeding or hemorrhagic stroke There appears to be little advantage in using fondaparinux as the initial treatment in patients undergoing primary PCI OASIS-6 Trial Group. JAMA. 2006;295:1519-30.

14. VBWG The OASIS program: Safety and efficacy of fondaparinux in a broad range of patients with ACS OASIS-5: N = 20,078 with UA/NSTEMI: Fondaparinux vs enoxaparin –Similar efficacy in reducing risk of death, MI, and refractory ischemia at 9 days –Significantly lower rate of major bleeding (P < 0.001) at 9 days OASIS-6: N = 12,092 with STEMI: Fondaparinux vs UFH/placebo –Significantly lower rate of death and reinfarction at 30 days (P = 0.008) Benefit principally in patients who did not undergo primary PCI –Nonsignificant trend towards lower rate of severe bleeding at 30 days In both trials, efficacy and net clinical benefit remained consistent through study end OASIS-5 Investigators. N Engl J Med. 2006; epublished March 14. OASIS-6 Trial Group. JAMA. 2006;295:1519-30.