3. Compared to Heparin/Enoxaparin with GP IIb/IIa inhibitors,Bivalirudin monotherapy significantly reduces major bleeding while providing similar ischemic protection, and improves net clinical outcome. Bivalirudin Advantage

4. AT IIa Hep UFH IIa S C Direct antithrombin LMWH AT Xa AT Xa Pentasaccharide

5. IIaII Fibrinogen Fibrin clot Extrinsic pathway Intrinsicpathway AT Xa Fondaparinux Xa Antithrombin Fondaparinux: A Synthetic Factor Xa Inhibitor Adapted with permission from Turpie AGG et al. N Engl J Med. 2001;344:619. THROMBIN

6. Key Steps in Coagulation Pathway Inhibition of one molecule of factor Xa can inhibit the generation of 50 molecules of thrombin 2 Intrinsic pathwayExtrinsic pathway 1. Rosenberg RD, Aird WC. N Engl J Med 1999;340(20):1555–64. 2. Wessler S, Yin ET. Thrombo Diath Haemorrh 1974;32(1):71–8. Intrinsic pathway 1 50 Xa X II Fibrin Fibrinogen Clot Xa Va PL Ca 2+ IIa VIIIa Ca 2+ PL IXa

7. Herbert JM et al. Cardiovasc Drug Rev. 1997;15:1. van Boeckel CAA et al. Angew Chem, Int Ed Engl. 1993;32:1671.  Once daily administration  Rapid onset (C max /2=25 min)  Half life: 15-18 h.  Effects reversible with administration of activated Factor VII (Novoseven®)  No liver metabolism  Renal clearance  No protein binding (other than AT)  No reported cases of HIT  No dose adjustment necessary in elderly Fondaparinux: A Synthetic Inhibitor of Factor Xa

8. 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 OASIS-6: Randomized, Double Blind 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 JAMA 2006;295:1519-30

9. Primary Efficacy Outcome Death/MI at 30 Days Days Cumulative Hazard 0.0 0.02 0.04 0.06 0.08 0.10 0.12 036912151821242730 UFH/Placebo Fondaparinux HR 0.86 95% CI 0.77-0.96 P=0.008 The OASIS-6 Trial Group. JAMA 2006;295:1519-30

10. Death or MI 3 or 6 months Days Cumulative Hazard 0.0 0.02 0.04 0.06 0.08 0.10 0.12 01836547290108126144162180 UFH/Placebo Fondaparinux HR 0.88 95% CI 0.79-0.99 P=0.029 The OASIS-6 Trial Group. JAMA 2006;295:1519-30

11. Primary: Efficacy: Death, MI, refractory ischemia 9 day Safety: Major bleeds Risk benefit: Death, MI, refractory ischemia, major bleeds Secondary: Above & each component (especially deaths) at 30 & 180 d Hypothesis: First test non-inferiority, then test superiority Primary: Efficacy: Death, MI, refractory ischemia 9 day Safety: Major bleeds Risk benefit: Death, MI, refractory ischemia, major bleeds Secondary: Above & each component (especially deaths) at 30 & 180 d Hypothesis: First test non-inferiority, then test superiority

12. Death at 6 Months Days Cumulative Hazard 0.0 0.02 0.04 0.06 020406080100120140160180 HR 0.89 95% CI 0.79-0.99 p=0.037 Enoxaparin Fondaparinux

13. Death or MI: 6 Months Days Cumulative Hazard 0.0 0.02 0.04 0.06 0.08 0.10 0.12 020406080100120140160180 HR 0.91 95% CI 0.84-0.99 p=0.036 Enoxaparin Fondaparinux

14. Major Bleeding: 6 Months Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 0.05 0.06 020406080100120140160180 HR 0.72 95% CI 0.63-0.82 p<<0.00001 Enoxaparin Fondaparinux

15. Death, MI, RI or Major Bleeding at 6 Months Days Cumulative Hazard 0.0 0.05 0.10 0.15 020406080100120140160180 Enoxaparin Fondaparinux HR 0.87 95% CI 0.81-0.93 p<<0.00001

16. Fondaparinux Difficult to monitor (no aPTT or ACT) Long half-life Catheter thrombosis during PCI DisadvantagesAdvantages SC administration ― Potential exists for outpatient management Once-daily administration Predictable anticoagulant response Fixed dose No antigenicity Potentially no need for serologic parameters Does not cross the placenta HIT antibodies do not cross- react Decreased bleeding complications vs UFH or LMWH Simoons ML, et al. J Am Coll Cardiol. 2004;43:2183-2190. Yusuf S, et al. N Engl J Med. 2066;354:1464-1476.