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

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

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

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– 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

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: 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

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:

Primary Efficacy Outcome Death/MI at 30 Days Days Cumulative Hazard UFH/Placebo Fondaparinux HR % CI P=0.008 The OASIS-6 Trial Group. JAMA 2006;295:

Death or MI 3 or 6 months Days Cumulative Hazard UFH/Placebo Fondaparinux HR % CI P=0.029 The OASIS-6 Trial Group. JAMA 2006;295:

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

Death at 6 Months Days Cumulative Hazard HR % CI p=0.037 Enoxaparin Fondaparinux

Death or MI: 6 Months Days Cumulative Hazard HR % CI p=0.036 Enoxaparin Fondaparinux

Major Bleeding: 6 Months Days Cumulative Hazard HR % CI p<< Enoxaparin Fondaparinux

Death, MI, RI or Major Bleeding at 6 Months Days Cumulative Hazard Enoxaparin Fondaparinux HR % CI p<<

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: Yusuf S, et al. N Engl J Med. 2066;354: