10. Major Hemorrhagic Events (Acute Phase) No significant increase in rate of major hemorrhage 0 20 40 60 ESSENCE n = 3171 TIMI 11B n = 3910 TESSMA n = 7081 UFH Enoxaparin Antman EM et al. Circulation 1999;100:1602-8 UFH, unfractionated heparin; NS, not significant NS Number of patients

11. GUSTO V Benefit vs. risk Death or re-MI Severe / moderate hemorrhageReteplase Abciximab + reteplase 8.8% 7.4% 2.3% 4.6% D = 2.3% P < 0.001 D = 1.4% P = 0.001 0246810246 Percentage of patients GUSTO V Investigators. Lancet. 2001;357:1905.

15. Low-Molecular-Weight Heparin  Indirect thrombin inhibitor  Less reversible  Difficult to monitor (no aPTT or ACT)  Renally cleared  Long half-life  Risk of HIT Disadvantages  Increased anti-Xa to anti-IIa activity  inhibits thrombin generation more effectively  Induces ↑ release of TFPI vs UFH  Not neutralized by platelet factor 4  Less binding to plasma proteins (eg, acute-phase reactant proteins)  more consistent anticoagulation  Lower rate of HIT vs UFH  Lower fibrinogen levels  Easy to administer (SC administration)  Long history of clinical studies and experience, FDA-approved indications  Monitoring typically unnecessary Advantages Hirsh J, et al. Circulation. 2001;103:2994-3018. TFPI = tissue factor pathway inhibitor; UFH = unfractionated heparin; SC = subcutaneous; aPTT = activated partial thromboplastin time; ACT = activated coagulation time.

16. AT IIa Hep UFH IIa S C Direct antithrombin LMWH AT Xa

17. Clot Burden in ACS patient

18. Heparin fails to effectively inhibit Clot-bound Thrombin

19. Bivalirudin inhibits Clot-Bound and Circulating Thrombin

20. Bivalirudin Does not activate Platelets

21. Bivalirudin: Unique mechanism of action overcomes the limitation of Heparin

27. 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

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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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.