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Major Hemorrhagic Events (Acute Phase) No significant increase in rate of major hemorrhage

Major Hemorrhagic Events (Acute Phase) No significant increase in rate of major hemorrhage. 60. Number of patients. NS. UFH. Enoxaparin. 40. NS. NS. 20. 0. ESSENCE n = 3171. TIMI 11B n = 3910. TESSMA n = 7081. UFH, unfractionated heparin; NS, not significant.

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Major Hemorrhagic Events (Acute Phase) No significant increase in rate of major hemorrhage

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

  2. Severe / moderate hemorrhage Death or re-MI Abciximab + 7.4% 4.6% reteplase D = 2.3% P < 0.001 D = 1.4% P = 0.001 8.8% Reteplase 2.3% 6 4 2 0 2 4 6 8 10 Percentage of patients GUSTO V Benefit vs. risk GUSTO V Investigators. Lancet. 2001;357:1905.

  3. Low-Molecular-Weight Heparin Advantages 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 • Indirect thrombin inhibitor • Less reversible • Difficult to monitor(no aPTT or ACT) • Renally cleared • Long half-life • Risk of HIT 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.

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

  5. Clot Burden in ACS patient

  6. Heparin fails to effectively inhibit Clot-bound Thrombin

  7. Bivalirudin inhibits Clot-Bound and Circulating Thrombin

  8. Bivalirudin Does not activate Platelets

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

  10. Bivalirudin Advantage 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.

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

  12. Fondaparinux: ASynthetic Factor Xa Inhibitor Intrinsic pathway Extrinsic pathway Antithrombin Xa Xa AT AT AT Fondaparinux THROMBIN II IIa Fibrinogen Fibrin clot Adapted with permission from Turpie AGG et al. NEngl J Med. 2001;344:619.

  13. IXa VIIIa Ca2+ PL Xa Va Ca2+ PL Key Steps in Coagulation Pathway Intrinsic pathway Intrinsic pathway Extrinsic pathway 1 Inhibition of one molecule of factor Xa can inhibit the generation of 50 molecules of thrombin2 X Xa 50 IIa II Fibrin Fibrinogen 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. Clot

  14. Fondaparinux:A Synthetic Inhibitor of Factor Xa • Once daily administration • Rapid onset (Cmax/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 Herbert JM et al. Cardiovasc Drug Rev. 1997;15:1. van Boeckel CAA et al. Angew Chem, Int EdEngl. 1993;32:1671.

  15. OASIS-6: Randomized, Double Blind 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. Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (eg. late) Stratification UFH not indicated UFH indicated Randomization Randomization Fondaparinux 2.5 mg Placebo Fondaparinux 2.5 mg UFH JAMA 2006;295:1519-30

  16. Primary Efficacy OutcomeDeath/MI at 30 Days 0.12 UFH/Placebo 0.10 Fondaparinux 0.08 0.06 Cumulative Hazard HR 0.86 95% CI 0.77-0.96 P=0.008 0.04 0.02 0.0 0 3 6 9 12 15 18 21 24 27 30 Days The OASIS-6 Trial Group. JAMA 2006;295:1519-30

  17. Death or MI 3 or 6 months 0.12 UFH/Placebo 0.10 Fondaparinux 0.08 0.06 Cumulative Hazard HR 0.88 95% CI 0.79-0.99 P=0.029 0.04 0.02 0.0 0 18 36 54 72 90 108 126 144 162 180 Days The OASIS-6 Trial Group. JAMA 2006;295:1519-30

  18. 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

  19. Death at 6 Months Enoxaparin 0.06 Fondaparinux 0.04 Cumulative Hazard HR 0.89 95% CI 0.79-0.99 p=0.037 0.02 0.0 0 20 40 60 80 100 120 140 160 180 Days

  20. Death or MI: 6 Months Enoxaparin 0.12 0.10 Fondaparinux 0.08 Cumulative Hazard 0.06 HR 0.91 95% CI 0.84-0.99 p=0.036 0.04 0.02 0.0 0 20 40 60 80 100 120 140 160 180 Days

  21. Major Bleeding: 6 Months 0.06 Enoxaparin 0.05 0.04 Fondaparinux 0.03 Cumulative Hazard HR 0.72 95% CI 0.63-0.82 p<<0.00001 0.02 0.01 0.0 0 20 40 60 80 100 120 140 160 180 Days

  22. Death, MI, RI or MajorBleedingat 6 Months Enoxaparin 0.15 Fondaparinux 0.10 Cumulative Hazard HR 0.87 95% CI 0.81-0.93 p<<0.00001 0.05 0.0 0 20 40 60 80 100 120 140 160 180 Days

  23. Fondaparinux Advantages Disadvantages • Difficult to monitor (no aPTT or ACT) • Long half-life • Catheter thrombosis during PCI • 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.

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