6. The Procoagulant State Vascular Injury Activation of Platelets And Coagulation Fibrin formation Xa Thrombin (IIa)
7. Actions of thrombin Activation of platelets THROMBIN Factor XIII -> XIIIa cross linked fibrin Fibrinogen -> Fibrin Prothrombin -> Thrombin Factor V -> Va Factor VIII -> VIIIa
8. Clotting cascade The details Clotting Clotting cascade Diseases to know Anticoagulants Heparin LMWH Enoxaparin
21. Anti coagulants What? Why? Where? Clotting Clotting cascade Diseases to know Anticoagulants Heparin LMWH Enoxaparin
22. Drugs in coagulation disorders Heparin Unfractionated Heparin Low molecular weight Heparin warfarin Direct Thrombin inhibitor Streptokinase Aspirin Clopidogrel Abiciximab Antiplatelets Thrombolytics Anticoagulants Drugs used in Coagulation disorders Hirudin Argotraban
23. Drugs in coagulation disorders Thrombogenesis Vascular injury Platelet adherence and activation Thrombin generation and fibrin formation Plasma generation and fibrinolysis Therapy Reduce risk factors Platelet inhibitors Anticoagulants Fibrinolytics
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25. Heparin And allied products Clotting Clotting cascade Diseases to know Anticoagulants Heparin LMWH Enoxaparin
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30. Heparin - molecular Heterogeneity High Molecular Weight Medium Molecular Weight Small Molecular Weight Both functional and molecular heterogeneity is observed.
46. LMWHs: FDA Approvals X X UA X Total knee replacement X X X Total hip replacement X X X General surgery Prophylaxis in: X X Treatment DVT/PE X DVT-OPT Tinzaparin Enoxaparin Dalteparin Ardeparin Indications
47. LMWH Comparisons 4500 1.9: 1 Tinzaparin 3.5: 1 3.6: 1 3.8: 1 2.7: 1 1.9: 1 Xa: IIa ratio LMWHs have a relatively higher antifactor Xa, and lower antifactor II activity compared to unfractionated heparin. Potency of LMWH is reflected by the ratio of antifactor Xa to antifactor IIa activity (Xa:IIa ratio) 4653 Reviparin 4855 Nadroparin 4371 Enoxaparin 5819 Dalteparin 6000 Ardeparin 11,400 Heparin Mol. Wt. Product
62. Structure Average Molecular Weight: 4500 Da Distribution: <2000 Da 20% 2000 – 8000 Da 68% >8000 Da 18% Prescribing Information, Sanofi-Aventis, 2007
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64. Enoxaparin & Heparin - Differences Enoxaparin Heparin Half-life (hr) 4.5 dose-dependent Anti-Xa:IIa 14:1 1:1 Molecular wt (avg) 4,500 15,000 Time to peak activity 3-5 2-4 Dosing units mg IU
65. Enoxaparin - MOA AT LMWH Hirsh, J., MD, FCCP, et. al., Heparin and Low Molecular Weight Heparin, Chest , 2001 ; 119, 64S-94S Xa AT LMWH LMWH Xa AT LMWH Xa AT Xa
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71. Enoxaparin in DVT Prophylaxis Average duration: 7 -10 days 30 mg q12h SC; initiate 12-24h postop In patients undergoing knee replacement surgery 3 weeks post discharge 40 mg qid SC Extended prophylaxis in hip replacement Average duration: 7 -10 days Upto 14 days 30 mg q12h SC; initiate 12-24h postop 40 mg qid SC; initiate 12h postop In patients undergoing hip replacement surgery average duration: 7-10 days 40 mg qid SC; initiate 2h postop In patients undergoing abdominal surgery DURATION DOSAGE
72. Enoxaparin - Therapy in acute DVT with or without PE continue enoxaparin for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (INR 2.0 to 3.0). 1 mg/kg q12h SC initiate warfarin sodium therapy when appropriate (usually within 72h of enoxaparin administration For patients who can be treated at home for acute DVT without PE average duration: 7 days 1.5 mg/kg qd SC or 1 mg/kg q12h SC at the same time every day. For hospitalized patients with acute DVT with or without PE DURATION DOSAGE
73. Enoxaparin - UA and non-Q MI minimum 2 days; usual duration of therapy: 2 to 8 days 1 mg/kg q12h SC with oral aspirin therapy (100 to 325 mg once daily) For the prevention of ischemic complications of unstable angina and non-Q-wave myocardial infarction (MI) when concurrently administered with aspirin DURATION DOSAGE
84. ESSENCE Trial - Efficacy and Safety of Subcutaneous enoxaparin in non-Q-Wave Coronary Events Study Enoxaparin 1.0 mg/kg q 12 h subcutaneous UFH 5,000 U bolus + inf aPTT 55-85 sec Unstable Angina Non-Q Wave MI Acute Phase min 48h, max 8 Days 30 days Enox Hep Incidence of death, MI, angina 14 d 16.6% 19.8% p=.019 30 d 19.8% 23.3% p=.016 Minor bleeding 30 d 13.8% 8.8% p<.001 Major bleeding 30 d 6.5% 7.0% NS Death alone 14 d 2.2% 2.3% NS 30 d 2.9% 3.6% NS
85. TIMI 11B - Study Design Enoxaparin 30 mg IV bolus + 1.0 mg/kg q 12 h subcutaneous UFH 70 U/kg IV bolus + 15U/Kg/h UFH IV Unstable Angina Non-Q Wave MI Acute Phase min 72h, max 8 Days Chronic Phase Fixed Dose < 65 kg > 65 kg 40 mg 60 mg q 12 h 43 days Fixed Dose placebo q 12 h
During the acute phase, all eligible patients were treated with aspirin and were then randomized to double-blind, double-dummy treatment either with UFH for a minimum of 3 days beginning with a bolus of 70 units/kg and an initial infusion of 15 units/kg/hour to target aPTT of 1.5-2.5 x control (coordinated through an unblinded third party) or enoxaparin given as an intravenous bolus of 30 mg followed by subcutaneous injections of 1 mg/kg every 12 hours. Enoxaparin was administered for at least 24 hours before any coronary interventional procedure and ended at hospital discharge or day 8 whichever came first. The primary efficacy endpoint was a composite of all cause mortality, recurrent myocardial infarction based on standard ECG and serum marker criteria, and urgent revascularization defined as an episode of recurrent angina prompting revascularization on the index hospitalization or on readmission. The primary safety endpoint was major bleeding resulting either in death, a bleed in a retroperitoneal, intracranial, or intraocular location, a hemoglobin drop of at least 3 grams/deciliter or the requirement of transfusion of at least 2 units of blood. As specified in the protocol, patients who completed the acute phase were excluded from enrollment in the chronic phase if they underwent bypass surgery, had no clinically significant coronary artery disease, sustained a major hemorrhage, developed severe thrombocytopenia, or had an indication for chronic anticoagulation. During the chronic phase of the trial, patients who had originally been assigned to IV UFH received placebo subcutaneous injections. Those patients originally assigned to enoxaparin received twice daily subcutaneous injections of 40 mg for those patients weighing less than 65 kg and 60 mg for those weighing at least 65 kg. Double-blind chronic phase therapy continued through day 43. About 60% of patients in both treatment groups progressed to the chronic phase. The major reasons for not entering the chronic phase were referral for a revascularization procedure, adverse event, and patient preference.
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