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  • 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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  • Enoxaparin

    1. 1. Enoxaparin training slides Dr. B. K. Iyer
    2. 2. Topics for discusssion today <ul><li>Clotting </li></ul><ul><li>Clotting cascade </li></ul><ul><li>Diseases to know </li></ul><ul><li>Anticoagulants </li></ul><ul><li>Heparin </li></ul><ul><li>LMWH </li></ul><ul><li>Enoxaparin </li></ul>
    3. 3. Clotting Clotting Clotting cascade Diseases to know Anticoagulants Heparin LMWH Enoxaparin
    4. 4. Clotting- why must we know? <ul><li>Vascular disease - leading cause of death like </li></ul><ul><ul><li>Acute Myocardial Infarction (AMI – Heart Attack) </li></ul></ul><ul><ul><li>Cerebrovascular Accident (CVA – Stroke) </li></ul></ul><ul><ul><li>Pulmonary Embolism (PE) </li></ul></ul><ul><ul><li>Venous Thrombosis (DVT) </li></ul></ul>Stastically: 1 in 3 die from Vascular Disease Complications
    5. 5. Clotting phenomenon Haemostasis, vessel disruption Platelet adherence aggregation & release Thrombin generation and fibrin formation Thrombosis, endothelial injury External Internal
    6. 6. The Procoagulant State Vascular Injury Activation of Platelets And Coagulation Fibrin formation Xa Thrombin (IIa)
    7. 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. 8. Clotting cascade The details Clotting Clotting cascade Diseases to know Anticoagulants Heparin LMWH Enoxaparin
    9. 9. Clotting Cascade <ul><li>Clotting begins with certain abnormalities of the blood or blood vessel, triggering a cascade of enzymatic reactions of clotting factors. </li></ul><ul><li>Central to the coagulation cascade is the generation of thrombin (factor IIa) </li></ul><ul><ul><li>Thrombin is generated from prothrombin by the action of activated factor X (Xa) </li></ul></ul><ul><li>Thrombin then acts on fibrinogen to generate fibrin clot </li></ul>
    10. 10. Clotting Cascade - extrinsic <ul><li>The extrinsic pathway begins when trauma exposes a membrane protein called tissue factor [TF] which then attaches to factor VII. </li></ul><ul><li>Factor VII then gets activated to factor VIIa. </li></ul><ul><li>The TF-VIIa complex then activates factor X. </li></ul><ul><li>With the activation of factor Xa, the extrinsic pathway ends. </li></ul>
    11. 11. Clotting Cascade - intrinsic <ul><li>The intrinsic pathway begins when collagen in the damaged wall is exposed to blood, triggering the activation of clotting factors. </li></ul><ul><li>One of the first factors to get activated is Factor XII </li></ul><ul><li>Activated factor XII [XIIa] then activates factor XI. </li></ul><ul><li>Factor XIa then activates factor IX. </li></ul><ul><li>Activated factor IXa then activates factor VIII and combines with factor VIIIa to form tenase complex. </li></ul><ul><li>Tenase complex activates factor X forming factor Xa, leading to end of intrinsic pathway and beginning of common pathway. </li></ul>
    12. 12. Clotting Cascade - common <ul><li>Activated factor Xa combines with factor Va to form a complex which converts prothrombin [II] to thrombin [IIa]. </li></ul><ul><li>Next, thrombin converts fibrinogen to fibrin, a mesh like web in which the platelets get trapped as do the RBCs. </li></ul>
    13. 13. Clotting Cascade Intrinsic Pathway (surface contact) aPTT PT Thrombin ( IIa ) Thrombin-Fibrin Clot XIIa XIa IXa Xa Heparin / LMWH (AT-III dependent) Hirudin/Hirulog (direct antithrombin) Extrinsic Pathway (tissue factor) VIIa
    14. 14. Clotting Cascade
    15. 15. Clotting Cascade XIIa XIa IXa Xa IIa Fibrinogen Fibrin Hirsh, J., MD, FCCP, et. al., Heparin and Low Molecular Weight Heparin, Chest , 2001 ; 119, 64S-94S AT/LMWH Complex
    16. 16. Diseases To know with relation to LMWH usage Clotting Clotting cascade Diseases to know Anticoagulants Heparin LMWH Enoxaparin
    17. 17. The veins
    18. 18. Deep vein thrombosis <ul><li>Annual incidence of venous thromboembolism (VTE) is 1/1000 and DVT accounts for over one half of VTE </li></ul><ul><li>The other half is PE </li></ul><ul><ul><li>Carefully evaluated, up to 80% of patients with VTE have one or more risk factors </li></ul></ul><ul><ul><li>Majority of lower extremity DVT arise from calf veins but ~20% begin in proximal veins </li></ul></ul><ul><ul><li>About 20% of calf-limited DVTs will propagate proximally. </li></ul></ul>
    19. 19. Pulmonary embolism [PE] <ul><li>Blockage of the pulmonary artery or one of its branches, </li></ul><ul><li>Usually occurs when a deep vein thrombus (blood clot from a vein) becomes dislodged from its site of formation and travels to the arterial blood supply of one of the lungs. </li></ul>
    20. 20. Pulmonary embolism [PE] <ul><li>Common symptoms include difficult breathing, chest pain on inspiration, and palpitations. </li></ul><ul><li>Clinical signs include low blood oxygen saturation (hypoxia), rapid breathing (tachypnea), and rapid heart rate (tachycardia). </li></ul><ul><li>Severe cases of untreated PE can lead to collapse, circulatory instability & sudden death </li></ul>
    21. 21. Anti coagulants What? Why? Where? Clotting Clotting cascade Diseases to know Anticoagulants Heparin LMWH Enoxaparin
    22. 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. 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
    24. 24. Ideal Anticoagulant <ul><li>Administered orally, fixed oral dose daily </li></ul><ul><li>Highly effective in reducing venous thromboembolism </li></ul><ul><li>Predictable dose response and kinetics </li></ul><ul><li>Low rate of bleeding events </li></ul><ul><li>No routine coagulation monitoring required </li></ul><ul><li>Wide therapeutic window </li></ul><ul><li>No dose adjustment required </li></ul><ul><li>Little interaction with food or other drugs </li></ul><ul><li>Low, nonspecific plasma protein binding </li></ul><ul><li>Inhibition of both free and clot-bound coagulation factors </li></ul>
    25. 25. Heparin And allied products Clotting Clotting cascade Diseases to know Anticoagulants Heparin LMWH Enoxaparin
    26. 26. History of heparin <ul><li>Heparin-discovered n 1916 by Jay McLean and William Howell (Johns Hopkins University) </li></ul><ul><li>Sulfated form perfected and deemed safe for use as an anticoagulant by Connaught Medical Labs (University of Toronto) - 1937 </li></ul>Heparin, sulfated form Hirsh, J., MD, FCCP, et. al., Heparin and Low Molecular Weight Heparin, Chest , 2001 ; 119, 64S-94S Garrett R., Grisham, C., Biochemistry With a Human Focus, Thompson Learning, 1997, p. 238
    27. 27. Heparin - structure <ul><li>Glycosaminoglycan – polysaccharide polymer consisting of 2 types of monosaccharide that together provide the disaccharide building blocks for the heparin polymer: </li></ul><ul><ul><li>a uronic acid residue and </li></ul></ul><ul><ul><li>a glucosamine residue </li></ul></ul>
    28. 28. Heparin - types <ul><li>Obtained from porcine intestine and bovine lung tissues. </li></ul><ul><li>This is processed by chemical or enzymatic degradation to provide LMWH that are chemically distinct products. </li></ul><ul><li>Anticoagulant efficacy and pharmacologic properties vary with the size of the molecules. </li></ul><ul><li>Parenteral agents: </li></ul><ul><ul><li>administered either IV or SC. </li></ul></ul>
    29. 29. Heparin - differences <ul><li>UFH (mw 3k - 30k) is a heterogeneous mixture of polysacchride chains (glycosaminoglycans) </li></ul><ul><li>LMWH (mw 5k) is </li></ul><ul><ul><li>obtained by alkaline degradation of heparin benzyl ester </li></ul></ul><ul><ul><li>enriched with short chains to better the anti-Xa:IIa ratio </li></ul></ul>
    30. 30. Heparin - molecular Heterogeneity High Molecular Weight Medium Molecular Weight Small Molecular Weight Both functional and molecular heterogeneity is observed.
    31. 31. LMWH manufacturing process Depolymerization inflicts other changes Heparin derived oligosaccharides < 2.5 kDa UFH 15 kDa Anti-Xa/IIa = 1.0 LMWH 4-6 kDa Anti-Xa/IIa = 2.5 - 7.5 Ultra LMWH 2-4 kDa Anti-Xa/IIa = 10 - 50 Pentasaccharide 1-7 kDa Anti-Xa/IIa = > 50
    32. 32. Heparin - differences due to heterogeneity <ul><li>UFH binds to plasma proteins, platelets (platelet factor 4), macrophages, and endothelial cells. </li></ul><ul><ul><li>Limits bioavailability and accounts for the highly variable anticoagulant response. </li></ul></ul><ul><li>LMWHs have reduced binding to plasma proteins, platelets, and other cells. </li></ul><ul><ul><li>As a result, LMWHs have a more predictable dose response. </li></ul></ul>
    33. 33. Heparin - action similarity <ul><li>Both UH and LMWH exert their anticoagulation activity by catalyzing antithrombin (AT or AT III) </li></ul><ul><ul><li>Catalyzed AT is accelerated in its inactivation of the coagulation enzymes thrombin (factor IIa) and factor Xa. </li></ul></ul><ul><ul><li>Prolongs aPTT by inactivating thrombin and blocking Xa generation </li></ul></ul>
    34. 34. aPTT <ul><li>Activated partial thromboplastin time (aPTT) is a commonly used test to monitor heparin therapy and is a performance indicator measuring the efficacy of both the &quot;intrinsic&quot; and the common coagulation pathways. </li></ul><ul><li>The prothrombin time (PT) measures the extrinsic pathway. </li></ul><ul><li>Values < 25 seconds or > 39 seconds are generally abnormal. </li></ul>
    35. 35. Heparin Inhibits Hemostasis THROMBOSIS Collagen   XIa Tissue Factor   IXa Platelet Clumping Thrombus Formation Thrombus Growth HEMOSTASIS Tissue Factor & Collagen Platelet Aggregation Platelet-rich Hemostatic Plug Xa Fluid Thrombin HEPARIN HEPARIN & HIRUDIN
    36. 36. UFH – a few things to remember <ul><li>Will affect PTT- how much depends dosing and your reagent system </li></ul><ul><li>Easily monitored (accurately!) with the Anti-Xa method </li></ul><ul><li>Can be used in patients with renal failure </li></ul><ul><li>HAS an antidote (protamine sulfate) </li></ul>THE BIG QUESTION Why Use LMWH vs. UFH?
    37. 37. Why Use LMWH vs. UFH? <ul><li>LMWH more expensive drug but overall costs about the same </li></ul><ul><ul><li>No monitoring in majority of patients - when given on a weight-adjusted basis, the LMWH anticoagulant response is predictable and reproducible </li></ul></ul><ul><ul><li>Higher bioavailability - 90% vs 30% </li></ul></ul><ul><ul><li>Subcutaneous vs. IV </li></ul></ul><ul><ul><li>Outpatient vs. inpatient </li></ul></ul><ul><ul><li>Lower incidence of HIT </li></ul></ul>
    38. 38. Why Use LMWH vs. UFH? <ul><li>More predictable anticoagulant response needing little or no laboratory monitoring </li></ul><ul><ul><li>Unfractionated heparin is mixture of large and small heparin fractions </li></ul></ul><ul><ul><li>Unfractionated heparin metabolism </li></ul></ul><ul><ul><ul><li>Removes larger biologically inactive fractions quickly </li></ul></ul></ul><ul><ul><ul><li>Leaves behind smaller active fractions removed more slowly </li></ul></ul></ul><ul><ul><li>LMWH = uniform size </li></ul></ul><ul><ul><li>LMWH = metabolized at a slower rate </li></ul></ul><ul><ul><ul><li>Longer half-life - 4 to 6 hours vs 0.5 to 1 hour and renal (slower) vs hepatic clearance </li></ul></ul></ul>
    39. 39. Why Use LMWH vs. UFH? <ul><li>Decreased “heparin resistance” </li></ul><ul><ul><li>pharmacokinetics of UH are influenced by its bindings to plasma protein, endothelial cell surfaces, macrophages, and other acute phase reactants </li></ul></ul><ul><ul><li>LMWH has decreased binding to nonanticoagulant-related plasma proteins </li></ul></ul>
    40. 40. Why Use LMWH vs. UFH? <ul><li>Less inhibition of platelet function </li></ul><ul><ul><li>potentially less bleeding risk, but not shown in clinical use </li></ul></ul><ul><li>Lower incidence of thrombocytopenia and thrombosis (HIT syndrome) </li></ul><ul><ul><li>less interaction with platelet factor 4 </li></ul></ul><ul><ul><li>fewer heparin-dependent IgG antibodies </li></ul></ul><ul><li>Lower incidence of bone loss </li></ul><ul><li>Safe for use during pregnancy </li></ul><ul><li>More practical for long term use </li></ul>
    41. 41. LMWHs - clinical advantages <ul><li>Greater bioavailability </li></ul><ul><ul><li>100% versus 30% for heparin </li></ul></ul><ul><li>Longer duration of action </li></ul><ul><ul><li>slower clearance [ but can be a problem in renal dysfunction]; </li></ul></ul><ul><li>Less bleeding </li></ul><ul><li>↓ risk of heparin induced thrombocytopenia </li></ul><ul><li>↓ risk of osteoporosis </li></ul>
    42. 42. Differential inhibitory activity against factor Xa & IIa activity AT Unfractionated Heparin AT LMWH <ul><li>By binding to AT, most UFH and LMWH can inhibit Xa activity. </li></ul><ul><li>Fewer than half the chains of LMWH are of sufficient length to also bind factor IIa, therefore has decreased anti-IIa activity. </li></ul>Thrombin (IIa) H F S C Thrombin (IIa) H F S C
    43. 43. LMWH The different ones
    44. 44. LMWH properties - differences
    45. 45. LMWHs - currently developed <ul><li>Enoxaparin </li></ul><ul><ul><li>(Aventis, France) </li></ul></ul><ul><li>Dalteparin </li></ul><ul><ul><li>(Pfizer, USA) </li></ul></ul><ul><li>Tinzaparin </li></ul><ul><ul><li>(Leo, Denmark) </li></ul></ul><ul><li>Parnaparin </li></ul><ul><ul><li>(Opocrin, Italy) </li></ul></ul><ul><li>Each LMWH product has a specific molecular weight distribution. </li></ul><ul><li>This determines its anticoagulant activity and duration of action. </li></ul>
    46. 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. 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
    48. 48. LMWH - MOA
    49. 49. Differences in Mechanism of Action <ul><li>Any heparin chain can inhibit the action of factor Xa by binding to antithrombin (AT) </li></ul><ul><li>But, in order to inactivate thrombin (IIa), the heparin molecule must be long enough to bind both antithrombin and thrombin </li></ul><ul><ul><li>< half the chains of LMWH are long enough </li></ul></ul>AT Unfractionated Heparin Thrombin (IIa) H F S C AT LMWH Thrombin (IIa) H F S C
    50. 50. Xa: IIa ratio of heparin <ul><li>Heparin produces its anticoagulant effects by binding to antithrombin III and inhibiting thrombogenesis primarily through inactivation of factors, IIa and Xa </li></ul><ul><li>The interaction with antithrombin III is mediated through a unique pentasaccharide molecule distributed randomly in the unfractionated heparin molecule. </li></ul><ul><li>The antithrombotic effects of unfractionated heparin require interaction with antithrombin III and factor Xa. </li></ul><ul><li>Binding of the unfractionated heparin antithrombin III complex to factor Xa causes a conformational change leading to inactivation of factor Xa. </li></ul>
    51. 51. Xa: IIa ratio of heparin <ul><li>Unfractionated heparin can also bind to and inactivate factor II (thrombin). </li></ul><ul><li>However, this process requires simultaneous binding of the unfractionated heparin antithrombin III complex with thrombin, which necessitates that the unfractionated heparin be at least 18 saccharide units. </li></ul><ul><li>The longer saccharide units ([lt] 18 units) comprise less than 50% of the total fraction of low molecular weight heparins, so LMWHs have a relatively higher antifactor Xa, and lower antifactor II activity compared to unfractionated heparin. </li></ul><ul><li>Potency of LMWH is reflected by the ratio of antifactor Xa to antifactor IIa activity (Xa:IIa ratio). </li></ul>
    52. 52. LMWHs Structural Features <ul><li>The molecular weight threshold under which anti-IIa activity is lost is 5400 daltons. </li></ul>
    53. 53. LMWH <ul><li>Doesn’t change the APTT (much) – an increased APTT may signify an overdose of LMWH or some other influence on the APTT (platelet antibodies) </li></ul><ul><li>Difficult to reverse with protamine sulfate (antidote for UFH) </li></ul><ul><li>Cleared through the kidneys </li></ul>
    54. 54. LMWH administration <ul><li>Subcutaneous injection </li></ul><ul><li>Once every 12 or 24 hours </li></ul><ul><li>Outpatient </li></ul>
    55. 55. LMWH Monitoring - When? <ul><li>Unnecessary in majority of patients </li></ul><ul><li>Trough – right before next dose </li></ul><ul><li>May be useful in specific instances and patients that need monitoring are- </li></ul><ul><ul><li>Pregnant </li></ul></ul><ul><ul><li>Pediatric </li></ul></ul><ul><ul><li>Renal insufficiency [ creatinine >2.0 mg/dl] </li></ul></ul><ul><ul><li>Prolonged therapy </li></ul></ul><ul><ul><li>Those at risk for bleeding </li></ul></ul><ul><ul><li>Obese patients with altered drug pK </li></ul></ul>
    56. 56. LMWH - Who to monitor? <ul><li>Patients with kidney problems (need to check creatinine clearance) </li></ul><ul><li>Patients that are obese or have a very low body weight </li></ul><ul><li>Children, burn patients </li></ul>
    57. 57. LWMH and PTT <ul><li>“ LMWH fractions … have progressively less effect on the aPTT as they are reduced in molecular size, while still inhibiting activated factor X. </li></ul><ul><li>The aPTT activity of heparin reflects mainly its anti-factor IIa activity.” Hirsh J., Circulation 2001; 103:2994 </li></ul>AT Unfractionated Heparin AT LMWH Thrombin (IIa) H F S C Thrombin (IIa) H F S C
    58. 58. LMWH - How to monitor? <ul><li>Unfractionated heparin has primarily antithrombin (factor IIa) activity that results in a linear increase in the PTT </li></ul><ul><ul><li>Monitor UFH with PTT </li></ul></ul><ul><li>Low molecular weight heparin has anti-Xa activity but PTT not sensitive enough to pick this up consistently, therefore need a more sensitive test </li></ul><ul><ul><li>Monitoring LMWH with anti-Xa, is more appropriate, but not widely available. Samples should be drawn 4 hours after dosing. </li></ul></ul>
    59. 59. Heparin induced thrombocytopenia <ul><li>Mode of action – Immune </li></ul><ul><ul><li>Heparin acts as a “cofactor” with PF4 </li></ul></ul><ul><ul><li>Causes platelet </li></ul></ul><ul><ul><ul><li>activation </li></ul></ul></ul><ul><ul><ul><li>aggregation </li></ul></ul></ul><ul><li>Rate of occurrence </li></ul><ul><ul><li>Bovine - 15% </li></ul></ul><ul><ul><li>Porcine - 5% </li></ul></ul><ul><li>Type I – HIT </li></ul><ul><li>Type II – HITT(with thrombosis) </li></ul><ul><ul><li>Arterial thrombosis - 0.4% </li></ul></ul>
    60. 60. Heparin induced thrombocytopenia <ul><li>Begins 3 - 15 days after start of heparin </li></ul><ul><li>If patient exposed to drug before thrombocytopenia can occur within a few hours. </li></ul><ul><li>Platelet count returns 4 days after stopping heparin. </li></ul><ul><li>Treatment </li></ul><ul><ul><li>Stop heparin immediately </li></ul></ul><ul><ul><li>Use other drugs for anticoagulation. </li></ul></ul>
    61. 61. Enoxaparin Better value for money
    62. 62. Structure Average Molecular Weight: 4500 Da Distribution: <2000 Da 20% 2000 – 8000 Da 68% >8000 Da 18% Prescribing Information, Sanofi-Aventis, 2007
    63. 63. Enoxaparin <ul><li>Enoxaparin is a low molecular weight heparin (LMWH) with anti-thrombotic properties </li></ul><ul><ul><li>FDA Approval – December, 1998 </li></ul></ul><ul><li>Enoxaparin acts primarily on the coagulation factor Xa, and also, but to a lesser degree, on thrombin (factor IIa). </li></ul><ul><li>Centered at the convergence of the intrinsic and extrinsic coagulation pathways, factor Xa transforms prothrombin into thrombin. </li></ul>
    64. 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. 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
    66. 66. Enoxaparin - MOA Enoxaparin joins with antithrombin III (ATIII) to form a complex Enoxaparin thereby inhibits the subsequent step in the cascade, the generation of thrombin and other changes The enoxaparin-ATIII complex also prevents thrombin’s amplification effects on factor XIII, thus preventing stabilization of the clot. <ul><li>Enoxaparin-ATIII complex then binds and inhibits factor Xa, thus - </li></ul><ul><li>prevents the Xa-Va complex, and subsequently </li></ul><ul><li>prevents the conversion of prothrombin to thrombin by the Xa-Va complex. </li></ul>
    67. 67. Pharmacology <ul><li>Low molecular weight heparin with Antithrombotic properties </li></ul><ul><ul><li>Binds to antithrombin (AT) and the LMWH-AT complex inactivates coagulation enzymes (specifically IIa, IXa, Xa, XIa, XIIa) </li></ul></ul><ul><li>Enoxaparin </li></ul><ul><ul><li>increases ratio of anti-Factor Xa to anti-Factor IIa. </li></ul></ul><ul><ul><li>Increases thrombin time up to 1.8 times that of control (slowing clotting time). </li></ul></ul>
    68. 68. Pharmacodynamics / kinetics <ul><li>Max. anti-Factor Xa and anti-Factor IIa (anti-thrombin) occur 3-5 hours post administration. </li></ul><ul><li>Peak activity concentration: 1.58 μg/mL </li></ul><ul><li>Primarily metabolized in Liver </li></ul><ul><ul><li>By desulfation and depolymerization </li></ul></ul><ul><ul><li>t½: 4.5 hours </li></ul></ul><ul><li>Eliminated in urine </li></ul><ul><ul><li>Up to 20% of anti-Factor Xa recovered in urine after 24 hours </li></ul></ul><ul><ul><li>99Tc radio labeling method </li></ul></ul>
    69. 69. Indications <ul><li>Prophylaxis/Treatment of DVT </li></ul><ul><li>Presurgical / Postsurgical </li></ul><ul><li>PE </li></ul><ul><li>Inpatient Tx./ Outpatient Tx. </li></ul>
    70. 70. Indications <ul><li>Therapy of AMI </li></ul><ul><ul><li>Ischemic complications of Unstable Angina </li></ul></ul><ul><ul><li>STEMI (ST Segment Elevation Myocardial Infarction) </li></ul></ul>
    71. 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. 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. 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
    74. 74. Pharmacological differences between LMWHs
    75. 75. Enoxaparin – ↓ in SMC proliferation
    76. 76. Pharmacokinetics of IV / SC
    77. 77. Administration <ul><li>Must be given parenterally </li></ul><ul><ul><li>IV and SC. Why? </li></ul></ul><ul><ul><ul><li>Destroyed in GI Tract </li></ul></ul></ul><ul><ul><ul><li>IM administration causes hematoma </li></ul></ul></ul><ul><li>Supplied in Prefilled syringes and multi-dose vials </li></ul>
    78. 78. Contraindications <ul><li>Active, major bleeding </li></ul><ul><li>Thrombocytopenia </li></ul><ul><li>Sensitivity to: </li></ul><ul><ul><li>Heparin </li></ul></ul><ul><ul><li>Pork or pork products </li></ul></ul><ul><li>Dose adjustment in hepatic or renal impairment </li></ul>
    79. 79. Adverse Reactions <ul><li>Hemorrhage </li></ul><ul><li>Anemia </li></ul><ul><li>Thrombocytopenia </li></ul><ul><ul><li>(decreased platelet count) </li></ul></ul><ul><li>Diarrhea </li></ul><ul><li>Nausea </li></ul><ul><li>LD50 46.4 mg/kg </li></ul>OD Treatment: Protamine Sulfate infusion
    80. 80. Enoxaparin Clinical trial outcomes
    81. 81. Clinical trial outcomes
    82. 82. Clinical trial outcomes
    83. 83. ESSENCE Trial - Efficacy and Safety of Subcutaneous enoxaparin in non-Q-Wave Coronary Events Study <ul><li>A randomized study comparing the clinical efficacy of UFH vs enoxaparin LMWH in 3171 patients with rest angina or non-Q-wave MI </li></ul><ul><li>at 30 days, there was a relative risk reduction of 15% -16% in the rate of death, MI, or refractory ischemia as compared to standard heparin </li></ul>N Eng J Med 1997;337:447-452
    84. 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. 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
    86. 86. TIMI 11B - LMWH in Unstable Angina <ul><li>4,021 pts with acute coronary syndrome </li></ul><ul><li>Two treatment groups: UFH: 70 U/kg bolus  15 u/kg/hr iv LMWH: 30 mg bolus  1 mg/kg s.q. bid </li></ul><ul><li>Primary endpoint (death, MI, urgent revascularization) 48-72 hr 26% 14 days 15% p<0.03 </li></ul>Circulation 1999; 100:1593-1601
    87. 87. Meta-Analysis - ESSENCE & TIMI 11B <ul><li>Primary endpoint Death / MI / Urgent Revscularization </li></ul><ul><li>Odds ratio Risk Reduction p-val </li></ul><ul><li>Day 8 0.71 21% 0.02 </li></ul><ul><li>Day 14 0.79 21% 0.0005 </li></ul><ul><li>Day 43 0.80 20% 0.0006 </li></ul>European Society of Cardiology - August 1998
    88. 88. Primary Endpoint : Day 43 Death/MI/Urgent Revasc
    89. 89. Economic Assessment of LMWH vs UFH - results from the ESSENCE Trial <ul><li> enoxaparin heparin </li></ul><ul><li>Need for coronary angioplasty (initial) 15% 20% p=.04 coronary angioplasty (30d) 18% 22% p=.08 diagnostic cath (30d) 57% 63% p=.04 Initial hospitalization mean drug cost in U.S.* $155 $80 mean total cost of care $11,857 $12,620 mean duration of treatment 2.3 days mutidose vial enoxaparin - 1 mg/kg at $0.38/mg </li></ul>Circulation 1998;97:1702-1707
    90. 90. Warfarin A brief understanding
    91. 91. Oral Anticoagulants <ul><li>Warfarin (Coumadin  ) and its derivatives [phenprocoumon; acenocoumarol] have been used for over 50 years. </li></ul><ul><ul><li>Prophylactic use: </li></ul></ul><ul><ul><ul><li>Prevention of thrombotic disorders </li></ul></ul></ul><ul><ul><li>Therapeutic use: </li></ul></ul><ul><ul><ul><li>Treatment of established thrombus </li></ul></ul></ul><ul><li>Approx 50% of Atrial fibrillation patients receive warfarin </li></ul>
    92. 92. Heparin vs. warfarin
    93. 93. Warfarin: Structure <ul><li>Warfarin is an Analogue of Vitamin K </li></ul><ul><li>interferes with vitamin-K dependent carboxylation of several coagulation factors including II, VII, IX, and X, as well as anticoagulant proteins C and S. </li></ul><ul><li>Full anticoagulant effect is delayed </li></ul><ul><li>Average daily dose 4-5mg. </li></ul>
    94. 94. Warfarin: MOA <ul><li>International Normalized Ratio (INR) is the ratio of a patient's prothrombin time to a normal (control) sample, raised to the power of the ISI value for the analytical system used. </li></ul><ul><li>The result (in seconds) for a prothrombin time performed on a normal individual will vary depending on what type of analytical system it is performed. </li></ul><ul><li>This is due to the differences between different batches of manufacturer's tissue factor used in the reagent to perform the test. </li></ul><ul><li>The INR was devised to standardize the results. </li></ul>
    95. 95. Warfarin: Precautions in Use <ul><li>A narrow therapeutic index (range between effective and toxic doses) </li></ul><ul><li>Non-linear pharmacokinetics </li></ul><ul><li>Small changes in dose can result in considerable changes in the anticoagulant response </li></ul>
    96. 96. Warfarin: Control of Dose <ul><li>Response can vary greatly </li></ul><ul><li>Many factors affect the dose of warfarin: </li></ul><ul><ul><li>Patient age </li></ul></ul><ul><ul><li>Nutrition </li></ul></ul><ul><ul><li>Dietary vitamin K </li></ul></ul><ul><ul><li>Alcohol use </li></ul></ul><ul><ul><li>Concomitant disease state </li></ul></ul><ul><ul><ul><li>Anemia </li></ul></ul></ul><ul><ul><ul><li>Liver disease </li></ul></ul></ul><ul><ul><ul><li>Biliary obstruction </li></ul></ul></ul><ul><ul><li>Concomitant drug use </li></ul></ul><ul><ul><li>Compliance </li></ul></ul>
    97. 97. Warfarin: Drug Interactions <ul><li>Drugs potentiate warfarin: </li></ul><ul><ul><li>By causing vitamin K deficiency </li></ul></ul><ul><ul><li>by displacing warfarin from protein binding sites </li></ul></ul><ul><ul><li>by decreasing clotting factor synthesis </li></ul></ul><ul><ul><li>by suppressing or competing for microsomal enzymes </li></ul></ul><ul><ul><li>by having antiplatelet aggregating properties </li></ul></ul><ul><li>Drugs inhibit warfarin: </li></ul><ul><ul><li>by decreasing warfarin absorption </li></ul></ul><ul><ul><li>by enhancing warfarin metabolism </li></ul></ul>