5/00MedSlides.com1 Low-Molecular-Weight Heparin and Unfractionated Heparin

5/98MedSlides.com2 The Coagulation Cascade Central to the coagulation cascade is the generation of thrombin (factor IIa) thrombin is generated from prothrombin by the action of activated factor X (Xa) thrombin then acts on fibrinogen to generate fibrin clot

5/98MedSlides.com3 Coagulation Cascade XIIa XIa IXa Intrinsic Pathway (surface contact) Xa Extrinsic Pathway (tissue factor) VIIa Thrombin (IIa) Thrombin-Fibrin Clot aPTT PT Heparin / LMWH (AT-III dependent) Hirudin/Hirulog (direct antithrombin) Courtesy of VTI

5/98MedSlides.com4 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 HEP HEP & HIR Heparin Inhibits Hemostasis

5/98MedSlides.com5 The Procoagulant State in Thrombolysis Amplification Vascular Injury Activation of Platelets And Coagulation Xa Thrombin (IIa)

5/98MedSlides.com6 Low-molecular-weight heparin UH (mw 3k - 30k) is a heterogeneous mixture of polysacchride chains (glycosaminoglycans) LMWH (mw 5k) is obtained by alkaline degradation of heparin benzyl ester LMWH molecules are enriched with short chains with higher anti-Xa:IIa ratio

5/98MedSlides.com7 Mechanism of Action Both UH and LMWH exert their anticoagulation activity by catalyzing antithrombin (AT or AT III) catalyzed AT is accelerated in its inactivation of the coagulation enzymes thrombin (factor IIa) and factor Xa. prolongs aPTT

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5/98MedSlides.com9 AT HC II Interaction of Heparin Co-Factors with Thrombin Thrombin HF S C HF S C Heparin has a higher affinity for AT than for HC II and there is more AT in plasma than HC II

5/98MedSlides.com10 AT Free Thrombin Antithrombin and Free Thrombin AT alone does not inactivate free-thrombin Thrombin HF S C

5/98MedSlides.com11 Heparin binds to antithrombin and increases the rate of thrombin inactivation AT Heparin Inactivation of Thrombin by Heparin-AT Complexes Thrombin HF S C

5/98MedSlides.com12 AT Fibrin-Bound Thrombin The rate at which AT inactivates fibrin-bound thrombin is reduced 50-fold Effect of Antithrombin on Fibrin-Bound Thrombin Thrombin HF S C

5/98MedSlides.com13 Inactivation of Thrombin by Heparin-AT Complexes When thrombin binds to fibrin, it becomes resistant to inactivation by heparin. AT Heparin Fibrin Thrombin HF S C

5/98MedSlides.com14 Mechanism of Action Summary –Catalyzes ATIII –Specific for fluid-phase thrombin –Prolongs aPTT by inactivating thrombin and blocking Xa generation

5/98MedSlides.com15 Differences in Mechanism of Action Any size of heparin chain can inhibit the action of factor Xa by binding to antithrombin (AT) In contrast, in order to inactivate thrombin (IIa), the heparin molecule must be long enough to bind both antithrombin and thrombin < half the chains of LMWH are long enough

5/98MedSlides.com16 AT Unfractionated Heparin Differential inhibitory activity against factor Xa and IIa activity Thrombin (IIa) HF S C AT LMWH Thrombin (IIa) HF S C By binding to AT, most UH and LMWH can inhibit Xa activity. Fewer than half the chains of LMWH are of sufficient length to also bind factor IIa, therefore has decreased anti-IIa activity.

5/98MedSlides.com17 Low-Molecular-Weight Heparins Anti-Facotr Xa : Anti - Factor IIa Ratios AgentTradeXa:IIaMol Wt (d) EnosaparinLovenox 3.8 : 1 4,200 DalteparinFragmin 2.7 : 1 6,000 ArdeparinNormiflo 1.9 : 1 6,000 Nadroparin 3.6 : 1 4,500 Reviparin 3.5 : 1 4,000 Tinzaparin 1.9 : 1 4,500

5/98MedSlides.com18 Advantages of LMWH over UH Decreased “heparin resistance” –pharmacokinetics of UH are influenced by its bindings to plasma protein, endothelial cell surfaces, macrophages, and other acute phase reactants –LMWH has decreased binding to nonanticoagulant-related plasma proteins

5/98MedSlides.com19 Advantages of LMWH over UH No need for laboratory monitoring –when given on a weight-adjusted basis, the LMWH anticoagulant response is predictable and reproducible Higher bioavailability - 90% vs 30% Longer plasma half-life –4 to 6 hours vs 0.5 to 1 hour –renal (slower) vs hepatic clearance

5/98MedSlides.com20 Advantages of LMWH over UH Less inhibition of platelet function –potentially less bleeding risk, but not shown in clinical use Lower incidence of thrombocytopenia and thrombosis (HIT syndrome) –less interaction with platelet factor 4 –fewer heparin-dependent IgG antibodies

5/98MedSlides.com21 Monitoring of LMWH Unnecessary in majority of patients May be useful in specific instances –renal insufficiency (creatinine >2.0 mg/dl) –obese patients with altered drug pK –major bleeding risk factors aPTT not useful - low anti-IIa activity anti-factor Xa assay is more appropriate, but not widely available

5/98MedSlides.com22 ESSENCE Trial Efficacy and Safety of Subcutaneous Enoxaparin in non-Q-Wave Coronary Events Study A randomized study comparing the clinical efficacy of UFH vs enoxaparin LMWH in 3171 patients with rest angina or non-Q-wave MI 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 N Eng J Med 1997;337:

5/98MedSlides.com23 ESSENCE Enoxaparin 1.0 mg/kg q 12 hsubcutaneous UFH 5,000 U bolus + inf aPTT 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= 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

5/98MedSlides.com24 TIMI 11B - Study Design Enoxaparin 30 mg IV bolus 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 Fixed Dose 65 kg 65 kg 40 mg 60 mg 40 mg 60 mg q 12 h q 12 h Fixed Dose Fixed Dose placebo placebo q 12 h q 12 h 43 days

5/98MedSlides.com25 TIMI 11B LMWH in Unstable Angina 4,021 pts with acute coronary syndrome Two treatment groups: UFH: 70 U/kg bolus  15 u/kg/hr iv LMWH: 30 mg bolus  1 mg/kg s.q. bid Primary endpoint (death, MI, urgent revascularization) hr26% 14 days15%p<0.03 Circulation 1999; 100:

5/98MedSlides.com26 Meta-Analysis ESSENCE and TIMI 11B Primary endpoint Death / MI / Urgent Revscularization Odds ratioRisk Reductionp-val Day %0.02 Day % Day % European Society of Cardiology - August 1998

5/98MedSlides.com27 Primary Endpoint : Day 43 Death/MI/Urgent Revasc

5/98MedSlides.com28 Difference Between Lovenox and Heparin LovenoxHeparin 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 Dosing units mg IU

4/00MedSlides.com29 Enoxaparin in DVT Prophylaxis DOSAGEDURATION in patients undergoing30 mg q12h SCaverage duration: 7 to 10 days hip-replacement surgeryinitiate 12-24h postopup to 14 days 40 mg qd SC initiated 12h (  3) preop extended prophylaxis in40 mg qd SC3 weeks post discharge hip replacement in patients undergoing30 mg q12h SCaverage duration: 7 to 10 days knee-replacement surginitiate 12-24h postop in patients undergoing40 mg qd SCaverage duration: 7 to 10 days abdominal surgeryinitiate 2h preop

4/00MedSlides.com30 Enoxaparin in Treatment of in acute DVT with or without PE DOSAGEDURATION For patients who can be1 mg q12h SCcontinue LOVENOX for a treated at home for acute initiate warfarin sodiumminimal of 5 days and until DVT without PEtherapy when appropriatea therapeutic oral anticoagulant (usually within 72h ofeffect has been achieved (INR Lovenox administration)2.0 to 3.0). average duration: 7 days For hospitalized patients 1.5 mg/kg qd SC at the with acute DVT with or same time every day or without PE1 mg/kg q12h SC

4/00MedSlides.com31 Enoxaparin for UA and non-Q MI DOSAGEDURATION For the prevention of1 mg/kg q12h SCminimum 2 days; usual duration ischemic complicationswith oral aspirin therapyof therapy: 2 to 8 days of unstable angina and(100 to 325 mg once daily) non-Q-wave myocardial infarction (MI) when concurrently administered with aspirin

5/98MedSlides.com32 Economic Assessment of LMWH vs UFH Results from the ESSENCE Trail enoxaparin heparin 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 Circulation 1998;97:

5/98MedSlides.com33 References Low-molecular weight heparins. Weitz JI. N Eng J Med 1997;337: Biochemistry and pharmacology of low molecular weight heparin. Rosenberg RD. Semin Hematol 1997;34(suppl 4):2-8. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionaed heparin. Warkentin TE, Levine MN, Hirsh J, Horsewood P, Roberts RS, Gent M, et al. N Engl J Med 1995;332: Use of LMWH in the treatment of venous thromboembolic disease. Litin SC, Heit JA, Mees KA, for the Thrombophilia Center Investigators. Mayo Clin Proc 1998;73: