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Direct Thrombin Inhibitor Pharmacology and Pharmacotherapy Mary Jane E. Mattern, PharmD Pharmacist William W. Backus Hospital Learning Objectives At the conclusion of this activity, participants will be able to: Discuss the pharmacology of the direct thrombin inhibitors Discuss the indications and contraindications for the direct thrombin inhibitors Thrombin Molecule Personal Disclosure There are no actual or potential conflicts of interest associated with this presentation. Approved Products in US Argatroban Hirudins: found in salivary glands of leeches (Hirudo medicinalis) Lepirudin: recombinant hirudin expressed in yeast Bivalirudin: Synthetic analog of hirudin Thrombin Molecule Active site is set deep within groove, highly specific binding Exosite 1 = major binding site: fibrinogen, factor V, protein C, thrombomodulin Exosite 2 = heparin and heparan sulfate binding 1 Direct Thrombin Inhibitor (DTI): Mechanism of Action Act directly by binding to thrombin and blocking it’s activity Argatroban binds non-covalently and reversibly to active site on thrombin, no effect on exosites Pharmacokinetics Onset of action: Immediate Metabolism: Bind exosite 1 on thrombin molecule Argatroban: hepatic via hydroxylation, aromatization, and to a lesser extent CYP3A4/5 (metabolite formed in low amounts and is ~5 times weaker than parent) Bivalirudin forms reversible complex Bivalirudin: blood proteases Lepirudin forms irreversible complex Lepirudin: catabolic hydrolysis Hirudins inhibit thrombin bivalently Bind active site on thrombin molecule Pharmacokinetics t1/2 Elimination Argatroban: 40-50 minutes, impaired hepatic function lengthens up to 3 hours Take a moment to reflect... Among the 3 available DTIs, which difference is most likely to affect clinical care: Bivalirudin: normal renal function = 25 minutes, CrCl 10-29 ml/min = 1 hour, <10 ml/min = 3.5 hours a) Argatroban only binds active site on thrombin while hirudins also bind exosites Lepirudin: normal renal function = 10 minutes, impaired renal function lengthens up to 2 days b) Bivalirudin is metabolized by blood proteases Excretion Argatroban: feces, urine Bivalirudin: urine, proteolytic cleavage Lepirudin: urine (35% as unchanged drug) Contraindications c) Lepirudin and bivalirudin’s half lives are extended in renal dysfunction d) Argatroban is excreted in the urine and feces Indications Argatroban: Treatment and prevention of thrombosis in patients with heparin induced thrombocytopenia Hypersensitivity to drug or any component of formulation Active major bleeding Adjunct to percutaneous coronary intervention (PCI) in patients with confirmed or high risk of HIT Bivalirudin: Adjunct to percutaneous coronary intervention (PCI) in patients with confirmed or high risk of HIT In addition to aspirin in unstable angina patients undergoing percutaneous transluminal coronary angioplasty (PTCA) or PCI with GPIIb/IIIa inhibitor Lepirudin Treatment of thrombosis secondary to HIT 2 Take a moment to reflect... Which DTI is approved for both the prophylaxis AND the treatment of thrombosis associated with HIT? a) Argatroban b) Bivalirudin c) Lepirudin HIT: Early vs. Delayed Onset Heparin Induced Thrombocytopenia: Type 1 vs. Type 2 HIT Type 1: fall in platelet count within 2 days of initiation, then rebound no clinical consequences non-immune, probably due to heparin effects on platelet activation HIT Type II Immune mediated Antibodies formed against heparin-platelet factor 4 complex Thrombotic sequelae (venous and arterial) Typical onset: Days 5-10 and 7-14 after exposure HIT: Risk Factors Early onset: Median time from heparin exposure = 10.5 hours Heparin preparation: bovine > porcine > LMWH May be due to heparin exposure in past 3 months, antibody formation Patient diagnosis: post-surgical > medical > pregnant Delayed onset: Patient sex: female > male Duration of exposure Occurs 5-19 days after heparin exposure Take a moment to reflect... Which of the following statements regarding HIT is true? a) Typical onset is within 10.5 hours of exposure b) Risk of HIT in pregnancy is > medical patients c) HIT Type 1 is an immune mediated reaction d) HIT Type 2 is associated with serious clinical consequence of venous and arterial thrombosis CHEST Guidelines Diagnostic recommendations: Patients receiving or have received heparin within past 2 weeks, investigate HIT diagnosis if platelet count falls by ≥ 50% and/or a thrombotic event occurs between days 5 and 14 (even if patient is no longer receiving heparin) (Grade 1C) Treatment recommendations: HIT suspected or confirmed +/- thrombosis: Recommend use of an alternative, non-heparin anticoagulant (lepirudin-Grade 1C, argatroban-Grade 1C, fondaparinux-Grade 2C, bivalirudin-Grade 2C) (Grade 1B) HIT suspected or confirmed: recommend against VKA therapy until platelet count has recovered to at least 150K (Grade 1B) HIT suspected or confirmed: recommend against LMWH (Grade 1B) 3 Argatroban Dosing Initial dosing: Intravenous continuous infusion of 2 mcg/kg/min Use ABW up to 130 kg Check aPTT in 2 hours and adjust until aPTT is 1.5-3 times baseline (NTE 100 seconds or 10 mcg/kg/min) Special populations: Critically ill with multiple organ dysfunction (MOD), severe anasarca, heart failure, post-cardiac surgery require dose reduction Suggested starting dose in these patients: 0.5-1.2 mcg/kg/min (Grade 2C) Argatroban per Protocol Take a moment to reflect... RS, a 65 year old female was admitted to the ICU 6 days ago for respiratory failure. RS is on warfarin at home for atrial fibrillation, but this was discontinued on admission due to NPO status. RS has been on IV heparin infusion for anticoagulation since admission. RS’s baseline platelet count was = 400K, and today is 185K. Due to large drop in platelet count, and heparin exposure of 6 days duration, HIT is highly suspected. Heparin is immediately discontinued and the attending physician asks for your recommendation on what to do next... Argatroban and VKA Bridging Thrombin (Factor II) affects PT/INR Argatroban elevates PT/INR as well as aPTT How do we know when INR target has been met? Measure combined INR with argatroban and warfarin Stop argatroban when combined INR > 4 Repeat INR in 4-6 hours, this is “true” INR If subtherapeutic, restart argatroban If in goal range, continue with VKA alone Repeat daily until desired target achieved Take a moment to reflect... RS has been on argatroban anticoagulation while NPO, but is now being transferred to the medical floor and is able to take oral medications. The attending physician again asks for your recommendation on how to transition RS back onto warfarin. You give the following recommendations... Direct Thrombin Inhibitors...the Future of Anticoagulation? Heparin/warfarin: Narrow TI Variable dose response requires frequent monitoring UFH binds non-specifically to other sites (PF4, endothelial cells, acute phase reactants) UFH cannot inactivate thrombin or factor Xa within a thrombus 4 Direct Thrombin Inhibitors...the Future of Anticoagulation? DTI: the future? 1st must prove Oral availability Less need for monitoring Wider TI Equivalent or better efficacy References Arepally, Gowthami M., and Thomas L. Ortel. "Heparin-Induced Thrombocytopenia." Annual Review of Medicine 61 (2010): 77-90. “Argatroban.” In DRUGDEX® System. Intranet database. Version 2.0. Greenwood Village, Colo:Thomson Reuters (Healthcare) Inc. Argatroban. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2010. “Bivalirudin.” In DRUGDEX® System. Intranet database. Version 2.0. Greenwood Village, Colo:Thomson Reuters (Healthcare) Inc. Bivalirudin. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2010. Franchini, Massimo. "Heparin-induced thrombocytopenia: an update." Thrombosis Journal 3.14 (2005): 1-5.51. “Lepirudin.” In DRUGDEX® System. Intranet database. Version 2.0. Greenwood Village, Colo:Thomson Reuters (Healthcare) Inc. Lepirudin. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2010. The William W. Backus Hospital [internal protocol]. Argatroban protocol. Norwich, CT; rev 1/2009. Warkentin, Theodore E., Andreas Greinacher, Andreas Koster, and A. Michael Lincoff. "Treatment and Prevention of Heparin-Induced Thrombocytopenia." Chest 133 (2008): 340S-80S. Zinkovsky, Daniel A., and Marilena S. Antonopoulos. "Heparin-Induced Thrombocytopenia: Overview and Treatment." P&T 33.11 (2008): 642- 5