ATLANTIC HEALTH GUIDELINES FOR ANTICOAGULANT, ANTIPLATELET, AND THROMBOLYTIC REVERSAL IN ADULT PATIENTS

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1 ATLANTIC HEALTH GUIDELINES FOR ANTICOAGULANT, ANTIPLATELET, THROMBOLYTIC REVERSAL IN ADULT PATIENTS Several of the below interventions are based on low-level evidence and are intended as suggestions only. This guideline should not replace though clinical judgement. Warnings Regarding Use of Prothrombin Complex Concentrates (PCCs) : Kcentra, Profilnine SD, FEIBA NF 1. PCC use increases risk of thrombotic events! 2. Not recommended f: A. Reversal of anticoagulation pri to elective, non-urgent surgical interventions 3. Not studied in/ limited data in: A. Patients with a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectis, severe peripheral vascular disease within the pri 3 months. B. F patients with ICH: Glasgow coma sce (GCS) < 7; intracerebral hematoma volume > 30cc as assessed by ABC/2; f subdural hematomas: maximum thickness 10 mm, midline shift 5 mm; f subarachnoid hemrhage: any evidence of hydrocephalus; infratential ICH location; epidural hematomas; intraventricular extension of hemrhage; modified Rankin sce (mrs) of >3 pri to ICH C. Known histy of antiphospholipid antibody syndrome lupus anticoagulant antibodies D. Known inhibits to coagulation facts II, VII, IX, X; hereditary protein C protein S deficiency; heparin-induced, type II thrombocytopenia E. Pregnant breast-feeding women Agents Effect on coagulation doses with al direct thrombin inhibits DIRECT THROMBIN INHIBITORS (DTIs) IV: Argatroban : Hepatic impairment: 181 Bivalirudin (Angiomax) CrCl 90: 25 ; CrCl 10-29: 57 ; Dialysis dependent patients (off dialysis): 3.5 hours PO: Dabigatran (Pradaxa) CrCl > 80: hours CrCl 50-79: 16.6 hours CrCl 30-49: 18.7 hours CrCl < 30: 27.5 hours IV DTIs can falsely elevate the INR level. aptt Thrombin Time (TT) most useful f determining if any dabigatran is present Ecarin Clotting Time (ECT) the kits have not been standardized Reversal Consider holding discontinue agent if clinically appropriate Consider activated charcoal if ingestion less than 2 hours (dabigatran) Blood product transfusion f hemodynamic Consider hemodialysis (dabigatran and bivalirudin) Maj/Life-threatening (F IV DTIs there are no clinical studies but may use recommendations below) (preferred) Feiba NF 20 units/kg IV x 1 dose over 10. If no improvement in after first dose, may consider second dose of 20 units/kg after 30 OR Kcentra 50 units/kg IV at a rate not to exceed 8.4 ml/min (max 5,000 units) Round to the nearest whole vial size If Suspected Documented HIT: Profilnine SD 50 units/kg IV at a rate not Comments There are no specific antidotes f direct thrombin inhibits documented HIT; it give PCC and rfviia together due to high risk of thrombosis

2 FACTOR XA INHIBITORS Fondaparinux (Arixtra) hours in nmal renal function Rivaroxaban (Xarelto) CrCl > 80: 5-9hours CrCl 50-79: 9.7hours CrCl 30-49: 9 hours CrCl < 30: 9.5hours Apixaban (Eliquis) CrCl > 80: 8-15hours CrCl 50-79: 14.6 CrCl 30-49: 17.6 CrCl < 30: 17.3 validated with dabigatran (Not available at AHS) doses (most sensitive f rivaroxaban/apix aban) aptt at doses Consider holding discontinue agent if clinically appropriate Consider activated charcoal if ingestion less than 8 hours (rivaroxaban) less than 3 hours (apixaban) Blood product transfusion f hemodynamic Hemodialysis (fondaparinux) increases clearance of fondaparinux by 20% Maj/Life-threatening (preferred) Kcentra 50 units/kg IV at a rate not to exceed 8.4 ml/min (max 5,000 units) Round to the nearest whole vial size If Suspected Documented HIT: Profilnine SD 50 units/kg IV at a rate not There are no specific antidotes f fact Xa inhibits give PCC and rfviia together due to high risk of thrombosis Hemodialysis not recommended f rivaroxaban/ apixaban documented HIT; it HEPARIN 1-2 hours LMWHs Enoxaparin IV: 2-4 hours Subcutaneous: 8 hours aptt Heparin Bolus Heparin Subcutaneous Time since Recommendation heparin Less than 30 Protamine 1 mg f every 100 units of heparin received Protamine 0.5 mg f every 100 units of heparin received Greater than 60 Protamine 0.25 mg f every 100 units of heparin received Heparin Infusion Protamine 1 mg f every 100 units of heparin received in previous 2-3 hours Example: A patient is receiving a heparin infusion of 1,000 units/hour would require a protamine dose of about 25 mg Time since dose Less than equal to 8 hours Greater than 8 hours Recommendation Protamine 1 mg f every 1 mg of received Protamine 0.5 mg f every 1 mg of received Protamine 1 mg will neutralize the effects of approximately 100 units of heparin Protamine administration rate should not exceed 5 mg/min Do not exceed 50 mg in any 10 minute period 100 mg in 2 hours Protamine neutralizes the anti-iia activity, but has incomplete neutralization of anti-xa activity Protamine administration rate should not exceed 5 mg/min Do not exceed 50 mg in any 10 minute period 100 mg in 2 hours

3 WARFARIN 36 hours doses Non-Maj/ Non-Life-Threatening Bleeding INR Recommendation INR me than Hold warfarin until therapeutic range INR returns to goal but less than 4.5 If urgent surgery: No significant Vitamin K 2.5 mg PO ( 1 mg IV by INR 4.5 to 10 No significant INR greater than 10 No significant ( min ) Hold warfarin until INR returns to goal Omit dose and give vitamin K mg PO If urgent surgery: Vitamin K 2.5 mg PO ( 1 mg IV by Hold warfarin and give: Vitamin K mg PO ( 1 mg IV by Blood product transfusion f hemodynamic May repeat Vitamin K IV after hours f persistent INR elevation Vitamin K administered subcutaneously has not been shown to have any effect on decreasing INR Intravenous administration of Vitamin K should not exceed a rate of 1 mg/min; use filter needle and dilute to 50 ml NSS DO NOT give Vitamin K as IV Push IM documented HIT; it Note INR cutoff at Atlantic Health lab is >7, if INR is repted >7 it is recommended to err on the side of caution Maj/Life-threatening at any INR Vitamin K 10mg IV slow infusion (infused no faster than 1mg/min) PLUS (preferred) Kcentra based on INR value: INR between 2 to 25 units/kg 4 (max 2,500 units) INR 4 to 6: INR greater than 6 35 units/kg (max 3,500 units) 50 units/kg (max 5,000 units) Round to the nearest whole vial size If Suspected Documented HIT: Profilnine SD 50 units/kg IV at a rate not FFP 15-30mL/kg

4 ASPIRIN CLOPIDOGREL 8 hours ~5 days f platelet recovery PRASUGREL 7 hours TICAGRELOR ~9 hours GP IIb-IIIa Abciximab(Reopro ) Eptifibatide (Integrilin ) Irreversible platelet inhibition 5-7 days needed f platelet recovery (aspirin, clopidogrel, prasugrel) Ticagrel is a reversible platelet inhibit 72 hours f platelet recovery Platelet transfusions often needed to attenuate Consider DDAVP 0.3mcg/kg IV x 1 over min Due to a relative sht half-life, supptive care and discontinuation of GP IIb-IIIa inhibits are primary treatment Platelet transfusions often needed to attenuate Tolerance to DDAVP may develop with repeat doses. Note DDAVP has the potential to induce hyponatremia and/ seizure Hemodialysis (f life threatening associated with eptifibatide) THROMBOLYTICS IV: Alteplase Note: About 50% cleared ~ 5 after infusion terminated; About 80% cleared in 10 : : May decrease fibrinogen level Clot lysis releases D- Dimers, which may exert antiplatelet effect Consider DDAVP 0.3mcg/kg IV x 1 over min Terminate infusion (note: 80% of alteplase cleared in 10 from plasma) Blood product transfusion f hemodynamic (PRBCs, cryoprecipitate, platelets, FFP) Guidelines do not suppt specific therapy f of thrombolytic associated There are no antidotes f thrombolytics give PCC rfviia due to lack of evidence and thrombotic risk Tenecteplase biphasic: initial ; terminal PT= prothrombin time; INR = International Nmalized Ratio; aptt=activated partial thromboplastin time; AHS=Atlantic Health System; CrCl=creatinine clearance, repted in ml/minute; PCC=partial complex concentrates; rfviia=recombinant Fact VIIa; HIT=heparin induced thrombocytopenia; LMWH= low molecular weight heparin; FFP=fresh frozen plasma; PRBC=packed red blood cells FEIBA NF is a PCC product that contains Facts II, IX, and X, mainly non-activated, and Fact VII mainly in the activated fm Kcentra is a 4-fact PCC product that contains Facts II, VII, IX, X Profilnine SD is a 3-fact product that contains Facts II, IX, X References 1. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis. CHEST 2012 f Antithrombotic and Thrombolytic Therapy. CHEST 2012;141:24S-43S 2. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis. CHEST 2012 f Antithrombotic and Thrombolytic Therapy. CHEST 2012;141:44S-87S 3. Evidence-based of anticoagulant therapy. Antithrombotic Therapy and Prevention of Thrombosis. CHEST 2012 f Antithrombotic and Thrombolytic Therapy. CHEST 2012;141:152S177S

5 4. Lemon SJ, Crannage AJ. Pharmacologic anticoagulation reversal in emergency department. Adv Emerg Nurs J 2011;33: Kalus JS. Pharmacologic interventions f reversing the effects of al anticoagulants. Am J Health Syst Pharm 2013;70:S Khoo TL et al. The use of FEIBA( ) in the crection of coagulation abnmalities induced by dabigatran. Int J Lab Hematol [Epub ahead of print] 7. Daeger W et al. Reversing dabigatran with FEIBA in a patient with transseptal perfation during cardiac ablation. Crit Care Med. 2011;39(12), Abstract 8. Marlu R et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. J Thromb Haemost. 2012;108(2): Eerenberg ES et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124(14): Eikelboom JW, Hirsh J. Bleeding and of. Eur Heart J Suppl. 2006;8:G Peter FW, Benkovic C, Muehlberger T, et al. Effects of desmopressin on thrombogenesis in aspirininduced platelet dysfunction. Br J Haematol. 2002;117(3): Tcheng JE. Clinical challenges of platelet glycoprotein IIb/IIIa recept inhibit therapy: Bleeding, reversal, thrombocytopenia, and retreatment. Am Heart J. 2000;139:S38-S Ranucci M, Nano G, Pazzaglia A, et al. Platelet mapping and desmopressin reversal of platelet inhibition during emergency carotid endarterectomy. J Cardiothac Vasc Anesth.2007;21(6): Epub 2007 Jul Pernod G et al. Reversal of anticoagulant properties of antixa and antiiia anticoagulant by non specific haemostatic drugs: an ex vivo study in healthy voluteers. J Thromb Haemost 2011;9: Hursting MJ et al. Transitioning from argatroban to warfarin therapy in patients with heparin- induced thrombocytopenia. Clin Appl Thromb Hemost Jul;11(3): Becker JC, Hursting MJ, Joffrion JL, et al. Clinical effect of concurrent warfarin on the efficacy of argatroban therapy in heparin-induced thrombocytopenia (abstract). Blood 1997;90(Suppl):110b. 17. Nutescu EA. New approaches to reversing al anticoagulant therapy. Am J Health-Syst Pharm. 2013; 70(Suppl 1):S French KF et al. Treatment of intracerebral hemrhage with tranexemic acid after thrombolysis with tissue plasminogen activat. Neurocrit Care 2012;17: Goldstin JN et al. Management of thrombolysis-associated symptomatic intracerebral hemrhage. Arch Neurol 2010;67(8): Approved by Overlook Pharmacy and Therapeutics Committee on October 8 th, 2013 Approved by Mristown Pharmacy and Therapeutics Committee on October 10 th, 2013 Approved by Newton Pharmacy and Therapeutics Committee on September 3 rd, 2013