Pomona Valley Hospital Medical Center GUIDELINES FOR REVERSAL OF ANTITHROMBOTICS Table 1: ANTICOAGULATION REVERSAL RECOMMENDATIONS ACT = activated clotting time, aPCC = activated prothrombin complex concentrate, aPTT = activated partial thromboplastin time, ECT = ecarin clotting time, FFP = fresh frozen plasma, INR = international normalized ratio, PCC = prothrombin complex concentrate, PT = prothrombin time, TT = thrombin time Dialyza Lab Class Drug Half-Life Recommendations ble Assessment Terminal: 5-9 hrs 3 Rivaroxaban • Anti-Xa • Activated charcoal 50 Gm within 2 hrs of ingestion ® Longer in renal No (Xarelto ) • ® impairment assay 4-factor PCC (KCentra ) 25 - 50 units/kG x1 at 0.12 mL/kG/min (~3 units/kG/min). • Do not exceed 8.4mL/min (~210 units/min). 8 8-15 hrs May prolong Factor Xa Apixaban PT • Possible antifibrinolytic agents ® Longer in renal No Inhibitors (Eliquis ) • 1 impairment aPTT is less o Tranexamic acid 1 Gm over 10 minutes then 1 Gm over 8 hrs sensitive Aminocaproic acid 5 Gm IV over 30 minutes, followed by 1 Gm/hr (max 24 10-14 hrs o Edoxaban than PT Gm/day)2 ® Longer in renal No (Savaysa ) • Consider 15-20 mL/kG FFP if volume needed impairment 17-21 hrs ® 3 • rFVIIa (NovoSeven ) 90 mCg/kG IV x1 or Pentasacc Fondaparinux Longer in renal • Anti-Xa ® 3 ® No • aPCC (FEIBA ) (non-formulary) 20 units/kG IV x1 haride (Arixtra ) impairment and assay • May consider 4-factor PCC (KCentra®) 50 units/kG (weak data) elderly 39-51 min Argatroban 3 h in hepatic 20% • Turn off infusion. Monitor aPTT/ACT to confirm clearance impairment • aPTT • May consider 4-factor PCC (KCentra®) 50 units/kG x1 at 3 units/kG/min (max dose 25 min • ACT 5000 units) if there is renal or hepatic insufficiency leading to continued drug Bivalirudin 1 hr in severe renal 25% exposure beyond 3 to 5 half-lives (Off-label, low-quality evidence) (Angiomax®) impairment Direct • Activated charcoal 50 Gm within 2 hrs of ingestion3 Thrombin • Hemodialysis 12-17 hrs Inhibitors • Idarucizumab (Praxbind®) 5 Gm (two 2.5 Gm/50mL vials) IV bolus infusion. Vials 15-18 hrs in mild- should be given no more than 15 minutes apart. May repeat x1 dose for refractory Dabigatran mod renal ® 57% • aPTT bleeding (limited data) (non-formulary) (Pradaxa ) impairment • Possible antifibrinolytic agents 29 hrs in severe Tranexamic acid 1 Gm over 10 minutes then 1 Gm over 8 hrs1 renal impairment o o Aminocaproic acid 5 Gm IV over 30 minutes, followed by 1 Gm/hr (max 24 Gm/day)2 Prepared by Jackie Vo, PharmD, MBA, BCNSP, BCPS, Minh Phuc Nguyen, PharmD Candidate | Reviewed/Approved by P&T 5/2016 Page 1 Pomona Valley Hospital Medical Center Table 1 continued: ANTICOAGULATION REVERSAL RECOMMENDATIONS Class Drug Half-Life Dialyzable Lab Assessment Recommendations • Protamine 1 mG IV for every 100 units of heparin administered in the previous 2-3 hrs. No more than 50 mG over 10-min period 3,4 Time since Protamine dose per 100 units Unfractionated 1-2 hrs (dose- • aPTT Heparin Heparin administered Heparin No Heparin dependent) Less than 30 min 1 mG 30 min – 2 hrs 0.5 mG Greater than 2 hrs 0.25 mG • Protamine partially reverses the anticoagulant effect of LMWHs (~ 60%). No more than 50 mg over 10-min period 3, 4 Time since Protamine dose per 1mg 4.5-7 hrs based on enoxaparin enoxaparin administered Low molecular anti-Xa activity Enoxaparin 8 hrs 1 mG weight heparin ® No • Anti-Xa assay (Lovenox ) (longer in severe (LMWH) 8-12 hrs 0.5 mG renal impairment) Greater than 12 hrs not likely to be beneficial • If life-threatening bleeding persists or patient has renal insufficiency, may repeat protamine 0.5 mG per 1 mG of enoxaparin x 1 Prepared by Jackie Vo, PharmD, MBA, BCNSP, BCPS, Minh Phuc Nguyen, PharmD Candidate | Reviewed/Approved by P&T 5/2016 Page 2 Pomona Valley Hospital Medical Center Table 1 continued: ANTICOAGULATION REVERSAL RECOMMENDATIONS Class Drug Recommendations Elevated INR Without Clinically Significant Bleeding • Skip a dose. Resume at lower dose when INR therapeutic INR less than 4.5 • No dose reduction needed if INR is minimally supratherapeutic • Skip 1 to 2 doses of warfarin. • Resume warfarin at lower dose when INR is in therapeutic range INR 4.5 - 10 • Routine use of vitamin K is not recommended if no evidence of bleeding • Consider vitamin K 1 to 2.5 mG PO x1 if high risk for bleeding • D/C warfarin INR greater than 10 • Vitamin K 2.5 to 5 mG PO x1 • Resume warfarin at a lower dose when INR is in therapeutic range Warfarin Minor Bleeding at any INR Elevation (Coumadin®, ® • D/C warfarin. Vitamin K 2.5-5 mG PO x1 and repeat x1 dose after 24 hrs if INR correction incomplete Jantoven ) Vitamin K • Resume warfarin at lower dose when INR is in therapeutic range Antagonist Half-life 20-60 hrs Dialyzable: No Serious or Life Threatening Bleeding or Surgery/Procedure Requiring Emergent Warfarin Reversal • D/C warfarin • Vitamin K 10 mG IV infusion over 30 minutes AND • 4-factor PCC (KCentra®) o INR 2 – less than 4: 25 units/kG (max 2500 units) o INR 4 - 6: 35 units/kG (max 3500 units) o INR greater than 6: 50 units/kG (max 5000 units) • Repeat INR 4 – 6 hrs after 4-factor PCC (KCentra®) administration and in am. • Consider FFP 10-15 mL/kG if volume is needed • Repeat dose of Kcentra is not recommended Prepared by Jackie Vo, PharmD, MBA, BCNSP, BCPS, Minh Phuc Nguyen, PharmD Candidate | Reviewed/Approved by P&T 5/2016 Page 3 Pomona Valley Hospital Medical Center Table 2: ANTIPLATELET REVERSAL RECOMMENDATIONS Antiplatelet Half-life Dialyzable Recommendations COX inhibitor Aspirin 20 min Yes Clopidogrel ® 3 ® 6-8 hrs No Desmopressin (DDAVP ) 0.4 mCg/kG IV x 1 over 15 minutes Irreversible ADP (Plavix ) Onset: Immediate receptor inhibitors Prasugrel ® 2-15 hrs No (Effient ) Caution: Serial doses associated with tachyphylaxis, hyponatremia, and seizures May consider platelet transfusion for patient who will undergo neurosurgical Reversible ADP Ticagrelor 7 hrs ® No procedure receptor inhibitor (Brilinta ) Metabolite 9 hrs Phosphodiesterase Cilostazol ® 11 – 13 hrs No III inhibitor (Pletal ) Tirofiban ® 20-45 min (Aggrastat ) Yes D/C of GP IIb-IIIa are primary means of attenuating bleed due to short half-life Eptifibatide Desmopressin (DDAVP®) 0.4 mCg/kG IV x 1 over 15 minutes3 GP IIb-IIIa inhibitors (Integrilin®) 20-40 min Yes Onset: Immediate Free drug: 30min Abciximab (Reopro®) Receptor bound: No 24-48 hrs Table 3: THROMBOLYTIC REVERSAL RECOMMENDATIONS Thrombolytic Half-life Dialyzable Recommendations ® Plasma: 3–6 min Alteplase (tPA ) No Terminal: 26–77 min Cryoprecipitate 10 units IV. Can give an additional dose if fibrinogen is less than 100 - 150 mG/dL3 OR Tranexamic acid 10–15 mG/kG (or 1 Gm) IV over 20 min if cryoprecipitate is contraindicated 3 Tenecteplase 3 Plasma: 11–24 min No OR Aminocaproic acid 5 g IV over 1 hr (TNKase®) Terminal: 90–138 min Prepared by Jackie Vo, PharmD, MBA, BCNSP, BCPS, Minh Phuc Nguyen, PharmD Candidate | Reviewed/Approved by P&T 5/2016 Page 4 Pomona Valley Hospital Medical Center Dosing Guideline for 4-factor Prothrombin Complex Concentrate (Kcentra®)8,4 Black Box Warning May not be suitable in patients with thromboembolic events in the prior 3 months FDA-Approved Indications: Urgent reversal of warfarin in adult patients with Acute major or life-threatening bleeding Emergent surgery/invasive procedure within 8 hours Off-label Indications: Urgent reversal of rivaroxaban, apixaban, and edoxaban in adult patients with major or life-threatening bleeding STOP if patient has any of these CONTRAINDICATIONS: Disseminated intravascular coagulation (DIC) Heparin-induced thrombocytopenia (HIT) Anaphylactic or severe systemic reactions to 4-PCC or its components including Heparin Factor II Factor X Protein C Factor VII Antithrombin III Protein S Factor IX Human albumin Dosing calculations based on actual body weight up to 100kg Patient’s actual body weight = _________ kg Dose is expressed as units of Factor IX. Note: exact contents are labeled on the vial and will vary from vial to vial Repeat dosing is not recommended WARFARIN REVERSAL 1. D/C warfarin 2. Dosing based on pre-treatment INR 3. Concurrent vitamin K 10 mg in 50 ml NS, IV infusion over 30 minutes x 1 dose STAT ® 4. 4-factor PCC (KCentra ) IVPB x 1 dose to be infused at a rate of 0.12mG/kG/min (~3 units/kG/min). Do not exceed 8.4 mL/min (~210 units/min). Patient’s weight used for dosing to be capped at 100 kG. Pre-treatment INR Dose (units of factor IX) Max dose (units of factor IX) 2 to less than 4 25 units/kG = ________ units 2,500 units 4 to 6 35 units/kG = ________ units 3,500 units Greater than 6 50 units/kG = ________ units 5,000 units 5. Repeat dosing is not recommended RIVAROXABAN (XARELTO®), APIXABAN (ELIQUIS®), EDOXABAN (SAVAYSA®) REVERSAL 1. D/C rivaroxban/apixaban/edoxaban 2. 4-factor PCC (KCentra®) 25 - 50 units/kG = ________units (max 5,000 units) infused at 0.12mL/kG/min (~3 units/kG/min). Do not exceed 8.4 mL/min (~210 units/min). 3. Repeat dosing is not recommended Prepared by Jackie Vo, PharmD, MBA, BCNSP, BCPS, Minh Phuc Nguyen, PharmD Candidate | Approved 5/2016 Page 5 Pomona Valley Hospital Medical Center Table 4: REVERSAL AGENTS Agent Mechanism of Comments action Dose: 1-10 mG IV or PO Phytonadione Promotes liver Vitamin K IV infusion over 30 minutes works faster than oral vitamin K, but is (Vitamin K, synthesis of clotting associated with anaphylactic reaction.