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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 = 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 agents ® Longer in renal No Inhibitors (Eliquis ) • 1 impairment aPTT is less o 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

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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

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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 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

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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 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

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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 (DIC)  Heparin-induced thrombocytopenia (HIT)  Anaphylactic or severe systemic reactions to 4-PCC or its components including  Heparin  Factor II   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

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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. Mephyton) factors (II, VII, IX, X) Subcutaneous route has delayed and unpredictable effects. Binds to heparin and Protamine Dose: see table 1 above neutralizes its sulfate anticoagulant effect Full reversal of UFH and partial reversal of LMWH.

Human plasma Pros: Inexpensive, widely available Fresh Frozen containing all clotting plasma (FFP) Cons: Clotting factor concentrations vary. Requires cross matching if group-specific factors plasma is used. Risk of infection and volume overload. Need to be thawed out. Dose: weight based, capped at 100kg (see Dosing Guideline page 5) Vitamin K must be given concurrently for warfarin reversal. Vitamin K not needed if 4- 4-factor Non-activated factors factor PCC (KCentra®) is used to reverse Factor Xa inhibitors. prothrombin II, VII, IX, X 8 complex Proteins C & S, Contains therapeutic levels of factor VII component. concentrate heparin, antithrombin Pros: Lower risk of infection than FFP. Proteins C and S thought to attenuate (Kcentra®) III thrombosis risk. Non-inferior to FFP for hemostasis, and normalize INR faster Cons: Expensive. Short half-life, repeated dose is not recommended Humanized Idarucizumab monoclonal antibody Dose: 5 Gm (2 X 2.5 Gm/50 mL vials) IV infusion no more than 15 minutes apart (Praxbind®) fragment binds to Use only for reversal of dabigatran (Pradaxa®) Non-formulary dabigatran to neutralize its effects Use is not recommended for warfarin-related intracranial hemorrhage Recombinant Factor VIIa Recombinant Pros: Not a blood product. Small volume activated factor VII (NovoSeven RT®) Cons: Limited data for reversing warfarin. Short duration of action. Higher risk of thrombosis than non-activated PCC. Expensive.

2 Aminocaproic Dose: 5 Gm IV over 30 minutes, followed by 1 Gm/hr (max 24 Gm/day) ® competitively bind to acid (Amicar ) Dose may require renal adjustment plasminogen and block its conversion to 1 Tranexamic acid , thereby Dose: Tranexamic acid 1 Gm over 10 minutes then 1 Gm over 8 hrs ® (Cyklokapron ) inhibiting fibrin Dose may require renal adjustment degradation Increases release of von Willebrand factor, enhances platelet Desmopressin adhesion and Dose: 0.4 mCg/kG x1 in 50 mL NS IV over 15 minutes ® aggregation, (DDAVP ) Caution: Serial doses associated with tachyphylaxis, hyponatremia, and seizures contributing to a shortened aPTT and bleeding time contains fibrinogen (200 mG/unit), Factor 10 units of cryoprecipitate will raise fibrinogen levels by roughly 70 mG/dL in a 70 kG Cryoprecipitate VIII, XIII, fibronectin, patient and von Willebrand factor

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Table 5: PERIOPERATIVE MANAGEMENT OF ORAL DIRECT THROMBIN INHIBITORS AND FACTOR XA INHIBITORS15

Interval between last dose and Resumption after procedure Renal function and procedure Anticoagulant dose High bleeding Low bleeding High bleeding Low bleeding risk risk risk risk Give last dose Give last dose two CrCl >50 mL/minute three days before days before procedure (ie, skip procedure (ie, skip Dose 150 mG twice four doses on the two doses on the daily two days before day before the Dabigatran the procedure) procedure) ® (Pradaxa ) Give last dose five Give last dose CrCl 30 to 50 days before three days before mL/minute procedure (ie, skip procedure (ie, skip Dose 150 mG twice eight doses on the four doses on the daily four days before two days before the procedure) the procedure) CrCl >50 mL/minute Dose 20 mG once Give last dose Give last dose two daily three days before days before procedure (ie, skip procedure (ie, skip Resume 48 to 72 Resume 24 hours Rivaroxaban CrCl 30 to 50 ® two doses on the one dose on the hours after after surgery (ie, (Xarelto ) mL/minute two days before day before the surgery (ie, postoperative day Dose 15 mG once the procedure) procedure) postoperative day 1) daily 2 to 3) CrCl >50 mL/minute Give last dose Give last dose two Dose 5 mG twice daily three days before days before CrCl 30 to 50 procedure (ie, skip procedure (ie, skip Apixaban ® mL/minute four doses on the two doses on the (Eliquis ) two days before day before the Dose 2.5 mG twice the procedure) procedure) daily CrCl 50 to 95 Give the last dose mL/minute Give the last dose three days before two days before Dose 60 mG once the procedure (ie, Edoxaban the procedure (ie, daily skip two doses on (Savaysa®) skip one dose on the two days CrCl 15 to 50 mL/min the day before the before the Dose 30 mG once procedure) procedure) daily

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Pomona Valley Hospital Medical Center

Table 6: PERIOPERATIVE MANAGEMENT OF ANTIPLATELETS16

ADP: Adenosine diphosphate; CABG: Coronary artery bypass grafting

Antiplatelet Recommendation

Stop 7 to 10 days before surgery May be continued through surgery for CABG or non-cardiac surgery in patients with moderate to high cardiac risk COX inhibitor Aspirin Aspirin should not be discontinued in patients with cardiac stents that have not completed their full course of dual antiplatelet therapy; patient- specific situations need to be discussed with cardiologist.

Stop 5 to 10 days before surgery Clopidogrel When urgent CABG is necessary, stop for at least 24 hours prior to (Plavix®) surgery Irreversible ADP receptor inhibitors Stop 5 to 7 days before surgery Prasugrel When urgent CABG is necessary, stop for at least 24 hours prior to (Effient®) surgery

Stop ticagrelor at least 5 days before surgery Reversible ADP Ticagrelor When urgent CABG is necessary, stop for at least 24 hours prior to receptor inhibitor (Brilinta®) surgery

Phosphodiesterase Cilostazol Stop 2 to 3 days before surgery III inhibitors (Pletal®)

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Figure 1: Coagulation Cascade

UFH

UFH

UFH

Warfarin Warfarin Fondaparinux UFH

Rivaroxaban, apixaban, edoxaban Warfarin LMWH

UFH Dabigatran Argatroban Bivalirudin Warfarin LMWH

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REFERENCES

1. Tranexamic Acid. In Lexi-Drugs Online. Hudson, OH : LexiComp, Inc.; Updated April 15, 2016; http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7798 2. Aminocaproic Acid. In Lexi-Drugs Online. Hudson, OH : LexiComp, Inc.; Updated April 15, 2016; http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6327 3. Frontera, J. A., Iii, J. J., Rabinstein, A. A., Aisiku, I. P., Alexandrov, A. W., Cook, A. M., . . . Zerfoss, C. L. (2015). Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage. Neurocritical Care Neurocrit Care, 24(1), 6-46 4. Brophy, G. M., Human, T., & Shutter, L. (2015). Emergency Neurological Life Support: Pharmacotherapy. Neurocritical Care Neurocrit Care, 23(S2), 48-68. 5. Garcia, D., Crowther, M. Management of bleeding in patients receiving direct oral anticoagulants. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, Updated January 4, 2016. Accessed January 28, 2016. 6. Praxbind. In Lexi-Drugs Online. Hudson, OH : LexiComp, Inc.; Updated October 10, 2015; Accessed January 26, 2016. http://online.lexi.com.proxy.westernu.edu/lco/action/doc/retrieve/docid/patch_f/590092y 7. Grandhi R, Newman WC, Zhang X, et al. Administration of 4-factor prothrombin complex concentrate as an antidote for intracranial bleeding in patients taking direct factor Xa inhibitors. World Neurosurg 2015 Sept 1 8. Kcentra. In Lexi-Drugs Online. Hudson, OH : LexiComp, Inc.; Updated January 27, 2016; Accessed January 26, 2016. http://online.lexi.com.proxy.westernu.edu/lco/action/search?q=kcentra&t=name 9. PL Detail-Document, How to Manage High INRs in Warfarin Patients. Pharmacist's Letter/Prescriber's Letter. May 2012. 10. PL Detail-Document, Clotting Factors for Reversing Anticoagulants. Pharmacist’s Letter/Prescriber’s Letter. October 2013 11. PL Detail-Document, Managing Bleeding with the New Oral Anticoagulants. Pharmacist’s Letter/Prescriber’s Letter. December 2015 12. Dale BJ, Chan NC, Eikelboom JW. Laboratory measurement of the direct oral anticoagulants. Br J Haematol 2015 Oct 22 13. Ageno W, Gallus AS, Wittkowsky A, et al, “Oral Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines,” Chest, 2012, 141(2 Suppl):e44-88. 14. Ansell J, Hirsh J, Hylek E, et al, “Pharmacology and Management of the Vitamin K Antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):160-98 15. Lip G, Douketis J, Leung L, Tirnauer J, Perioperative management of patients receiving anticoagulants. . In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, Updated March, 2016. Accessed May 2, 2016. 16. Oral Antiplatelet Comparison Chart. In LexiComp Online. Hudson, OH: LexiComp, Inc.; Accessed May 4, 2016. Available at https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/3891002

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