UNC MEDICAL CENTER GUIDELINE Emergent Anticoagulation Reversal

The purpose of this guideline is to provide guidance for the reversal of or management of bleeding while on treatment with anticoagulants. Recommendations provided in this document reflect current guidelines, clinical evidence and institutional initiatives. These recommendations are not intended to replace clinical judgement, but are intended to serve as a tool for decision-making.

Table of Contents by Anticoagulant:  Warfarin  Dabigatran  Edoxaban, Betrixaban, or Fondaparinux  Apixaban or Rivaroxaban  Unfractionated Heparin or Low Molecular Weight Heparin (Enoxaparin or Dalteparin)  Argatroban or Bivalirudin  Antiplatelet agents

I. Bleeding Definitions: See A p p e n d i x A

I I . Emergent Reversal of Oral Anticoagul a n t s

FIGURE 1. MANAGEMENT OF WARFARIN RELATED BLEEDING EVENTS

Patient currently taking warfarin

Major bleed or Non-major bleeding or routine/urgent procedure/surgery emergent procedure/surgery

Vitamin K 10 mg IV

AND See warfarin dosing guidelines for management of supratherapeutic international normalized ratio (INR) without INR 1.50-3.99: KCentra® 25 units/kg x 1 dose bleeding (Max dose: 2500 units)

For minor bleeding or a routine/urgent procedure consider INR 4.00-6.00: KCentra® 35 units/kg x 1 dose Vitamin K IV +/- 2 units of fresh frozen plasma (FFP) (Max dose: 3500 units)

INR > 6.00: KCentra® 50 units/kg x 1 dose (Max dose: 5000 units)

Recheck INR 10-30 minutes after KCentra® administration and Recheck INR in 6-12 hours every 6 hours for 24 hours.

Developed by: Lindsey Splinter, PharmD, Kelly Dehne, PharmD, BCCCP, Kalynn Rohde, PharmD, BCCCP Last updated: October 2019 Reviewed by: Stephan Moll, MD, Raj, Kasthuri, MD, Abhi Mehrotra, MD, MBA, Rhonda Cadena, MD Page 1 of 12 Approved by: Acute Care Services Pharmacy Practice Council, P&T Committee, MSEC

Ordering and Administration A. Vitamin K 1. Subcutaneous or intramuscular doses are not recommended as routine care. Subcutaneous administration leads to erratic absorption and intramuscular administration may lead to the development of hematomas in the setting of therapeutic anticoagulation. 2. Full effect of vitamin K on warfarin reversal occurs approximately 24 hours after administration. Partial effects may be seen 6-12 hours after administration. 3. Doses of vitamin K greater than 10 mg are excessive and do not reverse anticoagulation more quickly. B. 4-Factor Prothrombin Complex Concentration (KCentra®) 1. Ordering: i. KCentra® doses are calculated as units/kg using total body weight, with the maximum dosing weight of 100 kg. ii. During verification, the Sterile Products Area pharmacist will verify and prepare dose rounded to nearest vial size within 10% of originally ordered dose. 2. Administration: i. Administer via infusion pump at a rate of 3 units/kg/minute; do not exceed a rate of 8.4 mL/minute (504 mL/hour). ii. After KCentra® dose is complete, administer a 50 mL bag of normal saline using the same IV tubing at the same rate as KCentra® dose to ensure administration of full dose.

Developed by: Lindsey Splinter, PharmD, Kelly Dehne, PharmD, BCCCP, Kalynn Rohde, PharmD, BCCCP Last updated: October 2019 Reviewed by: Stephan Moll, MD, Raj, Kasthuri, MD, Abhi Mehrotra, MD, MBA, Rhonda Cadena, MD Page 2 of 12 Approved by: Acute Care Services Pharmacy Practice Council, P&T Committee, MSEC

FIGURE 2. MANAGEMENT OF DABIGATRAN RELATED BLEEDING EVENTS

Patient currently taking dabigatran*

Non-major bleeding or Major bleeding or routine/urgent procedure/surgery emergent procedure/surgery

1) Administer idarucizumab (Praxbind®) 5 g (2 vials) IV x 1 dose 2) For persistent refractory bleeding (> 1 hour), consider a hematology consult 3) To investigate potential causes of bleeding obtain the following: serum creatinine Delay next dose or discontinue (SCr), prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin dabigatran time (TT), complete blood count (CBC)

In the setting of acute renal failure, hemodialysis may be considered to assist with drug removal

*If presenting within 2 hours of ingestion of dabigatran dose, consider administering activated charcoal 50 g by mouth x 1 dose -Avoid activated charcoal in patients who may require a gastrointestinal procedure for suspected or confirmed bleeding

Ordering and Administration A. Idarucizumab (Praxbind®) 1. Administration: i. Praxbind® is stored in the refrigerator. ii. Administer promptly once vials have been removed from box (stability after light exposure is 6 hours). iii. Administer both vials undiluted as an IV bolus (2.5 g in each vial) over 5 minutes via an infusion pump (pump entry defaults to 600 mL/hour). iv. The second vial should be administered no later than 15 minutes after the end of the first vial. v. After Praxbind® dose is complete; administer a 50 mL bag of normal saline using the same IV tubing at the same rate as Praxbind® dose to ensure administration of full dose.

Developed by: Lindsey Splinter, PharmD, Kelly Dehne, PharmD, BCCCP, Kalynn Rohde, PharmD, BCCCP Last updated: October 2019 Reviewed by: Stephan Moll, MD, Raj, Kasthuri, MD, Abhi Mehrotra, MD, MBA, Rhonda Cadena, MD Page 3 of 12 Approved by: Acute Care Services Pharmacy Practice Council, P&T Committee, MSEC

F IGURE 3. MANAGEMENT OF EDOXABAN, BETRIXABAN, OR FONDAPARINUX RELATED BLEEDING EVENTS

Patient currently taking edoxaban*, betrixaban*, or fondaparinux

Non-major bleeding or Major bleeding or routine/urgent procedure/surgery emergent procedure/surgery

1) Administer KCentra® 50 units/kg IV x 1 dose (Max dose: 5000 units) 2) For persistent refractory bleeding (> 1 hour), consider a hematology consult Delay next dose or discontinue factor Xa inhibitor 3) To investigate potential causes of bleeding obtain the following: serum creatinine (SCr), prothrombin time (PT), activated partial thromboplastin time (aPTT), complete blood count (CBC)

*If presenting within 2 hours of ingestion of edoxaban or betrixaban dose, consider administering activated charcoal 50 g by mouth x 1 dose -Avoid activated charcoal in patients who may require a gastrointestinal procedure for suspected or confirmed bleeding

Ordering and Administration A. 4-Factor Prothrombin Complex Concentration (KCentra®) 1. Ordering: i. KCentra® doses are calculated as units/kg using total body weight, with the maximum dosing weight of 100 kg. ii. During verification, the Sterile Products Area pharmacist will verify and prepare dose rounded to nearest vial size within 10% of originally ordered dose. 2. Administration: i. Administer via infusion pump at a rate of 3 units/kg/minute; do not exceed a rate of 8.4 mL/minute (504 mL/hour). ii. After KCentra® dose is complete; administer a 50 mL bag of normal saline using the same IV tubing at the same rate as KCentra® dose to ensure administration of full dose.

Developed by: Lindsey Splinter, PharmD, Kelly Dehne, PharmD, BCCCP, Kalynn Rohde, PharmD, BCCCP Last updated: October 2019 Reviewed by: Stephan Moll, MD, Raj, Kasthuri, MD, Abhi Mehrotra, MD, MBA, Rhonda Cadena, MD Page 4 of 12 Approved by: Acute Care Services Pharmacy Practice Council, P&T Committee, MSEC

F I G U R E 4 . MANAGEMENT OF APIXABAN OR RIVAROXABAN RELATED BLEEDING EVENTS

Patient currently taking apixaban* or rivaroxaban*

Non-major bleeding or Major bleeding or routine/urgent procedure/surgery emergent procedure/surgery

All other bleeding or emergent Intracranial hemorrhage ONLY procedure/surgery

1) Administer KCentra® 50 units/kg IV x 1 (Max dose: 5000 units) Delay next dose or discontinue factor 2) For persistent refractory bleeding (> 1 Xa inhibitor hour), consider a hematology consult 1) Andexxa® with Neurocritical Care 3) To investigate potential causes of Attending approval only bleeding obtain the following: serum 2) See Table 1 for dosing creatinine (SCr), prothrombin time recommendations (PT), activated partial thromboplastin time (aPTT), complete blood count (CBC)

*If presenting within 2 hours of ingestion of apixaban or rivaroxaban dose, consider administering activated charcoal 50 g by mouth x 1 dose -Avoid activated charcoal in patients who may require a gastrointestinal procedure for suspected or confirmed bleeding

Ordering and Administration A. 4-Factor Prothrombin Complex Concentration (KCentra®) 1. Ordering: i. KCentra® doses are calculated as units/kg using total body weight, with the maximum dosing weight of 100 kg. ii. During verification, the Sterile Products Area pharmacist will verify and prepare dose rounded to nearest vial size within 10% of originally ordered dose. 2. Administration: i. Administer via infusion pump at a rate of 3 units/kg/minute; do not exceed a rate of 8.4 mL/minute (504 mL/hour). ii. After KCentra® dose is complete, administer a 50 mL bag of normal saline using the same IV tubing at the same rate as KCentra® dose to ensure administration of full dose. B. Coagulation factor Xa (recombinant), inactivated-zhzo (Andexxa®) 1. Ordering: i. Andexxa® is restricted to use for intracranial hemorrhage only and must be ordered or approved by a Neurocritical Care Attending ii. Select low or high dose based on anticoagulant dose and timing of last dose (see Table 1)

2. Administration:

Developed by: Lindsey Splinter, PharmD, Kelly Dehne, PharmD, BCCCP, Kalynn Rohde, PharmD, BCCCP Last updated: October 2019 Reviewed by: Stephan Moll, MD, Raj, Kasthuri, MD, Abhi Mehrotra, MD, MBA, Rhonda Cadena, MD Page 5 of 12 Approved by: Acute Care Services Pharmacy Practice Council, P&T Committee, MSEC

i. Administer bolus and infusion using a 0.2 or 0.22 micron in-line filter (supplied by Central Pharmacy). The same tubing and filter should be used for the bolus and infusion. ii. The infusion should begin within 2 minutes of completion of the bolus dose. iii. After Andexxa® dose is complete, administer a 50 mL bag of normal saline using the same IV tubing and filter at the same rate as Andexxa® dose to ensure administration of full dose.

Table 1. Andexxa® Dosing By Anticoagulant and Time of Last Dose Anticoagulant Last Dose Timing of Anticoagulant Last Dose Anticoagulant Administered (mg taken) < 8 hours or unknown 8 hours-18 hours < 5 mg Low dose Apixaban > 5 mg or unknown mg dose High dose Low dose < 10 mg Low dose Rivaroxaban > 10 mg or unknown mg dose High dose 1. Low dose: 400 mg IV bolus (30 mg/min (180 mL/hour)) followed by 480 mg (4 mg/min (24 mL/hour)) over 2 hours 2. High dose: 800 mg IV bolus (30 mg/min (180 mL/hour)) followed by 960 mg (8 mg/min (48 mL/hour)) over 2 hours

Developed by: Lindsey Splinter, PharmD, Kelly Dehne, PharmD, BCCCP, Kalynn Rohde, PharmD, BCCCP Last updated: October 2019 Reviewed by: Stephan Moll, MD, Raj, Kasthuri, MD, Abhi Mehrotra, MD, MBA, Rhonda Cadena, MD Page 6 of 12 Approved by: Acute Care Services Pharmacy Practice Council, P&T Committee, MSEC

I II. Emergent Reversal of Intravenous and Subcutaneous Anticoagula n t s

F I G U R E 5 . MANAGEMENT OF UNFRACTIONATED HEPARIN (UFH) OR LOW - MOLECULAR WEIGHT HEPARIN (LMWH) RELATED BLEEDING EVENTS

Patient currently taking UFH or LMWH

Non-major bleeding or Major bleeding or routine/urgent procedure/surgery emergent procedure/surgery

Unfractionated Heparin (IV) 1) Administer protamine sulfate*: Max dose: 50 mg a. Calculate the units of heparin administer within the last 3 hours b. Administer 1 mg of protamine for every 100 units of heparin administered in last 3 hours

Unfractionated Heparin (subcut) 1) Administer protamine sulfate*: Max dose: 50 mg a. Calculate the units of heparin administer within the last 3 hours b. Administer 1 mg of protamine for every 100 units of heparin administered in last 3 hours c. Monitor activated partial thromboplastin time (aPTT) every 3 hours and consider repeat protamine (0.5 mg per 100 units of heparin administered) if Delay next dose or discontinue heparin bleeding continues infusion or low molecular weight heparin Low Molecular Weight Heparin: injections 1) Administer protamine sulfate*: Max dose: 50 mg a. Enoxaparin: Determine timing of last dose i. If dose within the last 8 hours, give 1 mg of protamine for every 1 mg of enoxaparin administered ii. If dose within the last 8-12 hours, give 0.5 mg of protamine for every 1 mg of enoxaparin administered iii. If dose more than 12 hours ago, protamine sulfate is not recommended. Consider checking LMWH anti-factor Xa level in the setting of renal failure. Administer 0.5 mg of protamine for every 1 mg of enoxaparin administered if level elevated. b. Dalteparin: Determine timing of last dose i. If dose within last 8 hours, give 1 mg of protamine for every 100 units of dalteparin administered

*Patients with fish allergies or prior exposure to protamine are at increased risk for hypersensitivity reactions, including anaphylaxis, pre-medicate with the following:  Hydrocortisone 50 mg IV x 1 dose  Diphenhydramine 50 mg IV or by mouth x 1 dose

Ordering and Administration A. Protamine Sulfate 1. Administration: i. Administer protamine sulfate as a slow IV push with maximum rate of 5 mg/minute to prevent hypotension and bradycardia ii. Patients with history of fish allergies or prior exposure to protamine should receive pre-medications with hydrocortisone and diphenhydramine.

Developed by: Lindsey Splinter, PharmD, Kelly Dehne, PharmD, BCCCP, Kalynn Rohde, PharmD, BCCCP Last updated: October 2019 Reviewed by: Stephan Moll, MD, Raj, Kasthuri, MD, Abhi Mehrotra, MD, MBA, Rhonda Cadena, MD Page 7 of 12 Approved by: Acute Care Services Pharmacy Practice Council, P&T Committee, MSEC

F IGURE 6. MANAGEMENT OF DIRECT THROMBIN INHIBITOR RELATED BLEEDING EVENTS

Patient currently taking argatroban or bivalirudin

Non-major bleeding or Major bleeding or routine/urgent procedure/surgery emergent procedure/surgery

1) Administer KCentra® 50 units/kg IV x 1 (max dose: 5000 units) 2) For persistent refractory bleeding, consider a hematology consult Discontinue direct thrombin inhibitor continuous infusion 3) To investigate potential causes of bleeding obtain the following: serum creatinine (SCr), prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), complete blood count (CBC)

Ordering and Administration A. 4-Factor Prothrombin Complex Concentration (KCentra®) 1. Ordering: i. KCentra® doses are calculated as units/kg using total body weight, with the maximum dosing weight of 100 kg. ii. During verification, the Sterile Products Area pharmacist will verify and prepare dose rounded to nearest vial size within 10% of originally ordered dose. 2. Administration: i. Administer via infusion pump at a rate of 3 units/kg/minute; do not exceed a rate of 8.4 mL/minute (504 mL/hour). ii. After KCentra® dose is complete, administer a 50 mL bag of normal saline using the same IV tubing at the same rate as KCentra® dose to ensure administration of full dose.

Developed by: Lindsey Splinter, PharmD, Kelly Dehne, PharmD, BCCCP, Kalynn Rohde, PharmD, BCCCP Last updated: October 2019 Reviewed by: Stephan Moll, MD, Raj, Kasthuri, MD, Abhi Mehrotra, MD, MBA, Rhonda Cadena, MD Page 8 of 12 Approved by: Acute Care Services Pharmacy Practice Council, P&T Committee, MSEC

III. M a n a g e m e n t o f Antiplatelet A g e n t Related Bleeding E v e n t s

Duration of platelet inhibition by antiplatelet agents that irreversibly inhibit platelet function is not dependent on the agent half-life, but rather may persist for 5-7 days. Utilize Table 2 below as a guide for interpreting the peak and duration of action of these agents.

Table 2. Antiplatelet PK/PD profiles Time to Maximum Elimination Half- Platelet Agent Antiplatelet Notes Life Inhibition Effect Antiplatelet effects begin within one hour of Aspirin 30 minutes 15-30 minutes Irreversible dose and persist for at least 4 days after stopping therapy.

More rapid inhibition of platelet function is Clopidogrel achieved with loading doses; antiplatelet effect 3-7 days 8 hours Irreversible (Plavix®) persists for up to 10 days after stopping therapy.

Prasugrel Antiplatelet effect persists for 5-7 days after 30 minutes 7 hours Irreversible (Effient®) stopping therapy. Ticagrelor Antiplatelet effects are decreased to 30% 1.5 hours 7 hours Reversible Brilinta®) activity after stopping therapy for 2.5 days. Ticlopidine Antiplatelet effect persists for 5-7 days after 1-3 hours 24-36 hours Reversible (Ticlid®) stopping therapy. Cangrelor Seconds with IV Normal platelet function returns by 60 minutes 2-5 minutes Reversible (Kengreal®) administration after infusion is stopped. Table adapted from Ortel TL. Blood. 2012;120(24):4699-4705.

1. Management strategies for antiplatelet associated bleeding events: a. There are no specific reversal agents for antiplatelet agents, therefore treatment of bleeding involves general hemostatic measures. b. Discontinuation of antiplatelet agents due to bleeding must be weighed against the patient’s risk of arterial thrombosis. The risk of thrombosis is particularly high within 1 month of receiving a bare metal coronary stent and within 3 months of receiving a drug eluting coronary stent. Premature cessation of dual anti-platelet therapy in these situations can lead to stent thrombosis, which can potentially be fatal. c. Antiplatelet agents should be reinstated as soon as hemostasis is obtained d. Platelet infusion may be considered as additional measure for severe critical bleeds, or prevention of bleeds before emergency surgery, but it may confer a risk of arterial thrombosis. e. Tranexamic acid (Lysteda®) or Aminocaproic acid (Amicar®) can be considered i. Tranexamic acid: 10 mg/kg IV bolus administered over 10 minutes (maximum bolus dose: 1000 mg IV once) ii. Aminocaproic acid: 50 mg/kg IV bolus administered over 60 minutes (maximum bolus dose: 5000 mg IV once) iii. Continuation of tranexamic acid or aminocaproic acid after the bolus can be considered for continued bleeding f. DDAVP is likely not a safe option, as it can lead to arterial vasospasm. g. Hematology/Coagulation Consult Service may be consulted if a risk versus benefit evaluation is required.

Developed by: Lindsey Splinter, PharmD, Kelly Dehne, PharmD, BCCCP, Kalynn Rohde, PharmD, BCCCP Last updated: October 2019 Reviewed by: Stephan Moll, MD, Raj, Kasthuri, MD, Abhi Mehrotra, MD, MBA, Rhonda Cadena, MD Page 9 of 12 Approved by: Acute Care Services Pharmacy Practice Council, P&T Committee, MSEC

References: 1. Antithrombotic therapy and prevention of thrombosis 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. CHEST. 2012;141 (2_suppl). 2. Bijsterveld NR et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation. 2002;106:2550-2554. 3. Burnette AE et al. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis. 2016;41:206–232 4. Dager WE et al. Reversal of elevated INR and bleeding with low-dose recombinant activated factor VII in patients receiving warfarin. Pharmacotherapy. 2006;26(8):1091-8. 5. Eerenberg ES et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate. Circulation. 2011;124: 1573-1579. 6. Holland L et al. Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic INR due to warfarin overdose. Transfusion. 2009; 49(6):1171-1177 7. Levi M et al. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010; 363:1791-800. 8. Makris M et al Guideline on the management of bleeding in patients on antithrombotic agents. British Journal of Hematology. 2012;160(1):35-46. 9. Nishijima DK et al. The efficacy of factor VIIa in emergency department patients with warfarin use and traumatic intracranial hemorrhage. Acad Emerg Med. 2010;17(3):244-51. 10. Ortel TL. Perioperative management of patients on chronic antithrombotic therapy. Blood. 2012 Dec 6;120(24):4699-705. 11. Pollack CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015;373(6):511-20. 12. Van Ryn J et al. Dabigatran etexilate-a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010;103(6):1116- 1127 13. UNCH Blood Derivative Compendium v02012 06 21. 14. Vavra KA et a. Recombinant factor VIIa to manage major bleeding from newer parenteral anticoagulants. Ann Pharmacother. 2010;44:718-26. 15. www. Clotconnect.org 16. Product Information: PRAXBIND intravenous injection, idarucizumab intravenous injection. Boehringer Ingelheim Pharmaceuticals (per FDA), Ridgefield, CT, 2015. 17. Witt D et al. Guidance for the practical management of warfarin therapy in the treatment of venous thromboembolism. J Thromb Thrombolysis 2016;41:187–205. 18. Siegal DM, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015 Dec 17;373(25):2413-24 19. Connolly SJ, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Eng J Med 2016 Sep 22;375(12):1131-41 20. Kaatz S, Ahmad D, Spyropoulos AC, et al. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost. 2015;13(11):2119-2126. 21. Cuker, et al. Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum. Am J Hematol 2019;94(6):697-709. 22. Cushman M, et al. 2011 Clinical practice guide on anticoagulant dosing and management of anticoagulant-associated bleeding complications in adults. American Society of Hematology Clinical Pocket Guide. 2011. 23. Shi J, Ji H, Ren F, et al. Protective effects of tranexamic acid on clopidogrel before coronary artery bypass grafting: a multicenter randomized trial. JAMA Surg. 2013;148(6):538:547.

Developed by: Lindsey Splinter, PharmD, Kelly Dehne, PharmD, BCCCP, Kalynn Rohde, PharmD, BCCCP Last updated: October 2019 Reviewed by: Stephan Moll, MD, Raj, Kasthuri, MD, Abhi Mehrotra, MD, MBA, Rhonda Cadena, MD Page 10 of 12 Approved by: Acute Care Services Pharmacy Practice Council, P&T Committee, MSEC

24. Weber CF, Gorlinger K, Byhahn C, et al. Tranexamic acid partially improves platelet function in patients treated with dual antiplatelet therapy. Eur J Anaesthesiol. 2011;28(1):57-62.

A ppendix A: Bleedi ng Definitions

Major Bleed i n g :  Symptomatic bleeding into a critical site: o Intracranial o Intraspinal o Intraocular o Retroperitoneal o Intraarticular o Pericardial o Intramuscular with compartment syndrome  Bleeding leading to ≥ 2 g/dL hemoglobin decrease  Bleeding leading to transfusion of ≥ 2 units of packed red blood cells  Activation of the massive transfusion protocol  Bleeding leading to hypotension requiring vasopressors

M i n o r B l e e d :  Bleeding leading to < 2 g/dL hemoglobin decrease  Bleeding leading to transfusion of < 2 units of packed red blood cells  Gross hematuria not associated with trauma  Epistaxis and oral bleeding that is prolonged and unresponsive to topical therapies  Bruising, bleeding gums, oozing from injection sites  Bleeding at a compressible site

Developed by: Lindsey Splinter, PharmD, Kelly Dehne, PharmD, BCCCP, Kalynn Rohde, PharmD, BCCCP Last updated: October 2019 Reviewed by: Stephan Moll, MD, Raj, Kasthuri, MD, Abhi Mehrotra, MD, MBA, Rhonda Cadena, MD Page 11 of 12 Approved by: Acute Care Services Pharmacy Practice Council, P&T Committee, MSEC

Appendix B: Anticoagulant Pharmacokinetic Considerations

Mechanism of Removed by In-House Laboratory Values for Drug Elimination Half-Life Clearance Dialysis Detecting Drug Presence

Prothrombin time (PT) 12 hours Apixaban (prolonged or normal) Renal/Hepatic No (Eliquis®) (prolonged in renal impairment) LMWH anti-factor Xa level (elevated)

40-50 minutes Activated partial thromboplastin time Argatroban (prolonged in hepatic Hepatic 20% (aPTT) dysfunction) (prolonged)

Betrixaban Prothrombin Time (PT) 19 to 27 hours Renal/Hepatic No (Bevyxxa®) (prolonged or normal) Prothrombin time (PT) (prolonged)

25 minutes Thrombin time (TT) Bivalirudin (up to 1 hr in severe renal Renal 25% (prolonged) (Angiomax®) impairment) Activated partial thromboplastin time (aPTT) (prolonged) Thrombin time (TT) 14 hours (prolonged) Dabigatran (up to 34 hrs in severe renal Renal 62-68% (Pradaxa®) Activated partial thromboplastin time impairment) (aPTT) (prolonged or normal)

10 to 14 hours Edoxaban Prothrombin time (PT) (prolonged in renal Renal/Hepatic No (Savaysa®) (prolonged or normal) impairment)

LMWH anti-factor-Xa (elevated) 3-5 hours Enoxaparin Prothrombin time (PT) (prolonged in renal Renal 20% (Lovenox®) (prolonged) impairment) Thrombin time (TT) (prolonged)

Prothrombin time (PT) (prolonged or normal) 17-21 hours Fondaparinux (significantly prolonged in Renal No (Arixtra®) Activated partial thromboplastin time renal impairment) (aPTT) (prolonged or normal)

Activated partial thromboplastin time (aPTT) (prolonged) Heparin 30-90 minutes Hepatic Partial

UFH anti-factor Xa level (elevated)

Healthy: 5-9 hours Prothrombin time (PT) Rivaroxaban Elderly: 11-13 hours (prolonged or normal)

® Renal/Hepatic No (Xarelto ) (prolonged in renal LMWH anti-factor Xa level impairment) (elevated) Prothrombin time (PT) Warfarin 20-60 hours Hepatic No (prolonged)

Developed by: Lindsey Splinter, PharmD, Kelly Dehne, PharmD, BCCCP, Kalynn Rohde, PharmD, BCCCP Last updated: October 2019 Reviewed by: Stephan Moll, MD, Raj, Kasthuri, MD, Abhi Mehrotra, MD, MBA, Rhonda Cadena, MD Page 12 of 12 Approved by: Acute Care Services Pharmacy Practice Council, P&T Committee, MSEC