53/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate Dabigatran CrCl >50 mL/minute Give last dose 3 days before Give last dose 2 days before procedure (ie, skip 4 doses procedure (ie, skip 2 doses Dose 150 mg twice daily on the 2 days on the day before the procedure) before the procedure) CrCl 30 to 50 Give last dose Give last dose mL/minute 5 days before procedure (ie, 3 days before procedure (ie, Dose 150 mg skip 8 doses skip 4 doses twice daily on the 4 days before the procedure) on the 2 days before the procedure) Rivaroxaban CrCl >50 mL/minute Give last dose 3 days before procedure (ie, skip 2 doses on the 2 days before the procedure) Give last dose 2 days before procedure (ie, skip 1 dose on the day before the procedure) Dose 20 mg once daily Resume 48 to 72 hours after surgery (ie, postoperative day 2 to 3) Resume 24 hours after surgery (ie, postoperative day 1) CrCl 30 to 50 mL/minute Dose 15 mg once daily Apixaban CrCl >50 mL/minute Give last dose 3 days before procedure (ie, Give last dose 2 days before procedure (ie, Dose 5 mg twice daily skip 4 doses on the 2 days before the procedure) skip 2 doses on the day before the procedure) CrCl 50 mL/minute Dose 2.5 mg twice daily Edoxaban CrCl 51 to 95 Give the last Give the last mL/minute dose 3 days dose 2 days before the procedure (ie, before the procedure (ie, Dose 60 mg once daily skip 2 doses on the 2 days skip 2 dose on the day CrCl 50 mL/minute* before the before the procedure) procedure) Dose 30 mg once daily Bleeding risk is determined primarily by the type of surgery; patient comorbidities may also play a role. In patients undergoing neuraxial anesthesia or a very high bleeding risk procedure, a longer https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 54/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate period of interruption may be warranted. In many low bleeding risk procedures, the anticoagulant does not need to be interrupted. Bridging anticoagulation may be appropriate preoperatively in patients with a very high thromboembolic risk who require more prolonged interruption of the anticoagulant (eg, for renal insufficiency) and/or postoperatively in patients who are unable to resume the anticoagulant (eg, unable to take oral medication due to intestinal ileus). Refer to the UpToDate topics on perioperative management of patients receiving anticoagulants for further details. CrCl: creatinine clearance. Product information varies in different countries regarding a lower limit of CrCl below which the drug should not be used. As an example, product information in the United States specifies avoiding use with CrCl <15 mL/minute. Graphic 93260 Version 12.0 https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 55/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate Expected effects of anticoagulant drugs on commonly used coagulation tests Brand Anti-factor Drug class Drug PT aPTT name(s) Xa activity / * Vitamin K Warfarin Jantoven antagonists / * Acenocoumarol Sintrom Heparins Unfractionated heparin / LMW heparins Enoxaparin Lovenox Dalteparin Fragmin Nadroparin Fraxiparine / Fondaparinux Arixtra Direct thrombin inhibitors Argatroban Acova / Dabigatran Pradaxa / / Direct factor Xa inhibitors Rivaroxaban Xarelto / / Apixaban Eliquis Edoxaban Lixiana, Savaysa PT and aPTT are measured in seconds; anti-factor Xa activity is measured in units/mL. Upward arrow ( ) signifies an increase above normal due to the anticoagulant (prolongation of PT or aPTT; increase in anti-factor Xa activity). The effect magnitude will vary depending on the reagent formulation and instrument used. Dash ( ) signifies no appreciable effect. Normal ranges for the PT, aPTT, and anti-factor Xa activity vary among laboratories and should be reported from the testing laboratory along with the patient result. Refer to the UpToDate topic on coagulation testing for details. PT: prothrombin time; aPTT: activated partial thromboplastin time; LMW heparin: low molecular weight heparin. Warfarin has a weak effect on most aPTT reagents. However, warfarin use will increase the sensitivity of the aPTT to heparin effect. While heparin, LMW heparin, and fondaparinux should, in theory, prolong the PT as indirect thrombin inhibitors, in practice most PT reagents contain heparin-binding chemicals that block any heparin effect below a concentration of 1 unit/mL. Above concentrations of 1 unit/mL, heparin effect on the PT may be observed. https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 56/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate Anti-factor Xa activity testing must be calibrated for the specific anticoagulant; this information should be verified with the clinical laboratory. Some of the data are from: Samuelson BT, Cuker A, Crowther M, Garcia DA. Laboratory assessment of the anticoagulant activity of direct oral anticoagulants: A systematic review. Chest 2017; 151:127. Graphic 91267 Version 9.0 https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 57/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate Recommendations for preoperative and postoperative anticoagulation in patients on a vitamin K antagonist Indication Before surgery After surgery Venous thromboembolism Within first month IV heparin or SQ LMWH IV heparin or SQ LMWH Second/third month No change* IV heparin or SQ LMWH 3 months No change* SQ heparin or LWMH Arterial thromboembolism Recent, within one month IV heparin or SQ LMWH IV heparin or SQ LMWH Prophylaxis (eg, non-valvular AF, mechanical heart valve) No change* Resume oral anticoagulation NOTE: Warfarin should be withheld to allow the INR to fall spontaneously to 1.5 to 2 before surgery is performed. IV: intravenous; SQ: subcutaneous; LMWH: low molecular weight heparin; AF: atrial fibrillation; INR: international normalized ratio. If the patient is hospitalized, SQ heparin or LMWH should be administered, but hospitalization is not recommended solely for this purpose. Can use SQ heparin or SQ LMWH if the surgery carries a high risk of postoperative thromboembolism. Graphic 81389 Version 4.0 https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 58/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate Reversing anticoagulation in warfarin-associated bleeding Management Time to anticoagulation Comments and cautions option reversal Discontinuing 5 to 14 days Five days is typical for patients with an warfarin therapy INR in the therapeutic range Vitamin K* 6 to 24 hours to correct the INR, longer to fully reverse anticoagulation Recovery of factors X and II (prothrombin) takes longer than 24 hours Risk of anaphylaxis with intravenous injection Impaired response to warfarin lasting up to one week may occur after large doses (ie, >5 mg) Fresh frozen Depends on the time it takes to Effect is transient and concomitant plasma complete the infusion; typically 12 to 32 hours for complete reversal vitamin K must be administered Potential for volume overload (2 to 4 L to normalize INR) Potential for TRALI Potential for viral transmission Prothrombin complex 15 minutes after 10-minute to 1-hour infusion Effect is transient, and concomitant vitamin K must be administered; concentrate limited availability Cost Variable factor VII content depending on the product: a 4-factor PCC is preferred Potentially prothrombotic Recombinant 15 minutes after bolus infusion Effect is transient, and concomitant factor VIIa vitamin K must be administered Cost Potentially prothrombotic Please refer to the UpToDate topic on warfarin reversal in intracerebral hemorrhage for further details of management. INR: international normalized ratio; TRALI: transfusion-related acute lung injury; PCC: prothrombin complex concentrate. https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 59/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate A total of 10 mg intravenously by slow infusion given over 10 minutes. Adapted with permission from: Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intercerebral hemorrhage: Literature review and expert opinion. Mayo Clin Proc 2007; 82:82. Copyright 2007 Dowden Health Media. Graphic 79151 Version 16.0 https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 60/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate Emergency reversal of anticoagulation from warfarin for life-threatening hemorrhage in adults: Suggested approaches based upon available resources A. If 4-factor prothrombin complex concentrate (4F PCC) is available (preferred approach): 1. Give 4F PCC* 1500 to 2000 units IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not 1.5, give additional 4F PCC (refer to topic or drug reference for details). 2. Give vitamin K 10 mg IV over 10 to 20 minutes. B. If 3-factor prothrombin complex concentrate (3F PCC) is available but 4F PCC is not available: 1. Give 3F PCC* 1500 to 2000 units IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not 1.5, give additional 3F PCC (refer to topic or drug reference for details). 2. Give Factor VIIa 20 mcg/kg IV OR give FFP 2 units IV by rapid infusion. Factor VIIa may be preferred if volume overload is a concern. 3. Give vitamin K 10 mg IV over 10 to 20 minutes. C. If neither 3F PCC nor 4F PCC is available: 1. Give FFP 2 units IV by rapid infusion. Check INR 15 minutes after completion of infusion. If INR 1.5, administer 2 additional units of FFP IV rapid infusion. Repeat process until INR 1.5. May wish to administer loop diuretic between FFP infusions if volume overload is a concern. 2. Give vitamin K 10 mg IV over 10 to 20 minutes. These products and doses are for use in life-threatening bleeding only. Evidence of life-threatening bleeding and over-anticoagulation with a vitamin K antagonist (eg, warfarin) are required. Anaphylaxis and transfusion reactions can occur. It may be reasonable to thaw 4 units of FFP while awaiting the PT/INR. The transfusion service may substitute other plasma products for FFP (eg, Plasma Frozen Within 24 Hours After Phlebotomy [PF24]); these products are considered clinically interchangeable. PCC will reverse anticoagulation within minutes of administration; FFP administration can take hours due to the volume required; vitamin K effect takes 12 to 24 hours, but administration of vitamin K is needed to counteract the long half-life of warfarin. Subsequent monitoring of the PT/INR is needed to guide further therapy. Refer to topics on warfarin reversal in individual situations for further management. PCC: unactivated prothrombin complex concentrate; 4F PCC: PCC containing coagulation factors II, VII, IX, X, protein S and protein C; 3F PCC: PCC containing factors II, IX, and X and only trace factor VII; FFP: fresh frozen plasma; PT: prothrombin time; INR: international normalized ratio; FEIBA: factor eight inhibitor bypassing agent. Before use, check product label to confirm factor types (3 versus 4 factor) and concentration. Activated complexes and single-factor IX products (ie, FEIBA, AlphaNine, Mononine, Immunine, BeneFix) are NOT used for warfarin reversal. https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 61/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate PCC doses shown are those suggested for initial treatment of emergency conditions. Subsequent treatment is based on INR and patient weight if available. Refer to topic and Lexicomp drug reference included with UpToDate for INR-based dosing. Graphic 89478 Version 10.0 https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 62/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate PCC products available in the United States* Unactivated prothrombin complex concentrates (PCCs) 4 factor: Contains inactive forms of 4 factors: Factors II, VII, IX, and X Kcentra Also contains heparin 3 factor: Contains inactive forms of 3 factors: Factors II, IX, and X Profilnine Contains little or no factor VII Does not contain heparin Activated prothrombin complex concentrate (aPCC) 4 factor: Contains 4 factors: Factors II, VII, IX, and X. Of these, only factor VII is mostly the activated form FEIBA Does not contain heparin The table lists 4-factor and 3-factor PCC products available in the United States. Kcentra is available as Beriplex in Canada. Bebulin (a 3-factor PCC) was discontinued in 2018 due to decreased demand for the product. Potency is determined differently for different products; refer to product information. All PCCs are plasma derived and contain other proteins, including anticoagulant proteins (proteins C and S). Unactivated factors are proenzymes (inactive precursor proteins). Activated factors have higher enzymatic activity. Refer to UpToDate topics for use of these products. US: United States; PCC: prothrombin complex concentrate; FEIBA: factor eight inhibitor bypassing activity. Other 4-factor PCCs available outside the US include Octaplex and Cofact Proplex. Single-factor recombinant activated factor VII (rFVIIa) products are also available. Graphic 94210 Version 8.0 https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 63/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate Direct oral anticoagulant reversal agents for life-threatening bleeding (imminent risk of death from bleeding) Reversal agent (all are given Anticoagulant intravenously) Dabigatran (Pradaxa; oral thrombin inhibitor) Idarucizumab (Praxbind). Dose: 5 grams* Oral factor Xa inhibitors: Andexanet alfa (AndexXa). Dosing for the initial bolus and subsequent infusion depend Apixaban (Eliquis) on the dose level of the factor Xa inhibitor and the interval since it was last taken. Edoxaban (Lixiana, Savaysa) Rivaroxaban (Xarelto) OR- 4-factor PCC (Kcentra, Beriplex P/N, Octaplex). Dosing can be done with a fixed dose of 2000 units OR a weight-based dose of 25 to 50 units per kg. Reversal agents carry a risk of life-threatening thrombosis and should only be used under the direction of a specialist with expertise in their use and/or in a patient at imminent risk of death from bleeding. In general, a single dose is given; dosing may be repeated in rare situations in which the oral anticoagulant persists for longer in the circulation, such as severe kidney dysfunction. Andexanet dosing is as follows: If the patient took rivaroxaban >10 mg, apixaban >5 mg, or dose unknown within the previous 8 hours: Andexanet 800 mg bolus at 30 mg/minute followed by 960 mg infusion at 8 mg/minute for up to 120 minutes. OR- If the patient took rivaroxaban 10 mg or apixaban 5 mg, or if 8 hours have elapsed since the last dose of a factor Xa inhibitor: Andexanet 400 mg bolus at 30 mg/minute followed by 480 mg infusion at 4 mg/minute for up to 120 minutes. Refer to UpToDate topics on treatment of bleeding in patients receiving a DOAC or perioperative management of patients receiving a DOAC for additional information on administration, risks, and alternative therapies. DOAC: direct oral anticoagulant; PCC: prothrombin complex concentrate; FEIBA: factor eight inhibitor bypassing activity. If idarucizumab is unavailable, an activated PCC (FEIBA, 50 to 80 units per kg intravenously) may be a reasonable alternative. Graphic 112299 Version 9.0 https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 64/65 7/5/23, 10:17 AM Perioperative management of patients receiving anticoagulants - UpToDate Contributor Disclosures James D Douketis, MD, FRCPC, FACP, FCCP Consultant/Advisory Boards: AstraZeneca [Reversal of anticoagulants for bleeding and perioperative management]; CytoSorb [Reversal of anticoagulants for bleeding and perioperative management]; PhaseBio [Reversal of anticoagulants for bleeding and perioperative management]; Servier [Anticoagulants for atrial fibrillation and cancer-associated thrombosis]. Other Financial Interest: Leo Pharma [Anticoagulants for the treatment of cancer-associated thrombosis]; Pfizer [Anticoagulants (LMWH, DOACs), management of COVID-19]. All of the relevant financial relationships listed have been mitigated. Gregory YH Lip, MD, FRCPE, FESC, FACC Consultant/Advisory Boards: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. Speaker's Bureau: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. All of the relevant financial relationships listed have been mitigated. Lawrence LK Leung, MD No relevant financial relationship(s) with ineligible companies to disclose. Jennifer S Tirnauer, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/perioperative-management-of-patients-receiving-anticoagulants/print 65/65