Advertisement

Perioperative Management of Direct Oral Anticoagulants in Cardiac Surgery: Practice Recommendations Based on Current Evidence

      An increasing number of patients on systemic oral anticoagulants present for cardiac surgery, and cardiac anesthesiologists should be well-informed on their management in the perioperative period. Direct oral anticoagulants (DOACs), including factor Xa inhibitors and direct thrombin inhibitors, are an attractive alternative to warfarin due to fewer dietary and drug interactions, less frequent monitoring requirements, and an improved patient adherence. Since the approval of DOACs by the Food and Drug Administration in 2010, the number of patients on these medications only has increased. The guidelines vary on the periprocedural management of DOACs for cardiac surgery. This review evaluated the current evidence for medication cessation before surgery, based on timing as well as plasma drug concentration. The practice recommendations of various monitoring tests and new evolving point-of-care testing are examined herein. The different reversal agents were discussed by the authors for both elective and urgent procedures. The cardiac anesthesiologist needs to be intimately familiar with the management and current best practices of DOACs for safe and appropriate patient care.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Cardiothoracic and Vascular Anesthesia
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Zhu J
        • Alexander GC
        • Nazarian S
        • et al.
        Trends and variation in oral anticoagulant choice in patients with atrial fibrillation, 2010-2017.
        Pharmacotherapy. 2018; 38: 907-920
        • January CT
        • Wann LS
        • Calkins H
        • et al.
        2019 AHA/ACC/HRS Focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.
        J Am Coll Cardiol. 2019; 74: 104-132
        • Van Ganse E
        • Danchin N
        • Mahe I
        • et al.
        Comparative safety and effectiveness of oral anticoagulants in nonvalvular atrial fibrillation: The NAXOS study.
        Stroke. 2020; 51: 2066-2075
        • Giugliano RP
        • Ruff CT
        • Braunwald E
        • et al.
        Edoxaban versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2013; 369: 2093-2104
        • Berglund E
        • Wallentin L
        • Oldgren J
        • et al.
        Effects of apixaban compared with warfarin as gain in event-free time - a novel assessment of the results of the ARISTOTLE trial.
        Eur J Prev Cardiol. 2020; 27: 1311-1319
        • Halperin JL
        • Hankey GJ
        • Wojdyla DM
        • et al.
        Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).
        Circulation. 2014; 130: 138-146
        • Ezekowitz MD
        • Nagarakanti R
        • Noack H
        • et al.
        Comparison of dabigatran and warfarin in patients with atrial fibrillation and valvular heart disease: The RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulant Therapy).
        Circulation. 2016; 134: 589-598
        • Doherty JU
        • Gluckman TJ
        • Hucker WJ
        • et al.
        2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation: A report of the American College of Cardiology Clinical Expert Consensus Document Task Force.
        J Am Coll Cardiol. 2017; 69: 871-898
        • Ferrandis R
        • Castillo J
        • de Andres J
        • et al.
        The perioperative management of new direct oral anticoagulants: A question without answers.
        Thromb Haemost. 2013; 110: 515-522
        • Kaneko T
        • Yammine M
        • Aranki SF.
        New oral anticoagulants–what the cardiothoracic surgeon needs to know.
        J Thorac Cardiovasc Surg. 2014; 148 (1794-801.e1791)
        • Schulman S
        • Carrier M
        • Lee AY
        • et al.
        Perioperative management of dabigatran: A prospective cohort study.
        Circulation. 2015; 132: 167-173
        • Spyropoulos AC
        • Al-Badri A
        • Sherwood MW
        • et al.
        Periprocedural management of patients receiving a vitamin K antagonist or a direct oral anticoagulant requiring an elective procedure or surgery.
        J Thromb Haemost. 2016; 14: 875-885
        • Steffel J
        • Verhamme P
        • Potpara TS
        • et al.
        The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: Executive summary.
        Europace. 2018; 20: 1231-1242
        • Erdoes G
        • Martinez Lopez De Arroyabe B
        • Bolliger D
        • et al.
        International consensus statement on the peri-operative management of direct oral anticoagulants in cardiac surgery.
        Anaesthesia. 2018; 73: 1535-1545
        • Wiggins BS
        • Dixon DL
        • Neyens RR
        • et al.
        Select drug-drug interactions with direct oral anticoagulants: JACC review topic of the week.
        J Am Coll Cardiol. 2020; 75: 1341-1350
        • Douketis JD
        • Spyropoulos AC
        • Duncan J
        • et al.
        Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant.
        JAMA Intern Med. 2019; 179: 1469-1478
        • Douxfils J
        • Adcock DM
        • Bates SM
        • et al.
        2021 Update of the International Council for Standardization in Haematology recommendations for laboratory measurement of direct oral anticoagulants.
        Thromb Haemost. 2021; 121: 1008-1020
        • Shaw JR
        • Li N
        • Vanassche T
        • et al.
        Predictors of preprocedural direct oral anticoagulant levels in patients having an elective surgery or procedure.
        Blood Adv. 2020; 4: 3520-3527
        • Fox V
        • Kleikamp A
        • Dittrich M
        • et al.
        Direct oral anticoagulants and cardiac surgery: A descriptive study of preoperative management and postoperative outcomes.
        J Thorac Cardiovasc Surg. 2021; 161 (1864-74.e1862)
        • Kramer RS
        • Zemrak W.
        Commentary: One size fits most, but not all when discontinuing direct oral anticoagulants before cardiac surgery.
        J Thorac Cardiovasc Surg. 2021; 161: 1875
        • Spahn DR
        • Bouillon B
        • Cerny V
        • et al.
        The European guideline on management of major bleeding and coagulopathy following trauma: Fifth edition.
        Crit Care. 2019; 23: 98
        • Tripodi A
        • Braham S
        • Scimeca B
        • et al.
        How and when to measure anticoagulant effects of direct oral anticoagulants?.
        Practical issues. Pol Arch Intern Med. 2018; 128: 379-385
        • Seiffge DJ
        • Traenka C
        • Polymeris A
        • et al.
        Feasibility of rapid measurement of rivaroxaban plasma levels in patients with acute stroke.
        J Thromb Thrombolysis. 2017; 43: 112-116
        • Sennesael AL
        • Larock AS
        • Douxfils J
        • et al.
        Rivaroxaban plasma levels in patients admitted for bleeding events: Insights from a prospective study.
        Thromb J. 2018; 16: 28
        • Cini M
        • Legnani C
        • Padrini R
        • et al.
        DOAC plasma levels measured by chromogenic anti-Xa assays and HPLC-UV in apixaban- and rivaroxaban-treated patients from the START-Register.
        Int J Lab Hematol. 2020; 42: 214-222
        • Godier A
        • Dincq AS
        • Martin AC
        • et al.
        Predictors of pre-procedural concentrations of direct oral anticoagulants: A prospective multicentre study.
        Eur Heart J. 2017; 38: 2431-2439
        • Douxfils J
        • Ageno W
        • Samama CM
        • et al.
        Laboratory testing in patients treated with direct oral anticoagulants: A practical guide for clinicians.
        J Thromb Haemost. 2018; 16: 209-219
        • Levy JH
        • Ageno W
        • Chan NC
        • et al.
        When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH.
        J Thromb Haemost. 2016; 14: 623-627
        • Levy JH.
        Discontinuation and management of direct-acting anticoagulants for emergency procedures.
        Am J Med. 2016; 129: S47-S53
        • Bonar R
        • Favaloro EJ
        • Mohammed S
        • et al.
        The effect of dabigatran on haemostasis tests: A comprehensive assessment using in vitro and ex vivo samples.
        Pathology. 2015; 47: 355-364
        • Gosselin RC
        • Adcock D
        • Hawes EM
        • et al.
        Evaluating the use of commercial drug-specific calibrators for determining PT and APTT reagent sensitivity to dabigatran and rivaroxaban.
        Thromb Haemost. 2015; 113: 77-84
        • Dale BJ
        • Chan NC
        • Eikelboom JW.
        Laboratory measurement of the direct oral anticoagulants.
        Br J Haematol. 2016; 172: 315-336
        • Morishima Y
        • Kamisato C.
        Laboratory measurements of the oral direct factor Xa inhibitor edoxaban: Comparison of prothrombin time, activated partial thromboplastin time, and thrombin generation assay.
        Am J Clin Pathol. 2015; 143: 241-247
        • Pernod G
        • Albaladejo P
        • Godier A
        • et al.
        Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: Proposals of the working group on perioperative haemostasis (GIHP) - March 2013.
        Arch Cardiovasc Dis. 2013; 106: 382-393
        • Basu D
        • Gallus A
        • Hirsh J
        • et al.
        A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time.
        N Engl J Med. 1972; 287: 324-327
        • Auer J
        • Huber K
        • Granger CB.
        Interruption of non-vitamin K antagonist anticoagulants in patients undergoing planned invasive procedures: How long is long enough?.
        Eur Heart J. 2017; 38: 2440-2443
        • Yamaji H
        • Murakami T
        • Hina K
        • et al.
        Activated clotting time on the day of atrial fibrillation ablation for minimally interrupted and uninterrupted direct oral anticoagulation therapy: Sequential changes, differences among direct oral anticoagulants, and ablation safety outcomes.
        J Cardiovasc Electrophysiol. 2019; 30: 2823-2833
        • Dincq AS
        • Lessire S
        • Chatelain B
        • et al.
        Impact of the direct oral anticoagulants on activated clotting time.
        J Cardiothorac Vasc Anesth. 2017; 31: e24-e27
        • Martin AC
        • Kyheng M
        • Foissaud V
        • et al.
        Activated clotting time monitoring during atrial fibrillation catheter ablation: Does the anticoagulant matter?.
        J Clin Med. 2020; 9: 350
        • Härtig F
        • Birschmann I
        • Peter A
        • et al.
        Point-of-care testing for emergency assessment of coagulation in patients treated with direct oral anticoagulants including edoxaban.
        Neurol Res Pract. 2021; 3: 9
        • Härtig F
        • Birschmann I
        • Peter A
        • et al.
        Specific point-of-care testing of coagulation in patients treated with dabigatran.
        Thromb Haemost. 2021; 121: 782-791
        • von Horn H
        • Rasmusson A
        • Soderblom L
        • et al.
        Using a low-molecular weight heparin-calibrated anti-factor Xa assay to assess the concentration of apixaban and rivaroxaban.
        Int J Lab Hematol. 2022; 44: 163-167
        • Fontana P
        • Alberio L
        • Angelillo-Scherrer A
        • et al.
        Impact of rivaroxaban on point-of-care assays.
        Thromb Res. 2017; 153: 65-70
        • Groene P
        • Wagner D
        • Kammerer T
        • et al.
        Viscoelastometry for detecting oral anticoagulants.
        Thromb J. 2021; 19: 18
        • Cuker A
        • Burnett A
        • Triller D
        • et al.
        Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum.
        Am J Hematol. 2019; 94: 697-709
        • Hoffman M
        • Goldstein JN
        • Levy JH.
        The impact of prothrombin complex concentrates when treating DOAC-associated bleeding: A review.
        Int J Emerg Med. 2018; 11: 55
        • Cada DJ
        • Levien TL
        • Baker DE.
        Prothrombin complex concentrate.
        Hosp Pharm. 2013; 48: 951-957
        • Momin JH
        • Candidate P
        • Hughes GJ.
        Andexanet alfa (Andexxa((R))) for the reversal of direct oral anticoagulants.
        P T. 2019; 44: 530-549
        • Tomaselli GF
        • Mahaffey KW
        • Cuker A
        • et al.
        2020 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: A report of the American College of Cardiology Solution Set Oversight Committee.
        J Am Coll Cardiol. 2020; 76: 594-622
        • Schulman S
        • Ritchie B
        • Nahirniak S
        • et al.
        Reversal of dabigatran-associated major bleeding with activated prothrombin concentrate: A prospective cohort study.
        Thromb Res. 2017; 152: 44-48
        • Majeed A
        • Agren A
        • Holmstrom M
        • et al.
        Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: A cohort study.
        Blood. 2017; 130: 1706-1712
        • Schulman S
        • Gross PL
        • Ritchie B
        • et al.
        Prothrombin complex concentrate for major bleeding on factor Xa inhibitors: A prospective cohort study.
        Thromb Haemost. 2018; 118: 842-851
        • Pollack Jr, CV
        • Reilly PA
        • van Ryn J
        • et al.
        Idarucizumab for dabigatran reversal - full cohort analysis.
        N Engl J Med. 2017; 377: 431-441
        • Reilly PA
        • van Ryn J
        • Grottke O
        • et al.
        Idarucizumab, a specific reversal agent for dabigatran: Mode of action, pharmacokinetics and pharmacodynamics, and safety and efficacy in phase 1 subjects.
        Am J Med. 2016; 129: S64-S72
      1. Praxbind. Prescribing information. Ingelheim, Germany: Boehringer Ingelheim International GmbH; 2015.

        • Buchheit J
        • Reddy P
        • Connors JM.
        Idarucizumab (Praxbind) formulary review.
        Crit Pathw Cardiol. 2016; 15: 77-81
        • Tomaselli GF
        • Mahaffey KW
        • Cuker A
        • et al.
        2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: A report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways.
        J Am Coll Cardiol. 2017; 70: 3042-3067
        • Khadzhynov D
        • Wagner F
        • Formella S
        • et al.
        Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease.
        Thromb Haemost. 2013; 109: 596-605
        • Connolly SJ
        • Crowther M
        • Eikelboom JW
        • et al.
        Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors.
        N Engl J Med. 2019; 380: 1326-1335
        • Andexxa
        Prescribing information.
        Alexion Pharmaceuticals, Boston, MA2022
        • Levy JH
        • Welsby I.
        Andexanet alfa use in patients requiring cardiopulmonary bypass: Quo vadis?.
        A A Pract. 2019; 13: 477
        • Lu G
        • DeGuzman FR
        • Hollenbach SJ
        • et al.
        A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa.
        Nat Med. 2013; 19: 446-451
        • Maneno JN
        • Ness GL.
        Andexanet alfa, the possible alternative to protamine for reversal of unfractionated heparin.
        Ann Pharmacother. 2021; 55: 261-264
        • Apostel H
        • Winckers K
        • Bidar E
        • et al.
        Successful antithrombin administration in andexanet alfa-associated heparin resistance.
        J Cardiothorac Vasc Anesth. 2021; 35: 904-907
        • Kainz M
        • Bsuchner P
        • Schellongowski P
        • et al.
        Intraoperative off-label reversal of apixaban by andexanet alfa while on VA-ECMO immediately after emergent surgery for acute type A aortic dissection.
        J Cardiothorac Vasc Anesth. 2021; 35: 262-264
        • Jawitz OK
        • Wang TY
        • Lopes RD
        • et al.
        Rationale and design of PROACT Xa: A randomized, multicenter, open-label, clinical trial to evaluate the efficacy and safety of apixaban versus warfarin in patients with a mechanical On-X Aortic Heart Valve.
        Am Heart J. 2020; 227: 91-99
        • Didier R
        • Lhermusier T
        • Auffret V
        • et al.
        TAVR patients requiring anticoagulation: Direct oral anticoagulant or vitamin K antagonist?.
        JACC Cardiovasc Interv. 2021; 14: 1704-1713