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Semin Thromb Hemost 2017; 43(07): 706-715
DOI: 10.1055/s-0037-1602667
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Novel (Oral) Anticoagulant Challenges in Surgery

Richard Blennerhassett
1   Department of Laboratory Haematology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, NSW Health Pathology, Westmead, New South Wales, Australia
2   Sydney Medical School, University of Sydney, Westmead, New South Wales, Australia
,
Emmanuel J. Favaloro
1   Department of Laboratory Haematology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, NSW Health Pathology, Westmead, New South Wales, Australia
3   Sydney Centres for Thrombosis and Haemostasis, Westmead, New South Wales Australia
,
Leonardo Pasalic
1   Department of Laboratory Haematology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, NSW Health Pathology, Westmead, New South Wales, Australia
3   Sydney Centres for Thrombosis and Haemostasis, Westmead, New South Wales Australia
› Author Affiliations
Further Information

Publication History

Publication Date:
08 June 2017 (online)

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Summary

Non-vitamin K oral anticoagulants (NOACs) are a relatively recent therapeutic modality for the prevention of systemic thromboembolic complications of atrial fibrillation and the prevention and management of venous thromboembolic disease. Approved indications for this class of anticoagulants are likely to further expand as the results of ongoing and new clinical trials are published and clinical experience grows. Despite their convenience compared with traditional methods of anticoagulation, there remain a few potential pitfalls associated with their use in the perioperative setting. In particular, there is limited experience and evidence base regarding anticoagulant management in the perioperative setting, especially given the different NOACs available, which in turn are different from the classical anticoagulants. This narrative review synthesizes the recent advances in development of specific NOAC reversal agents and the understanding of the complexities of laboratory measurement of NOAC anticoagulant effects, and aims to provide practicing clinicians with basic evidence-based tools for perioperative management of patients taking NOACs.

Keywords

rivaroxaban - apixaban - dabigatran - perioperative - surgery - NOACs - anticoagulation
 

  • References

  • 1 Connolly SJ, Ezekowitz MD, Yusuf S. , et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
    CrossrefPubMedGoogle Scholar
  • 2 Patel MR, Mahaffey KW, Garg J. , et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
    CrossrefPubMedGoogle Scholar
  • 3 Granger CB, Alexander JH, McMurray JJ. , et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
    CrossrefPubMedGoogle Scholar
  • 4 Schulman S, Kearon C, Kakkar AK. , et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361 (24) 2342-2352
    CrossrefPubMedGoogle Scholar
  • 5 Bauersachs R, Berkowitz SD, Brenner B. , et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
    CrossrefPubMedGoogle Scholar
  • 6 Büller HR, Prins MH, Lensin AW. , et al; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366 (14) 1287-1297
    CrossrefPubMedGoogle Scholar
  • 7 Agnelli G, Buller HR, Cohen A. , et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369 (09) 799-808
    CrossrefPubMedGoogle Scholar
  • 8 Mega JL, Braunwald E, Wiviott SD. , et al; ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366 (01) 9-19
    CrossrefPubMedGoogle Scholar
  • 9 Connolly SJ, Eikelboom J, Joyner C. , et al; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364 (09) 806-817
    CrossrefPubMedGoogle Scholar
  • 10 Kearon C, Akl EA, Ornelas J. , et al. Antithrombotic therapy for VTE disease: chest guideline and expert panel report. Chest 2016; 149 (02) 315-352
    CrossrefPubMedGoogle Scholar
  • 11 Lauffenburger JC, Farley JF, Gehi AK, Rhoney DH, Brookhart MA, Fang G. Factors driving anticoagulant selection in patients with atrial fibrillation in the United States. Am J Cardiol 2015; 115 (08) 1095-1101
    CrossrefPubMedGoogle Scholar
  • 12 Beyer-Westendorf J, Forster K, Pannach S, Ebertz F, Gelbricht V, Thieme C. Rates, management and outcome of bleeding complications during rivaroxaban therapy in daily care: results from the Dresden NOAC registry. Blood 2014; 124 (06) 955-962
    CrossrefPubMedGoogle Scholar
  • 13 Zolfaghari S, Harenberg J, Frölich L. , et al. Development of recommendations to continue anticoagulation with one of the two types of oral anticoagulants based on the identification of patients’ preference. Semin Thromb Hemost 2015; 41 (02) 166-177
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Wysokinski WE, McBane II RD. Periprocedural bridging management of anticoagulation. Circulation 2012; 126 (04) 486-490
    CrossrefPubMedGoogle Scholar
  • 15 Healey JS, Eikelboom J, Douketis J. , et al; RE-LY Investigators. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized trial. Circulation 2012; 126 (03) 343-348
    CrossrefPubMedGoogle Scholar
  • 16 Douketis JD, Healey JS, Brueckmann M. , et al. Urgent surgery or procedures in patients taking dabigatran or warfarin: analysis of perioperative outcomes from the RE-LY trial. Thromb Res 2016; 139: 77-81
    CrossrefPubMedGoogle Scholar
  • 17 Beyer-Westendorf J, Gelbricht V, Förster K. , et al. Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry. Eur Heart J 2014; 35 (28) 1888-1896
    CrossrefPubMedGoogle Scholar
  • 18 Deharo JC, Sciaraffia E, Leclercq C. , et al; Coordinated by the Scientific Initiatives Committee of the European Heart Rhythm Association. Perioperative management of antithrombotic treatment during implantation or revision of cardiac implantable electronic devices: the European Snapshot Survey on Procedural Routines for Electronic Device Implantation (ESS-PREDI). Europace 2016; 18 (05) 778-784
    CrossrefPubMedGoogle Scholar
  • 19 Faraoni D, Levy JH, Albaladejo P, Samama C-M. ; Groupe d'Intérêt en Hémostase Périopératoire. Updates in the perioperative and emergency management of non-vitamin K antagonist oral anticoagulants. Crit Care 2015; 19 (01) 203
    CrossrefPubMedGoogle Scholar
  • 20 Shaw J, de Wit C, Le Gal G, Carrier M. Bleeding and Thrombotic Outcomes Following Perioperative Interruption of Direct Oral Anticoagulants in Patients with Prior Venous Thromboembolic Disease. Poster presented at the Annual Meeting/of American Society of Hematology; December 3–6, 2016; San Diego, CA
    PubMedGoogle Scholar
  • 21 Mueck W, Borris LC, Dahl OE. , et al. Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost 2008; 100 (03) 453-461
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Weitz JI, Connolly SJ, Patel I. , et al. Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb Haemost 2010; 104 (03) 633-641
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Mueck W, Lensing AW, Agnelli G, Decousus H, Prandoni P, Misselwitz F. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. [Erratum appears in Clin Pharmacokinet. 2012 Feb;51(2):136] Clin Pharmacokinet 2011; 50 (10) 675-686
    CrossrefPubMedGoogle Scholar
  • 24 Bristol-Myers-Squibb. Summary of product information—Eliquis. 2011 . Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf . Accessed January 9, 2017
    PubMedGoogle Scholar
  • 25 Ruff CT, Giugliano RP, Braunwald E. , et al. Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet 2015; 385 (9984): 2288-2295
    CrossrefPubMedGoogle Scholar
  • 26 Skeppholm M, Al-Aieshy F, Berndtsson M. , et al. Clinical evaluation of laboratory methods to monitor apixaban treatment in patients with atrial fibrillation. Thromb Res 2015; 136 (01) 148-153
    CrossrefPubMedGoogle Scholar
  • 27 Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005; 78 (04) 412-421
    CrossrefPubMedGoogle Scholar
  • 28 Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939--an oral, direct Factor Xa inhibitor--after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005; 61 (12) 873-880
    CrossrefPubMedGoogle Scholar
  • 29 Stangier J, Rathgen K, Stähle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007; 64 (03) 292-303
    CrossrefPubMedGoogle Scholar
  • 30 Stangier J, Stähle H, Rathgen K, Fuhr R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008; 47 (01) 47-59
    CrossrefPubMedGoogle Scholar
  • 31 Kubitza D, Becka M, Mueck W. , et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol 2010; 70 (05) 703-712
    CrossrefPubMedGoogle Scholar
  • 32 Leil TA, Feng Y, Zhang L, Paccaly A, Mohan P, Pfister M. Quantification of apixaban's therapeutic utility in prevention of venous thromboembolism: selection of phase III trial dose. Clin Pharmacol Ther 2010; 88 (03) 375-382
    CrossrefPubMedGoogle Scholar
  • 33 Ogata K, Mendell-Harary J, Tachibana M. , et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol 2010; 50 (07) 743-753
    CrossrefPubMedGoogle Scholar
  • 34 Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010; 49 (04) 259-268
    CrossrefPubMedGoogle Scholar
  • 35 Janssen-Pharmaceuticals. Xarelto Highlights of Prescribing Information. 2011 . Available at: http://www.xareltohcp.com/shared/product/xarelto/prescribing-information.pdf . Accessed January 9, 2017
    PubMedGoogle Scholar
  • 36 Frost C, Wang J, Nepal S. , et al. Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Br J Clin Pharmacol 2013; 75 (02) 476-487
    CrossrefPubMedGoogle Scholar
  • 37 Yin OQP, Tetsuya K, Miller R. Edoxaban population pharmacokinetics and exposure-response analysis in patients with non-valvular atrial fibrillation. Eur J Clin Pharmacol 2014; 70 (11) 1339-1351
    CrossrefPubMedGoogle Scholar
  • 38 Boehringer-Ingelheim-Pharmaceuticals. Pradaxa - Highlights of Prescribing Information. 2015 . Available at: http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf . Accessed January 9, 2017
    PubMedGoogle Scholar
  • 39 Daiichi-Sankyo. Savaysa Highlights of Prescribing Information. 2015 . Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf . Accessed January 9, 2017
    PubMedGoogle Scholar
  • 40 Parasrampuria DA, Marbury T, Matsushima N. , et al. Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis. Thromb Haemost 2015; 113 (04) 719-727
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Bristol-Myers-Squibb. Eliquis Highlights of Prescribing Information. 2016 . Available at: http://packageinserts.bms.com/pi/pi_eliquis.pdf . Accessed January 9, 2017
    PubMedGoogle Scholar
  • 42 Husted S, Verheugt FW, Comuth WJ. Reversal strategies for NOACs: state of development, possible clinical applications and future perspectives. Drug Saf 2016; 39 (01) 5-13
    CrossrefPubMedGoogle Scholar
  • 43 Douketis JD. Pharmacologic properties of the new oral anticoagulants: a clinician-oriented review with a focus on perioperative management. Curr Pharm Des 2010; 16 (31) 3436-3441
    CrossrefPubMedGoogle Scholar
  • 44 European Medicines Agency. Pradaxa - Procedural steps taken and scientific information after the authorisation. 2016 . Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Procedural_steps_taken_and_scientific_information_after_authorisation/human/000829/WC500041063.pdf . Accessed January 9, 2017
    PubMedGoogle Scholar
  • 45 Bristol-Myers-Squibb. Eliquis - Highlights of prescribing information. 2012 . Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202155s000lbl.pdf . Accessed January 9, 2017
    PubMedGoogle Scholar
  • 46 Liesenfeld KH, Lehr T, Dansirikul C. , et al. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost 2011; 9 (11) 2168-2175
    CrossrefPubMedGoogle Scholar
  • 47 Janssen Pharmaceuticals. Xarelto - Highlights of prescribing information. 2016 . Available at: https://www.xareltohcp.com/shared/product/xarelto/prescribing-information.pdf . Accessed January 9, 2017
    PubMedGoogle Scholar
  • 48 Alfredsson J, Roe MT. Risks and benefits of triple oral anti-thrombotic therapies after acute coronary syndromes and percutaneous coronary intervention. Drug Saf 2015; 38 (05) 481-491
    CrossrefPubMedGoogle Scholar
  • 49 Elewa H, Ahmed D, Barnes GD. Triple oral antithrombotic therapy in atrial fibrillation and coronary artery stenting: searching for the best combination. Semin Thromb Hemost 2016; 42 (06) 662-670
    Article in Thieme ConnectPubMedGoogle Scholar
  • 50 Kepplinger J, Prakapenia A, Barlinn K. , et al. Standardized use of novel oral anticoagulants plasma level thresholds in a new thrombolysis decision making protocol. J Thromb Thrombolysis 2016; 41 (02) 293-300
    CrossrefPubMedGoogle Scholar
  • 51 Lippi G, Favaloro EJ. Recent guidelines and recommendations for laboratory assessment of the direct oral anticoagulants (DOACs): is there consensus?. Clin Chem Lab Med 2015; 53 (02) 185-197
    CrossrefPubMedGoogle Scholar
  • 52 Favaloro EJ, Lippi G. Laboratory testing in the era of direct or non-vitamin K antagonist oral anticoagulants: a practical guide to measuring their activity and avoiding diagnostic errors. Semin Thromb Hemost 2015; 41 (02) 208-227
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 Bonar R, Favaloro EJ, Mohammed S, Pasalic L, Sioufi J, Marsden K. The effect of dabigatran on haemostasis tests: a comprehensive assessment using in vitro and ex vivo samples. Pathology 2015; 47 (04) 355-364
    CrossrefPubMedGoogle Scholar
  • 54 Bonar R, Favaloro EJ, Mohammed S. , et al. The effect of the direct factor Xa inhibitors apixaban and rivaroxaban on haemostasis tests: a comprehensive assessment using in vitro and ex vivo samples. Pathology 2016; 48 (01) 60-71
    CrossrefPubMedGoogle Scholar
  • 55 Dias JD, Norem K, Doorneweerd DD, Thurer RL, Popovsky MA, Omert LA. Use of thromboelastography (TEG) for detection of new oral anticoagulants. Arch Pathol Lab Med 2015; 139 (05) 665-673
    CrossrefPubMedGoogle Scholar
  • 56 Heidbuchel H, Verhamme P, Alings M. , et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015; 17 (10) 1467-1507
    CrossrefPubMedGoogle Scholar
  • 57 Sié P, Samama CM, Godier A. , et al; Working Group on Perioperative Haemostasis; French Study Group on Thrombosis and Haemostasis. Surgery and invasive procedures in patients on long-term treatment with direct oral anticoagulants: thrombin or factor-Xa inhibitors. Recommendations of the Working Group on Perioperative Haemostasis and the French Study Group on Thrombosis and Haemostasis. Arch Cardiovasc Dis 2011; 104 (12) 669-676
    CrossrefPubMedGoogle Scholar
  • 58 Burnett AE, Mahan CE, Vazquez SR, Oertel LB, Garcia DA, Ansell J. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis 2016; 41 (01) 206-232
    CrossrefPubMedGoogle Scholar
  • 59 Pollack Jr CVJ, Reilly PA, Eikelboom J. , et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015; 373 (06) 511-520
    CrossrefPubMedGoogle Scholar
  • 60 Siegal DM, Curnutte JT, Connolly SJ. , et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015; 373 (25) 2413-2424
    CrossrefPubMedGoogle Scholar
  • 61 Arbit B, Nishimura M, Hsu JC. Reversal agents for direct oral anticoagulants: a focused review. Int J Cardiol 2016; 223: 244-250
    CrossrefPubMedGoogle Scholar
  • 62 Tran H, Joseph J, Young L. , et al; Australasian Society of Thrombosis and Haemostasis. New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management. Intern Med J 2014; 44 (06) 525-536
    CrossrefPubMedGoogle Scholar
  • 63 Heidbuchel H, Verhamme P, Alings M. , et al; European Heart Rhythm Association. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013; 15 (05) 625-651
    CrossrefPubMedGoogle Scholar
  • 64 Munson CF, Reid AJ. Novel oral anticoagulants in plastic surgery. J Plast Reconstr Aesthet Surg 2016; 69 (05) 585-593
    CrossrefPubMedGoogle Scholar
  • 65 Reilly PA, van Ryn J, Grottke O, Glund S, Stangier J. Idarucizumab, a specific reversal agent for dabigatran: mode of action, pharmacokinetics and pharmacodynamics, and safety and efficacy in phase 1 subjects. Am J Emerg Med 2016; 34 (11S, 11s): 26-32
    CrossrefPubMedGoogle Scholar
  • 66 Weitz JI, Pollack Jr CV. Practical management of bleeding in patients receiving non-vitamin K antagonist oral anticoagulants. Thromb Haemost 2015; 114 (06) 1113-1126
    Article in Thieme ConnectPubMedGoogle Scholar
  • 67 Liew A, Douketis J. Perioperative management of patients who are receiving a novel oral anticoagulant. Intern Emerg Med 2013; 8 (06) 477-484
    CrossrefPubMedGoogle Scholar
  • 68 Douketis JD, Healey JS, Brueckmann M. , et al. Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery or procedure. Substudy of the RE-LY trial. Thromb Haemost 2015; 113 (03) 625-632
    Article in Thieme ConnectPubMedGoogle Scholar
  • 69 Ortel TL. Perioperative management of patients on chronic antithrombotic therapy. Blood 2012; 120 (24) 4699-4705
    CrossrefPubMedGoogle Scholar
  • 70 Douketis JD, Spyropoulos AC, Kaatz S. , et al; BRIDGE Investigators. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med 2015; 373 (09) 823-833
    CrossrefPubMedGoogle Scholar
  • 71 Mar PL, Familtsev D, Ezekowitz MD, Lakkireddy D, Gopinathannair R. Periprocedural management of anticoagulation in patients taking novel oral anticoagulants: review of the literature and recommendations for specific populations and procedures. Int J Cardiol 2016; 202: 578-585
    CrossrefPubMedGoogle Scholar
  • 72 Ward C, Conner G, Donnan G, Gallus A, McRae S. Practical management of patients on apixaban: a consensus guide. Thromb J 2013; 11 (01) 27
    CrossrefPubMedGoogle Scholar
  • 73 Untereiner O, Seince P-F, Chterev V. , et al. Management of direct oral anticoagulants in the perioperative setting. J Cardiothorac Vasc Anesth 2015; 29 (03) 741-748
    CrossrefPubMedGoogle Scholar
  • 74 Breuer G, Weiss DR, Ringwald J. ‘New’ direct oral anticoagulants in the perioperative setting. Curr Opin Anaesthesiol 2014; 27 (04) 409-419
    CrossrefPubMedGoogle Scholar
  • 75 Gombotz H, Knotzer H. Preoperative identification of patients with increased risk for perioperative bleeding. Curr Opin Anaesthesiol 2013; 26 (01) 82-90
    CrossrefPubMedGoogle Scholar
  • 76 Douketis JD. Perioperative management of patients who are receiving warfarin therapy: an evidence-based and practical approach. Blood 2011; 117 (19) 5044-5049
    CrossrefPubMedGoogle Scholar
  • 77 Chai-Adisaksopha C, Hillis C, Lim W, Boonyawat K, Moffat K, Crowther M. Hemodialysis for the treatment of dabigatran-associated bleeding: a case report and systematic review. J Thromb Haemost 2015; 13 (10) 1790-1798
    CrossrefPubMedGoogle Scholar
  • 78 Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010; 363 (19) 1791-1800
    CrossrefPubMedGoogle Scholar
  • 79 Dentali F, Marchesi C, Giorgi Pierfranceschi M. , et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost 2011; 106 (03) 429-438
    Article in Thieme ConnectPubMedGoogle Scholar
  • 80 Dickneite G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence?. Thromb Haemost 2014; 111 (02) 189-198
    Article in Thieme ConnectPubMedGoogle Scholar
  • 81 Lee FM, Chan AK, Lau KK, Chan HH. Reversal of new, factor-specific oral anticoagulants by rFVIIa, prothrombin complex concentrate and activated prothrombin complex concentrate: a review of animal and human studies. Thromb Res 2014; 133 (05) 705-713
    CrossrefPubMedGoogle Scholar
  • 82 Grottke O, van Ryn J, Spronk HM, Rossaint R. Prothrombin complex concentrates and a specific antidote to dabigatran are effective ex-vivo in reversing the effects of dabigatran in an anticoagulation/liver trauma experimental model. Crit Care 2014; 18 (01) R27
    CrossrefPubMedGoogle Scholar
  • 83 Martin AC, Le Bonniec B, Fischer AM. , et al. Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis. Int J Cardiol 2013; 168 (04) 4228-4233
    CrossrefPubMedGoogle Scholar
  • 84 Pragst I, Zeitler SH, Doerr B, Kaspereit FJ, Herzog E, Dickneite G. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thrombos Haemost 2012; 10 (09) 1841-1848
    PubMedGoogle Scholar
  • 85 Godier A, Miclot A, Le Bonniec B. , et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology 2012; 116 (01) 94-102
    CrossrefPubMedGoogle Scholar
  • 86 Escolar G, Arellano-Rodrigo E, Reverter JC. , et al. Reversal of apixaban induced alterations of hemostasis by different coagulation factor concentrates: studies in vitro with circulating human blood. Abstracts from the emerging science series. Circulation 2012; 126 (04) 520-521
    CrossrefPubMedGoogle Scholar
  • 87 Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124 (14) 1573-1579
    CrossrefPubMedGoogle Scholar
  • 88 Shih A, Crowther MA. Reversal of direct oral anticoagulants: a practical approach. Presented at the Annual Meeting/ of the American Society of Hematology; December 3–6, 2016; San Diego, CA
    PubMedGoogle Scholar
  • 89 Reilly PA, Lehr T, Haertter S. , et al; RE-LY Investigators. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014; 63 (04) 321-328
    CrossrefPubMedGoogle Scholar
  • 90 Mueck W, Stampfuss J, Kubitza D, Becka M. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet 2014; 53 (01) 1-16
    CrossrefPubMedGoogle Scholar