PDF herunterladen
Thromb Haemost 2013; 110(03): 515-522
DOI: 10.1160/TH12-11-0868
Review Article
Schattauer GmbH

The perioperative management of new direct oral anticoagulants: a question without answers

Raquel Ferrandis
1   Department of Anaesthesiology, Critical Care and Pain Therapy, Hospital Clínic Universitari, Valencia; University of Valencia, Spain
,
Jordi Castillo
2   Department of Anaesthesiology, Critical Care and Pain Therapy, Hospital del Mar, Barcelona, Spain
,
José de Andrés
3   Department of Anaesthesiology, Critical Care and Pain Therapy, Consorcio Hospital General Universitario de Valencia, University of Valencia, Spain
,
Carmen Gomar
4   Department of Anaesthesiology, Critical Care and Pain Therapy, Hospital Clínic de Barcelona, Universitat de Barcelona, Spain
,
Aurelio Gómez-Luque
5   Department of Anaesthesiology, Critical Care and Pain Therapy, Hospital Universitario Virgen de la Victoria, University of Málaga, Spain
,
Francisco Hidalgo
6   Department of Anaesthesiology, Critical Care and Pain Therapy, Clínica University of Navarra, Spain
,
Juan V. Llau
1   Department of Anaesthesiology, Critical Care and Pain Therapy, Hospital Clínic Universitari, Valencia; University of Valencia, Spain
,
Pilar Sierra
7   Department of Anaesthesiology, Critical Care and Pain Therapy, Fundación Puigvert (IUNA), Barcelona, Spain
,
Luis M. Torres
8   Department of Anaesthesiology, Critical Care and Pain Therapy, Hospital Universitario Puerta del Mar, Cádiz, Spain
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received: 26. November 2012

Accepted after major revision: 25. Mai 2013

Publikationsdatum:
22. November 2017 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Summary

New direct oral anticoagulant agents (DOAC) are currently licensed for thromboprophylaxis after hip and knee arthroplasty and for longterm prevention of thromboembolic events in non-valvular atrial fibrillation as well as treatment and secondary prophylaxis of venous thromboembolism. Some other medical indications are emerging. Thus, anaesthesiologists are increasingly likely to encounter patients on these drugs who need elective or emergency surgery. Due to the lack of experience and data, the management of DOAC in the perioperative period is controversial. In this article, we review available information and recommendations regarding the periprocedural management of the currently most clinically developed DOAC, apixaban, dabigatran, and rivaroxaban. We discuss two trends of managing patients on DOAC for elective surgery. The first is stopping the DOAC 1–5 days before surgery (depending on the drug, patient and bleeding risk) without bridging. The second is stopping the DOAC 5 days preoperatively and bridging with low-molecular-weight heparin. The management of patients on DOAC needing emergency surgery is also reviewed. As no data exist for the use of haemostatic products for the reversal of the anticoagulant effect in these cases, rescue treatment recommendations are proposed.

Keywords

Anticoagulants - thrombosis - haemorrhage - perioperative - dabigatran - apixaban - rivaroxaban
 

  • References

  • 1 Bounameaux H. The novel anticoagulants: entering a new era. Swiss Med Wkly 2009; 139: 60-64.
    PubMedGoogle Scholar
  • 2 Wittkowsky AK. Novel oral anticoagulants and their role in clinical practice. Pharmacotherapy 2011; 31: 1175-1191.
    CrossrefPubMedGoogle Scholar
  • 3 Weitz JI, Eikelboom JW, Samama MM. New antithrombotic drugs. Chest 2012; 141 Suppl e120S-e151S.
    CrossrefPubMedGoogle Scholar
  • 4 Mavrakanas T, Bounameaux H. The potential role of new oral anticoagulants in the prevention and treatment of thromboembolism. Pharmacol Ther 2011; 130: 46-58.
    CrossrefPubMedGoogle Scholar
  • 5 Schulman S, Crowther MA. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood 2012; 119: 3016-3023.
    CrossrefPubMedGoogle Scholar
  • 6 García D, Libby E, Crowter MA. The new oral anticoagulants. Blood 2010; 115: 15-20.
    CrossrefPubMedGoogle Scholar
  • 7 Eikelboom JW, Weitz JI. New anticoagulants. Circulation 2010; 121: 1523-1532.
    CrossrefPubMedGoogle Scholar
  • 8 Nieto JA, Espada NG, Merino RG. et al. Dabigatran, Rivaroxaban and Apixaban versus Enoxaparin for thomboprophylaxis after total knee or hip arthroplasty: pool-analysis of phase III randomized clinical trials. Thromb Res 2012; 130: 183-191.
    CrossrefPubMedGoogle Scholar
  • 9 De Caterina R, Husted S, Wallentin L. et al. New Oral Anticoagulants in Atrial Fibrillation and Acute Coronary Syndromes: ESC Working Group on Thrombosis - Task Force on Anticoagulants in Heart Disease Position Paper. J Am Coll Cardiol 2012; 59: 1413-1425.
    CrossrefPubMedGoogle Scholar
  • 10 Becattini C, Vedovati MC, Agnelli G. Old and new oral anticoagulants for venous thromboembolism and atrial fibrillation: a review of the literature. Thromb Res 2012; 129: 392-400.
    CrossrefPubMedGoogle Scholar
  • 11 Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs. Chest 2008; 133: 234S-256S.
    CrossrefPubMedGoogle Scholar
  • 12 Llau JV, Ferrandis R. New anticoagulants and regional anesthesia. Curr Opin Anaesthesiol 2009; 22: 661-666.
    CrossrefPubMedGoogle Scholar
  • 13 Raghavan N, Frost CE, Yu Z. et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 2009; 37: 74-81.
    CrossrefPubMedGoogle Scholar
  • 14 Eliquis (apixaban). Summary of product characteristics. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public /human/002148/WC500107773.pdf Accessed February 28, 2012
    PubMedGoogle Scholar
  • 15 Lassen MR, Raskob GE, Gallus A. et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009; 361: 594-604.
    CrossrefPubMedGoogle Scholar
  • 16 Lassen MR, Raskob GE, Galus A. et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomized double-blind trial. Lancet 2010; 375: 807-815.
    CrossrefPubMedGoogle Scholar
  • 17 Lassen MR, Gallus A, Raskob GE. et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010; 363: 2487-2498.
    CrossrefPubMedGoogle Scholar
  • 18 Connolly SJ, Eikelboom J, Joyner C. et al. Apixaban in Patients with Atrial Fibrillation. N Engl J Med 2011; 364: 806-817.
    CrossrefPubMedGoogle Scholar
  • 19 Lopes RD, Alexander JH, Al-Khatib SM. et al. Apixaban for reduction in stroke and other Thromboembolic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J 2010; 159: 331-339.
    CrossrefPubMedGoogle Scholar
  • 20 Goldhaber SZ, Leizorovicz A, Kakkar AK. et al. Apixaban versus Enoxaparin for Thromboprophylaxis in Medically Ill Patients. N Engl J Med 2011; 365: 2167-2177.
    CrossrefPubMedGoogle Scholar
  • 21 Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet 2009; 48: 1-22.
    CrossrefPubMedGoogle Scholar
  • 22 Kubitza D, Becka M, Voith B. et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939 an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005; 78: 412-421.
    CrossrefPubMedGoogle Scholar
  • 23 Xarelto (rivaroxaban). Summary of product characteristics. Bayer Schering Pharma. Available at http://www.xarelto.com/html/downloads/Xarelto-prescribing_information-Nov-2012.pdf Accessed February 26, 2012
    PubMedGoogle Scholar
  • 24 Eriksson BI, Borris LC, Friedman RJ. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358: 2765-2775.
    CrossrefPubMedGoogle Scholar
  • 25 Kakkar AK, Brenner B, Dahl OE. et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind randomized controlled trial. Lancet 2008; 372: 31-39.
    CrossrefPubMedGoogle Scholar
  • 26 Lassen MR, Ageno W, Borris LC. et al. Rivaroxaban for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358: 2776-2785.
    CrossrefPubMedGoogle Scholar
  • 27 Turpie Ag, Lassen MR, Davidson BL. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD 4): a randomised trial. Lancet 2009; 373: 1673-1680.
    CrossrefPubMedGoogle Scholar
  • 28 Patel MR, Mahaffey KW, Garg J. et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med 2011; 365: 883-891.
    CrossrefPubMedGoogle Scholar
  • 29 EINSTEIN Investigators, Bauersachs R, Berkowitz SD. et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Eng J Med 2010; 363: 2499-2510.
    CrossrefPubMedGoogle Scholar
  • 30 The EINSTEIN-PE Investigators, Buller HR, Prins MH. et al. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism. N Engl J Med 2012; 366: 1287-1297.
    CrossrefPubMedGoogle Scholar
  • 31 Baetz BE, Spinler SA. Dabigatran etexilate: an oral direct thrombin inhibitor for thromboprophylaxis and treatment of thromboembolic diseases. Pharmacotherapy 2008; 28: 1354-1373.
    CrossrefPubMedGoogle Scholar
  • 32 Stangier J, Rathgen K, Staehle H. et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007; 64: 292-303.
    CrossrefPubMedGoogle Scholar
  • 33 Di Nisio M, Middeldorp S, Buller HR. Direct thrombin inhibitors. N Engl J Med 2005; 353: 1028-1040.
    CrossrefPubMedGoogle Scholar
  • 34 Boehringer Ingelheim International GmbH. Pradaxa (dabigatran etexilate) Summary of Product Characteristics. 2012 Available at http://www.ema.europa.eu/docs/en_GB/document_library/Other/2012/05/WC500127777.pdf Accessed February 28, 2012
    PubMedGoogle Scholar
  • 35 Eriksson BI, Dahl OE, Rosencher N. et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomized, double-blind, noninferiority trial. Lancet 2007; 370: 949-956.
    CrossrefPubMedGoogle Scholar
  • 36 Eriksson BI, Dahl OE, Huo MH. et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial. Thromb Haemost 2011; 105: 721-729.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 37 RE-MOBILIZE Writing Committee. Ginsberg JS, Davidson BL. et al. The oral thrombin inhibitor dabigatran etexilate vs the North American enoxaparin regimen for the prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009; 02: 1-9.
    PubMedGoogle Scholar
  • 38 Eriksson BI, Dahl OE, Rosencher N. et al. Oral dabigatran etexilate versus subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007; 05: 2178-2185.
    CrossrefPubMedGoogle Scholar
  • 39 Connolly SJ, Esekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
    CrossrefPubMedGoogle Scholar
  • 40 Schulman S, Kearon C, Kakkar AK. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J 2009; 361: 2342-2352.
    CrossrefPubMedGoogle Scholar
  • 41 Schulman S, Eriksson H, Goldhaber SZ. et al. Dabigatran or warfarin for extended maintenance therapy of venous thromboembolism. J Thromb Haemost 2011; 09 (Suppl. 02) 731-732.
    PubMedGoogle Scholar
  • 42 Schulman S, Baanstra D, Eriksson H. et al. Dabigatran versus placebo for extended maintenance therapy of venous thromboembolism. J Thromb Haemost 2011; 09 (Suppl. 02) 22.
    PubMedGoogle Scholar
  • 43 Douketis JD, Spyropoulos AC, Spencer FA. et al. Perioperative management of antithrombotic therapy. Chest 2012; Suppl e326S-e350S.
    CrossrefPubMedGoogle Scholar
  • 44 Kaatz S, Kouides PA, Garcia DA. et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol 2012; 87: S141-S145.
    CrossrefPubMedGoogle Scholar
  • 45 Zhou W, Schwarting S, Illanes S. et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke 2011; 42: 3594-3599.
    CrossrefPubMedGoogle Scholar
  • 46 Eerenberg ES, Kamphuisen PW, Sijpkens MK. et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate. A randomized, Placebo-Controlled, Crossover Study in healthy subjects Circulation 2011; 124: 1573-1579.
    PubMedGoogle Scholar
  • 47 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: 94-102.
    CrossrefPubMedGoogle Scholar
  • 48 Tinel H, Huetter J, Perzborn E. Recombinant factor VIIA partially reverses the anticoagulant effect of high-dose rivaroxaban a novel, oral, direct factor XA inhibitor in rats. J Thromb Haemost. 2007. 5. Abstract P-W-652
    Google Scholar
  • 49 van Ryn J, Ruehl D, Priepke H. et al. Reversibility of the anticoagulant effect of high doses of the direct thrombin inhibitor Dabigatran, by recombinant factor VIIA or activated prothrombin complex concentrate. 13th Congress of the European Hematology Association. Copenhagen, Denmark: 2008. p 148.
    Google Scholar
  • 50 Levi M, Eerenberg ES, Kamphuisen PW. Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents. J Thromb Haemost 2011; 09: 1705-1712.
    CrossrefPubMedGoogle Scholar
  • 51 Lu G, DeGuzman FR, Lakhotia S. et al. Recombinant antidote for reversal of anticoagulation by factor-Xa inhibitors. Blood 2008. 112 Abstract 983
    Google Scholar
  • 52 Study in healthy volunteers of the reversion by haemostatic drugs of the anticoagulant effect of new anti-thrombotics. http://clinicaltrials.gov/show/NCT01210755 Accessed February 28, 2012
    PubMedGoogle Scholar
  • 53 van Ryn J, Litzenburger T, Waterman A. et al. Dabigatran anticoagulant activity is neutralized by an antibody elective to dabigatran in in vitro and in vivo models. J Am Coll Cardiol 2011; 57: E1130.
    CrossrefPubMedGoogle Scholar
  • 54 Lip GYH, Banerjee A, Lagrenade I. et al. Assessing the risk of bleeding in patients with atrialfibrillation. Circ Arrhythm Electrophysiol 2012; 05: 941-948.
    CrossrefPubMedGoogle Scholar
  • 55 Lane DA, Lip GYH. Use of CHA2DS2-VASc and HAS-BLED scores to aid decision making for thromborpophylaxis in nonvalvular atrial fibrillation. Circulation 2012; 126: 860-865.
    CrossrefPubMedGoogle Scholar
  • 56 Omran H, Bauersachs R, Rübenacker S. et al. The HAS-BLED score predicts bleeding during bridging of chronic oral anticoagulation. Thromb Haemost 2012; 108: 65-73.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 57 Garcia DA, Granger CB. Anticoagulation, novel agents, and procedures: Can we pardon the interruption?. Circulation 2012; 126: 255-257.
    CrossrefPubMedGoogle Scholar
  • 58 Turpie AGG, Kreutz R, Llau J. et al. Management consensus guidance for the use of rivaroxaban- an oral, direct factor Xa inhibitor. Thromb Haemost 2012; 108: 876-886.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 59 van Ryn J, Stangier J, Haertter S. et al. Dabigatran etexilate - a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116-1127.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 60 Weltermann A, Brodmann M, Domanovits H. et al. Dabigatran in patients with atrial fibrillation: perioperative and periinterventional management. Wien Klin Wochenschr 2012; 124: 340-347.
    CrossrefPubMedGoogle Scholar
  • 61 Gallego P, Apostalakis S, Lip GYH. Bridging evidence-based practice and practice-based evidence in periprocedural anticoagulation. Circulation 2012; 126: 1573-1576.
    CrossrefPubMedGoogle Scholar
  • 62 Llau JV, Ferrandis R, Castillo J. et al. en representaciόn de los participantes en el Foro de Consenso de la ESRA-España de fármacos que alteran la hemostasia. Manejo de los anticoagulantes orales de acciόn directa en el periodo perioperatorio y técnicas invasivas. Rev Esp Anestesiol Reanim 2012; 59: 321-330.
    CrossrefPubMedGoogle Scholar
  • 63 Sié P, Samama CM, Godier A. et al. Surgery and invasive prodecures 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 Trombosis and Haemostasis. Arch Cardiovasc Dis 2011; 104: 669-676.
    CrossrefPubMedGoogle Scholar
  • 64 Sierra P, Gόmez-Luque A, Castillo J. et al. Guía de práctica clínica sobre el manejo de antiagregantes plaquetarios en cirugía no cardiaca (Sociedad Española de Anestesiología y Reanimaciόn). Rev Esp Anestesiol Reanim 2011; (Suppl. 01) 1-16.
    PubMedGoogle Scholar
  • 65 Singer DE, Albers GW, Dalen JE. et al. Antithrombotic therapy in atrial fibrillation. Chest 2008; 133: 546S-592S.
    CrossrefPubMedGoogle Scholar
  • 66 Gogarten W, Vandermeulen E, Van Aken H. et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol 2010; 27: 999-1015.
    CrossrefPubMedGoogle Scholar
  • 67 Healey JS, Eikelboom J, Douketis J. et al. 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: 343-348.
    CrossrefPubMedGoogle Scholar
  • 68 Huisman MV, Lip GYH, Diener HC. et al. Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: Resolving uncertainties in routine practice. Thomb Haemost 2012; 107: 838-847.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 69 Pengo V, Cippa L, Falanga A. et al. Phase III studies on novel anticoagulants for stroke prevention in atrial fibrillation: a look beyond the excellent results. J Throm Haemost 2012; 18: 1979-1987.
    CrossrefPubMedGoogle Scholar
  • 70 Siegal DM, Crowther MA. Acute management of bleeding in patients on novel oral anticoagulants. Eur Heart J 2013; 34: 489-498.
    CrossrefPubMedGoogle Scholar
  • 71 Camm AJ, Lip GYH, De Caterina R. et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation. Eur Heart J 2012; 33: 2719-2747.
    CrossrefPubMedGoogle Scholar