Einsatz von spezifischen Antidots bei DOAK-assoziierter schwerer gastrointestinaler Blutung – ein Expertenkonsensus

Zusammenfassung

Gastrointestinale (GI) Blutungen gehören zu den häufigsten Komplikationen beim Einsatz direkt wirkender oraler Antikoagulanzien (DOAK). Für die Maßnahmen bei (vermuteter) GI-Blutung existieren klare (Notfall-)Algorithmen, bei denen im präendoskopischen Management die anamnestische Erfragung einer medikamentösen Antikoagulation und einfache Gerinnungstests erfolgen sollen. Zur Gerinnungsoptimierung werden beispielsweise Thrombozyten-Konzentrate, Frischplasma (FFP) oder Prothrombinkomplex-Präparate (PPSB) eingesetzt. Für schwere Blutungen unter dem Thrombin-Inhibitor Dabigatran steht Idarucizumab, für Blutungen unter den Faktor Xa-Inhibitoren Rivaroxaban oder Apixaban steht Andexanet alfa als spezifisches Antidot zur DOAK-Antagonisierung zur Verfügung. Diese Antidote stellen Notfallpräparate dar, die typischerweise erst nach Durchführung leitlinienkonformer multimodaler Maßnahmen einschließlich Notfallendoskopie eingesetzt werden. Eine Antagonisierung oraler Antikoagulanzien sollte bei schwerer gastrointestinaler Blutung in folgenden Situationen erfolgen: (1) refraktärer hämorrhagischer Schock, (2) endoskopisch unstillbare Blutungen, oder (3) nicht vermeidbare Verzögerungen bis zur Notfallendoskopie bei lebensbedrohlicher Blutung. Nach erfolgreicher (endoskopischer) Blutstillung sollte die Antikoagulation (z.B. DOAK, Vitamin-K-Antagonist, Heparin) unter Berücksichtigung des individuellen Blutungsrisikos und des Thromboembolierisikos wieder zeitnah (d.h. in der Regel innerhalb einer Woche) fortgeführt werden.

Abstract

Gastrointestinal (GI) bleeding is one of the most common complications associated with the use of direct oral anticoagulants (DOAC). Clear algorithms exist for the emergency measures in (suspected) GI bleeding, including assessing the medication history regarding anti-platelet drugs and anticoagulants as well as simple coagulation tests during pre-endoscopic management. Platelet transfusions, fresh frozen plasma (FFP), or prothrombin complex concentrate (4F-PCC) are commonly used for optimizing the coagulation status. For severe bleeding under the thrombin inhibitor dabigatran, idarucizumab is available, and for bleeding under the factor Xa inhibitors rivaroxaban or apixaban, andexanet alfa is available as specific antidotes for DOAC antagonization. These antidotes represent emergency drugs that are typically used only after performing guideline-compliant multimodal measures including emergency endoscopy. Antagonization of oral anticoagulants should be considered for severe gastrointestinal bleeding in the following situations: (1) refractory hemorrhagic shock, (2) endoscopically unstoppable bleeding, or (3) nonavoidable delays until emergency endoscopy for life-threatening bleeding. After successful (endoscopic) hemostasis, anticoagulation (DOACs, vitamin K antagonist, heparin) should be resumed timely (i.e. usually within a week), taking into account individual bleeding and thromboembolic risk.

Schlüsselwörter

Antikoagulation - obere gastrointestinale Blutung - Antidote - Leberzirrhose

Keywords

anticoagulation - upper gastrointestinal bleeding - antidot - liver cirrhosis

Publication History

Received: 15 January 2023

Accepted after revision: 16 June 2023

Article published online:
16 August 2023

• Literatur

• 1 Lui B, Wee B, Lai J. et al. A ten-year review of the impact of the transition from warfarin to direct oral anticoagulant – Has venous thromboembolism treatment become safer?. Thromb Res 2022; 219: 112-120 DOI: 10.1016/j.thromres.2022.09.006.
• 2 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 in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140: e125-e151 DOI: 10.1161/CIR.0000000000000665.
• 3 Konstantinides SV, Meyer G, Becattini C. et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41: 543-603 DOI: 10.1093/eurheartj/ehz405.
• 4 Stevens SM, Woller SC, Kreuziger LB. et al. Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. Chest 2021; 160: e545-e608 DOI: 10.1016/j.chest.2021.07.055. (PMID: 34352278)
• 5 Koh JH, Liew ZH, Ng GK. et al. Efficacy and safety of direct oral anticoagulants versus vitamin K antagonist for portal vein thrombosis in cirrhosis: A systematic review and meta-analysis. Dig Liver Dis 2022; 54: 56-62 DOI: 10.1016/j.dld.2021.07.039. (PMID: 34393072)
• 6 Ruff CT, Giugliano RP, Braunwald E. et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383: 955-962 DOI: 10.1016/S0140-6736(13)62343-0.
• 7 Patel MR, Mahaffey KW, Garg J. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891 DOI: 10.1056/NEJMoa1009638. (PMID: 21830957)
• 8 Granger CB, Alexander JH, McMurray JJ. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992 DOI: 10.1056/NEJMoa1107039.
• 9 Held C, Hylek EM, Alexander JH. et al. Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial. Eur Heart J 2015; 36: 1264-1272 DOI: 10.1093/eurheartj/ehu463. (PMID: 25499871)
• 10 Verso M, Giustozzi M, Vinci A. et al. Risk factors and one-year mortality in patients with direct oral anticoagulant-associated gastrointestinal bleeding. Thromb Res 2021; 208: 138-144 DOI: 10.1016/j.thromres.2021.10.022.
• 11 Ingason AB, Hreinsson JP, Agustsson AS. et al. Rivaroxaban Is Associated With Higher Rates of Gastrointestinal Bleeding Than Other Direct Oral Anticoagulants : A Nationwide Propensity Score-Weighted Study. Ann Intern Med 2021; 174: 1493-1502 DOI: 10.7326/M21-1474.
• 12 Radadiya D, Devani K, Brahmbhatt B. et al. Major gastrointestinal bleeding risk with direct oral anticoagulants: Does type and dose matter? – A systematic review and network meta-analysis. Eur J Gastroenterol Hepatol 2021; 33: e50-e58 DOI: 10.1097/MEG.0000000000002035.
• 13 Lau LH, Guo CL, Yip TC. et al. Risks of post-colonoscopic polypectomy bleeding and thromboembolism with warfarin and direct oral anticoagulants: a population-based analysis. Gut 2022; 71: 100-110 DOI: 10.1136/gutjnl-2020-323600.
• 14 Oh HJ, Ryu KH, Park BJ. et al. The risk of gastrointestinal hemorrhage with non-vitamin K antagonist oral anticoagulants: A network meta-analysis. Medicine (Baltimore) 2021; 100: e25216 DOI: 10.1097/MD.0000000000025216.
• 15 Steinberg BA, Gao H, Shrader P. et al. International trends in clinical characteristics and oral anticoagulation treatment for patients with atrial fibrillation: Results from the GARFIELD-AF, ORBIT-AF I, and ORBIT-AF II registries. Am Heart J 2017; 194: 132-140 DOI: 10.1016/j.ahj.2017.08.011.
• 16 Gotz M, Anders M, Biecker E. et al. S2k Guideline Gastrointestinal Bleeding – Guideline of the German Society of Gastroenterology DGVS. Z Gastroenterol 2017; 55: 883-936 DOI: 10.1055/s-0043-116856. (PMID: 29186643)
• 17 Gotz M, Biecker E, Dechene A. et al. Addendum zur S2k-Leitlinie Gastrointestinale Blutungen der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS). Z Gastroenterol 2022; 60: 1139-1145 DOI: 10.1055/a-1788-3501.
• 18 Biondi-Zoccai GG, Lotrionte M, Agostoni P. et al. A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery disease. Eur Heart J 2006; 27: 2667-2674 DOI: 10.1093/eurheartj/ehl334. (PMID: 17053008)
• 19 Gralnek IM, Stanley AJ, Morris AJ. et al. Endoscopic diagnosis and management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH): European Society of Gastrointestinal Endoscopy (ESGE) Guideline – Update 2021. Endoscopy 2021; 53: 300-332 DOI: 10.1055/a-1369-5274. (PMID: 33567467)
• 20 Halt-It Trial Collaborators. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet 2020; 395: 1927-1936 DOI: 10.1016/S0140-6736(20)30848-5. (PMID: 32563378)
• 21 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 DOI: 10.1055/a-1450-8178. (PMID: 33742436)
• 22 Koscielny J, Rutkauskaite E, Sucker C. et al. How Do I Reverse Oral and Parenteral Anticoagulants?. Hamostaseologie 2020; 40: 201-213 DOI: 10.1055/a-1113-0557. (PMID: 32455460)
• 23 Steiner T, Schmitz LS, Grau A. et al. Direkte orale Antikoagulanzien: Was im Notfall zu beachten ist. Dtsch Arztebl 2021; 118: A-25 / B
• 24 Meihandoest T, Studt JD, Mendez A. et al. Accuracy of a Single, Heparin-Calibrated Anti-Xa Assay for the Measurement of Rivaroxaban, Apixaban, and Edoxaban Drug Concentrations: A Prospective Cross-Sectional Study. Front Cardiovasc Med 2022; 9: 817826 DOI: 10.3389/fcvm.2022.817826. (PMID: 35369293)
• 25 Margetic S, Celap I, Delic Brkljacic D. et al. Chromogenic anti-FXa assay calibrated with low molecular weight heparin in patients treated with rivaroxaban and apixaban: possibilities and limitations. Biochem Med (Zagreb) 2020; 30: 010702 DOI: 10.11613/BM.2020.010702.
• 26 Margetic S, Celap I, Huzjan AL. et al. DOAC Dipstick Testing Can Reliably Exclude the Presence of Clinically Relevant DOAC Concentrations in Circulation. Thromb Haemost 2022; 122: 1542-1548 DOI: 10.1055/a-1753-2748. (PMID: 35088395)
• 27 Milling TJ, Refaai MA, Sengupta N. Anticoagulant Reversal in Gastrointestinal Bleeding: Review of Treatment Guidelines. Dig Dis Sci 2021; 66: 3698-3714 DOI: 10.1007/s10620-020-06728-y. (PMID: 33403486)
• 28 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 DOI: 10.1038/nm.3102. (PMID: 23455714)
• 29 Dzik WH. Reversal of oral factor Xa inhibitors by prothrombin complex concentrates: a re-appraisal. J Thromb Haemost 2015; 13: S187-194 DOI: 10.1111/jth.12949. (PMID: 26149022)
• 30 Schulman S. Bleeding Complications and Management on anticoagulant therapy. Semin Thromb Hemost 2017; 43: 886-892 DOI: 10.1055/s-0037-1602377. (PMID: 28364736)
• 31 Chai-Adisaksopha C, Hillis C, Siegal DM. et al. Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal. A systematic review and meta-analysis. Thromb Haemost 2016; 116: 879-890 DOI: 10.1160/TH16-04-0266. (PMID: 27488143)
• 32 White K, Faruqi U, Cohen AAT. New agents for DOAC reversal: a practical management review. Br J Cardiol 2022; 29: 1 DOI: 10.5837/bjc.2022.001. (PMID: 35747314)
• 33 Pollack CV, Reilly PA, van Ryn J. et al. Idarucizumab for Dabigatran Reversal – Full Cohort Analysis. N Engl J Med 2017; 377: 431-441 DOI: 10.1056/NEJMoa1707278. (PMID: 28693366)
• 34 Van der Wall SJ, Lopes RD, Aisenberg J. et al. Idarucizumab for Dabigatran Reversal in the Management of Patients With Gastrointestinal Bleeding. Circulation 2019; 139: 748-756 DOI: 10.1161/CIRCULATIONAHA.118.036710.
• 35 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 DOI: 10.1056/NEJMoa1814051.
• 36 Kaatz S, Bhansali H, Gibbs J. et al. Reversing factor Xa inhibitors – clinical utility of andexanet alfa. J Blood Med 2017; 8: 141-149 DOI: 10.2147/JBM.S121550. (PMID: 28979172)
• 37 Siegal D, Beyer-Westendorf J, Yue P. et al. The Efficacy and Safety of Andexanet Alfa in Patients With Acute Gastrointestinal Bleeding While Taking Factor Xa Inhibitors: An ANNEXA-4 Sub-Analysis. The American Journal of Gastroenterology 2019; 114: S332-S333
• 38 Cohen AT, Lewis M, Connor A. et al. Thirty-day mortality with andexanet alfa compared with prothrombin complex concentrate therapy for life-threatening direct oral anticoagulant-related bleeding. J Am Coll Emerg Physicians Open 2022; 3: e12655 DOI: 10.1002/emp2.12655.
• 39 Green L, Tan J, Morris JK. et al. A three-year prospective study of the presentation and clinical outcomes of major bleeding episodes associated with oral anticoagulant use in the UK (ORANGE study). Haematologica 2018; 103: 738-745 DOI: 10.3324/haematol.2017.182220.
• 40 Coleman CI, Dobesh PP, Danese S. et al. Real-world management of oral factor Xa inhibitor-related bleeds with reversal or replacement agents including andexanet alfa and four-factor prothrombin complex concentrate: a multicenter study. Future Cardiol 2021; 17: 127-135 DOI: 10.2217/fca-2020-0073. (PMID: 32618210)
• 41 Abraham NS, Barkun AN, Sauer BG. et al. American College of Gastroenterology-Canadian Association of Gastroenterology Clinical Practice Guideline: Management of Anticoagulants and Antiplatelets During Acute Gastrointestinal Bleeding and the Periendoscopic Period. Am J Gastroenterol 2022; 117: 542-558 DOI: 10.14309/ajg.0000000000001627.
• 42 Pauls LA, Rathor R, Pennington BT. Andexanet Alfa-Induced Heparin Resistance Missing From SCA Blood Management in Cardiac Surgery Guidelines. J Cardiothorac Vasc Anesth 2022; 36: 4557-4558 DOI: 10.1053/j.jvca.2022.07.018. (PMID: 36050215)