Management von Blutungen unter Aggregationshemmung und Antikoagulation

Zusammenfassung

Durch eine weltweit alternde Bevölkerung nehmen Vorhofflimmern und venöse Thromboembolien und dadurch auch der Einsatz direkter oraler Antikoagulantien (DOAK) deutlich zu. Das Management von Blutungskomplikationen und Notfalloperationen bei dieser Gruppe von Patienten stellt eine Herausforderung im klinischen Alltag dar. Bei Auftreten schwerer Blutungen sollten der Ort der Blutung, der Beginn und Schweregrad sowie die Nierenfunktion und Begleitmedikationen wie Thrombozytenaggregationshemmer oder nichtsteroidale Antirheumatika (NSAR) Berücksichtigung finden. Der Zeitpunkt der letzten Tabletteneinnahme als auch die Restkonzentration des DOAK bei Aufnahme sind ebenfalls relevant. Die Antikoagulation sollte sofort unterbrochen und lokale Maßnahmen ergriffen werden, um die Blutung zu stillen; der anti-koagulierende Effekt sollte sofort aufgehoben werden. Die Gabe von PPSB kann erwogen werden, wenn spezifische Antidots nicht zur Verfügung stehen. Wenn relevante DOAK-Restkonzentrationen vermutet werden und eine Operation nicht aufgeschoben werden kann, dann sollten PPSB und/ oder ein spezifisches Antidot präoperativ appliziert werden. Als spezifisches Antidot für Dabigatran steht Idarucizumab zur Verfügung; während Andexanet Alfa als Antidot gegen Faktor X-Inhibitoren seit Mai diesen Jahres bisher nur in den USA zur Behandlung zugelassen ist.

Schlüsselwörter

Direkte orale Antikoagulanzien - lebensbedrohliche Blutung - Notfalloperation - Gegenmittel

Interessenkonflikt

Frau Prof. Dr. Lindhoff-Last: Bayer Vital, Boehringer Ingelheim, Pfizer/BMS, Daiichi Sankyo, CSL Behring, Werfen, Service Dialog GmbH Frau Dr. Barbara Zydek: keine Interessenkonflikte.

• Literatur

• 1 Lopes BS, Steffel J. Triple Antikoagulation – Triple Threat. Je kürzer, desto besser?. Therap Umschau 2016; 73 (10) 551-559.
• 2 Hansen ML, Sorensen R, Clausen MT. et al. Risk of bleeding with single, dual or triple therapy with warfarin, aspirin and Clopidogrel in patients with atrial fibrillation. Arch Intern Med 2010; 170 (16) 1433-1441.
• 3 Hsu PI, Tsai TJ. Epidemiology of upper gastrointestinal damage associated with low-dose aspirin. Curr Pharm Des 2015; 21: 5049-5055.
• 4 Zeymer U, Koscielny J. von Heymann et al. Interdisziplinäres Management von Blutungen unter dualer antithrombozytärer Therapie nach akutem Koronarsyndrom. Dtsch Med. Wochenschr 2016; 141: 1007-1111.
• 5 Garcia LARodriguez, Lin KJ, Hernandez-Diaz S. et al. Risk of upper gastrointestinal bleeding with low-dose acetylsalicylic acid alone and in combination with Clopidogrel and other medications. Circulation 2011; 123: 1108-1115.
• 6 Baharoglu MI, Cordonnier C, Al Sahi RSalman. et al for the PATCH Investigators. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet 2016; 387: 2605-2613.
• 7 Prodan CI. Platelets after intracerebral haemorrhage: more is not better. Lancet 2016; 387: 2577-2578.
• 8 Baschin M, Selleng S, Hummel A, Diedrich S, Schroeder HW, Kohlmann T, Westphal A, Greinacher A, Thiele T. Preoperative platelet transfusions to reverse antiplatelet therapy for urgent non-cardiac surgery: an oberservational cohort study. J Thromb Haemost 2018; 16 (04) 709-717.
• 9 Kato ET, Giugliano RP, Ruff CT. et al. Efficacy and safety of Edoxaban in elderly patients with atrial fibrillation in the ENGAGE AF-TIMI 48 Trial. J Am Heart Assoc 2016; 05: e003432.
• 10 Vanasche T, Hirsh J, Eikelboom JW, Ginsberg JS. Organ-specific bleeding patterns of anticoagulant therapy: lessons from clinical trials. Thromb Haemost 2014; 112: 918-923.
• 11 Quinlan DJ, Eikelboom JW, Weitz J. Four factor prothrombin complex concentrate for urgent reversal of vitamin K antagonists in patients with major bleeding. Circulation 2013; 128: 1179-1181.
• 12 Milling TJ, Refaai MA, Sarode R. et al. Safety of four-factor prothrombin complex concentrate versus plasma for vitamin K antagonist reversal: an integrated analysis of two phase IIIb clinical trials. Acaemic Emergency Medicine 2016; 23: 466-475.
• 13 Goldstein JN, Refaai MA, Milling TJ. et al. Fourfactor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet 2015; 385: 2077-2087.
• 14 Halbritter K, Beyer-Westendorf J, Nowotny J, Pannach S, Kuhlisch E, Schellong SM. Hospitalization for vitamin-K-antagonist-related bleeding: treatment patterns and outcome. J Thromb Haemost 2013; 11: 651-659.
• 15 Lindhoff-Last E. Direct oral anticoagulants (DOAC) – Management of emergency situations. Rationale and design of the RADOA-Registry. Hamostaseologie 2017; 37: 257-266.
• 16 Kirchhof P, Benussi S, Kotecha D. et al. 2016 ESC Guidelines for the management of atrial fibrillation developd in collaboration with EACTS. Eur Heart J 2016; 37: 2893-2962.
• 17 Gosselin RC, Adcock DM, Bates SM, Douxfils J, Favaloro EJ, Gouin-Thibault I, Guillermo C, Kawai Y, Lindhoff-Last E, Kitchen S. International Concil for standardization in Haematology (ICSH) Recommendations for Laboratory Measurement of Direct Oral Anticoagulants. Thromb Haemost 2018; 118 (03) 437-450.
• 18 Mani H, Kasper A, Lindhoff-Last E. Measuring the anticoagulant effects of target specific oral anticoagulants-reasons, methods and current limitations. J Thromb Thrombolysis 2013; 36: 187-194.
• 19 Raval AN, Cigarroa JE, Chung MK. et al. Management of Patients on Non-Vitamin K Antogonist Oral Anticoagulants in the Acute Care and Peripro-cedural Setting: A Scientific Statement From the American Heart Association. Circulation 2017; 135: e604-e633.
• 20 Aronis KN, Hylek EM. Who, when and how to reverse non vitamin-Koral anticoagulants. J Thromb Thrombolysis 2016; 41: 243-272.
• 21 Lindahl TL, Wallstedt M, Gustafsson KM, Persson E, Hillarp A. More efficient reversal of dabigatran inhibition of coagulation by activated prothrombin complex concentrates and recombinant factor VIIa than by four-factor prothormbin complex concentrate. Thromb Res 2015; 135: 544-547.
• 22 Escolar G, Fernandez-Gallego V, Arellano-Rodrigo E, Roquer J, Reverter JC, Sanz VV, Molina P, Lopez-Vilchez I, Diaz-Ricart M, Galan AM. Reversal of apixaban induced alterations in hemostasis by different coagulation factor concentrates: significance of studies in vitro with circulating human blood. PLoS ONe 2013; 08: e78696.
• 23 Halim AB, Samama MM, Mendell J. Ex vivo reversal of the anticoagulant effects of edoxaban. Thromb Res 2014; 134: 909-913.
• 24 Arellano-Rodrigo E, Lopez-Vilchez I, Galan AM, Molina P, Reverter JC, Carne X, Villalta J, Tassies D, Lozano M, Diaz-Ricart M, Escolar G. Coagulation factor concentrates fail to restore alterations in fibrin formation caused by rivaroxaban or dabigatran in studies with flowing blood from treated healthy volunteers. Transfus Med Rev 2015; 29: 242-249.
• 25 Herzog E, Kaspereit F, Krege W, Mueller-Cohrs J, Doerr B, Niebl P, Dickneite G. Correlation of coagulation markers and 4F-PCC-mediated reversal of rivaroxaban in a rabbit model of acute bleeding. Thromb Res 2015; 135: 554-560.
• 26 Siegal DM, Garcia DA, Crowther MA. How I treat target-specific oral anticoagulant associated bleeding. Blood 2014; 123: 1152-1158.
• 27 Schulman S, Ritchie B, Nahirniak S, Gross PL. et al. Reversal of dabigatran-associated major bleeding with activated prothrombin concentrate: a prospective cohort study. Thromb Res 2017; 152: 44-48.
• 28 Majeed A, Agren A, Holmström M, Bruzelius M, Chaireti R, Odeberg J, Hempel EL, Magnusson M, Frisk T, Schulman S. Management of rivaroxabanor apixabanassociated major bleeding with prothrombin complex concentrates: a cohort study. Blood 2017; 130: 1706-1712.
• 29 Bouchard J, Ghannoum M, Bernier-Jean A, Williamson D, Kershaw G, Weatherburn C. et al. Comparison of intermittent and continuous extracorporal treatments for the enhanced elimination of dabigatran. Clin Toxicol 2015; 53: 156-163.
• 30 Parasrampuria DA, Marbury T, Matsushima N, Chen S, Wickremasingha PK, He L, Dishy V, Brown KS. Pharmacokinetics, safety and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis. Thromb Haemost 2015; 113: 719-727.
• 31 Greinacher A, Thiele T, Selleng K. Reversal of anticoagulants: an overview of current developments. Thromb Haemost 2015; 113: 931-942.
• 32 Glund S, Stangier J, Schmohl M, Gansser D, Norris S, van Ryn J, Lang B, Ramael S, Moschetti V, Gruenenfelder F, Reilly P, Kreuzer J. Safety, tolerability and efficacy fo idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double blind phase 1 trial. Lancet 2015; 386: 680-690.
• 33 Pollack CV, Reilly PA, Eikelboom J. et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015; 373: 511-520.
• 34 Pollack CV, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, Dubiel R, Huisman MV, Hylek EM. et al. Idarucizumab for Dabigatran Reversal – full cohort analysis. N Engl J Med 2017; 377: 431-441.
• 35 Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, Mathur VS, Castillo J, Bronson MD, Leeds JM, Mar FA, Gold A, Crowther MA. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015; 373: 2413-2424.
• 36 Connolly SJ, Milling TJ, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Goodman S, Leeds J. for the ANNEXA-4-Investigators. Andexanet Alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 2016; 375: 1131-41.
• 37 Levy JH, Ageno W, Chan C, Crowther M, Verhamme P, Weitz JI. for the Subcommittee on control of anticoagulation. 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.