Spezifische Pharmakotherapie bei intrazerebralen Blutungen unter oraler Antikoagulation

Intrazerebrale Blutungen (ICB) gehen mit einer hohen Mortalität und Morbidität einher. Insbesondere die ICB unter oraler Antikoagulation (OAK) stellt eine therapeutische Herausforderung dar. Bei einer OAK-assoziierten ICB ist ein wesentliches Therapieziel die Wiederherstellung der Hämostase. Dieser Übersichtsartikel beschreibt die Indikationen, Anwendung und Wirksamkeit der spezifischen Gegenmittel bei ICB unter OAK anhand der aktuellen Literatur.

Kernaussagen

• Patienten, die eine intrazerebrale Blutung (ICB) unter Vitamin-K-Antagonisten (VKA) bei einer INR (= International Normalized Ratio) > 1,2 erleiden, sollten Prothrombin-Komplex-Konzentrat (PPSB) (je nach INR-Wert, mindestens 30 U/l) und Vitamin K 10 mg i. v. erhalten.

• Patienten mit ICB unter Dabigatran können Idarucizumab erhalten (2 × 2,5 g i. v.).

• Bei einer intrazerebralen Blutung unter den FXa-Hemmern Rivaroxaban und Apixaban kann eine Antagonisierung mit Andexanet alfa erwogen werden.

• Die Dosierung von Andexanet alfa richtet sich nach dem Zeitpunkt der letzten Einnahme und Tagesdosis des Antikoagulans. Alternativ kann eine Antagonisierung mit PPSB (50 U/kgKG) erwogen werden.

• Für Patienten mit intrakraniellen Blutungen unter dem FXa-Hemmer Edoxaban steht keine spezifische zugelassene Therapie zur Verfügung. Es kann eine Antagonisierung mit PPSB (50 U/kgKG) erwogen werden.

• Bei hohem Rezidivrisiko für eine intrazerebrale Blutung kann bei Patienten mit Vorhofflimmern alternativ die Implantation eines Vorhofohrokkluders erwogen werden.

Schlüsselwörter

intrakranielle Blutungen - Andexanet alfa - Idarucizumab - Antagonisierung - Antikoagulanzien

Publication History

Article published online:
30 June 2023

• Literatur

• 1 Foerch C, Misselwitz B, Sitzer M. Hesse Stroke Study Group. et al. Die Schlaganfallzahlen bis zum Jahr 2050. Dtsch Arztebl 2008; 105: 467-473
• 2 Gross BA, Jankowitz BT, Friedlander RM. Cerebral intraparenchymal hemorrhage: a review. JAMA 2019; 321: 1295-1303
• 3 Grundtvig J, Ovesen C, Havsteen I. et al. Trends in incidence of oral anticoagulant-related intracerebral hemorrhage and sales of oral anticoagulants in capital region of Denmark 2010–2017. Eur Stroke J 2021; 6: 143-150
• 4 Dawwas GK, Barnes GD, Cuker A. et al. Effectiveness and safety of direct oral anticoagulants versus warfarin in patients with valvular atrial fibrillation. Ann Intern Med 2021; 174: 1490
• 5 Patel MR, Mahaffey KW, Garg J. ROCKET AF Investigators. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891
• 6 Granger CB, Alexander JH, McMurray JJ. ARISTOTLE Committees and Investigators. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992
• 7 Connolly SJ, Ezekowitz MD, Yusuf S. RE-LY Steering Committee and Investigators. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151
• 8 Giugliano RP, Ruff CT, Braunwald E. ENGAGE AF-TIMI 48 Investigators. et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369: 2093-2104
• 9 Tsivgoulis G, Lioutas VA, Varelas P. et al. Direct oral anticoagulant- vs vitamin K antagonist-related nontraumatic intracerebral hemorrhage. Neurology 2017; 89: 1142-1151
• 10 Hostettler IC, Seiffge DJ, Werring DJ. Intracerebral hemorrhage: an update on diagnosis and treatment. Expert Rev Neurother 2019; 19: 679-694
• 11 Steiner T, Poli S, Griebe M. et al. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol 2016; 15: 566-573
• 12 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
• 13 Connolly SJ, Milling jr. TJ, Eikelboom JW. ANNEXA-4 Investigators. et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 2016; 375: 1131-1141
• 14 Greenberg SM, Ziai WC, Cordonnier C. American Heart Association/American Stroke Association. et al. 2022 Guideline for the management of patients with spontaneous intracerebral hemorrhage: a guideline from the American Heart Association/American Stroke Association. Stroke 2022; 53: e282-e361
• 15 Steiner T, Unterberg A. Kommission Leitlinien der Deutschen Gesellschaft für Neurologie. Behandlung von spontanen intrazerebralen Blutungen, S2k-Leitlinie. Leitlinien für Diagnostik und Therapie in der Neurologie. 2021 Accessed August 08, 2022 at: https://dgn.org/wp-content/uploads/2021/06/030002_LL_Intrazerebrale-Blutungen_-2021_6.1.pdf
• 16 Huttner HB. Kommission Leitlinien der Deutschen Gesellschaft für Neurologie. Intrakranieller Druck (ICP), S1-Leitlinie. Leitlinien für Diagnostik und Therapie in der Neurologie. 2018 Accessed August 08, 2022 at: https://dgn.org/wp-content/uploads/2013/01/030105_LL_Intrakranieller_Druck_2018.pdf
• 17 Cervera A, Amaro S, Chamorro A. Oral anticoagulant-associated intracerebral hemorrhage. J Neurol 2012; 259: 212-224
• 18 Seiffge DJ, Goeldlin MB, Tatlisumak T. et al. Meta-analysis of haematoma volume, haematoma expansion and mortality in intracerebral haemorrhage associated with oral anticoagulant use. J Neurol 2019; 266: 3126-3135
• 19 Inohara T, Xian Y, Liang L. et al. Association of intracerebral hemorrhage among patients taking non-vitamin K antagonist vs vitamin K antagonist oral anticoagulants with in-hospital mortality. JAMA 2018; 319: 463-473
• 20 Rosand J, Eckman MH, Knudsen KA. et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med 2004; 164: 880-884
• 21 Parry-Jones AR, Di Napoli M, Goldstein JN. et al. Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage. Ann Neurol 2015; 78: 54-62
• 22 Dentali F, Ageno W, Crowther M. Treatment of coumarin-associated coagulopathy: a systematic review and proposed treatment algorithms. J Thromb Haemost 2006; 4: 1853-1863
• 23 Haller JT, Wiss AL, May CC. et al. Acute management of hypertension following intracerebral hemorrhage. Crit Care Nurs Q 2019; 42: 129-147
• 24 Anderson CS, Huang Y, Wang JG. INTERACT Investigators. et al. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol 2008; 7: 391-399
• 25 Burgess LG, Goyal N, Jones GM. et al. Evaluation of acute kidney injury and mortality after intensive blood pressure control in patients with intracerebral hemorrhage. J Am Heart Assoc 2018; 7: e008439
• 26 Qureshi AI, Palesch YY, Barsan WG. et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. N Engl J Med 2016; 375: 1033-1043
• 27 Morotti A, Boulouis G, Dowlatshahi D. International NCCT ICH Study Group. et al. Standards for detecting, interpreting, and reporting noncontrast computed tomographic markers of intracerebral hemorrhage expansion. Ann Neurol 2019; 86: 480-492
• 28 Schiele F. et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013; 121: 3554-3562
• 29 Boehringer Ingelheim Pharma GmbH & Co. KG.. Fachinformation Praxbind, S.A. Anhang 1: Zusammenfassung der Merkmale des Arzneimittels. Accessed August 08, 2022 at: https://www.ema.europa.eu/en/documents/product-information/praxbind-epar-product-information_de.pdf
• 30 Gosselin RC, Adcock DM, Douxfils J. An update on laboratory assessment for direct oral anticoagulants (DOACs). Int J Lab Hematol 2019; 41 (Suppl. 01) 33-39
• 31 Glund S, Stangier J, van Ryn J. et al. Effect of age and renal function on idarucizumab pharmacokinetics and idarucizumab-mediated reversal of dabigatran anticoagulant activity in a randomized, double-blind, crossover phase Ib study. Clin Pharmacokinet 2017; 56: 41-54
• 32 Kermer P, Eschenfelder CC, Diener HC. Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany-updated series of 120 cases. Int J Stroke 2020; 15: 609-618
• 33 Purrucker JC, Rizos T, Haas K. et al. Coagulation testing in intracerebral hemorrhage related to non-vitamin K antagonist oral anticoagulants. Neurocrit Care 2017; 27: 208-213
• 34 Alexion Europe SAS. Ondexxya Fachinformation. Anhang 1: Zusammenfassung der Merkmale des Arzneimittels. Accessed March 31, 2022 at: https://www.ema.europa.eu/en/documents/product-information/ondexxya-epar-product-information_de.pdf
• 35 Connolly SJ, Crowther M, Eikelboom JW. ANNEXA-4 Investigators. et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med 2019; 380: 1326-1335
• 36 ClinicalTrials.gov. NCT03661528. Trial of andexanet alfa in ICH patients receiving an oral FXa inhibitor. Accessed March 31, 2022 at: https://clinicaltrials.gov/ct2/show/NCT03661528
• 37 Huttner HB, Gerner ST, Kuramatsu JB. et al. Hematoma expansion and clinical outcomes in patients with factor-Xa inhibitor-related atraumatic intracerebral hemorrhage treated within the ANNEXA-4 trial versus real-world usual care. Stroke 2022; 53: 532-543
• 38 Gómez-Outes A, Alcubilla P, Calvo-Rojas G. et al. Meta-analysis of reversal agents for severe bleeding associated with direct oral anticoagulants. J Am Coll Cardiol 2021; 77: 2987-3001
• 39 Purrucker JC, Haas K, Rizos T. et al. Early clinical and radiological course, management, and outcome of intracerebral hemorrhage related to new oral anticoagulants. JAMA Neurol 2016; 73: 169-177
• 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
• 41 Ammar AA, Ammar MA, Owusu KA. et al. Andexanet alfa versus 4-factor prothrombin complex concentrate for reversal of factor Xa inhibitors in intracranial hemorrhage. Neurocrit Care 2021; 35: 255-261
• 42 Shrestha DB, Budhathoki P, Adhikari A. et al. Efficacy and safety of andexanet alfa for bleeding caused by factor Xa inhibitors: a systematic review and meta-analysis. Cureus 2021; 13: e20632
• 43 Biffi A, Kuramatsu JB, Leasure A. et al. Oral anticoagulation and functional outcome after intracerebral hemorrhage. Ann Neurol 2017; 82: 755-765
• 44 Pennlert J, Overholser R, Asplund K. et al. Optimal timing of anticoagulant treatment after intracerebral hemorrhage in patients with atrial fibrillation. Stroke 2017; 48: 314-320
• 45 SoSTART Collaboration. Effects of oral anticoagulation for atrial fibrillation after spontaneous intracranial haemorrhage in the UK: a randomised, open-label, assessor-masked, pilot-phase, non-inferiority trial. Lancet Neurol 2021; 20: 842-853
• 46 Schreuder FHBM, van Nieuwenhuizen KM, Hofmeijer J. APACHE-AF Trial Investigators. et al. Apixaban versus no anticoagulation after anticoagulation-associated intracerebral haemorrhage in patients with atrial fibrillation in the Netherlands (APACHE-AF): a randomised, open-label, phase 2 trial. Lancet Neurol 2021; 20: 907-916
• 47 ClinicalTrials.gov. NCT03950076. EdoxabaN foR IntraCranial Hemorrhage survivors with Atrial Fibrillation (ENRICH-AF). 15.05.2019 Accessed August 08, 2022 at: https://clinicaltrials.gov/ct2/show/NCT03950076
• 48 ClinicalTrials.gov. NCT03996772. Veltkamp R. PREvention of STroke in intracerebral haemorrhaGE survivors with Atrial Fibrillation (PRESTIGE-AF). 25.06.2019 Accessed August 08, 2022 at: https://clinicaltrials.gov/ct2/show/NCT03996772
• 49 Greenberg SM, Charidimou A. Diagnosis of cerebral amyloid angiopathy: evolution of the Boston criteria. Stroke 2018; 49: 491-497
• 50 Charidimou A, Karayiannis C, Song TJ. International META-MICROBLEEDS Initiative. et al. Brain microbleeds, anticoagulation, and hemorrhage risk: meta-analysis in stroke patients with AF. Neurology 2017; 89: 2317-2326
• 51 Kelly J. New horizons: managing antithrombotic dilemmas in patients with cerebral amyloid angiopathy. Age Ageing 2021; 50: 347-355
• 52 Wilson DAmbler G, Shakeshaft C. CROMIS-2 collaborators. et al. Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2): a multicentre observational cohort study. Lancet Neurol 2018; 17: 539-547
• 53 Osmancik P, Herman D, Neuzil P. PRAGUE-17 Trial Investigators. et al. Left Atrial Appendage Closure Versus Direct Oral Anticoagulants in High-Risk Patients With Atrial Fibrillation. J Am Coll Cardiol 2020; 75: 3122-3135
• 54 ClinicalTrials.gov. NCT02830152. Prevention of stroke by left atrial appendage closure in atrial fibrillation patients after intracerebral hemorrhage (STROKECLOSE). Accessed August 08, 2022 at: https://clinicaltrials.gov/ct2/show/NCT02830152
• 55 ClinicalTrials.gov. NCT03463317 – Left atrial appendage CLOSURE in patients with atrial fibrillation compared to medical therapy (CLOSURE-AF). 13.03.2018 Accessed August 08, 2022 at: https://clinicaltrials.gov/ct2/show/NCT03463317
• 56 Zahir H, Brown KS, Vandell AG. et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation 2015; 131: 82-90
• 57 Kuramatsu JB, Gerner ST, Schellinger PD. et al. Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage. JAMA 2015; 313: 824-836