Notfallmedizin up2date 2023; 18(01): 81-98
DOI: 10.1055/a-1724-4900
Neurologische Notfälle

Spezifische Pharmakotherapie bei intrazerebralen Blutungen unter oraler Antikoagulation

Ida Rangus
,
Regina von Rennenberg
,

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.



Publication History

Article published online:
13 March 2023

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  • 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, Hüsing J. 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. et al. , ANNEXA-4 Investigators. 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