Spezifische Pharmakotherapie bei intrazerebralen Blutungen unter oraler Antikoagulation

Ida Rangus; Regina von Rennenberg; Christian H Nolte

doi:10.1055/a-2073-2291

Gefäßmedizin Scan - Zeitschrift für Angiologie, Gefäßchirurgie, diagnostische und interventionelle Radiologie, Table of Contents

Gefäßmedizin Scan - Zeitschrift für Angiologie, Gefäßchirurgie, diagnostische und interventionelle Radiologie 2023; 10(02): 149-164
DOI: 10.1055/a-2073-2291

CME-Fortbildung

Spezifische Pharmakotherapie bei intrazerebralen Blutungen unter oraler Antikoagulation

Authors

Ida Rangus‡

¹Klinik für Neurologie mit Experimenteller Neurologie und Center for Stroke Research Berlin, Charité – Universitätsmedizin Berlin, Berlin, Deutschland
Regina von Rennenberg‡

²AG Klinische Schlaganfallforschung, Klinik für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Deutschland

³Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Bonn, Deutschland
Christian H Nolte

²AG Klinische Schlaganfallforschung, Klinik für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Deutschland

⁴Berlin Institute of Health (BIH), Berlin, Deutschland

⁵Deutsches Zentrum für Herz-Kreislaufforschung e.V. (DZHK), Berlin, Deutschland

Abstract

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.

Schlüsselwörter

intrakranielle Blutungen - Andexanet alfa - Idarucizumab - Antagonisierung - Antikoagulanzien

Full Text

References

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