Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage

Connolly SJ, Sharma M, Cohen AT, Demchuk AM, Członkowska A, Lindgren AG, Molina CA, Bereczki D, Toni D, Seiffge DJ, Tanne D, Sandset EC, Tsivgoulis G, Christensen H, Beyer-Westendorf J, Coutinho JM, Crowther M, Verhamme P, Amarenco P, Roine RO, Mikulik R, Lemmens R, Veltkamp R, Middeldorp S, Robinson TG, Milling TJ, Tedim-Cruz V, Lang W, Himmelmann A, Ladenvall P, Knutsson M, Ekholm E, Law A, Taylor A, Karyakina T, Xu L, Tsiplova K, Poli S, Kallmünzer B, Gumbinger C, Shoamanesh A (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Book Volume: 390

Pages Range: 1745-1755

Journal Issue: 19

DOI: 10.1056/NEJMoa2313040

Abstract

Background Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. Methods We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. Results A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P=0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P=0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. Conclusions Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).

Authors with CRIS profile

Involved external institutions

McMaster University Canada (CA) King’s College London United Kingdom (GB) Alexion Pharmaceuticals United States (USA) (US) Lund University / Lunds universitet Sweden (SE) Vall d'Hebron University Hospital / Hospital Universitari Vall d'Hebron Spain (ES) Semmelweis University / Semmelweis Egyetem Hungary (HU) Inselspital, Universitätsspital Bern Switzerland (CH) Technion - Israel Institute of Technology Israel (IL) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra Netherlands (NL) Hôpital Bichat-Claude-Bernard (CHU, APHP) France (FR) Turku University Hospital / Turun yliopistollinen keskussairaala (TYKS) Finland (FI) Tomas Bata University in Zlín (TBU) / Univerzita Tomáše Bati ve Zlíně (UTB) Czech Republic (CZ) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) Imperial College London / The Imperial College of Science, Technology and Medicine United Kingdom (GB) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL) University of Leicester United Kingdom (GB) University of Texas at Austin United States (USA) (US) Universidade do Porto Portugal (PT) Sigmund-Freud-Privatuniversität Wien (SFU) / Sigmund Freud University Austria (AT) AstraZeneca UK Limited United Kingdom (GB) University of Calgary Canada (CA) Università degli studi "La Sapienza" Italy (IT) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) National and Kapodistrian University of Athens Greece (GR) Bispebjerg Hospital Denmark (DK) Alfried Krupp Krankenhaus Germany (DE) Eberhard Karls Universität Tübingen Germany (DE) Universitätsklinikum Heidelberg Germany (DE)

How to cite

APA:

Connolly, S.J., Sharma, M., Cohen, A.T., Demchuk, A.M., Członkowska, A., Lindgren, A.G.,... Shoamanesh, A. (2024). Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage. New England Journal of Medicine, 390(19), 1745-1755. https://doi.org/10.1056/NEJMoa2313040

MLA:

Connolly, Stuart J., et al. "Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage." New England Journal of Medicine 390.19 (2024): 1745-1755.

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