دورية أكاديمية
Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial.
| العنوان: | Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial. |
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| المؤلفون: | Shoamanesh A; Division of Neurology, McMaster University, Population Health Research Institute, Hamilton, ON, Canada. Electronic address: ashkan.shoamanesh@phri.ca., Mundl H; TA Thrombosis and Vascular Medicine, Bayer AG, Wuppertal, Germany., Smith EE; Department of Clinical Neurosciences, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Radiology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada., Masjuan J; Neurology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain; Departamento de Medicina, Facultad de Medicina, Universidad de Alcalá, IRYCIS, RICORS-ICTUS, Madrid, Spain., Milanov I; Medical University, University Hospital for Neurology and Psychiatry 'St Naum', Sofia, Bulgaria., Hirano T; Department of Stroke and Cerebrovascular Medicine, School of Medicine, Kyorin University, Tokyo, Japan., Agafina A; Clinical Research Department, City Hospital #40, Saint Petersburg, Russia., Campbell B; Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia., Caso V; Stroke Unit, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy., Mas JL; Department of Neurology, GHU Paris, Hôpital Sainte-Anne, Université Paris-Cité, Inserm U1266, Paris, France., Dong Q; Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China., Turcani P; 1st Department of Neurology, Medical Faculty, Comenius University, Bratislava, Slovakia., Christensen H; Department of Neurology, University Hospital of Copenhagen, Bispebjerg, Denmark., Ferro JM; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal., Veltkamp R; Neurology Department, Alfried-Krupp Hospital, Essen, Germany., Mikulik R; International Clinical Research Center and Neurology Department, St Anne's University Hospital, Brno, Czech Republic; Medical Faculty, Masaryk University, Brno, Czech Republic., De Marchis GM; Department of Neurology and Stroke Center, University Hospital of Basel and University of Basel, Basel, Switzerland., Robinson T; College of Life Sciences, University of Leicester, Leicester, UK., Lemmens R; Department of Neurosciences, Experimental Neurology, KU Leuven - University of Leuven, Leuven, Belgium; VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium; Department of Neurology, University Hospitals Leuven, Leuven, Belgium., Stepien A; Department of Neurology, Military Institute of Medicine, Warsaw, Poland., Greisenegger S; Department of Neurology, Medical University of Vienna, Vienna, Austria., Roine R; Division of Clinical Neurosciences, University of Turku, Turku, Finland., Csiba L; DE Clinical Center (DEKK), Health Service Units, Clinics, Department of Neurology, University of Debrecen, Debrecen, Hungary., Khatri P; Department of Neurology and Rehabilitation Sciences, University of Cincinnati, Cincinnati, OH, USA., Coutinho J; Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands., Lindgren AG; Department of Clinical Sciences Lund (Neurology), Lund University, Lund, Sweden; Department of Neurology, Skåne University Hospital, Lund, Sweden., Demchuk AM; Department of Clinical Neurosciences, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Radiology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada., Colorado P; Bayer US Pharmaceuticals, Whippany, NJ, USA., Kirsch B; Statistics and Data Insights, Bayer AG, Berlin, Germany., Neumann C; Bayer AG, Wuppertal, Germany., Heenan L; Department of Statistics, McMaster University, Population Health Research Institute, Hamilton, ON, Canada., Xu L; Department of Statistics, McMaster University, Population Health Research Institute, Hamilton, ON, Canada., Connolly SJ; Department of Medicine, McMaster University, Population Health Research Institute, Hamilton, ON, Canada., Hart RG; Division of Neurology, McMaster University, Population Health Research Institute, Hamilton, ON, Canada. |
| مؤلفون مشاركون: | PACIFIC-Stroke Investigators |
| المصدر: | Lancet (London, England) [Lancet] 2022 Sep 24; Vol. 400 (10357), pp. 997-1007. Date of Electronic Publication: 2022 Sep 02. |
| نوع المنشور: | Journal Article; Randomized Controlled Trial |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: England NLM ID: 2985213R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1474-547X (Electronic) Linking ISSN: 01406736 NLM ISO Abbreviation: Lancet Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2004- : London : Elsevier Original Publication: London : J. Onwhyn |
| مواضيع طبية MeSH: | Brain Ischemia*/drug therapy , Brain Ischemia*/prevention & control , Ischemic Stroke* , Stroke*/drug therapy , Stroke*/prevention & control , Thrombosis*, Aged ; Anticoagulants/therapeutic use ; Double-Blind Method ; Factor XIa ; Female ; Hemorrhage/chemically induced ; Hemorrhage/drug therapy ; Humans ; Male ; Platelet Aggregation Inhibitors/therapeutic use ; Treatment Outcome |
| مستخلص: | Background: Asundexian (Bayer AG, Leverkusen, Germany), an oral small molecule factor XIa (FXIa) inhibitor, might prevent thrombosis without increasing bleeding. Asundexian's effect for secondary prevention of recurrent stroke is unknown. Methods: In this randomised, double-blind, placebo-controlled, phase 2b dose-finding trial (PACIFIC-Stroke), patients with acute (within 48 h) non-cardioembolic ischaemic stroke were recruited from 196 hospitals in 23 countries. Patients were eligible if they were aged 45 years or older, to be treated with antiplatelet therapy, and able to have a baseline MRI (either before or within 72 h of randomisation). Eligible participants were randomly assigned (1:1:1:1), using an interactive web-based response system and stratified according to anticipated antiplatelet therapy (single vs dual), to once daily oral asundexian (BAY 2433334) 10 mg, 20 mg, or 50 mg, or placebo in addition to usual antiplatelet therapy, and were followed up during treatment for 26-52 weeks. Brain MRIs were obtained at study entry and at 26 weeks or as soon as possible after treatment discontinuation. The primary efficacy outcome was the dose-response effect on the composite of incident MRI-detected covert brain infarcts and recurrent symptomatic ischaemic stroke at or before 26 weeks after randomisation. The primary safety outcome was major or clinically relevant non-major bleeding as defined by International Society on Thrombosis and Haemostasis criteria. The efficacy outcome was assessed in all participants assigned to treatment, and the safety outcome was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04304508, and is now complete. Findings: Between June 15, 2020, and July 22, 2021, 1880 patients were screened and 1808 participants were randomly assigned to asundexian 10 mg (n=455), 20 mg (n=450), or 50 mg (n=447), or placebo (n=456). Mean age was 67 years (SD 10) and 615 (34%) participants were women, 1193 (66%) were men, 1505 (83%) were White, and 268 (15%) were Asian. The mean time from index stroke to randomisation was 36 h (SD 10) and median baseline National Institutes of Health Stroke Scale score was 2·0 (IQR 1·0-4·0). 783 (43%) participants received dual antiplatelet treatment for a mean duration of 70·1 days (SD 113·4) after randomisation. At 26 weeks, the primary efficacy outcome was observed in 87 (19%) of 456 participants in the placebo group versus 86 (19%) of 455 in the asundexian 10 mg group (crude incidence ratio 0·99 [90% CI 0·79-1·24]), 99 (22%) of 450 in the asundexian 20 mg group (1·15 [0·93-1·43]), and 90 (20%) of 447 in the asundexian 50 mg group (1·06 [0·85-1·32]; t statistic -0·68; p=0·80). The primary safety outcome was observed in 11 (2%) of 452 participants in the placebo group versus 19 (4%) of 445 in the asundexian 10 mg group, 14 (3%) of 446 in the asundexian 20 mg group, and 19 (4%) of 443 in the asundexian 50 mg group (all asundexian doses pooled vs placebo hazard ratio 1·57 [90% CI 0·91-2·71]). Interpretation: In this phase 2b trial, FXIa inhibition with asundexian did not reduce the composite of covert brain infarction or ischaemic stroke and did not increase the composite of major or clinically relevant non-major bleeding compared with placebo in patients with acute, non-cardioembolic ischaemic stroke. Funding: Bayer AG. Competing Interests: Declaration of interests All coauthors or their institutions received financial support from Bayer for participation in the PACIFIC-Stroke trial except HM, PC, BK, and CN who are employees of Bayer. HM, PC, BK, and CN do not hold any stock or stock options with Bayer. (Copyright © 2022 Elsevier Ltd. All rights reserved.) |
| سلسلة جزيئية: | ClinicalTrials.gov NCT04304508 |
| المشرفين على المادة: | 0 (Anticoagulants) 0 (Platelet Aggregation Inhibitors) EC 3.4.21.27 (Factor XIa) |
| تواريخ الأحداث: | Date Created: 20220905 Date Completed: 20220928 Latest Revision: 20220930 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1016/S0140-6736(22)01588-4 |
| PMID: | 36063821 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1474-547X |
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| DOI: | 10.1016/S0140-6736(22)01588-4 |