Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial,The Lancet

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Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial
The Lancet ( IF 98.4 ) Pub Date : 2022-09-02 , DOI: 10.1016/s0140-6736(22)01588-4
Ashkan Shoamanesh ₁ , Hardi Mundl ₂ , Eric E Smith ₃ , Jaime Masjuan ₄ , Ivan Milanov ₅ , Teruyuki Hirano ₆ , Alina Agafina ₇ , Bruce Campbell ₈ , Valeria Caso ₉ , Jean-Louis Mas ₁₀ , Qiang Dong ₁₁ , Peter Turcani ₁₂ , Hanne Christensen ₁₃ , Jose M Ferro ₁₄ , Roland Veltkamp ₁₅ , Robert Mikulik ₁₆ , Gian Marco De Marchis ₁₇ , Thompson Robinson ₁₈ , Robin Lemmens ₁₉ , Adam Stepien ₂₀ , Stefan Greisenegger ₂₁ , Risto Roine ₂₂ , Laszlo Csiba ₂₃ , Pooja Khatri ₂₄ , Jonathan Coutinho ₂₅ , Arne G Lindgren ₂₆ , Andrew M Demchuk ₃ , Pablo Colorado ₂₇ , Bodo Kirsch ₂₈ , Christoph Neumann ₂₉ , Laura Heenan ₃₀ , Lizhen Xu ₃₀ , Stuart J Connolly ₃₁ , Robert G Hart ₁ ,

Affiliation

Division of Neurology, McMaster University, Population Health Research Institute, Hamilton, ON, Canada.
TA Thrombosis and Vascular Medicine, Bayer AG, Wuppertal, Germany.
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.
Neurology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain; Departamento de Medicina, Facultad de Medicina, Universidad de Alcalá, IRYCIS, RICORS-ICTUS, Madrid, Spain.
Medical University, University Hospital for Neurology and Psychiatry "St Naum", Sofia, Bulgaria.
Department of Stroke and Cerebrovascular Medicine, School of Medicine, Kyorin University, Tokyo, Japan.
Clinical Research Department, City Hospital #40, Saint Petersburg, Russia.
Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia.
Stroke Unit, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy.
Department of Neurology, GHU Paris, Hôpital Sainte-Anne, Université Paris-Cité, Inserm U1266, Paris, France.
Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
1st Department of Neurology, Medical Faculty, Comenius University, Bratislava, Slovakia.
Department of Neurology, University Hospital of Copenhagen, Bispebjerg, Denmark.
Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Neurology Department, Alfried-Krupp Hospital, Essen, Germany.
International Clinical Research Center and Neurology Department, St Anne's University Hospital, Brno, Czech Republic; Medical Faculty, Masaryk University, Brno, Czech Republic.
Department of Neurology and Stroke Center, University Hospital of Basel and University of Basel, Basel, Switzerland.
College of Life Sciences, University of Leicester, Leicester, UK.
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.
Department of Neurology, Military Institute of Medicine, Warsaw, Poland.
Department of Neurology, Medical University of Vienna, Vienna, Austria.
Division of Clinical Neurosciences, University of Turku, Turku, Finland.
DE Clinical Center (DEKK), Health Service Units, Clinics, Department of Neurology, University of Debrecen, Debrecen, Hungary.
Department of Neurology and Rehabilitation Sciences, University of Cincinnati, Cincinnati, OH, USA.
Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
Department of Clinical Sciences Lund (Neurology), Lund University, Lund, Sweden; Department of Neurology, Skåne University Hospital, Lund, Sweden.
Bayer US Pharmaceuticals, Whippany, NJ, USA.
Statistics and Data Insights, Bayer AG, Berlin, Germany.
Bayer AG, Wuppertal, Germany.
Department of Statistics, McMaster University, Population Health Research Institute, Hamilton, ON, Canada.
Department of Medicine, McMaster University, Population Health Research Institute, Hamilton, ON, Canada.

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.

中文翻译：

急性非心源性缺血性脑卒中 (PACIFIC-Stroke) 后使用腹股沟炎抑制因子 XIa：一项国际、随机、双盲、安慰剂对照、2b 期试验

背景

Asundexian (Bayer AG, Leverkusen, Germany) 是一种口服小分子因子 XIa (FXIa) 抑制剂，可在不增加出血的情况下预防血栓形成。Asundexian 对复发性卒中二级预防的作用尚不清楚。

方法

在这项随机、双盲、安慰剂对照、2b 期剂量寻找试验（PACIFIC-Stroke）中，从 23 个国家的 196 家医院招募了急性（48 小时内）非心源性缺血性卒中患者。如果患者年龄在 45 岁或以上，接受抗血小板治疗，并且能够进行基线 MRI（随机分组之前或 72 小时内），则符合条件。符合条件的参与者被随机分配（1:1:1:1），使用基于网络的交互式响应系统，并根据预期的抗血小板治疗（单一与双重），每天一次口服 asundexian (BAY 2433334) 10 毫克、20 毫克或 50 毫克，或安慰剂加常规抗血小板治疗，并在治疗期间随访 26-52 周。在研究开始时和 26 周或治疗停止后尽快获得脑 MRI。主要疗效结果是在随机分组后 26 周或之前对 MRI 检测到的隐匿性脑梗死和复发性症状性缺血性卒中复合材料的剂量反应效应。主要安全性结果是国际血栓形成和止血协会标准定义的大出血或临床相关的非大出血。在分配到治疗的所有参与者中评估疗效结果，并在接受至少一剂研究治疗的所有参与者中评估安全性结果。

发现

在 2020 年 6 月 15 日至 2021 年 7 月 22 日期间，对 1880 名患者进行了筛查，1808 名参与者被随机分配到 10 mg (n=455)、20 mg (n=450) 或 50 mg (n=447) 组，或安慰剂（n = 456）。平均年龄为 67 岁 (SD 10)，615 名 (34%) 参与者为女性，1193 名 (66%) 为男性，1505 名 (83%) 为白人，268 名 (15%) 为亚洲人。从指数卒中到随机化的平均时间为 36 小时（标准差 10），中位基线美国国立卫生研究院卒中量表评分为 2·0（IQR 1·0-4·0）。783 名 (43%) 参与者在随机分组后接受了平均 70·1 天 (SD 113·4) 的双重抗血小板治疗。在 26 周时，安慰剂组 456 名参与者中有 87 名（19%）观察到主要疗效结果，而 10 mg 组 455 名参与者中有 86 名（19%）观察到主要疗效结果（粗发病率 0·99 [90% CI 0· 79–1·24]), asundexian 20 mg 组 450 人中有 99 人 (22%) (1·15 [0·93–1·43])，asundexian 50 mg 组 447 人中有 90 人 (20%) (1·06 [0·85] –1·32]；t 统计量 –0·68；p=0·80)。安慰剂组 452 名参与者中有 11 名（2%）观察到主要安全性结局，而 10 mg 组 445 名参与者中有 19 名（4%）、20 mg 组 446 名参与者中有 14 名（3%）和 19 (4%) 443 的 asundexian 50 mg 组（所有 asundexian 剂量合并与安慰剂的风险比为 1·57 [90% CI 0·91–2·71]）。