小柯机器人

加拿大麦克马斯特大学人口健康研究所Ashkan Shoamanesh团队研究了抑制因子XIa Asundexian治疗急性非心源性缺血性卒中的疗效与安全性。这一研究成果发表在2022年9月2日出版的《柳叶刀》杂志上。

Asundexian（德国拜耳公司）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对复发性中风的二级预防效果尚不清楚。

在这项随机、双盲、安慰剂对照、2b期剂量发现试验（PACIFIC-卒中）中，研究组从23个国家的196家医院招募急性（48小时内）非心源性缺血性卒中患者。如果患者年龄在45岁及以上，接受抗血小板治疗，并能够进行基线MRI（随机分组前或72小时内），则符合条件。

对合格参与者使用基于网络的互动应答系统进行随机分配（1:1:1:1），并根据预期抗血小板治疗（单次与双次）进行分层，除常规抗血小板治疗外，每天口服一次asundexian（BAY 2433334）10 mg、20 mg或50 mg，或安慰剂，并在治疗期间随访26-52周。在研究开始时、26周时或治疗中断后尽快获得脑磁共振成像。

主要疗效结局是随机分组后26周或以内，MRI检测到的隐匿性脑梗塞和复发性症状性缺血性中风的剂量反应效应。主要安全性结局是国际血栓和止血标准协会定义的严重或临床相关非严重出血。对所有接受治疗的参与者进行疗效结局评估，并对至少接受一剂研究治疗的所有参与者进行安全性结局评估。

2020年6月15日至2021年7月22日，研究组对1880名患者进行了筛查，并将1808名参与者随机分祖，其中为asundexian 10 mg组455例，20 mg组450例，50 mg组447例，安慰剂组456例。平均年龄为67岁，615名（34%）参与者为女性，1193名（66%）为男性，1505名（83%）为白人，268名（15%）为亚裔。

从发生卒中到随机分组的平均时间为36小时，美国国家卫生研究院卒中量表中位基线评分为2.0。783名（43%）参与者在随机分组后接受了平均持续70.1天的双重抗血小板治疗。26周时，安慰剂组456名参与者中有87名（19%）观察到主要疗效结局，而asundexian 10 mg组455名中有86名（19%）（粗发生率为0.99），asundexian 20 mg组450名中有99名（22%）（1.15），asundexian 50 mg组447名中有90名（20%）（1.06）。

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asundexian 10mg组445名参与者中有19名（4%），asundexian 20mg组446名参与者中有14名（3%），asundexian 50mg组443名参与者中有19名（3%），所有asundexian剂量汇总与安慰剂的风险比1.57。

研究结果表明，在这项2b期临床试验中，与安慰剂相比，Asundexian对FXIa的抑制并未降低急性非心源性缺血性中风患者隐性脑梗塞或缺血性中风的综合结局，也未增加重大或临床相关非重大出血的综合结局。

附：英文原文

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

Author: Ashkan Shoamanesh, Hardi Mundl, Eric E Smith, Jaime Masjuan, Ivan Milanov, Teruyuki Hirano, Alina Agafina, Bruce Campbell, Valeria Caso, Jean-Louis Mas, Qiang Dong, Peter Turcani, Hanne Christensen, Jose M Ferro, Roland Veltkamp, Robert Mikulik, Gian Marco De Marchis, Thompson Robinson, Robin Lemmens, Adam Stepien, Stefan Greisenegger, Risto Roine, Laszlo Csiba, Pooja Khatri, Jonathan Coutinho, Arne G Lindgren, Andrew M Demchuk, Pablo Colorado, Bodo Kirsch, Christoph Neumann, Laura Heenan, Lizhen Xu, Stuart J Connolly, Robert G Hart

Issue&Volume: 2022-09-02

Abstract:

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.

DOI: 10.1016/S0140-6736(22)01588-4

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01588-4/fulltext

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