小柯机器人

荷兰鹿特丹伊拉斯谟大学医学中心Wouter van der Steen团队研究了血管内卒中治疗中阿司匹林和未分离肝素的安全性和有效性。相关论文发表在2022年2月28日出版的《柳叶刀》杂志上。

阿司匹林和未分离肝素常用于血管内卒中治疗，以改善再灌注和预后。然而，抗血栓药物对该适应症的影响和风险尚不清楚。因此，该研究旨在评估缺血性卒中患者血管内治疗期间静脉注射阿司匹林或未分离肝素、或两者均有、或都不注射的安全性和有效性。

研究组在荷兰的15个中心进行了一项开放标签、多中心、随机对照试验，对参与者进行了一项2×3析因设计。招募因前循环颅内大血管闭塞而导致缺血性中风的成年患者（≥18岁），可在症状出现后6小时内开始血管内治疗。

符合条件的患者在美国国立卫生研究院卒中量表上得分均为2分及以上，CT或MRI排除颅内出血。采用基于网络的程序进行随机分组，并按中心分层。将患者按1：1随机分配接受围手术期静脉注射阿司匹林或不注射阿司匹林，并按1：1：1随机分配接受中等剂量的未分离肝素、低剂量未分离肝素、或不接受未分离肝素。

主要结局是90天时改良Rankin量表的得分。症状性颅内出血是主要的安全结局。基于治疗意向进行分析，治疗效果以优势比（OR）或常见OR表示，并校正基线预后因素。

2018年1月22日至2021年1月27日，研究组共随机分配了663名患者；其中628人（95%）提供了延期同意书，或在要求同意书之前死亡，并被纳入修改后的意向治疗人群。2021年2月4日，在对数据进行盲测和分析之后，试验指导委员会永久停止了患者招募，并且出于安全考虑停止了试验。

接受阿司匹林的310例患者中有43例（14%）出现症状性颅内出血，显著高于未接受阿司匹林治疗的患者（318例中23例[7%]），校正后的OR为1.95。接受未分离肝素的332例患者中有44例（13%）出现症状性颅内出血，显著高于未接受未分离肝素治疗的患者（296例中22例[7%]），校正后的OR为1.98。阿司匹林和未分离肝素均未导致更差的改良Rankin量表评分的显著变化。

研究结果表明，血管内卒中治疗期间围手术期静脉注射阿司匹林和未分离肝素均与症状性颅内出血的风险增加有关，但没有证据表明对功能预后有有益影响。

附：英文原文

Title: Safety and efficacy of aspirin, unfractionated heparin, both, or neither during endovascular stroke treatment (MR CLEAN-MED): an open-label, multicentre, randomised controlled trial

Author: Wouter van der Steen, Rob A van de Graaf, Vicky Chalos, Hester F Lingsma, Pieter Jan van Doormaal, Jonathan M Coutinho, Bart J Emmer, Inger de Ridder, Wim van Zwam, H Bart van der Worp, Irene van der Schaaf, Rob A R Gons, Lonneke S F Yo, Jelis Boiten, Ido van den Wijngaard, Jeannette Hofmeijer, Jasper Martens, Wouter Schonewille, Jan Albert Vos, Anil Man Tuladhar, Karlijn F de Laat, Boudewijn van Hasselt, Michel Remmers, Douwe Vos, Anouk Rozeman, Otto Elgersma, Maarten Uyttenboogaart, Reinoud P H Bokkers, Julia van Tuijl, Issam Boukrab, René van den Berg, Ludo F M Beenen, Stefan D Roosendaal, Alida Annechien Postma, Menno Krietemeijer, Geert Lycklama, Frederick J A Meijer, Sebastiaan Hammer, Anouk van der Hoorn, Albert J Yoo, Dick Gerrits, Martine T B Truijman, Sanne Zinkstok, Peter J Koudstaal, Sanne Manschot, Henk Kerkhoff, Daan Nieboer, Olvert Berkhemer, Lennard Wolff, P Matthijs van der Sluijs, Henk van Voorst, Manon Tolhuisen, Yvo B W E M Roos, Charles B L M Majoie, Julie Staals, Robert J van Oostenbrugge, Sjoerd F M Jenniskens, Lukas C van Dijk, Heleen M den Hertog, Adriaan C G M van Es, Aad van der Lugt, Diederik W J Dippel, Bob Roozenbeek

Issue&Volume: 2022-02-28

Abstract:

Background

Aspirin and unfractionated heparin are often used during endovascular stroke treatment to improve reperfusion and outcomes. However, the effects and risks of anti-thrombotics for this indication are unknown. We therefore aimed to assess the safety and efficacy of intravenous aspirin, unfractionated heparin, both, or neither started during endovascular treatment in patients with ischaemic stroke.

Methods

We did an open-label, multicentre, randomised controlled trial with a 2×3 factorial design in 15 centres in the Netherlands. We enrolled adult patients (ie, ≥18 years) with ischaemic stroke due to an intracranial large-vessel occlusion in the anterior circulation in whom endovascular treatment could be initiated within 6 h of symptom onset. Eligible patients had a score of 2 or more on the National Institutes of Health Stroke Scale, and a CT or MRI ruling out intracranial haemorrhage. Randomisation was done using a web-based procedure with permuted blocks and stratified by centre. Patients were randomly assigned (1:1) to receive either periprocedural intravenous aspirin (300 mg bolus) or no aspirin, and randomly assigned (1:1:1) to receive moderate-dose unfractionated heparin (5000 IU bolus followed by 1250 IU/h for 6 h), low-dose unfractionated heparin (5000 IU bolus followed by 500 IU/h for 6 h), or no unfractionated heparin. The primary outcome was the score on the modified Rankin Scale at 90 days. Symptomatic intracranial haemorrhage was the main safety outcome. Analyses were based on intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. This trial is registered with the International Standard Randomised Controlled Trial Number, ISRCTN76741621.

Findings

Between Jan 22, 2018, and Jan 27, 2021, we randomly assigned 663 patients; of whom, 628 (95%) provided deferred consent or died before consent could be asked and were included in the modified intention-to-treat population. On Feb 4, 2021, after unblinding and analysis of the data, the trial steering committee permanently stopped patient recruitment and the trial was stopped for safety concerns. The risk of symptomatic intracranial haemorrhage was higher in patients allocated to receive aspirin than in those not receiving aspirin (43 [14%] of 310 vs 23 [7%] of 318; adjusted OR 1·95 [95% CI 1·13–3·35]) as well as in patients allocated to receive unfractionated heparin than in those not receiving unfractionated heparin (44 [13%] of 332 vs 22 [7%] of 296; 1·98 [1·14–3·46]). Both aspirin (adjusted common OR 0·91 [95% CI 0·69–1·21]) and unfractionated heparin (0·81 [0·61–1·08]) led to a non-significant shift towards worse modified Rankin Scale scores.

Interpretation

Periprocedural intravenous aspirin and unfractionated heparin during endovascular stroke treatment are both associated with an increased risk of symptomatic intracranial haemorrhage without evidence for a beneficial effect on functional outcome.

DOI: 10.1016/S0140-6736(22)00014-9

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00014-9/fulltext

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