近日，英国伦敦大学学院David J Werring研究了急性缺血性脑卒中合并房颤患者的最佳抗凝时间。相关论文发表在2024年10月24日出版的《柳叶刀》杂志上。

急性缺血性脑卒中合并房颤患者的最佳抗凝时间尚不确定。课题组研究了早期与延迟开始直接口服抗凝剂（DOAC）治疗与房颤相关的急性缺血性卒中患者的疗效和安全性。

研究组在100家英国医院进行了一项多中心、开放标签、盲法终点、平行组、4期、随机对照试验。患有房颤、临床诊断为急性缺血性卒中且医生不确定DOAC启动最佳时机的成年人有资格纳入研究。使用独立的在线随机服务，将参与者（1:1）随机分配到任何DOAC的早期（即，中风症状发作后≤4天）或延迟（即，7-14天）抗凝治疗，该服务具有随机排列的区块和不同的区块长度，在随机分组时按中风严重程度分层。参与者和治疗临床医生对治疗分配知情，但所有结果都由一个单盲的独立外部裁决委员会使用所有可用的临床记录、脑成像报告和源图像进行评估。主要结局是改良意向治疗人群中90天内复发性缺血性卒中、症状性颅内出血、不可分类卒中或全身性栓塞发生率的综合结果。研究组使用了一种把关方法，依次测试2个百分点的非劣效性，然后测试优效性。

2019年7月5日至2024年1月31日，3648名患者被随机分配到早期或延迟DOAC启动。27名参与者不符合资格标准或撤回同意纳入他们的数据，在改良意向治疗分析中留下3621名患者（早期组1814名，延迟组1807名；1981名男性和1640名女性）。DOAC早期启动组1814名参与者中有59名（3.3%）出现主要结局，而延迟DOAC启动组1807名参与者中亦有59名（3.4%）出现主要结局（调整后的风险差异[RD]为0.000，95%CI为0.011至0.012）。调整后的RD的95%置信区间上限小于2个百分点的非劣效性界限（pnon劣效性=0.0003）。未发现优势（伪优势=0.96）。分配到早期DOAC启动组的11名参与者（0.6%）发生了症状性颅内出血，而分配到延迟DOAC启动小组的12名参与者（0.7%）发生了这种情况（调整后的RD为0.001，-0.004至0.006；p=0.78）。

研究结果表明，对于90天时缺血性卒中、颅内出血、不可分类卒中或全身性栓塞的综合结局，在与房颤相关的缺血性卒中后4天内早期DOAC启动并不逊于延迟启动。该研究结果不支持目前常见和指南支持的延迟缺血性卒中合并房颤后DOAC启动的做法。

附：英文原文

Title: Optimal timing of anticoagulation after acute ischaemic stroke with atrial fibrillation (OPTIMAS): a multicentre, blinded-endpoint, phase 4, randomised controlled trial

Author: David J Werring, Hakim-Moulay Dehbi, Norin Ahmed, Liz Arram, Jonathan G Best, Maryam Balogun, Kate Bennett, Ekaterina Bordea, Emilia Caverly, Marisa Chau, Hannah Cohen, Mairead Cullen, Caroline J Doré, Stefan T Engelter, Robert Fenner, Gary A Ford, Aneet Gill, Rachael Hunter, Martin James, Archana Jayanthi, Gregory Y H Lip, Sue Massingham, Macey L Murray, Iwona Mazurczak, Philip S Nash, Amalia Ndoutoumou, Bo Norrving, Hannah Sims, Nikola Sprigg, Tishok Vanniyasingam, Nick Freemantle, Benjamin Jelley, Tom Hughes, Mim Evans, Diego Garcia Esteban, Lucy Knibbs, Lauren Broad, Rebecca Price, Liz Hamer Griebel, Sian Hewson, Kamy Thavanesan, Louise Mallon, Anna Smith, Miranda White, Liqun Zhang, Brian Clarke, Youssif Abousleiman, Lauren Binnie, Cai Hua Sim, Margarida Castanheira, Fiona Humphries, Sabaa Obarey, Shez Feerick, Yee Chin Lee, Alex Lewis, Riham Muhammad, Nina Francia, Ndifreke Atang, Azra Banaras, Marilena Marinescu, Philip Ferdinand, Resti Varquez, Ida Ponce, Surabhi Saxena, Eoin OBrien, Juliana Delos Reyes, Jennifer Mitchell-Douglas, Jobbin Francis, Soma Banerjee, Vaishali Dave, Sheila Mashate, Tulsi Patel, Lakshmanan Sekaran, Wahid Murad, Asokanathan Asaipillai, Sethuraman Sakthivel, Margaret Tate, Jane Angus, Lisa Reid, Caroline Fornolles, Saul Sundayi, Lincy Poolon, Francis Justin, Sophy Hunte, Mohit Bhandari, Jules Kho, Vera Cvoro, Ruwan Parakramawansha, Mandy Couser, Hannah Hughes, Aaizza Naqvi, Kirsty Harkness, Emma Richards, Jo Howe, Chris Kamara, Jon Gardner, Harjit Bains, Rachel Teal, Jeethu Joseph, Jithen Benjamin, Samer Al-Hussayni, George Thomas, Faye Robinson, Lynn Dixon, Manju Krishnan, Peter Slade, Tal Anjum, Sharon Storton, Katja Adie, Keren Northcott, Katie Morgan, Emilie Williams, Harinath Chanashekar

Issue&Volume: 2024-10-24

Abstract:

Background

The optimal timing of anticoagulation for patients with acute ischaemic stoke with atrial fibrillation is uncertain. We investigated the efficacy and safety of early compared with delayed initiation of direct oral anticoagulants (DOACs) in patients with acute ischaemic stroke associated with atrial fibrillation.

Methods

We performed a multicentre, open-label, blinded-endpoint, parallel-group, phase 4, randomised controlled trial at 100 UK hospitals. Adults with atrial fibrillation and a clinical diagnosis of acute ischaemic stroke and whose physician was uncertain of the optimal timing for DOAC initiation were eligible for inclusion in the study. We randomly assigned participants (1:1) to early (ie, ≤4 days from stroke symptom onset) or delayed (ie, 7–14 days) anticoagulation initiation with any DOAC, using an independent online randomisation service with random permuted blocks and varying block length, stratified by stroke severity at randomisation. Participants and treating clinicians were not masked to treatment assignment, but all outcomes were adjudicated by a masked independent external adjudication committee using all available clinical records, brain imaging reports, and source images. The primary outcome was a composite of recurrent ischaemic stroke, symptomatic intracranial haemorrhage, unclassifiable stroke, or systemic embolism incidence at 90 days in a modified intention-to-treat population. We used a gatekeeper approach by sequentially testing for a non-inferiority margin of 2 percentage points, followed by testing for superiority. OPTIMAS is registered with ISRCTN (ISRCTN17896007) and ClinicalTrials.gov (NCT03759938), and the trial is ongoing.

Findings

Between July 5, 2019, and Jan 31, 2024, 3648 patients were randomly assigned to early or delayed DOAC initiation. 27 participants did not fulfil the eligibility criteria or withdrew consent to include their data, leaving 3621 patients (1814 in the early group and 1807 in the delayed group; 1981 men and 1640 women) in the modified intention-to-treat analysis. The primary outcome occurred in 59 (3·3%) of 1814 participants in the early DOAC initiation group compared with 59 (3·3%) of 1807 participants in the delayed DOAC initiation group (adjusted risk difference [RD] 0·000, 95% CI –0·011 to 0·012). The upper limit of the 95% CI for the adjusted RD was less than the non-inferiority margin of 2 percentage points (pnon-inferiority=0·0003). Superiority was not identified (psuperiority=0·96). Symptomatic intracranial haemorrhage occurred in 11 (0·6%) participants allocated to the early DOAC initiation group compared with 12 (0·7%) participants allocated to the delayed DOAC initiation group (adjusted RD 0·001, –0·004 to 0·006; p=0·78).

Interpretation

Early DOAC initiation within 4 days after ischaemic stroke associated with atrial fibrillation was non-inferior to delayed initiation for the composite outcome of ischaemic stroke, intracranial haemorrhage, unclassifiable stroke, or systemic embolism at 90 days. Our findings do not support the current common and guideline-supported practice of delaying DOAC initiation after ischaemic stroke with atrial fibrillation.

DOI: 10.1016/S0140-6736(24)02197-4

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)02197-4/abstract