Werring David J, Dehbi Hakim-Moulay, Ahmed Norin, Arram Liz, Best Jonathan G, Balogun Maryam, Bennett Kate, Bordea Ekaterina, Caverly Emilia, Chau Marisa, Cohen Hannah, Cullen Mairead, Doré Caroline J, Engelter Stefan T, Fenner Robert, Ford Gary A, Gill Aneet, Hunter Rachael, James Martin, Jayanthi Archana, Lip Gregory Y H, Massingham Sue, Murray Macey L, Mazurczak Iwona, Nash Philip S, Ndoutoumou Amalia, Norrving Bo, Sims Hannah, Sprigg Nikola, Vanniyasingam Tishok, Freemantle Nick
Stroke Research Centre, Department of Brain Repair and Rehabilitation, University College London Queen Square Institute of Neurology, London, UK; Comprehensive Stroke Service, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK.
Comprehensive Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK.
Lancet. 2024 Oct 23. doi: 10.1016/S0140-6736(24)02197-4.
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.
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.
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 (p=0·0003). Superiority was not identified (p=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).
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.
British Heart Foundation.
急性缺血性卒中合并心房颤动患者的最佳抗凝时机尚不确定。我们比较了急性缺血性卒中合并心房颤动患者早期与延迟启动直接口服抗凝剂（DOACs）的疗效和安全性。
我们在英国100家医院进行了一项多中心、开放标签、盲终点、平行组、4期随机对照试验。患有心房颤动且临床诊断为急性缺血性卒中，且其医生不确定启动DOAC最佳时机的成年人符合纳入本研究的条件。我们使用独立的在线随机化服务，通过随机排列的区组和不同的区组长度，根据随机分组时的卒中严重程度进行分层，将参与者（1:1）随机分配至早期（即卒中症状发作后≤4天）或延迟（即7 - 14天）启动任何DOAC进行抗凝治疗。参与者和治疗临床医生未对治疗分配进行设盲，但所有结局均由一个设盲的独立外部判定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判定。主要结局是在意向性治疗人群中，90天时复发性缺血性卒中、症状性颅内出血、无法分类的卒中或全身性栓塞发生率的复合指标。我们采用把关人方法，先检验非劣效性界值为2个百分点，然后检验优效性。OPTIMAS在国际标准随机对照试验编号注册库（ISRCTN17896007）和美国国立医学图书馆临床试验注册库（NCT03759938）注册，试验正在进行中。
在2019年7月5日至2024年1月31日期间，3648例患者被随机分配至早期或延迟启动DOAC治疗组。27名参与者不符合纳入标准或撤回同意纳入其数据，在改良意向性分析中留下3621例患者（早期组1814例，延迟组1807例；男性1981例，女性1640例）。早期启动DOAC治疗组的1814例参与者中有59例（3.3%）发生主要结局，而延迟启动DOAC治疗组的1807例参与者中有59例（3.3%）发生主要结局（调整后风险差[RD]0.000，95%置信区间 - 0.011至0.012）。调整后RD的95%置信区间上限小于2个百分点的非劣效性界值（p = 0.0003）。未发现优效性（p = 0.96）。分配至早期启动DOAC治疗组的11例（0.6%）参与者发生症状性颅内出血，而分配至延迟启动DOAC治疗组的12例（0.7%）参与者发生症状性颅内出血（调整后RD 0.001， - 0.004至0.006；p = 0.78）。
对于急性缺血性卒中合并心房颤动患者，在缺血性卒中后4天内早期启动DOAC治疗在90天时缺血性卒中、颅内出血、无法分类卒中或全身性栓塞的复合结局方面不劣于延迟启动治疗。我们的研究结果不支持目前常见的、指南支持的在急性缺血性卒中合并心房颤动后延迟启动DOAC治疗的做法。
英国心脏基金会。
