Department of Radiology, The Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia.
Department of Medicine and Neurology, Melbourne Brain Centre, The Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia.
Lancet. 2022 Jul 9;400(10346):116-125. doi: 10.1016/S0140-6736(22)00564-5.
The benefit of combined treatment with intravenous thrombolysis before endovascular thrombectomy in patients with acute ischaemic stroke caused by large vessel occlusion remains unclear. We hypothesised that the clinical outcomes of patients with stroke with large vessel occlusion treated with direct endovascular thrombectomy within 4·5 h would be non-inferior compared with the outcomes of those treated with standard bridging therapy (intravenous thrombolysis before endovascular thrombectomy).
DIRECT-SAFE was an international, multicentre, prospective, randomised, open-label, blinded-endpoint trial. Adult patients with stroke and large vessel occlusion in the intracranial internal carotid artery, middle cerebral artery (M1 or M2), or basilar artery, confirmed by non-contrast CT and vascular imaging, and who presented within 4·5 h of stroke onset were recruited from 25 acute-care hospitals in Australia, New Zealand, China, and Vietnam. Eligible patients were randomly assigned (1:1) via a web-based, computer-generated randomisation procedure stratified by site of baseline arterial occlusion and by geographic region to direct endovascular thrombectomy or bridging therapy. Patients assigned to bridging therapy received intravenous thrombolytic (alteplase or tenecteplase) as per standard care at each site; endovascular thrombectomy was also per standard of care, using the Trevo device (Stryker Neurovascular, Fremont, CA, USA) as first-line intervention. Personnel assessing outcomes were masked to group allocation; patients and treating physicians were not. The primary efficacy endpoint was functional independence defined as modified Rankin Scale score 0-2 or return to baseline at 90 days, with a non-inferiority margin of -0·1, analysed by intention to treat (including all randomly assigned and consenting patients) and per protocol. The intention-to-treat population was included in the safety analyses. The trial is registered with ClinicalTrials.gov, NCT03494920, and is closed to new participants.
Between June 2, 2018, and July 8, 2021, 295 patients were randomly assigned to direct endovascular thrombectomy (n=148) or bridging therapy (n=147). Functional independence occurred in 80 (55%) of 146 patients in the direct thrombectomy group and 89 (61%) of 147 patients in the bridging therapy group (intention-to-treat risk difference -0·051, two-sided 95% CI -0·160 to 0·059; per-protocol risk difference -0·062, two-sided 95% CI -0·173 to 0·049). Safety outcomes were similar between groups, with symptomatic intracerebral haemorrhage occurring in two (1%) of 146 patients in the direct group and one (1%) of 147 patients in the bridging group (adjusted odds ratio 1·70, 95% CI 0·22-13·04) and death in 22 (15%) of 146 patients in the direct group and 24 (16%) of 147 patients in the bridging group (adjusted odds ratio 0·92, 95% CI 0·46-1·84).
We did not show non-inferiority of direct endovascular thrombectomy compared with bridging therapy. The additional information from our study should inform guidelines to recommend bridging therapy as standard treatment.
Australian National Health and Medical Research Council and Stryker USA.
在急性大血管闭塞性卒中患者中，静脉溶栓联合血管内血栓切除术的获益尚不清楚。我们假设在发病 4.5 小时内接受直接血管内血栓切除术治疗的大血管闭塞性卒中患者的临床结局与接受标准桥接治疗（血管内溶栓后血管内血栓切除术）的患者相比不劣。
DIRECT-SAFE 是一项国际、多中心、前瞻性、随机、开放标签、盲法终点试验。来自澳大利亚、新西兰、中国和越南的 25 家急性护理医院招募了发病 4.5 小时内的颅内颈内动脉、大脑中动脉（M1 或 M2）或基底动脉大血管闭塞的成人卒中患者，通过非对比 CT 和血管成像确认，并进行了随机分组（1:1），采用基于基线动脉闭塞部位和地理区域的在线、计算机生成的随机分组程序，分为直接血管内血栓切除术或桥接治疗组。将桥接治疗组的患者按标准治疗（各中心）分配静脉溶栓（阿替普酶或替奈普酶）；血管内血栓切除术也按标准治疗进行，使用 Trevo 装置（Stryker Neurovascular，美国弗里蒙特）作为一线干预。评估结果的人员对分组情况进行了盲法；患者和治疗医生没有盲法。主要疗效终点为功能独立性定义为改良 Rankin 量表评分 0-2 分或 90 天恢复基线水平，非劣效性边界为 -0.1，采用意向治疗（包括所有随机分配和同意的患者）和按方案进行分析。安全性分析包括意向治疗人群。该试验在 ClinicalTrials.gov 上注册，NCT03494920，现已不再招募新的参与者。
2018 年 6 月 2 日至 2021 年 7 月 8 日，共有 295 名患者被随机分配至直接血管内血栓切除术组（n=148）或桥接治疗组（n=147）。直接血栓切除术组 146 例患者中有 80 例（55%）和桥接治疗组 147 例患者中有 89 例（61%）达到功能独立性（意向治疗风险差异-0.051，双侧 95%CI-0.160 至 0.059；按方案风险差异-0.062，双侧 95%CI-0.173 至 0.049）。两组安全性结局相似，直接组 146 例患者中有 2 例（1%）发生症状性颅内出血，桥接组 147 例患者中有 1 例（1%）发生症状性颅内出血（调整后的比值比 1.70，95%CI 0.22-13.04），直接组 146 例患者中有 22 例（15%）死亡，桥接组 147 例患者中有 24 例（16%）死亡（调整后的比值比 0.92，95%CI 0.46-1.84）。
我们没有显示直接血管内血栓切除术与桥接治疗相比不劣效。我们研究的附加信息应该为指南提供信息，建议将桥接治疗作为标准治疗。
澳大利亚国家卫生和医学研究委员会和美国史赛克公司。
