Zhou Ying, He Yaode, Campbell Bruce C V, Liebeskind David S, Yuan Changzheng, Chen Hui, Zhang Yanxing, Yi Tingyu, Luo Zhongyu, Zhang Zuowen, Meng Changcai, Cheng Jianhua, Ouyang Hezhong, Hu Jin, Wang Fei, Zhang Sheng, Fang Qi, Hu Haitao, Zhang Xuting, Chen Yi, Zhong Wansi, Lansberg Maarten G, Yan Shenqiang, Lou Min
Department of Neurology, the Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China.
State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China.
JAMA. 2025 Aug 7. doi: 10.1001/jama.2025.12063.
The safety and efficacy of intravenous thrombolytics beyond 4.5 hours after ischemic stroke onset remain inadequately studied.
To evaluate the safety and efficacy of intravenous alteplase administered 4.5 to 24 hours after stroke onset in patients with salvageable brain tissue, regardless of the presence of large vessel occlusion.
DESIGN, SETTING, AND PARTICIPANTS: This randomized, open-label, blinded end-point trial was conducted at 26 stroke centers across China. A total of 372 patients with acute ischemic stroke and salvageable brain tissue identified by perfusion imaging were enrolled between June 21, 2021, and June 30, 2024 (final follow-up October 2, 2024). Eligibility criteria included stroke onset (or the midpoint between last known well and symptom recognition if onset was unknown) of 4.5 to 24 hours prior to presentation, and no initial plan for endovascular thrombectomy. Data were analyzed from December 2024 to February 2025.
Patients were randomly assigned (1:1) using a minimization algorithm to receive intravenous alteplase (0.9 mg/kg; maximum dose, 90 mg; n = 186) or standard medical treatment (n = 186).
The primary efficacy outcome was functional independence, defined as a modified Rankin Scale score of 0 to 1 at 90 days. Safety outcomes included symptomatic intracranial hemorrhage within 36 hours and all-cause mortality within 90 days.
Among 372 patients who were enrolled (median [IQR] age, 72 [64-80] years; 160 [43%] women), all completed the trial. The primary outcome occurred in 75 of 186 patients (40%) in the alteplase group and 49 of 186 (26%) in the control group (adjusted risk ratio, 1.52 [95% CI, 1.14-2.02]; P = .004; unadjusted risk difference, 13.98% [95% CI, 4.50%-23.45%]). The incidence of symptomatic intracranial hemorrhage was higher with alteplase at 3.8% compared with 0.51% with standard treatment (adjusted risk ratio, 7.34 [95% CI, 1.54-34.84]; P = .01; unadjusted risk difference, 3.23% [0.28%-6.19%]), and mortality was 11% in both groups (adjusted risk ratio, 0.91 [95% CI, 0.52-1.62]; P = .76; unadjusted risk difference, 0% [95% CI, -6.30% to 6.30%]).
In patients with acute ischemic stroke with salvageable brain tissue identified by perfusion imaging who did not initially receive thrombectomy, intravenous alteplase administered 4.5 to 24 hours after onset provided functional benefit, despite an increase in symptomatic intracranial hemorrhage.
ClinicalTrials.gov Identifier: NCT04879615.
缺血性卒中发病4.5小时后静脉溶栓的安全性和有效性仍研究不足。
评估在有可挽救脑组织的患者中，卒中发病4.5至24小时后静脉注射阿替普酶的安全性和有效性，无论是否存在大血管闭塞。
设计、地点和参与者：这项随机、开放标签、盲法终点试验在中国的26个卒中中心进行。2021年6月21日至2024年6月30日（最终随访时间为2024年10月2日）共纳入372例经灌注成像确定为急性缺血性卒中和有可挽救脑组织的患者。纳入标准包括就诊前卒中发病（或若发病时间未知则为最后一次已知健康状态与症状识别之间的中点）4.5至24小时，且无初始血管内血栓切除术计划。2024年12月至2025年2月对数据进行分析。
采用最小化算法将患者随机分组（1:1），分别接受静脉注射阿替普酶（0.9mg/kg；最大剂量90mg；n = 186）或标准药物治疗（n = 186）。
主要疗效结局为功能独立性，定义为90天时改良Rankin量表评分为0至1分。安全性结局包括36小时内症状性颅内出血和90天内全因死亡率。
在纳入的372例患者中（中位[四分位间距]年龄，72[64 - 80]岁；160例[43%]为女性），所有患者均完成试验。阿替普酶组186例患者中有75例（40%）达到主要结局，对照组186例中有49例（26%）（调整后风险比，1.52[95%置信区间，1.14 - 2.02]；P = 0.004；未调整风险差异，13.98%[95%置信区间，4.50% - 23.45%]）。阿替普酶治疗组症状性颅内出血发生率为3.8%，高于标准治疗组的0.51%（调整后风险比，7.34[95%置信区间，1.54 - 34.84]；P = 0.01；未调整风险差异，3.23%[0.28% - 6.19%]），两组死亡率均为11%（调整后风险比，0.91[95%置信区间，0.52 - 1.62]；P = 0.76；未调整风险差异，0%[95%置信区间， - 6.30%至6.30%]）。
在经灌注成像确定有可挽救脑组织且最初未接受血栓切除术的急性缺血性卒中患者中，发病4.5至24小时后静脉注射阿替普酶可带来功能获益，尽管症状性颅内出血有所增加。
ClinicalTrials.gov标识符：NCT04879615
