大血管闭塞性卒中再灌注成功后动脉内Tenecteplase

IF 20.4 1区医学 Q1 CLINICAL NEUROLOGY

JAMA neurology Pub Date : 2025-07-05 DOI:10.1001/jamaneurol.2025.2036

Xianhua Hou, Jiacheng Huang, Li Wang, Yuxuan He, Jiaxing Song, Changwei Guo, Shihai Yang, Xiaolei Shi, Lin Chen, Qu Liu, Junfeng Su, Lin Zeng, Maojun Jiang, Boyu Chen, Xiangping Cheng, Shengli Chen, Honghua Pan, Xiaoping Shen, Youlin Wu, Xionglin Tang, Jian Wang, Shibo Han, Tianqiang Pu, Changchuan Wu, Fengguang Li, Lunxue Qu, Zhong Fu, Hua Liu, Yu Li, Bin Mei, Yanbo Cheng, Zicheng Hu, Haochun Zhang, Tao Lv, Min Wu, Ruchuang Xu, Qinglin Ye, Liangbo Kong, Shuai Mi, Junhua Wu, Yu Wang, Zhenxuan Tian, Wenzhe Sun, Jinfu Ma, Xu Xu, Yazhou Wu, Duolao Wang, Raul G. Nogueira, Thanh N. Nguyen, Jeffrey L. Saver, Wenjie Zi, Zhenhua Zhou

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引用次数: 0

摘要

对于大血管闭塞（LVO），在血管内取栓成功再灌注后，动脉内应用tenecteplase的最佳剂量、安全性和有效性尚不清楚。目的评价血栓切除术后再灌注成功的左左心室动脉内注射tenecteplase的剂量依赖性不良事件和疗效信号，以延长脑梗死治疗评分为2b-3。设计、环境和参与者这项开放标签、盲法结局评估试验，采用14 + 8剂量递增（1b期，非随机）和剂量扩大（2a期，随机）设计，于2023年至2024年在中国进行，随访持续到2024年11月。这是一项多中心临床试验，包括LVO患者，并在最后已知的24小时内成功再灌注。干预1b期，动脉内注射tenecteplase， 0.0313、0.0625、0.1250、0.1875 mg/kg；在2a期，动脉内使用tenecteplase 0.0313或0.0625 mg/kg，或对照（无动脉内溶栓）。1b期的主要终点是24小时内出现症状性颅内出血（siich）。2a期的主要结局是90天无残疾结局（修正Rankin量表评分0-1）。结果共纳入205例患者（1b期48例，2a期157例）。中位（IQR）年龄为71岁（60-77岁），男性113例（55.1%）。在1b期，14名sICH患者中有1名和22名sICH患者中有2名分别以0.0313和0.0625 mg/kg剂量进行观察。剂量等级为0.1250 mg/kg时，12例患者中有3例发生sICH，超过了预先规定的安全阈值（P = 0.04）。在2a期，符合条件的患者被随机分配接受tenecteplase， 0.0313 mg/kg （n = 46）和0.0625 mg/kg (n = 46)， 65例患者为对照组。对照组65例患者中有22例（33.8%）出现主要结局，替内替普酶0.0313 mg/kg组46例患者中有17例（37.0%）出现主要结局(校正风险比[RR] vs对照组，0.85；95% ci, 0.54-1.35；P = 0.50)， 0.0625 mg/kg替奈替普酶组46例患者中有20例（43.5%）(调整后RR为1.15；95% ci, 0.73-1.80；P = 0.55)。三组间安全性结果无显著差异。结论和相关性这项1期和2期随机临床试验的结果显示，在前循环LVO患者成功再灌注后，辅助动脉内注射tenecteplase剂量为0.0313 mg/kg或0.0625 mg/kg具有足够的安全性，可以进行更大规模的试验以确定潜在的治疗益处。试验注册号：ChiCTR2300073787和ChiCTR2400080624

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Intra-Arterial Tenecteplase After Successful Reperfusion in Large Vessel Occlusion Stroke

ImportanceThe optimal dose, safety, and efficacy of intra-arterial tenecteplase after successful reperfusion by endovascular thrombectomy for large vessel occlusion (LVO) is unknown.ObjectiveTo evaluate the dose-dependent adverse events and signals of efficacy of intra-arterial tenecteplase in LVO after successful reperfusion with thrombectomy, defined as an Extended Treatment in Cerebral Infarction score of 2b-3.Design, Setting, and ParticipantsThis open-label, blinded-outcome assessment trial, incorporating a 14 + 8 dose-escalation (phase 1b, nonrandomized) and dose-expansion (phase 2a, randomized) design, was conducted in China between 2023 and 2024, with follow-up continuing through November 2024. This was a multicenter clinical trial including patients with LVO and successful reperfusion within 24 hours of last known well.InterventionsIn phase 1b, intra-arterial tenecteplase, 0.0313, 0.0625, 0.1250, 0.1875 mg/kg; in phase 2a, intra-arterial tenecteplase 0.0313 or 0.0625 mg/kg, or control (without intra-arterial thrombolysis).Main Outcomes and MeasuresThe primary outcome in phase 1b was symptomatic intracranial hemorrhage (sICH) within 24 hours. The primary outcome in phase 2a was 90-day no-disability outcome (modified Rankin Scale score 0-1).ResultsA total of 205 patients (phase 1b: 48, phase 2a: 157) were enrolled and analyzed. The median (IQR) age was 71 (60-77) years, and 113 (55.1%) were male. In phase 1b, 1 of 14 and 2 of 22 patients with sICH were observed at dose tiers 0.0313 and 0.0625 mg/kg, respectively. Three of 12 patients had sICH at dose tier 0.1250 mg/kg, exceeding the prespecified safety threshold (P = .04). In phase 2a, eligible patients were randomly assigned to receive tenecteplase, 0.0313 mg/kg (n = 46) and 0.0625 mg/kg (n = 46), and 65 patients composed the control group. The primary outcome occurred in 22 of 65 patients (33.8%) in the control group, 17 of 46 patients (37.0%) in the tenecteplase, 0.0313 mg/kg, group (adjusted risk ratio [RR] vs control, 0.85; 95% CI, 0.54-1.35; P = .50), and 20 of 46 patients (43.5%) in the tenecteplase, 0.0625 mg/kg, group (adjusted RR, 1.15; 95% CI, 0.73-1.80; P = .55). No significant difference in the safety outcomes was observed among the 3 groups.Conclusions and RelevanceResults of this phase 1 and 2 randomized clinical trial reveal that adjunctive intra-arterial tenecteplase dosages of 0.0313 mg/kg or 0.0625 mg/kg after successful reperfusion in patients with anterior circulation LVO showed adequate safety to advance to larger trials to determine the potential therapeutic benefits.Trial RegistrationChiCTR.org.cn Identifier: ChiCTR2300073787 and ChiCTR2400080624

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来源期刊

JAMA neurology CLINICAL NEUROLOGY-

CiteScore

41.90

自引率

1.70%

发文量

250

期刊介绍： JAMA Neurology is an international peer-reviewed journal for physicians caring for people with neurologic disorders and those interested in the structure and function of the normal and diseased nervous system. The Archives of Neurology & Psychiatry began publication in 1919 and, in 1959, became 2 separate journals: Archives of Neurology and Archives of General Psychiatry. In 2013, their names changed to JAMA Neurology and JAMA Psychiatry, respectively. JAMA Neurology is a member of the JAMA Network, a consortium of peer-reviewed, general medical and specialty publications.