Safety and Efficacy of Dual Thrombolytic Therapy With Mutant Prourokinase and Small Bolus Alteplase for Ischemic Stroke: A Randomized Clinical Trial.-猫眼课题宝

DOI：

10.1001/jamaneurol.2023.1262

发表时间：

2023-05

期刊：

JAMA neurology

影响因子：

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

N. A. van der Ende;B. Roozenbeek;Lucas Smagge;Sven P. R. Luijten;L. Aerden;Petra Kraayeveld;I. R. van den Wijngaard;G. J. Lycklama à Nijeholt;H. D. den Hertog;H. Flach;A. Postma;S. Roosendaal;G. M. Krietemeijer;Lonneke S. F. Yo;M. D. de Maat;D. Nieboer;G. D. del Zoppo;W. Meurer;Hester F. Lingsma;A. van der Lugt;D. Dippel

重要性小剂量阿替普酶和突变型尿激酶原的双重溶栓治疗可能比单用阿替普酶更安全、更有效，因为突变型尿激酶原仅作用于降解的纤维蛋白，而不影响循环纤维蛋白原。目的与阿替普酶相比，评价双药溶栓治疗急性脑梗死的安全性和有效性。设计、地点和参与者本项对照、开放标签、随机、设盲终点的临床试验于2019年8月10日至2022年3月26日进行，总随访时间为30天。来自荷兰4个卒中中心的缺血性卒中成人患者入组。干预患者随机（1：1）接受静脉推注5 mg阿替普酶和静脉输注40 mg突变型尿激酶原（干预）或常规护理+静脉注射0. 9 mg/kg阿替普酶（对照）。主要结局和测量主要结局是24小时神经影像学检查显示的任何颅内出血（ICH）。次要结局包括30天时的功能结局、症状性ICH和24小时内的纤维蛋白原水平。通过意向治疗进行分析，治疗效果根据基线预后因素进行调整。结果共有268名患者被随机分组，其中238名（中位[IQR]年龄，69 [59-77]岁; 147名[61.8%]男性）提供了延迟同意并被纳入意向治疗人群（干预组121名，对照组117名）。美国国立卫生研究院卒中量表的中位基线评分为3分（IQR，2-5分）。干预组121例患者中有16例（13.2%）发生任何ICH，对照组117例患者中有16例（13.7%）发生任何ICH（校正比值比，0.98; 95%CI，0.46-2.12）。突变尿激酶原导致改良兰金量表评分向更好的方向变化，但无显著性意义（校正后的共同比值比为1.16; 95%CI为0.74-1.84）。干预组无一例发生症状性ICH，对照组117例患者中有3例（2.6%）发生症状性ICH。干预组1小时的血浆纤维蛋白原水平保持恒定，但对照组降低（β = 65 mg/dL; 95% CI，26-105 mg/dL）。结论和相关性在本试验中，小剂量阿替普酶和突变型尿激酶原双重溶栓治疗是安全的，不会导致纤维蛋白原耗竭。需要在更大规模的试验中进一步评价突变型尿激酶原溶栓治疗以改善较大面积缺血性卒中患者的结局。总体而言，在符合静脉溶栓治疗适应症但不适合接受血管内治疗的轻度缺血性卒中患者中，静脉内突变尿激酶原双联溶栓治疗并不上级静脉内阿替普酶单药治疗。试用注册ClinicalTrials.gov标识符：NCT 04256473。

Importance Dual thrombolytic treatment with small bolus alteplase and mutant prourokinase has the potential to be a safer and more efficacious treatment for ischemic stroke than alteplase alone because mutant prourokinase is designed to act only on degraded fibrin without affecting circulating fibrinogen. Objective To assess the safety and efficacy of this dual thrombolytic treatment compared with alteplase. Design, Setting, and Participants This controlled, open-label randomized clinical trial with a blinded end point was conducted from August 10, 2019, to March 26, 2022, with a total follow-up of 30 days. Adult patients with ischemic stroke from 4 stroke centers in the Netherlands were enrolled. Interventions Patients were randomized (1:1) to receive a bolus of 5 mg of intravenous alteplase and 40 mg of an intravenous infusion of mutant prourokinase (intervention) or usual care with 0.9 mg/kg of intravenous alteplase (control). Main Outcomes and Measures The primary outcome was any intracranial hemorrhage (ICH) on neuroimaging at 24 hours. Secondary outcomes included functional outcome at 30 days, symptomatic ICH, and fibrinogen levels within 24 hours. Analyses were by intention to treat. Treatment effects were adjusted for baseline prognostic factors. Results A total of 268 patients were randomized, and 238 (median [IQR] age, 69 [59-77] years; 147 [61.8%] male) provided deferred consent and were included in the intention-to-treat population (121 in the intervention group and 117 in the control group). The median baseline score on the National Institutes of Health Stroke Scale was 3 (IQR, 2-5). Any ICH occurred in 16 of 121 patients (13.2%) in the intervention group and 16 of 117 patients (13.7%) in the control group (adjusted odds ratio, 0.98; 95% CI, 0.46-2.12). Mutant prourokinase led to a nonsignificant shift toward better modified Rankin Scale scores (adjusted common odds ratio, 1.16; 95% CI, 0.74-1.84). Symptomatic ICH occurred in none of the patients in the intervention group and 3 of 117 patients (2.6%) in the control group. Plasma fibrinogen levels at 1 hour remained constant in the intervention group but decreased in the control group (β = 65 mg/dL; 95% CI, 26-105 mg/dL). Conclusions and Relevance In this trial, dual thrombolytic treatment with small bolus alteplase and mutant prourokinase was found to be safe and did not result in fibrinogen depletion. Further evaluation of thrombolytic treatment with mutant prourokinase in larger trials to improve outcomes in patients with larger ischemic strokes is needed. Overall, in patients with minor ischemic stroke who met indications for treatment with intravenous thrombolytics but were not eligible for treatment with endovascular therapy, dual thrombolytic therapy with intravenous mutant prourokinase was not superior to treatment with intravenous alteplase alone. Trial Registration ClinicalTrials.gov Identifier: NCT04256473.

Safety and Efficacy of Dual Thrombolytic Therapy With Mutant Prourokinase and Small Bolus Alteplase for Ischemic Stroke: A Randomized Clinical Trial.

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