北京天坛医院王伊龙教授团队比较了阿加曲班联合静脉注射阿替普酶与单独静脉注射阿替普酶对急性缺血性卒中患者神经功能的影响。该研究于2023年2月9日发表在《美国医学会杂志》上。

既往研究表明阿加曲班联合阿替普酶（重组组织型纤溶酶原激活剂）对急性缺血性卒中（AIS）患者有益处。然而，在大样本量的试验中缺乏有力的证据。

为了评价阿加曲班联合阿替普酶治疗AIS的疗效，研究组在中国50家医院进行了一项多中心、开放标签、盲法终点的随机临床试验，纳入808名AIS患者，入组时间为2019年1月18日至2021年10月30日，最终随访时间为2022年1月24日。

符合条件的患者在症状出现后4.5小时内随机分为阿加曲班+阿替普酶组（n = 402），其在阿替普酶（0.9 mg/kg；最大剂量，90 mg；10%作为1分钟推注给药，持续1小时）后1小时内接受静脉阿曲他班（100 μg/kg推注，持续3-5分钟，随后每分钟输注1.0 μg/kg，持续48小时），或仅阿替普蛋白酶组（n = 415），其单独静脉注射阿替普酶。两组均接受基于指南的治疗。主要终点为良好的功能结局，定义为90天的改良Rankin量表评分（范围0[无症状]至6[死亡]）为0至1。所有终点均采用盲法评估，并在完整的分析集上进行分析。

817名符合条件的AIS患者随机分组（中位IQR年龄为65岁；238名（29.1%）为女性；中位美国国立卫生研究院卒中量表评分为9分），760例（93.0%）完成试验。90天时，阿加曲班联合阿替普酶组329名参与者中有210名（63.8%），而阿替普酶单独组367名参与者中有238名（64.9%）具有良好的功能结局，风险差为-1.0%。阿加曲班加阿替普酶组出现症状性颅内出血、实质血肿2型和全身大出血的比例分别为2.1%（8/383）、2.3%（9/383）和0.3%（1/383），阿替普酶单独组分别为1.8%（7/397）、2.5%（10/397）和0.5%（2/397）。

研究结果表明，在急性缺血性脑卒中患者中，阿加曲班联合静脉注射阿替普酶与单独阿替普酶相比，在90天内没有显著改善患者的神经功能预后。

附：英文原文

Title: Effect of Argatroban Plus Intravenous Alteplase vs Intravenous Alteplase Alone on Neurologic Function in Patients With Acute Ischemic Stroke: The ARAIS Randomized Clinical Trial

Author: Hui-Sheng Chen, Yu Cui, Zhong-He Zhou, Ying-Jie Dai, Gao-Hua Li, Zhao-Long Peng, Yi Zhang, Xiao-Dong Liu, Zhi-Mei Yuan, Chang-Hao Jiang, Qing-Cheng Yang, Ying-Jie Duan, Guang-Bin Ma, Li-Wei Zhao, Rui-Xian Wang, Yuan-Lin Sun, Lei Shen, Er-Qiang Wang, Li-Hua Wang, Ye-Fang Feng, Feng-Yun Wang, Ren-Lin Zou, He-Ping Yang, Kai Wang, Duo-Lao Wang, Yi-Long Wang, ARAIS Investigators, Xue-Wen Liu, Zi-Long Chen, Ming-Zhe Yu, Shu-Man Huang, Lian-Qiang Wang, Shi-Mei Geng, Shi-Huo Chen, Wei-Zhong Wang, Ming Zou, Ling-Ling Hu, Dan Wang, Shi-Yong Zhang, Zai-Hui Zhang, Zhao Jiang, Li-Yun Wang, Su-Fang Wu, Run-Hui Li, Yong-Sheng Wang, Min Yu, Li Liu, Kui-Hua Yang, Hui Li, Hai-Jun Wang, Jun-Hai Wang, Run-Xiu Zhu, Guo-Qiang Wen, Yong-Jun Cao, Qi-Da Zhou, Wen-Hai Yang

Issue&Volume: 2023-02-09

Abstract:

Importance  Previous studies suggested a benefit of argatroban plus alteplase (recombinant tissue-type plasminogen activator) in patients with acute ischemic stroke (AIS). However, robust evidence in trials with large sample sizes is lacking.

Objective  To assess the efficacy of argatroban plus alteplase for AIS.

Design, Setting, and Participants  This multicenter, open-label, blinded end point randomized clinical trial including 808 patients with AIS was conducted at 50 hospitals in China with enrollment from January 18, 2019, through October 30, 2021, and final follow-up on January 24, 2022.

Interventions  Eligible patients were randomly assigned within 4.5 hours of symptom onset to the argatroban plus alteplase group (n=402), which received intravenous argatroban (100 μg/kg bolus over 3-5 minutes followed by an infusion of 1.0 μg/kg per minute for 48 hours) within 1 hour after alteplase (0.9 mg/kg; maximum dose, 90 mg; 10% administered as 1-minute bolus, remaining infused over 1 hour), or alteplase alone group (n=415), which received intravenous alteplase alone. Both groups received guideline-based treatments.

Main Outcomes and Measures  The primary end point was excellent functional outcome, defined as a modified Rankin Scale score (range, 0 [no symptoms] to 6 [death]) of 0 to 1 at 90 days. All end points had blinded assessment and were analyzed on a full analysis set.

Results  Among 817 eligible patients with AIS who were randomized (median [IQR] age, 65 [57-71] years; 238 [29.1%] women; median [IQR] National Institutes of Health Stroke Scale score, 9 [7-12]), 760 (93.0%) completed the trial. At 90 days, 210 of 329 participants (63.8%) in the argatroban plus alteplase group vs 238 of 367 (64.9%) in the alteplase alone group had an excellent functional outcome (risk difference, 1.0% [95% CI, 8.1% to 6.1%]; risk ratio, 0.98 [95% CI, 0.88-1.10]; P=.78). The percentages of participants with symptomatic intracranial hemorrhage, parenchymal hematoma type 2, and major systemic bleeding were 2.1% (8/383), 2.3% (9/383), and 0.3% (1/383), respectively, in the argatroban plus alteplase group and 1.8% (7/397), 2.5% (10/397), and 0.5% (2/397), respectively, in the alteplase alone group.

Conclusions and Relevance  Among patients with acute ischemic stroke, treatment with argatroban plus intravenous alteplase compared with alteplase alone did not result in a significantly greater likelihood of excellent functional outcome at 90 days.

DOI: 10.1001/jama.2023.0550

Source: https://jamanetwork.com/journals/jama/fullarticle/2801517