Effect of Argatroban Plus Intravenous Alteplase vs Intravenous Alteplase Alone on Neurologic Function in Patients With Acute Ischemic Stroke
Authors: Chen Hui-Sheng , Cui Yu , Zhou Zhong-He , Dai Ying-Jie , Li Gao-Hua , Peng Zhao-Long , Zhang Yi , Liu Xiao-Dong , Yuan Zhi-Mei , Jiang Chang-Hao , Yang Qing-Cheng , Duan Ying-Jie , Ma Guang-Bin , Zhao Li-Wei , Wang Rui-Xian , Sun Yuan-Lin , Shen Lei , Wang Er-Qiang , Wang Li-Hua , Feng Ye-Fang , Wang Feng-Yun , Zou Ren-Lin , Yang He-Ping , Wang Kai , Wang Duo-Lao , Wang Yi-Long ,   ARAIS Investigators, Liu Xue-Wen , Chen Zi-Long , Yu Ming-Zhe , Huang Shu-Man , Wang Lian-Qiang , Geng Shi-Mei , Chen Shi-Huo , Wang Wei-Zhong , Zou Ming , Hu Ling-Ling , Wang Dan , Zhang Shi-Yong , Zhang Zai-Hui , Jiang Zhao , Wang Li-Yun , Wu Su-Fang , Li Run-Hui , Wang Yong-Sheng , Yu Min , Liu Li , Yang Kui-Hua , Li Hui , Wang Hai-Jun , Wang Jun-Hai , Zhu Run-Xiu , Wen Guo-Qiang , Cao Yong-Jun , Zhou Qi-Da , Yang Wen-Hai 
Published: February 2023

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.

Trial Registration

ClinicalTrials.gov Identifier: NCT03740958