Original Investigation 

February 9, 2023

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

Hui-Sheng Chen, Yu Cui, Zhong-He Zhou, et al

JAMA. Published online February 9, 2023. doi:10.1001/jama.2023.0550

Key Points

Question  Does argatroban improve neurologic function in patients with acute ischemic stroke who received intravenous recombinant tissue-type plasminogen activator (alteplase)?

Findings  In this randomized clinical trial that included 808 patients with acute ischemic stroke, excellent neurologic function at 90 days (modified Rankin Scale score of 0 to 1) in those randomized to receive argatroban plus intravenous alteplase compared with intravenous alteplase alone occurred in 63.8% vs 64.9% of participants, a difference that was not statistically significant.

Meaning  Among patients with acute ischemic stroke who received intravenous alteplase, argatroban was not significantly associated with better neurologic function.

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.

Trial Registration  ClinicalTrials.gov Identifier: NCT03740958