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

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.

Figure 1.. Patient Flow in the ARAIS Randomized Clinical Trial

^aA total of 383 patients in the argatroban plus alteplase group and 397 patients in the alteplase group were included in the safety population. ^bPatients lost to follow-up due to missing any follow-up assessments after treatment. ^cBaseline characteristics in patients missing primary outcome data are shown in eTable 4 in Supplement 3.

Figure 2.. Distribution of Modified Rankin Scale Scores at 90 Days in the Full Analysis Set

A total of 760 patients were included in the full analysis set; however, 696 patients (329 in the argatroban plus alteplase group and 367 in the alteplase alone group) with 90-day follow-up data were included in the analysis of the primary outcome. The raw distribution of scores is shown. Scores ranged from 0 to 6, with 0 indicating no symptoms; 1, symptoms without clinically significant disability; 2, slight disability; 3, moderate disability; 4, moderately severe disability; 5, severe disability; and 6, death. Treatment with argatroban plus alteplase was associated with an adjusted risk difference of −1.0% (95% CI, −7.6% to 5.7%; P = .78) for the outcome of a score of 0 or 1 on the modified Rankin Scale at 90 days. The overall distribution of scores was not statistically significant in the ordinal logistic analysis (odds ratio, 1.06 [95% CI, 0.81-1.39]; P = .66; adjusted odds ratio, 1.01 [95% CI, 0.58-1.76]; P = .98).