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Effect of Argatroban + Alteplase vs. Alteplase After Acute Ischemic Stroke
Quick Takes
- Treatment with argatroban plus IV alteplase compared with alteplase alone did not result in a significantly greater likelihood of excellent functional outcome at 90 days.
- There was no evidence of effect modification of prespecified subgroups on the treatment effect on the primary endpoint.
- The finding that no harmful profile of argatroban was observed in patients who received IV alteplase suggests the possible safety and feasibility of anticoagulants immediately after thrombolysis.
Study Questions:
What is the efficacy of argatroban plus alteplase versus alteplase alone for acute ischemic stroke (AIS)?
Methods:
The ARAIS (Argatroban Plus Recombinant Tissue-Type Plasminogen Activator for AIS) trial investigators conducted a multicenter, open-label, blinded endpoint randomized clinical trial including 808 patients with AIS at 50 hospitals in China with enrollment from January 18, 2019, through October 30, 2021, and final follow-up on January 24, 2022. Eligible patients were randomly assigned within 4.5 hours of symptom onset to the argatroban plus alteplase group (n = 402), which received intravenous (IV) argatroban (100 μg/kg bolus over 3-5 minutes followed by an infusion of 1.0 μg/kg/min 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 IV alteplase alone. Both groups received guideline-based treatments. The primary endpoint was excellent functional outcome, defined as a modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) of 0 to 1 at 90 days. All endpoints 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 [NIHSS] 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 versus 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 = 0.78). 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. The primary analyses of the primary and secondary outcomes were unadjusted. Covariate-adjusted generalized linear model analyses were also performed for all outcomes, adjusting for six prespecified prognostic factors: age, sex, NIHSS score at randomization, time from symptom onset to thrombolysis, premorbid function (mRS score of 0 or 1), and history of stroke or transient ischemic attack.
Conclusions:
The authors report that among patients with acute ischemic stroke, treatment with argatroban plus IV alteplase compared with alteplase alone did not result in a significantly greater likelihood of excellent functional outcome at 90 days.
Perspective:
This study reports that treatment with argatroban plus IV alteplase compared with alteplase alone did not result in a significantly greater likelihood of excellent functional outcome at 90 days or identify a signal of harm among patients with AIS. Furthermore, there was no evidence of effect modification of prespecified subgroups on the treatment effect on the primary endpoint. Despite the neutral results of this trial, the finding that no harmful profile of argatroban was observed in patients who received IV alteplase suggests the possible safety and feasibility of anticoagulants immediately after thrombolysis, which is prohibited by current guidelines.
Clinical Topics: Anticoagulation Management, Dyslipidemia, Prevention, Vascular Medicine, Lipid Metabolism
Keywords: Anticoagulants, Cerebral Hemorrhage, Functional Status, Hematoma, Hemorrhage, Ischemic Attack, Transient, Ischemic Stroke, Secondary Prevention, Stroke, Thrombolytic Therapy, Tissue Plasminogen Activator, Treatment Outcome, Vascular Diseases
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