Argatroban plus intravenous (IV) alteplase compared with IV alteplase alone did not significantly increase functional outcome at 90 days in patients with acute ischemic stroke (AIS), according to study findings published in the Journal of the American Medical Association.
The selective thrombin inhibitor, argatroban, has been used widely for the treatment of AIS, especially in Asian countries. The agent directly inhibits free and clot-related thrombin, as well as thrombin-generated events. Although treatment with argatroban plus the recombinant tissue-type plasminogen activator alteplase has been assessed in several early-phase trials, strong evidence evaluating this combination therapy in trials with large sample sizes is scant.
The multicenter, open-label, randomized, blinded endpoint study, Argatroban Plus Recombinant Tissue-Type Plasminogen for AIS (ARAIS; ClinicalTrials.gov Identifier: NCT03740958) was conducted at 50 medical sites in China between January 18, 2019, and October 30, 2021. The final follow-up visit occurred on January 24, 2022. The researchers sought to evaluate the efficacy of argatroban plus alteplase within
4.5 hours of symptom onset in patients with AIS.
The primary study endpoint was excellent functional outcome at 90 days, which was defined as a score of 0 to 1 on the modified Rankin Scale (mRS) for assessment of neurologic disability.
Secondary study endpoints included the following:
- Favorable functional outcome (ie, mRS score of 0 to 2) at 90 days
- Occurrence of early neurologic improvement, compared with baseline, at
48 hours (ie, a decrease in National Institutes of Health Stroke Scale [NIHSS] score of ≥2)
- Occurrence of early neurologic deterioration, compared with baseline, at
48 hours (ie, an increase in NIHSS score of ≥4)
- Change in NIHSS score, compared with baseline, at 14 days
- Occurrence of stroke or other vascular events (ie, transient ischemic attack, myocardial infarction, and vascular death) within 90 days
A total of 817 patients were randomly assigned to treatment — 402 individuals in the
argatroban plus alteplase arm and 415 in the alteplase alone arm. The median participant age was 65 years (range, 57-71 years). In all, 29.1% (238 of 817) of the patients were women. The median NIHSS score was 9 (range, 7-12). Following patient withdrawals and exclusions, the full analysis set population completing the study comprised 760 participants — 364 in the argatroban plus alteplase group and 396 in the alteplase alone group.
At 90 days, 63.8% (210 of 329) of the participants in the argatroban plus alteplase arm compared with 64.9% (238 of 367) of those in the alteplase-alone arm experienced an excellent functional outcome (unadjusted risk difference [RD], –1.0% [95% CI, –8.1% to 6.1%]; risk ratio [RR], 0.98 [95% CI, 0.88-1.10]; P =.78) — a difference that was not statistically significant.
Following adjustment for prespecified prognostic variables, the results remained nonsignificant (RD, –1.0% [95% CI, –7.6%-5.7%]; RR, 1.03 [95% CI, 0.86-1.23]; P =.78). Similar results were demonstrated for the per-protocol analysis (unadjusted RD, –0.3% [95% CI, –7.4%-6.9%]; RR, 1.00 [95% CI, 0.89-1.11]; P =.95; adjusted RD, –0.4% [95% CI, –7.0%-6.3%]; RR, 0.98 [95% CI, 0.89-1.08]; P =.65).
In both the adjusted and unadjusted analyses, no differences were observed in the secondary outcomes. In the per-protocol analysis, there were similar results reported in both the adjusted and unadjusted analyses. A post hoc regression analysis revealed no significant differences in improvement in mRS score at 90 days (P =.94).
The prespecified adverse event (AE) outcomes included symptomatic intracranial hemorrhage (ICH), parenchymal hematoma type 2, and major systemic bleeding that occurred during the study. Similar rates of AEs were reported across the 2 treatment arms, including ICH, major bleeding events, and other bleeding events.
Among the limitations of the analysis is that more patients from the argatroban plus alteplase group compared with the alteplase-alone group withdrew from the study because of less willingness on the part of the former group to adhere to the study protocol. Additionally, because of the open-label design of the study, the assigned treatment group was not concealed from the patients or from the physicians.
Overall, the findings suggest that treatment with argatroban was not associated with better neurologic function in patients with AIS.
The researchers concluded that “Despite the neutral results in this trial, the finding that no harmful profile of argatroban was observed in patients who received intravenous alteplase suggests the possible safety and feasibility of anticoagulants immediately after thrombolysis, which was prohibited by the current guidelines.”
Chen H-S, Cui Y, Zhou Z-H, et al; ARAIS Investigators. Effect of argatroban plus intravenous alteplase vs intravenous alteplase alone on neurologic function in patients with acute ischemic stroke: the ARAIS randomized clinical trial. JAMA. Published online February 9, 2023. doi:10.1001/jama.2023.0550