Effect of Intra-arterial Alteplase vs Placebo Following Successful Thrombectomy on Functional Outcomes in Patients With Large Vessel Occlusion Acute Ischemic Stroke: The CHOICE Randomized Clinical Trial

Abstract

Importance: It is estimated that only 27% of patients with acute ischemic stroke and large vessel occlusion who undergo successful reperfusion after mechanical thrombectomy are disability free at 90 days. An incomplete microcirculatory reperfusion might contribute to these suboptimal clinical benefits.

Objective: To investigate whether treatment with adjunct intra-arterial alteplase after thrombectomy improves outcomes following reperfusion.

Design, setting, and participants: Phase 2b randomized, double-blind, placebo-controlled trial performed from December 2018 through May 2021 in 7 stroke centers in Catalonia, Spain. The study included 121 patients with large vessel occlusion acute ischemic stroke treated with thrombectomy within 24 hours after stroke onset and with an expanded Treatment in Cerebral Ischemia angiographic score of 2b50 to 3.

Interventions: Participants were randomized to receive intra-arterial alteplase (0.225 mg/kg; maximum dose, 22.5 mg) infused over 15 to 30 minutes (n = 61) or placebo (n = 52).

Main outcomes and measures: The primary outcome was the difference in proportion of patients achieving a score of 0 or 1 on the 90-day modified Rankin Scale (range, 0 [no symptoms] to 6 [death]) in all patients treated as randomized. Safety outcomes included rate of symptomatic intracranial hemorrhage and death.

Results: The study was terminated early for inability to maintain placebo availability and enrollment rate because of the COVID-19 pandemic. Of 1825 patients with acute ischemic stroke treated with thrombectomy at the 7 study sites, 748 (41%) patients fulfilled the angiographic criteria, 121 (7%) patients were randomized (mean age, 70.6 [SD, 13.7] years; 57 women [47%]), and 113 (6%) were treated as randomized. The proportion of participants with a modified Rankin Scale score of 0 or 1 at 90 days was 59.0% (36/61) with alteplase and 40.4% (21/52) with placebo (adjusted risk difference, 18.4%; 95% CI, 0.3%-36.4%; P = .047). The proportion of patients with symptomatic intracranial hemorrhage within 24 hours was 0% with alteplase and 3.8% with placebo (risk difference, -3.8%; 95% CI, -13.2% to 2.5%). Ninety-day mortality was 8% with alteplase and 15% with placebo (risk difference, -7.2%; 95% CI, -19.2% to 4.8%).

Conclusions and relevance: Among patients with large vessel occlusion acute ischemic stroke and successful reperfusion following thrombectomy, the use of adjunct intra-arterial alteplase compared with placebo resulted in a greater likelihood of excellent neurological outcome at 90 days. However, because of study limitations, these findings should be interpreted as preliminary and require replication.

Trial registration: ClinicalTrials.gov Identifier: NCT03876119; EudraCT Number: 2018-002195-40.

Figure 1.. Flow of Patients Through the CHOICE Trial

ASPECTS indicates Alberta Stroke Program Early CT Score; mTICI, modified Treatment in Cerebral Ischemia; NIHSS, National Institutes of Health Stroke Scale. ^aPatients could have more than 1 exclusion. ^bMisplacement of balloon-guided catheter. ^cExcluded to limit exposure of the interventionalist team.

Figure 2.. Distribution of Functional Scores at 90 Days in the CHOICE Trial of Intra-arterial Alteplase

Scores on the modified Rankin Scale for patients in the intra-arterial alteplase group (n = 61) and the placebo group (n = 52) who were evaluated by local investigators via face-to-face interview. Scores range from 0 to 6, with 0 indicating no symptoms; 1, no clinically significant disability; 2, slight disability (able to handle own affairs without assistance but unable to carry out all previous activities); 3, moderate disability (requiring some help, but able to walk unassisted); 4, moderately severe disability (unable to attend body needs and unable to walk); 5, severe disability (requiring constant nursing care and attention); and 6, death. Scores of 5 and 6 were combined for the analysis. Treatment with intra-arterial alteplase was associated with a favorable outcome (a score of 0 or 1 on the modified Rankin Scale) at 90 days, with an adjusted risk difference of 18.4% (95% CI, 0.3%-36.4%; P = .047). The difference between the intra-arterial alteplase group and the placebo group in the overall distribution of scores was not statistically significant (shift analysis, adjusted common odds ratio for worsening of 1 point on the modified Rankin Scale, 1.54; 95% CI, 0.79-2.94).