1. Stroke patients with unknown time of stroke onset and DWI-FLAIR mismatch indicative of a stroke within the prior 4.5 hours who were randomized to alteplase were more likely to have a favorable outcome at 90 days than those receiving placebo.
2. Rates of death and symptomatic intracranial hemorrhage were higher amongst patients treated with alteplase, although these associations did not reach statistical significance.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Guidelines support the administration of alteplase to appropriately selected stroke patients with a time last seen well within 4.5 hours. The time of stroke onset is often unknown, as in the case of “wake-up strokes,” which excludes many patients from beneficial treatment. Previous work has demonstrated that in acute ischemic stroke, an MRI pattern of a diffusion-weighted imaging (DWI) lesion without a fluid-attenuated inversion recovery (FLAIR) lesion is predictive of the stroke happening within 4.5 hours. The investigators of this randomized controlled trial aimed to evaluate if DWI-FLAIR mismatch could select patients with stroke of unknown time that would benefit from intravenous thrombolysis. The primary endpoint was a favorable outcome at 90 days, defined as a modified Rankin scale score of 0 or 1. Patients with unknown stroke time and DWI-FLAIR mismatch who were treated with alteplase had significantly higher rates of a favorable outcome at 90 days compared to those treated with placebo. There were higher rates of death and symptomatic intracranial hemorrhage (ICH) in the treatment arm, but these associations did not reach statistical significance.
A major strength of this study is its randomized, multicenter study design. The trial was planned to enroll at least 800 patients to achieve adequate statistical power but was only able to enroll 503 patients. The study is thus likely underpowered for its primary outcome and would be expected to overestimate the effect size.
In-Depth [randomized controlled trial]: This multicenter randomized controlled trial enrolled 503 patients from 2012 to 2017 and assigned patients to alteplase (n=254) or placebo groups (n=249). The study sought to evaluate if alteplase would improve functional outcomes amongst patients with a stroke of unknown time of onset, but with a DWI-FLAIR mismatch. Key inclusion criteria included an unknown time of stroke onset and presence of a lesion on DWI but not FLAIR imaging. Important exclusion criteria included contraindications to thrombolysis, lesions larger than 1/3 the size of the middle cerebral artery territory, severe stroke defined as an NIH stroke scale score of greater than 25, and patients with a planned thrombectomy. The primary endpoint was a favorable outcome at 90 days, defined as a modified Rankin scale score of 0 or 1. Key secondary endpoints at 90 days included the ordinal score on the modified Rankin scale, quality of life scores, and MRI infarct volume at 22-36 hours after randomization. Key safety endpoints included death and symptomatic ICH.
Most patients (89%) included in the study experienced a ‘wake-up stroke’ (as opposed to confusion or aphasia confounding ascertainment of time of onset). At 90 days, the number of patients in the alteplase group who experienced a favorable outcome was 11.5% higher than in the placebo group (53.3% vs 41.8%; adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; p = 0.02). The median modified Rankin score was significantly better in the alteplase group at 90 days, as was the average total score on a quality of life scale. The MRI infarct volume at 22-36 hours post-randomization was not significantly different between the two groups. The number of deaths was higher in the alteplase group (10 vs. 3 in placebo), as was the number of symptomatic ICH (2% vs. 0.4% in placebo) events, but neither association was statistically significant.
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