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When time of ischemic stroke symptom onset is unknown, thrombolysis leads to better functional outcomes in cases imaging shows to be good candidates, the WAKE-UP trial investigators found.

If these stroke patients presented with an ischemic lesion on MRI but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR) -- a mismatch suggestive of stroke onset no more than 4.5 hours earlier -- they were more likely to score 0 or 1 on the modified Rankin scale (mRS) at 90 days when they were randomized to IV alteplase (Activase) versus placebo (53.3% versus 41.8%, adjusted OR 1.61, 95% CI 1.09 to 2.36).

Moreover, the median mRS score at 90 days was 1 for the alteplase group and 2 for the placebo group (adjusted common OR 1.62, 95% CI 1.17 to 2.23), according to the team led by Götz Thomalla, MD, of Germany's Universitätsklinikum Hamburg-Eppendorf.

Their study was conducted in eight European countries and presented at the European Stroke Organisation Conference in Gothenburg, Sweden. A report was simultaneously published in the .

"Our trial provides evidence of benefit from reperfusion treatment with alteplase in patients with minor or moderate stroke who would not usually be eligible for endovascular treatment," the authors concluded. "Since we enrolled patients with an unknown time of symptom onset, they would have been excluded from most previous trials of thrombolysis involving patients with stroke."

Safety measures, however, trended in the wrong direction for tissue plasminogen activator (tPA) recipients in terms of death (4.1% alteplase versus 1.2% placebo, OR 3.38, 95% CI 0.92 to 12.52) and symptomatic intracranial hemorrhage (2.0% versus 0.4%, OR 4.95, 95% CI 0.57 to 42.87).

Notably, WAKE-UP was stopped early when funding was cut off after enrolling 503 of the 800 planned patients. "This factor limits the interpretation of the safety results because the observed trend toward a higher rate of death in the alteplase group may have become significant with a larger sample size," the investigators cautioned.

Another limitation was exclusion of stroke patients with planned thrombectomy.

"Among the patients who do undergo MRI and have the imaging signature of stroke onset within the previous 4.5 hours, are these MRI findings adequate as stand-alone imaging eligibility criteria for thrombectomy? And should such patients be treated with intravenous alteplase before thrombectomy? The results of the WAKE-UP trial cannot answer either of these questions, mainly because planned thrombectomy was an exclusion criterion in this trial," commented Tudor Jovin, MD, of the University of Pittsburgh Medical Center.

In an accompanying editorial, Jovin also pointed out that the findings based on MRI-guided thrombolysis are not necessarily applicable to the many centers that use CT perfusion for first-line imaging for its ease of use and wider availability.

"Nevertheless, the MRI signature as applied in the WAKE-UP trial may be a useful selection method for systemic thrombolysis in patients who cannot undergo thrombectomy," he conceded.

Patients in both arms of the trial shared a median score of 6 on the NIH Stroke Scale at randomization. The bulk of the study population did not know their stroke onset time because they had woken up with stroke symptoms already present.

Baseline characteristics were comparable between groups except for a higher rate of intracranial occlusion of the internal carotid artery among alteplase recipients.