May 21, 2018
3 min read

WAKE-UP: Alteplase effective in acute stroke with suspected recent onset

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Among patients with acute stroke of unknown time of onset but MRI findings indicating onset was recent, IV thrombolysis with alteplase resulted in a better functional outcome than treatment with placebo, according to the results of the WAKE-UP trial.

The findings were presented at the European Stroke Organization Conference and published in The New England Journal of Medicine.

“Intravenous thrombolysis with alteplase, a recombinant tissue plasminogen activator, is the standard medical treatment for acute ischemic stroke within 4.5 hours after the onset of symptoms. In 14% to 27% of strokes, the time of symptom onset is not known, frequently because stroke symptoms are recognized when the patient awakes from sleeping,” Götz Thomalla, MD, from the department of neurology at the University Medical Center Hamburg-Eppendorf, Germany, and colleagues wrote. “Such patients are generally excluded from treatment with intravenous alteplase, and only some of them are candidates for mechanical thrombectomy.”

To determine whether treatment with alteplase (Activase, Genentech) would improve functional outcomes in patients with an unknown time of stroke onset and a mismatch between diffusion-weighted imaging and fluid-attenuated inversion recovery (FLAIR) findings on MRI, the researchers conducted an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled clinical trial.

According to the study, all the patients enrolled had an ischemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on FLAIR, which indicated that the stroke had occurred approximately within the previous 4.5 hours.

Patients who had planned thrombectomies were excluded.

The primary endpoint of the study was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic disability at 90 days.

The secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale compared with placebo.

The trial was stopped early due to the cessation of funding and 503 patients of a planned 800 were enrolled.

Of the cohort, 254 were randomly assigned alteplase (mean age, 65 years; 65% men) and 249 to placebo (mean age, 65 years; 64% men).

At 90 days, a favorable outcome was observed in 53.3% of patients in the alteplase group and in 41.8% of patients in the placebo group (adjusted OR = 1.61; 95% CI, 1.09-2.36).

At 90 days, there was a median score on the modified Rankin scale of 1 in the alteplase group and 2 in the placebo group (adjusted common OR = 1.62; 95% CI, 1.17-2.23).


Tudor Jovin, MD
Tudor G. Jovin

In the alteplase group, 4.1% of patients died vs. 1.2% in the placebo group (OR = 3.38; 95% CI, 0.92-12.52).

Thomalla and colleagues observed a rate of symptomatic intracranial hemorrhage of 2% in the alteplase group and 0.4% in the placebo group (OR = 4.95; 95% CI, 0.57-42.87).

“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,” Thomalla and colleagues wrote. “The treatment effect of alteplase among patients with mild or moderate stroke of the type included in our trial is consistent with a pooled analysis of thrombolysis trials, which did not show a significant difference in the efficacy of alteplase treatment depending on stroke severity.”

In a related editorial, Tudor G. Jovin, MD, from the Stroke Institute, department of neurology, University of Pittsburgh Medical Center, wrote that despite the positive outcomes of the WAKE-UP, there are still several questions that remain, noting that “the results may not apply to patients who only undergo CT perfusion to determine eligibility for thrombectomy.

“It is important that clinical equipoise be maintained so that confirmatory trials can be performed,” Jovin wrote. “If the results of such trials are positive, they would expand the population of patients with acute stroke who are eligible for intravenous thrombolysis.” – by Dave Quaile


Thomalla G, et al. Official Welcome and Large Clinical Trials. Presented at: European Stroke Organization Conference; May 16-18, 2018; Gothenburg, Sweden.

Jovin TG. N Engl J Med. 2018;doi:10.1056/NEJMe1805796.

Thomalla G, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1804355.

Disclosures: Jovin reports receiving funding from Anaconda Biomed, Blockade Medical, FreeOx Biotech, Road Medical, Route 92 Medical and personal fees from Codman Neurovascular. Thomalla reports that he receives personal fees from Acandis and grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daichi Sankyo and Stryker. Please see the full study for the other authors’ relevant financial disclosures.

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