WAKE-UP Time for Thrombolysis in Acute Stroke?

MRI image of ischemic stroke.

By Martina McGrath, MD
October 30, 2018

MRI thrombolysis for stroke of unknown time of onset

Current clinical guidelines recommend thrombolysis in acute stroke where patients present within 4.5 hours of onset of symptoms. However, for up to a quarter of patients, the time of symptom onset is unknown as they wake from sleep with neurological deficits.1 Such patients frequently do not meet criteria for therapies such as thrombolysis or mechanical thrombectomy.

Prior studies have suggested a particular pattern may be seen on an MRI of the brain in the early hours following stroke onset; a visible ischemic lesion on diffusion-weighted imaging along with the lack of a hyperintense signal in the same area on fluid-attenuated inversion recovery (FLAIR). The benefit of aggressive stroke intervention in patients with the combination of unknown time of symptom onset and this particular signal mismatch on MRI brain scans is unknown.

The Study

The WAKE-UP trial was conducted to determine if thrombolysis would improve outcomes in patients who had this particular clinical picture.2 The primary outcome was level of disability at 90 days; assessed as a score of 0 to 1 (either no symptoms, or no significant disability despite some symptoms) on the modified Rankin scale.

This randomized, double-blinded, placebo-controlled study was conducted across 70 centers in 8 European countries.2 The investigators initially planned to enroll 370 patients per group, but due to limitations in funding, enrollment was halted after around 250 patients had enrolled in each arm.

Enrolled patients were well matched at baseline, and the mean time from symptom recognition to administration of alteplase or placebo was 3.2 and 3.1 hours. The time from when the patient was last known to be well until treatment was also similar between the groups, at around 10.3 hours.

The Results

In terms of results, treatment with thrombolysis was associated with significantly improved outcomes at 90 days, with 53.3% of patients meeting the primary end point of no or minimal disability, as compared to 41.8% in the placebo group (adjusted OR 1.62, 95% CI 1.09-2.36; p=0.02). Quality-of-life scores at 90 days were also higher in the alteplase group, although infarct volume on follow-up imaging was not significantly different between the groups.

In terms of safety, there was a higher death rate in the alteplase group. There were 3 deaths in the placebo group, as compared to 10 deaths in the alteplase groups, of which 4 were from intracranial hemorrhage. In keeping with prior studies of thrombolysis for stroke, there were numerically more symptomatic intracranial hemorrhages in the treatment group. The difference in rates of death and cerebral hemorrhage is difficult to interpret in this study, where target enrollment was not achieved and a larger sample size may have more clearly revealed the safety of this approach.  Rates of other adverse events were similar between the two groups.


The findings of this study suggest that in selected patients with imaging suggestive of cerebral ischemia, but without a clear time of symptom onset, thrombolysis may lead to improved clinical outcomes. However, the safety of this approach remains unclear at this point.

The question then becomes – how widely applicable are these findings?  Two-thirds of screened patients were excluded from this study, mainly because they did not have the required mismatch finding on MRI scanning.  Secondly, using MRI scanning to identify suitable patients may limit the application of these findings—CT is generally more rapidly available to triage stroke patients and plan therapy, including for thrombectomy. Patients who were suitable for endovascular treatment of large vessel stroke were excluded from this study, and indeed, other clinical trials have indicated that selected patients with unknown time of symptom onset may also benefit from mechanical thrombectomy.3,4 Whether such patients would gain some benefit from thrombolysis is unknown. Perhaps it’s not yet time to wake up, and more studies will be needed to guide therapy for this subgroup of patients.

Learn more about diagnosing and managing patients with Venous Thrombosis in an online, self-paced CME course from Harvard Medical School.

1. Mackey J, Kleindorfer D, Sucharew H, et al. Population-based study of wake-up strokes. Neurology 2011; 76: 1662-7.

2. Thomalla G, Simonsen CZ, Boutitie F, et al. MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med. DOI: 10.1056/NEJMoa1804355.

3. Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med 2018; 378: 11-21.

4. Albers GW, Marks MP, Kemp S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med 2018; 378: 708-18.

Headshot of Dr. McGrathDr. Martina McGrath is an instructor in medicine at Harvard Medical School, and a member of the Renal Division, Department of Medicine at Brigham and Women’s Hospital, both in Boston. Dr. McGrath is the medical editor for the Trends in Medicine blog and the course director for the Update and Board Review in Internal Medicine online CME courses.


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