Gurmeen Kaur, MBBS

Thomalla G, Simonsen CZ, Boutitie F, Andersen G, Berthezene Y, Cheng B, et al. MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. NEJM. 2018

Recently, the impressive results of the MRI-Guided Thrombolysis trial, popularly known as WAKE UP, were announced at the European Stroke Organization Conference 2018.

In an investigator initiated, multicenter, randomized, double blind, placebo controlled clinical trial, patients waking up with stroke or those with undetermined last known well because of aphasia and confusion were included between 18-80 years of age.

All patients included did not have contraindications to getting IV tPA, but did not qualify because of the unclear LKW. Previous studies have determined that at the 4.5-hour mark, roughly estimating, the DWI shows positivity but the FLAIR does not show parenchymal involvement. Hence, the mismatch between DWI and FLAIR was used to screen and select patients to be divided into 2 groups: one that received alteplase and the other group that received placebo. Interestingly, patients that qualified for mechanical thrombectomy were excluded from this trial.

70 centers across 8 European countries screened 1362 patients, of which 503 underwent randomization: 254 received alteplase and 249 received placebo in the intention to treat analysis performed from September 24, 2012, to June 30, 2017. Median NIHSS was 6 in both groups, and 89% of patients enrolled were wake up strokes.

The two groups were very well matched except for the higher incidence of intracranial atherosclerosis in the alteplase arm. Last known well to treatment initiation was roughly 10 hours in both groups.

The primary efficacy end point was favorable outcome at 90 days, which was achieved in 53.3% in the alteplase arm and 41.8% in the placebo arm (p=0.02). Most secondary efficacy end points including median mRS at 90 days, global outcome at 90 days, and improvement in quality of life on a visual analogue scale approached significant improvement in the alteplase arm. The mRS shift analysis also showed improvement in the alteplase arm. Patients who got alteplase with FLAIR DWI mismatch had 11.5% higher rate of freedom from neurological disease at 90 days.

Numerically more deaths and significantly more PH2 type symptomatic hemorrhage were reported with alteplase, which is similar to the results obtained from pooled stroke trials. This statistically significant higher symptomatic intracranial hemorrhage rate is persistent despite the definition of symptomatic intracranial hemorrhage used. While clinical benefit was seen, there was no difference in infarct volume at 22-36 hours (similar to DEFUSE 3).

Some limitations of the study are that the exclusion of patients undergoing thrombectomy hampers the generalizability of the results. Since this study was prior to DAWN and DEFUSE 3, 20% of patients enrolled in this would have qualified for mechanical thrombectomy, which makes it difficult to use this data for patients with severe stroke syndromes. Because the trial stopped early, the sample size was too small for subgroup analysis to be performed.

The study concluded that in patients with acute stroke with unclear LKW, a mismatch between DWI and FLAIR can be used to guide IV tPA administration with better functional outcomes (and higher rates of symptomatic hemorrhage) at the 90-day mark.