By Matthew E. Fink, MD
Professor and Chairman, Department of Neurology, Weill Cornell Medical College; Neurologist-in-Chief, New York Presbyterian Hospital
Dr. Fink reports he is a retained consultant for Procter & Gamble and Pfizer.
SOURCE: Thomalla G, Simonsen CZ, Boutitie F, et al; for the WAKE-UP Investigators. MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med 2018;379:611-622.
Current guidelines for the use of intravenous thrombolysis state that this treatment should be given only if the onset of stroke symptoms clearly can be determined as occurring less than 4.5 hours before the time of administration. Currently, if the last known normal time cannot be ascertained, then intravenous thrombolysis is not recommended. In this multicenter randomized trial, patients who had an unknown time of onset for ischemic stroke were treated with either intravenous alteplase or placebo. All of the patients had an acute ischemic lesion that was visible on MRI diffusion-weighted imaging, but had no hyperintensity on FLAIR images, which indicated that the stroke occurred approximately within the previous 4.5 hours. The primary endpoint was a favorable outcome, defined as a score of 0 or 1 on the modified-Rankin scale at 90 days. The secondary outcome was that alteplase treatment would lead to a lower score on the modified-Rankin scale, indicating a better neurological outcome.
The researchers anticipated that 800 patients would be enrolled, but the trial was stopped after enrollment of 503 patients because of cessation of funding. Eighty-nine percent of all patients were diagnosed with ischemic stroke after they awakened in the morning, and the last known normal was more than seven hours earlier. The researchers randomly assigned 254 patients to alteplase and 249 to placebo. A favorable outcome at 90 days was reported in 53.3% of the alteplase group and in 41.8% in the placebo group (adjusted odds ratio, 1.61; P = 0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (P =0.003). There were 10 deaths in the alteplase group and three deaths in the placebo group, which most likely were attributed to symptomatic intracranial hemorrhage, which occurred in 2% of the alteplase group and 0.4% in the placebo group. In conclusion, in patients with acute ischemic stroke of unknown time of onset, a mismatch between diffusion-weighted imaging and FLAIR imaging in the region of ischemia resulted in better functional outcome if treated with intravenous alteplase, but with more symptomatic intracranial hemorrhages.
