Question: Can thrombolysis with alteplase improve stroke symptoms more than three hours after symptom onset?

Background: For acute ischemic stroke (AIS), trial evidence demonstrates tissue plasminogen activator (tPA) improves outcomes when given within three hours of symptom onset. Although the benefit of alteplase (a recombinant tPA therapeutic) decreases as the time from stroke symptom onset increases, some observational studies have suggested this drug may improve long-term neurologic outcomes even after the three-hour time limit.

Study Design: A multicenter, double blind, randomized placebo-controlled study with intention-to-treat analysis.

Setting: Multicenter, multinational study in Europe.

Synopsis: More than 800 patients presenting with stroke symptoms were diagnosed with ischemic stroke. Stroke severity was somewhat lower than prior tPA trials, and patients were randomized to receive either 0.9 mg per kg of alteplase by IV (up to 90 mg) or placebo.

Based on validated patient symptom scores, outcome was favorable in 52.4% of the alteplase group and 45.2% in the placebo group, leading to an absolute benefit of 7.2% and a number-needed-to-treat of 14. Although risk of any intracranial hemorrhage (ICH) was higher in the alteplase group (2.4% vs. 0.3%), symptomatic ICH was only marginally different, and mortality was similar in both groups, (7.7% vs. 8.4%).

This trial suggests the use of alteplase can be extended to four and a half hours after the onset of AIS symptoms without significantly increasing the overall mortality of these patients. A premium should be placed on earlier treatment, as the efficacy of alteplase decreases exponentially with time.

Bottom Line: Alteplase shows a statistically significant and clinically important improvement of AIS symptoms up to four and a half hours after the onset of stroke, without increasing mortality.

Citation: NEJM. 2008;359:1317-1329.

—Reviewed for the e-wire by Elbert Chun, MD, John Vazquez, MD, Larry Beer, MD, Maged Doss, MD, Vana Bollineni, MD, Mohammed S. Singapuri, MD, Dan Dressler, MD, MsCR, Emory University Hospital, Atlanta