Hacke W, Kaste M, Bluhmki E, Brozman M, et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008 Sep 25;359(13):1317-29. PMID: 18815396
What we already know about the topic
Last week we reviewed the 1995 NINDS trial that showed that t-PA given to ischemic stroke patients within 3 hours of onset of neurologic deficits might improve functional outcomes at 3 months (I say might because that trial data still remains hotly debated). European trials (ECASS, ECASS 2) looked at t-PA given up to 6 hours and found no difference in outcomes. However, a pooled analysis of data of several trials demonstrated that there might be some benefit for t-PA given between 3 and 4.5 hours. This was the impetus for ECASS 3.
Why this study is important
This study helped expand the t-PA window from up to 3 hours after onset of neurologic deficits to now up to 4.5 hours from onset of symptoms.
Brief overview of the study
ECASS3 was a double-blind, randomized, multicenter (130 sites in 19 European countries), placebo-controlled trial comparing t-PA to placebo that enrolled 821 ischemic stroke patients between the ages of 18 to 80 who presented between 3 and 4.5 hours after the onset of neurologic deficits. Patients were randomized to altepase 0.9mg/kg (10% bolus+90% as infusion over 60 minutes) versus placebo. The primary outcome was modified rankin score at 90 days. The authors found that patients who received alteplase were more likely to have a mRS of 0-1 (no or minimal symptoms) compared to placebo: 52.4% vs 45.2%, NNT 14. This remained significant after adjusting for baseline NIHSS, time from onset of symptoms, and history of smoking or hypertension. Additionally, they found an overall increased rate of intracranial hemorrhage in the alteplase group compared to placebo: 27% vs 17.6%, an absolute difference of 9.4% or NNH 10. Additionally, patients in the altepase group were more likely to have “symptomatic ICH” defined as a ICH with a reduction in NIHSS of 4 points or death: 2.4% vs 0.3% or a NNH of 45. Despite this higher incidence of symptomatic ICH, there was no difference in the overall mortality between the t-PA and placebo groups.
Overall, this was a very large multicenter trial that enrolled 821 patients across 19 European countries that allows the data to become somewhat generalizable to the United States. They did limit the initial NIHSS stroke score to less than 25, thus eliminating those patients who were likely to have poor outcomes regardless of treatment. One limitation is that patients in the placebo group did have a statistically significant difference in history of prior stroke, which may have affected their prognosis (14% in placebo vs. 7.7% in t-PA group). There was also a slightly higher initial mean/median stroke scores between the two groups that may have affected outcomes, although this was less of a difference than was seen in the NINDS trial (alteplase vs. placebo: mean 10.7 +/- 5.6 vs. 11.6 +/-5.9, median 9 vs. 10 respectively).
Take home points
Overall, acute ischemic stroke patients age 18-80 years with NIHSS less than 25 and who present within the 4.5 hour window should be considered for t-PA with a NNT of 14 for mRS of 0-1 at 90 days. While there is a risk of increased ICH (NNH: 10) and symptomatic ICH (NNH: 45), there was no overall difference in mortality between the two groups.