BACKGROUND: Intravenous thrombolysis with alteplase is the only approved treatment
for acute ischemic stroke, but its efficacy and safety when administered more than
3 hours after the onset of symptoms have not been established. We tested the efficacy
and safety of alteplase administered between 3 and 4.5 hours after the onset of a
stroke. METHODS: After exclusion of patients with a brain hemorrhage or major infarction,
as detected on a computed tomographic scan, we randomly assigned patients with acute
ischemic stroke in a 1:1 double-blind fashion to receive treatment with intravenous
alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was
disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the
modified Rankin scale, which has a range of 0 to 6, with 0 indicating no symptoms
at all and 6 indicating death) or an unfavorable outcome (a score of 2 to 6 on the
modified Rankin scale). The secondary end point was a global outcome analysis of four
neurologic and disability scores combined. Safety end points included death, symptomatic
intracranial hemorrhage, and other serious adverse events. RESULTS: We enrolled a
total of 821 patients in the study and randomly assigned 418 to the alteplase group
and 403 to the placebo group. The median time for the administration of alteplase
was 3 hours 59 minutes. More patients had a favorable outcome with alteplase than
with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02
to 1.76; P=0.04). In the global analysis, the outcome was also improved with alteplase
as compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P<0.05). The incidence
of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial
hemorrhage, 27.0% vs. 17.6%; P=0.001; for symptomatic intracranial hemorrhage, 2.4%
vs. 0.2%; P=0.008). Mortality did not differ significantly between the alteplase and
placebo groups (7.7% and 8.4%, respectively; P=0.68). There was no significant difference
in the rate of other serious adverse events. CONCLUSIONS: As compared with placebo,
intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms
significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase
was more frequently associated with symptomatic intracranial hemorrhage. (ClinicalTrials.gov
number, NCT00153036.) 2008 Massachusetts Medical Society
