Intravenous recombinant tissue plasminogen activator administered after 3 h following onset of ischaemic stroke: a metaanalysis.

Objective: To assess the efficacy of intravenous recombinant tissue plasminogen activator administered after 3 h following onset of ischaemic stroke.

Background: Some recent data indicate that treatment with intravenous recombinant tissue plasminogen activator may be beneficial even when administered to ischaemic stroke patients beyond 3 h from symptom onset.

Methods: We searched the medical literature using the MEDLINE, BIOSIS, and Cochrane databases for pertinent publications from 1966 to 2008 using the keywords 'alteplase', 'tissue plasminogen activator', and 'stroke'. Among the retrieved publications, we selected randomised controlled trials that administered recombinant tissue plasminogen activator during 3-6 h after symptom onset in patients with acute ischaemic stroke. We evaluated the effect of intravenous recombinant tissue plasminogen activator (compared with placebo) on the rate of good functional outcome (determined by modified Rankin Scale of 0-1) and mortality at three-months. A subset analysis was performed according to time of administration of intravenous recombinant tissue plasminogen activator (3-4·5 and 4·5-6 h). Odds ratios of individual trials were pooled using a random effects model.

Results: We analysed four randomised trials totaling 2104 patients (1053 control and 1051 recombinant tissue plasminogen activator-treated patients). Patients that received intravenous recombinant tissue plasminogen activator at 3-6 h following onset of symptoms had a significantly higher rate of favourable neurological outcome over the patients that received placebo (odds ratio 1·24, 95% confidence intervals 1·04-1·47, P=0·02). Treatment within the 3-4·5 time window was significantly associated with higher rate of favourable neurological outcome (OR 1·27, 95% confidence interval 1·01-1·60), but not for the 4·5-6 time window (OR 1·10, 95% confidence interval 0·75-1·51). There was no difference in mortality between patients that received intravenous recombinant tissue plasminogen activator than the patients that received pharmacologic placebo (OR 1·14, 95% confidence interval 0·76-1·70).

Conclusions: Treatment with intravenous recombinant tissue plasminogen activator from 3-4·5 h following symptom onset is associated with an increased rate of favourable outcome at 90-days in this analysis. Treatment with intravenous recombinant tissue plasminogen activator beyond 4·5 h did not show a benefit; however, improved patient selection is needed for future studies.