Stroke treatment with alteplase given 3.0-4.5 h after onset of acute ischaernic stroke (ECASS III): additional outcomes and subgroup analysis of a randomised controlled trial

Background In the European Cooperative Acute Stroke Study III (ECASS III), alteplase administered 3.0-4.5 h after the onset of stroke symptoms resulted in a significant benefit in the primary endpoint (modified Rankin scale [mRS] score 0-1) versus placebo, with no difference in mortality between the treatment groups. Compared with the 0-3 h window, there was no excess risk of symptomatic intracranial haemorrhage. We assessed the usefulness of additional endpoints and did subgroup and sensitivity analyses to further investigate the benefit of alteplase. Methods In a double-blind, multicentre study in Europe, patients with acute ischaemic stroke were randomly assigned to intravenous alteplase (0-9 mg/kg bodyweight) or placebo. Additional outcome analyses included functional endpoints at day 90 or day 30 (mRS 0-1 [day 30], mRS 0-2, Barthel index 85, and global outcome statistic [day 301) and treatment response (8-point improvement from baseline or 0-1 score on the National Institutes of Health stroke scale [NIHSS], and a stratified responder analysis by baseline NIHSS score). The subgroup analyses were based on the mRS 0-1 at day 90, symptomatic intracranial haemorrhage, and death. Analyses were by intention to treat and per protocol. This study is registered with ClinicalTrials.gov, number NCT00153036. Findings 418 patients were assigned to alteplase and 403 to placebo. Although not significant in every case, all additional endpoints showed at least a dear trend in favour of alteplase. Alteplase was effective in various subgroups, including older patients (<65 years: odds ratio 1.61, 95% CI 1.05-2.48; >= 65 years: 1.15, 0.80-1.64; p=0.230), and the effectiveness was independent of the severity of stroke at baseline (NIHSS 0.9: 1.28, 0.84-1.96; NIHSS 10.19: 1.16, 0.73-1.84; NIHSS >= 20: 2.32, 0.61-8.90; p=0.631). The incidence of symptomatic intracranial haemorrhage seemed to be independent of previous antiplatelet drug use (no: 2.41, 1.09-5.33; yes: 2.33, 0.79-6.90; p=0.962) and time from onset of symptoms to treatment (181-210 min: 1.62,0.26-10.25; 211-240 min: 1.97,0.82-4.76; 241-270 min: 3.15,1.01-9.79; p=0.761), but not of age dichotomised at 65 years (<65 years: 0.74, 0.28-1.96; >= 65 years: 5.79, 2.18-15.39; p=0.004). Interpretation Our results support the use of alteplase up to 4.5 h after the onset of stroke symptoms across a broad range of subgroups of patients who meet the requirements of the European product label but miss the approved treatment window of 0.3 h.