Fast track — ArticlesStroke treatment with alteplase given 3·0–4·5 h after onset of acute ischaemic stroke (ECASS III): additional outcomes and subgroup analysis of a randomised controlled trial
Introduction
In the randomised, placebo-controlled European Cooperative Acute Stroke Study III (ECASS III),1 we assessed whether the time window for initiation of alteplase could be safely increased from the standard 3 h after the onset of stroke symptoms to up to 4·5 h. Patients treated with alteplase had a significantly better outcome at day 90 than did controls for the primary endpoint—ie, a score of 0–1 on the modified Rankin scale (mRS)—and the secondary endpoint—ie, a global outcome statistic based on the results of four dichotomised endpoints (mRS score 0–1, Barthel index [BI] score ≥95, National Institutes of Health stroke scale [NIHSS] score 0–1, and the Glasgow outcome scale [GOS] score 1). Mortality rates were similar in the alteplase and placebo groups, despite the extended treatment window. As in previous studies in which thrombolytic treatment was initiated 0–3 h after stroke onset,2, 3, 4 the incidence of intracranial haemorrhage in ECASS III was significantly higher with alteplase than with placebo. However, the absolute number of symptomatic haemorrhages was notably low compared with other studies.2, 3, 4, 5 The safety results of ECASS III therefore indicated no exacerbated risk of intracranial haemorrhage in the extended time window compared with 0–3 h.
First, we undertook secondary analyses using different endpoints to confirm or refute the efficacy and safety outcomes in the primary analysis in ECASS III. Second, we sought evidence of confounding factors or subgroups that might differentially affect treatment outcome. Additionally, to further investigate the benefit of alteplase noted in the primary analysis, we did various sensitivity analyses.
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Patients
The study design, patient population, and inclusion and exclusion criteria have been described previously.1 Briefly, ECASS III was a double-blind, randomised, placebo-controlled trial in which patients were enrolled from several centres across Europe. The effect of alteplase (0·9 mg/kg bodyweight, with an upper limit of 90 mg) intravenously infused over 60 min was compared with that of placebo on disability and neurological outcomes in patients treated within 3·0–4·5 h after the onset of stroke
Results
We enrolled 821 patients from July, 2003, to November, 2007, and randomly assigned 418 to the alteplase group and 403 to the placebo group. Figure 1 shows the trial profile.
Table 1 shows the baseline demographic and clinical characteristics of the two groups. These were well balanced between groups, although there were numerical differences in stroke severity and the presence or absence of previous stroke. The distribution of the NIHSS score at baseline by 5-point categories was similar in both
Discussion
Almost all our additional outcome analyses strongly support the positive primary and secondary trial results of ECASS III.1 Although not significant in every analysis, all additional efficacy endpoints showed at least a clear pattern in favour of alteplase. The consistent treatment effects noted across nearly all subgroup analyses and all sensitivity analyses of the primary endpoint were also consistent with the effects noted in the overall population. In particular, within the severity range
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