Elsevier

The Lancet Neurology

Volume 8, Issue 12, December 2009, Pages 1095-1102
The Lancet Neurology

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Stroke 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

https://doi.org/10.1016/S1474-4422(09)70264-9Get rights and content

Summary

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 30]) 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 clear 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.

Funding

Boehringer Ingelheim.

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.

Section snippets

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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