Elsevier

The Lancet Neurology

Volume 7, Issue 4, April 2008, Pages 299-309
The Lancet Neurology

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Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial

https://doi.org/10.1016/S1474-4422(08)70044-9Get rights and content

Summary

Background

Whether intravenous tissue plasminogen activator (alteplase) is effective beyond 3 h after onset of acute ischaemic stroke is unclear. We aimed to test whether alteplase given 3–6 h after stroke onset promotes reperfusion and attenuates infarct growth in patients who have a mismatch in perfusion-weighted MRI (PWI) and diffusion-weighted MRI (DWI).

Methods

We prospectively and randomly assigned 101 patients to receive alteplase or placebo 3–6 h after onset of ischaemic stroke. PWI and DWI were done before and 3–5 days after therapy, with T2-weighted MRI at around day 90. The primary endpoint was infarct growth between baseline DWI and the day 90 T2 lesion in mismatch patients. Major secondary endpoints were reperfusion, good neurological outcome, and good functional outcome. Patients, caregivers, and investigators were unaware of treatment allocations. Primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00238537.

Findings

We randomly assigned 52 patients to alteplase and 49 patients to placebo. Mean age was 71·6 years, and median score on the National Institutes of Health stroke scale was 13. 85 of 99 (86%) patients had mismatch of PWI and DWI. The geometric mean infarct growth (exponential of the mean log of relative growth) was 1·24 with alteplase and 1·78 with placebo (ratio 0·69, 95% CI 0·38–1·28; Student's t test p=0·239); the median relative infarct growth was 1·18 with alteplase and 1·79 with placebo (ratio 0·66, 0·36–0·92; Wilcoxon's test p=0·054). Reperfusion was more common with alteplase than with placebo and was associated with less infarct growth (p=0·001), better neurological outcome (p<0·0001), and better functional outcome (p=0·010) than was no reperfusion.

Interpretation

Alteplase was non-significantly associated with lower infarct growth and significantly associated with increased reperfusion in patients who had mismatch. Because reperfusion was associated with improved clinical outcomes, phase III trials beyond 3 h after treatment are warranted.

Funding

National Health and Medical Research Council, Australia; National Stroke Foundation, Australia; Heart Foundation of Australia.

Introduction

Intravenous recombinant tissue plasminogen activator (alteplase) is the only licensed therapy for treatment of acute ischaemic stroke.1, 2 However, use of alteplase is limited by recommendations that it is given only within the first 3 h after stroke onset. Meta-analysis3 of trials of intravenous alteplase suggests that improved clinical outcomes extend beyond 3 h, but that these benefits rapidly diminish with time.

The aims of thrombolytic therapy are arterial recanalisation and salvage of the ischaemic penumbra, a region of critically hypoperfused but viable brain tissue around the irreversibly damaged infarct core.4 The ischaemic penumbra is present in at least 80% of patients within 3 h of stroke onset but this proportion diminishes with time.5, 6 The potential clinical gains from alteplase relate to tissue reperfusion and attenuation of infarct growth,7, 8 which depend on the degree of irreversible damage and the presence and extent of the ischaemic penumbra. The penumbra can be evaluated with echoplanar MRI, diffusion-weighted MRI (DWI), and perfusion-weighted MRI (PWI). DWI lesions are regions of cytotoxic oedema, which usually proceed to infarction, and the mismatch between a larger PWI lesion and smaller DWI lesion is thought to be a signature of the ischaemic penumbra.9, 10 The probability of infarction depends on the severity and duration of hypoperfusion in the ischaemic penumbra.11 Therefore, imaging of the penumbra might allow selection of patients for thrombolysis beyond 3 h.

No previous randomised trials of alteplase have used MRI scans before and after therapy to assess the effects on reperfusion, infarct evolution, and clinical outcome. Our primary hypothesis was that alteplase would attenuate infarct growth in patients who have a mismatch between DWI and PWI lesions. However, we did not plan to use mismatch in the selection of patients, because rapid online detection of mismatch was not feasible and we were keen to include a proportion of patients without mismatch for an exploratory analysis. Our aim was to establish the effect of intravenous alteplase on lesion growth, reperfusion, and clinical outcome in penumbral patients 3–6 h after stroke onset.

Section snippets

Study design and patients

The Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) was a phase II prospective, randomised, double-blinded, placebo-controlled, multinational trial in patients with acute ischaemic stroke who were imaged with serial echoplanar MRI and treated with intravenous alteplase or placebo 3–6 h after stroke onset.12, 13 The trial was done between 2001 and 2007 in 15 centres in Australia, New Zealand, Belgium, and the UK.

We included patients with acute hemispheric ischaemic stroke who

Results

Figure 1 shows the trial profile. Between April, 2001, and January, 2007, 3908 patients were screened when MRI was immediately available. 1224 of these patients were screened within 6 h, of whom 101 (8%) were enrolled. Principal reasons for exclusion among the 1123 patients who presented within 6 h were haemorrhage detected by screening CT (29%), alteplase treatment indicated within 3 h (20%), NIHSS of 4 or less (16%), symptoms that resolved rapidly (9%), declined consent (7%), other diagnoses

Discussion

The primary outcome, lower infarct growth with alteplase in mismatch patients, was negative when analysed by our prespecified primary method (ratio of geometric means). However, other growth measures (relative growth and proportion of patients with no infarct growth) supported the hypothesis of attenuated infarct growth with alteplase beyond 3 h. Treatment with intravenous alteplase within 3–6 h of stroke onset resulted in non-significantly lower infarct growth across all measures and a

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