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