ArticlesRandomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II)
Introduction
There have been several large, randomised, placebo-controlled trials of thrombolytic therapy in acute ischaemic stroke. Three of these trials, testing the effects of intravenous streptokinase given within 6 h of stroke onset, were terminated prematurely because there were more deaths and bleeding complications in the actively treated groups.1, 2, 3 The use of alteplase (recombinant tissue-type plasminogen activator) in acute ischaemic stroke has been investigated in two trials. The National Institute of Neurological Disorders and Stroke (NINDS) trial4 used a very short maximum interval from symptom onset to treatment (180 min), a dose of 0·9 mg/kg bodyweight, and very strict blood-pressure control. It found that 11–13% more patients in the alteplase group than in the placebo group had good functional outcome, with no increase in mortality, although symptomatic haemorrhages were increased ten-fold by thrombolysis. On the basis of these results, alteplase was approved in the USA for use within 3 h of onset of symptoms.
ECASS I,5 a European multicentre trial, used a maximum interval from onset to treatment of 6 h and a higher dose of alteplase (1·1 mg/kg). No significant differences between alteplase and placebo were seen in the median scores of the primary outcome measures, probably because a significant minority (17%) of patients included in the analysis had protocol violations (mostly with extensive ischaemic changes on the baseline computed tomography [CT] scan). The target population (per-protocol) analysis showed significant differences between the study groups in favour of alteplase, with effect sizes similar to those found in the NINDS trial. Mortality was increased in the alteplase group, however, and parenchymal haemorrhages were significantly more common in alteplase-treated than in placebo-treated patients.
ECASS II was therefore designed with a lower dose of alteplase (0·9 mg/kg, chosen to match NINDS criteria) given intravenously within 6 h of onset of symptoms, more rigorous application of the CT eligibility criteria, and strict guidelines for blood-pressure control. The objective of ECASS II was to find out whether alteplase given within 6 h of symptom onset (patients were randomised equally to alteplase and placebo for both time strata of 0–3 h and 3–6 h) improved clinical outcome in comparison with placebo.
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Participants
ECASS II was carried out in 108 centres in 14 European countries and Australia and New Zealand. The trial was non-angiographic. Therefore, in most patients the precise location of the causative cardiovascular thrombus or embolus was not identified. The exception was if a hyperdense middle-cerebral-artery sign was seen on the initial CT scan.
Eligible patients were men and women aged 18–80 years who had a clinical diagnosis of moderate to severe ischaemic hemispheric stroke, who could be treated
Patients
Patients were recruited for ECASS II between October, 1996, and January, 1998: 409 patients were assigned to the alteplase group and 391 to the placebo group (figure 1). All randomised patients were included in the intention-to-treat analysis, including seven patients (two alteplase, five placebo) who were randomised but not treated, because they withdrew consent (two), deteriorated (two), or improved clinically before infusion of alteplase or placebo (three). The alteplase and placebo groups
Discussion
The proportion of patients in ECASS II who had a baseline CT scan showing hypodensity in more than 33% of the middle-cerebral-artery territory is smaller than that in ECASS I (4·6% vs 83%). The difference probably reflects both the increased experience in diagnosing acute ischaemic changes on CT scans gained by the investigators since ECASS I, and the benefits of the training programmes undertaken in preparation for ECASS II.6 This increased diagnostic sensitivity did not lead to the selection
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