Elsevier

The Lancet

Volume 352, Issue 9136, 17 October 1998, Pages 1245-1251
The Lancet

Articles
Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II)

https://doi.org/10.1016/S0140-6736(98)08020-9Get rights and content

Summary

Background

Thrombolysis for acute ischaemic stroke has been investigated in several clinical trials, with variable results. We have assessed the safety and efficacy of intravenous thrombolysis with alteplase (0·9 mg/kg bodyweight) within 6 h of stroke onset.

Methods

This non-angiographic, randomised, double-blind, trial enrolled 800 patients in Europe, Australia, and New Zealand. Computed tomography was used to exclude patients with signs of major infarction. Alteplase (n=409) and placebo (n=391) were randomly assigned with stratification for time since symptom onset (0–3 h or 3–6 h). The primary endpoint was the modified Rankin scale (mRS) at 90 days, dichotomised for favourable (score 0–1) and unfavourable (score 2–6) outcome. Analyses were by intention to treat.

Findings

165 (40·3%) alteplase-group patients and 143 (36·6%) placebo-group patients had favourable mRS outcomes (absolute difference 3·7%, p=0·277). In a post-hoc analysis of mRS scores dichotomised for death or dependency, 222 (54·3%) alteplase-group and 180 (46·0%) placebo-group patients had favourable outcomes (score 0–2; absolute difference 8·3%, p=0·024). Treatment differences were similar whether patients were treated within 3 h or 3–6 h. 85 (10·6%) patients died, with no difference between treatment groups at day 90·14 days (43 alteplase, 42 placebo). Symptomatic intracranial haemorrhage occurred in 36 (8·8%) alteplase-group patients and 13 (3·4%) placebo-group patients.

Interpretation

The results do not confirm a statistical benefit for alteplase. However, we believe the trend towards efficacy should be interpreted in the light of evidence from previous trials. Despite the increased risk of intracranial haemorrhage, thrombolysis with alteplase at a dose of 0·9 mg/kg in selected patients may lead to a clinically relevant improvement in outcome.

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.

Section snippets

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

References (19)

  • Multicentre Acute Stroke Trial—Italy (MAST-I) Group

    Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke

    Lancet

    (1995)
  • DonnanGA et al.

    Streptokinase for acute ischaemic stroke with relationship to time administration

    JAMA

    (1996)
  • Multicenter Acute Stroke Trial—Europe Study Group

    Thrombolytic therapy with streptokinase in acute ischaemic stroke

    N Engl J Med

    (1996)
  • The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group

    Tissue plasminogen activator for acute ischaemic stroke

    N Engl J Med

    (1995)
  • HackeW et al.

    Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS)

    JAMA

    (1995)
  • von KummerR et al.

    Effect of training on the recognition of large ischemic lesions on CT scans obtained within 6 hours of stroke onset

    Stroke

    (1998)
  • HornigCR et al.

    Hemorrhagic cerebral infarction: a prospective study

    Stroke

    (1986)
  • OkadaY et al.

    Hemorrhagic transformation in cerebral embolism

    Stroke

    (1989)
  • Stroke Unit Trialists' Collaboration

    Collaborative systematic review of the randomised trials of organized inpatient (stroke unit) care after stroke

    BMJ

    (1997)
There are more references available in the full text version of this article.

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