Fast track — ArticlesImplementation and outcome of thrombolysis with alteplase 3–4·5 h after an acute stroke: an updated analysis from SITS-ISTR
Introduction
Intravenous thrombolysis with alteplase has been evaluated in randomised controlled trials,1, 2, 3, 4, 5, 6, 7 pooled analyses8, 9, 10 and safety-monitoring studies.11, 12, 13, 14 The early studies1, 2, 3, 4, 5 resulted in regulatory approval of intravenous alteplase within 3 h after onset of an ischaemic stroke. In September, 2008, the outcome of the European Acute Stroke Study III (ECASS III) randomised controlled trial6 and the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR)14 observational study provided evidence supporting an expansion of the alteplase treatment time window up to 4·5 h after stroke onset. On the basis of these studies, the European Stroke Organisation changed the guidelines for management of acute ischaemic stroke and transient ischaemic attack.15, 16 The American Heart Association and the American Stroke Association subsequently published a Science Advisory on the same topic,17 and now both these European and US organisations recommend use of intravenous alteplase within 4·5 h after stroke onset.16, 17
Although more patients should receive alteplase treatment because of the increased time window for thrombolysis, the investigators in the ECASS III6 and the SITS-ISTR14 studies were concerned that the increased time window would result in an increased delay from admission of patients with stroke at the emergency department to the start of alteplase treatment. This would be a negative effect of the prolonged time window because treatment benefit declines with time.8 SITS-ISTR14 reported a possible increase in symptomatic intracerebral haemorrhage (according to the SITS-Monitoring Study [SITS-MOST] definition12) (p=0·052) and mortality rates (p=0·053) with late (3–4·5 h) compared with early (<3 h) treatment with alteplase. In addition, a possible increase in mortality rates was reported in a pooled analysis.9
We therefore aimed to assess the implementation of the prolonged time window for thrombolysis with alteplase after September, 2008, to investigate whether the increased time window has resulted in prolongation of admission-to-treatment time, and to evaluate treatment safety and functional outcome in a large patient cohort of the SITS registry.
Section snippets
Study population
650 centres in Europe, Asia, and Australia participated in the study from December, 2002 to February, 2010. Patients were included if they presented with ischaemic stroke and were treated with intravenous alteplase (Actilyse, Boehringer-Ingelheim, Ingelheim, Germany) within 4·5 h after symptom onset. Patients were compliant with the European Summary of Product Characteristics criteria (see webappendix p 1), except for the time since stroke onset (per-protocol group). A full dose of alteplase
Results
From December, 2002, to February, 2010, data on 23 942 patients from 650 centres were recorded in SITS-ISTR. Up to the end of September, 2008, 15 789 (94·3%) of 16 750 patients from 566 centres were treated within 3 h and 961 (5·7%) of 16 750 patients from 255 centres were treated within 3–4·5 h of stroke onset. Between October, 2008, and February, 2010, 5777 (80·3%) of 7192 patients from 371 centres were treated within 3 h and 1415 (19·7%) of 7192 patients from 242 centres were treated within
Discussion
The publication in September, 2008, of the ECASS III6 and the SITS-ISTR14 studies of alteplase treatment 3–4·5 h after acute stroke has had an immediate and lasting effect on the implementation of intravenous thrombolysis within 3–4·5 h after stroke onset. The proportion of patients treated in the 3–4·5 h time window was two times higher in the last quarter of 2008 and three times higher during the last quarter of 2009 compared with the first three quarters in 2008. The number of patients
References (18)
- et al.
Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators
Lancet
(1998) - et al.
Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET)
Lancet Neurol
(2008) - et al.
Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials
Lancet
(2010) - et al.
Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study
Lancet
(2007) - et al.
Thrombolysis with alteplase 3–4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study
Lancet
(2008) The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: tissue plasminogen activator for acute ischemic stroke
N Engl J Med
(1995)- et al.
Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: The European Cooperative Acute Stroke Study (ECASS)
JAMA
(1995) - et al.
Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset: the ATLANTIS study: a randomized controlled trial: Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke
JAMA
(1999) - et al.
The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g): results of a double-blind, placebo-controlled, multicenter study. Thrombolytic therapy in acute ischemic stroke study investigators
Stroke
(2000)
Cited by (0)
- ‡
Scientific committee listed at end of paper