Elsevier

The Lancet Neurology

Volume 9, Issue 9, September 2010, Pages 866-874
The Lancet Neurology

Fast track — Articles
Implementation and outcome of thrombolysis with alteplase 3–4·5 h after an acute stroke: an updated analysis from SITS-ISTR

https://doi.org/10.1016/S1474-4422(10)70165-4Get rights and content

Summary

Background

In September, 2008, the European Acute Stroke Study III (ECASS III) randomised trial and the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR) observational study reported the efficacy and safety of the extension of the time window for intravenous alteplase treatment from within 3 h to within 4·5 h after stroke onset. We aimed to assess the implementation of the wider time window, its effect on the admission-to-treatment time, and safety and functional outcome in patients recorded in SITS-ISTR.

Methods

Patients treated according to the criteria of the European Summary of Product Characteristics, except for the time window, were included. Patients were grouped according to whether they were registered into SITS-ISTR before or after October, 2008. We measured admission-to-treatment time and rates of symptomatic intracerebral haemorrhage, mortality, and functional independence at 3 months.

Findings

23 942 patients were included in SITS-ISTR between December, 2002, and February, 2010, of whom 2376 were treated 3–4·5 h after symptom onset. The proportion of patients treated within 3–4·5 h by the end of 2009 was three times higher than in the first three quarters of 2008 (282 of 1293 [22%] vs 67 of 1023 [7%]). The median admission-to-treatment time was 65 min both for patients registered before and after October, 2008 (p=0·94). 352 (2%) of 21 204 patients treated within 3 h and 52 (2%) of 2317 treated within 3–4·5 h of stroke had symptomatic intracerebral haemorrhage at 3 months (adjusted odds ratio [OR] 1·44, 95% CI 1·05–1·97; p=0·02). 2287 (12%) of 18 583 patients who were treated within 3 h and 218 (12%) of 1817 who were treated within 3–4·5 h had died by the 3-month follow-up (adjusted OR 1·26, 95% CI 1·07–1·49; p=0·005); 10 531 (57%) of 18 317 patients treated within 3 h of stroke and 1075 (60%) of 1784 who were treated within 3–4·5 h were functionally independent at 3 months (adjusted OR 0·84, 95% CI 0·75–0·95; p=0·005).

Interpretation

Since October, 2008, thrombolysis within 3–4·5 h after stroke has been implemented rapidly, with a simultaneous increase in the number of patients treated within 3 h; admission-to-treatment time has not increased. Safety and functional outcomes are less favourable after 3 h, but the wider time window now offers an opportunity for treatment of those patients who cannot be treated earlier. Thrombolysis should be initiated within 4·5 h after onset of ischaemic stroke, although every effort should be made to treat patients as early as possible after symptom onset.

Funding

Boehringer Ingelheim, Ferrer, the European Union Public Health Executive Authority, and Medical Training and Research (ALF) from Stockholm County Council and Karolinska Institutet.

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)

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

Cited by (258)

  • Diabetes and the treatment of ischemic stroke

    2022, Journal of Diabetes and its Complications
View all citing articles on Scopus

Scientific committee listed at end of paper

View full text