Elsevier

The Lancet

Volume 369, Issue 9558, 27 January–2 February 2007, Pages 275-282
The Lancet

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Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study

https://doi.org/10.1016/S0140-6736(07)60149-4Get rights and content

Summary

Background

The aim of the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) was to assess the safety and efficacy of intravenous alteplase as thrombolytic therapy within the first 3 h of onset of acute ischaemic stroke. Under European Union regulations, SITS-MOST was required to assess the safety profile of alteplase in clinical practice by comparison with results in randomised controlled trials.

Methods

6483 patients were recruited from 285 centres (50% with little previous experience in stroke thrombolysis) in 14 countries between 2002 and 2006 for this prospective, open, monitored, observational study. Primary outcomes were symptomatic (a deterioration in National Institutes of Health stroke scale score of ≥4) intracerebral haemorrhage type 2 within 24 h and mortality at 3 months. We compared mortality, the proportion of patients with symptomatic intracerebral haemorrhage as per the Cochrane definition, and functional outcome at 3 months with relevant pooled results from randomised controlled trials.

Findings

Baseline characteristics of patients in SITS-MOST were much the same as those in the pooled randomised controlled trials. At 24 h, the proportion of patients with symptomatic intracerebral haemorrhage (per the SITS-MOST protocol) was 1·7% (107/6444; 95% CI 1·4–2·0); at 7 days, the proportion with the same condition as per the Cochrane definition was 7·3% (468/6438; 6·7–7·9) compared with 8·6% (40/465; 6·3–11·6) in the pooled randomised controlled trials. The mortality rate at 3 months in SITS-MOST was 11·3% (701/6218; 10·5–12·1) compared with 17·3% (83/479; 14·1–21·1) in the pooled randomised controlled trials.

Interpretation

These data confirm that intravenous alteplase is safe and effective in routine clinical use when used within 3 h of stroke onset, even by centres with little previous experience of thrombolytic therapy for acute stroke. The findings should encourage wider use of thrombolytic therapy for suitable patients treated in stroke centres.

Introduction

Stroke is one of the leading causes of death and disability in developed countries.1 Although considerable progress has been made in developing effective prevention and treatment, substantial challenges remain to improve the quality of care. In particular, concern has focused on the speed of emergency response, since the time taken to initiate thrombolytic treatment after the onset of stroke symptoms affects the extent of tissue damage and the possibility of recovery without impairment.2

Alteplase (recombinant tissue plasminogen activator) is currently the only approved medical therapy for patients with acute ischaemic stroke and is recommended as first-line treatment by most national and international stroke associations.3, 4, 5 Intravenous treatment of ischaemic stroke with alteplase within a 3-h window of stroke onset has been shown to be safe and effective in randomised controlled trials.2, 6, 7, 8, 9, 10 Studies have shown that patients treated with alteplase are at least 30% more likely to have little or no disability at 3 months than those who did not receive this treatment,10 and the estimated number of patients needed-to-treat to identify clinical benefit is only three.11 However, concerns have been voiced over the applicability of data from randomised controlled trials to individuals in daily clinical practice, especially considering the short time within which treatment must be given and the potential risks of intracerebral haemorrhages when thrombolytic therapy is applied.

Alteplase was licensed for the treatment of acute ischaemic stroke in the USA in 1996, and in Canada in 1999, for selected patients treated within 3 h of symptom onset.10 In the European Union (EU), a licence was granted in 2002 on two conditions: the setting in place of an observational safety study, the Safe Implementation of Thrombolysis in Stroke–Monitoring Study (SITS-MOST) to assess the safety profile of alteplase in routine clinical practice within 3 h of the onset of stroke symptoms, and the initiation of a new randomised trial, the European Cooperative Acute Stroke Study (ECASS) III, with a therapeutic window extended beyond 3 h. The results of both studies will serve as a basis for the reassessment of the benefit/risk profile of alteplase for the thrombolytic treatment of acute ischaemic stroke in the EU.

The main aim of SITS-MOST was to investigate whether treatment with intravenous alteplase within 3 h of ischaemic stroke symptoms is as safe as is reported in randomised controlled trials12, 13 when incorporated into clinical practice across a wide range of centres. Here, we report the primary and secondary outcome variables of SITS-MOST.

Section snippets

Patients and procedures

SITS-MOST was a prospective, open, multicentre, multinational, observational monitoring study for clinical centres practising thrombolysis for acute stroke within the member states of the EU as of 2002, plus Norway and Iceland. The study was established as a cohort of the existing SITS-International Stroke Thrombolysis Register (SITS-ISTR), an internet-based academic interactive thrombolysis register.14 SITS-ISTR allows the continuous monitoring of thrombolytic treatment in acute ischaemic

Results

6483 patients were included in SITS-MOST at 285 centres in 14 European countries between December, 2002, and April, 2006. The number of centres and patients recruited by country is shown in the webappendix.

Acute follow-up data (up to 7 days) were obtained in 6476 (99·9%) patients. NIHSS data were complete at baseline in 6474 (99·9%), at 2 h in 6151 (94·9%), at 24 h in 6211 (95·8%), and at 7 days in 5423 (83·6%) patients. Follow-up data for modified Rankin score at 3 months were available for

Discussion

The results from SITS-MOST confirm that alteplase, when used in routine clinical practice, has a safety profile at least as good as that seen in randomised controlled trials and is an effective treatment when used within 3 h of stroke onset, even in stroke centres with little previous experience of thrombolytic therapy for acute stroke. Although mortality was higher in less experienced centres than in those with previous experience, it was lower than in randomised controlled trials, and the

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