Elsevier

The Lancet

Volume 372, Issue 9646, 11–17 October 2008, Pages 1303-1309
The Lancet

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Thrombolysis with alteplase 3–4·5 h after acute ischaemic stroke (SITS-ISTR): an observational study

https://doi.org/10.1016/S0140-6736(08)61339-2Get rights and content

Summary

Background

Intravenous alteplase is approved for use within 3 h of ischaemic stroke onset, although a meta-analysis of randomised controlled trials suggests treatment benefit up to 4·5 h. We compared outcome in patients treated between 3 h and 4·5 h versus those treated within 3 h, who were recorded in the in the Safe Implementation of Treatments in Stroke (SITS), a prospective internet-based audit of the International Stroke Thrombolysis Registry (ISTR).

Methods

We compared 664 patients presenting with ischaemic stroke and given intravenous altepase (0·9 mg/kg total dose) between 3 h and 4·5 h with 11 865 patients treated within 3 h. All patients were otherwise compliant with European summary of product characteristics criteria and had been documented in the international stroke treatment registry between Dec 25, 2002, and Nov 15, 2007. Outcome measures were symptomatic intracerebral haemorrhage within 24 h (haemorrhage type 2 associated with National Institutes of Health Stroke Scale [NIHSS] ≥4 points deterioration), and mortality and independence (modified Rankin scale of 0–2) at 3 months.

Findings

In the 3–4·5-h cohort, treatment was started at a median of 55 min later after symptom onset (195 min [IQR 187–210] vs 140 min [115–165], p<0·0001), median age was 3 years younger (65 years [55–73] vs 68 years [58–74], p<0·0001), and stroke severity was lower (NIHSS score 11 [7–16] vs 12 [8–17], p<0·0001) than in the 3-h cohort. We recorded no significant differences between the 3–4·5-h cohort and the within 3-h cohort for any outcome measure—rate of symptomatic intracerebral haemorrhage: 2·2% (14 of 649) versus 1·6% (183 of 11 681) (odds ratio [OR] 1·18 [95% CI 0·89–1·55], p=0·24; adjusted OR 1·32 [1·00–1·75], p=0·052); mortality: 12·7% (70 of 551) versus 12·2% (1263 of 10 368) (OR 1·02 [0·90–1·17]; p=0·72; adjusted OR 1·15 [1·00–1·33]; p=0·053); and independence: 58·0% (314 of 541) versus 56·3% (5756 of 10231) (OR 1·04 [0·95–1·13], p=0·42; adjusted OR 0·93 [0·84–1·03], p=0·18).

Interpretation

Alteplase remains safe when given at 3–4·5 h after ischaemic stroke, offering an opportunity for patients who cannot be treated within the standard 3-h timeframe.

Funding

Boehringer-Ingelheim, European Union Public Health Executive Authority.

Introduction

Alteplase—a recombinant tissue plasminogen activator—was approved by the European Medicines Evaluation Agency (EMEA) in 2002 for the intravenous treatment of acute ischaemic stroke, with initiation within 3 h of stroke onset. The EMEA requested that treatment outcomes were monitored in the Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST). This study confirmed that the rates of symptomatic intracerebral haemorrhage, mortality, and independence in activities of daily living for patients treated in routine clinical practice were similar to the outcomes of randomised controlled trials.1 Minor differences were recorded in demographic factors and baseline variables between patients treated in randomised controlled trials versus those in the register, but outcomes were confirmed even after correction for these differences.2

Hacke and colleagues3 analysed pooled data from six trials on intravenous alteplase in stroke4, 5, 6, 7, 8 and noted that the proportion of patients with full recovery decreased successively with increased time between stroke onset and treatment initiation; however, a significant benefit persisted for treatment initiation up to 4·5 h.3

SITS (Safe Implementation of Treatments in Stroke)9 is a collaboration of more than 700 clinical centres in 35 countries for documentation of treatments for stroke in an interactive database over a secure internet portal. It is an international register of unselected patients who are given thrombolysis for acute stroke in accordance with broadly accepted guidelines10, 11 (SITS-international stroke treatment registry [SITS-ISTR]), but includes a subgroup of patients from European centres who were treated according to the SITS-MOST criteria approved under the European marketing licence for alteplase. In addition to these criteria, centres might decide to treat patients with thrombolysis after individual assessment of neurological status and imaging studies. Centres participating in SITS commit themselves to register all treated patients in SITS-ISTR, irrespective of whether they fulfil the SITS-MOST criteria.

We hypothesised that outcomes for patients treated in routine clinical practice with intravenous alteplase between 3 h and 4·5 h after ischaemic stroke onset, who were documented in SITS-ISTR, would be similar to outcomes for patients treated within 0–3 h. We compared these two cohorts of patients in whom time to treatment was the main difference, to test for differences in the rates of symptomatic haemorrhage, death, and functional recovery due to treatment delay.

Section snippets

Study population and design

Details of the method, including data collection and management for SITS-ISTR and SITS-MOST, have been described previously.1 We included patients presenting with ischaemic stroke who were given intravenous alteplase (Boehringer-Ingelheim, Ingelheim, Germany) between 3 h and 4·5 h after symptom onset and registered in SITS-ISTR—a prospective, multinational, internet-based register for patients given this drug after acute ischaemic stroke9—between Dec 25, 2002, and Nov 15, 2007. As a comparator

Results

We included data for 664 patients with alteplase treatment started between 3 h and 4·5 h after ischaemic stroke onset and for 11 865 patients treated within 3 h. Of 478 clinical centres in 31 countries that were actively documenting thrombolysis data, 203 centres from 25 countries registered treatments during 3–4·5 h.

Table 1 shows baseline and demographic characteristics of patients in both groups. In the 3–4·5-h cohort, treatment was started at a median of 55 min later after symptom onset,

Discussion

Our results show that the rates of symptomatic intracerebral haemorrhage, mortality, and independence at 3 months follow-up in routine clinical practice are similar between patients for whom treatment was started between 3 h and 4·5 h and for those treated within 3 h after ischaemic stroke onset. Our findings lend support to those of the meta-analysis suggesting a potentially longer timeframe for intravenous thrombolysis of 4·5 h.3 Although the meta-analysis findings need confirmation in a

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