Elsevier

The Lancet

Volume 363, Issue 9411, 6 March 2004, Pages 768-774
The Lancet

Articles
Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials

https://doi.org/10.1016/S0140-6736(04)15692-4Get rights and content

Summary

Background

Quick administration of intravenous recombinant tissue plasminogen activator (rt-PA) after stroke improved outcomes in previous trials. We aimed to analyse combined data for individual patients to confirm the importance of rapid treatment.

Methods

We pooled common data elements from six randomised placebo-controlled trials of intravenous rt-PA. Using multivariable logistic regression we assessed the relation of the interval from stroke onset to start of treatment (OTT) on favourable 3-month outcome and on the occurrence of clinically relevant parenchymal haemorrhage.

Findings

Treatment was started within 360 min of onset of stroke in 2775 patients randomly allocated to rt-PA or placebo. Median age was 68 years, median baseline National Institute of Health Stroke Scale (NIHSS) 11, and median OTT 243 min. Odds of a favourable 3-month outcome increased as OTT decreased (p=0·005). Odds were 2·8 (95% CI 1·8–4·5) for 0–90 min, 1·6 (1·1–2·2) for 91–180 min, 1·4 (1·1–1·9) for 181–270 min, and 1·2 (0·9–1·5) for 271–360 min in favour of the rt-PA group. The hazard ratio for death adjusted for baseline NIHSS was not different from 1·0 for the 0–90, 91–180, and 181–270 min intervals; for 271–360 min it was 1·45 (1·02–2·07). Haemorrhage was seen in 82 (5·9%) rt-PA patients and 15 (1·1%) controls (p<0·0001). Haemorrhage was not associated with OTT but was with rt-PA treatment (p=0·0001) and age (p=0·0002).

Interpretation

The sooner that rt-PA is given to stroke patients, the greater the benefit, especially if started within 90 min. Our results suggest a potential benefit beyond 3 h, but this potential might come with some risks.

Introduction

Thrombolysis with intravenous rt-PA is effective for strokes due to acute cerebral ischaemia when given within 3 h of symptom onset. In six large, multicentre, randomised, placebo-controlled trials researchers tested the benefits of rt-PA for acute stroke within 6 h of onset.1, 2, 3, 4, 5 The investigators used similar doses of rt-PA and had common outcome measures, but the maximum time allowed to start rt-PA infusion ranged from 3 to 6 h. The most appropriate interval for beginning thrombolytic treatment remains to be clarified. Better understanding of the therapeutic window for intravenous rt-PA is important because the short time currently allocated for treatment is the greatest barrier to wider application of thrombolytic therapy.

The chance of benefit from intravenous rt-PA diminishes as time elapses during the first 3 h after onset of the stroke.6 By combining individual patients' data from six trials, we have extended this analysis to 6 h. The trials were: two National Institute of Neurological Disorders and Stroke (NINDS) trials (parts 1 and 2, 3-h window), two ECASS trials (6-h window), and two ATLANTIS trials (part A, 6-h window and part B, 5-h window). We sought to determine whether time-to-treatment with intravenous thrombolytic therapy is a critical predictor of therapeutic benefit.

Section snippets

Patients

The trials we analysed represent all major investigations of rt-PA for acute stroke and more than 99% of all patients treated with intravenous rt-PA in randomised controlled clinical trials of acute ischaemic stroke identified in an ongoing cumulative meta-analysis.7 From all investigations of rt-PA identified in that meta-analysis, the results of only one small (n=27) randomised pilot feasibility trial were not included because different endpoints were used.8 For our combined analysis, a

Results

The ITT analysis included 2775 patients treated at more than 300 hospitals from 18 countries. All trials included some community hospitals. Median age was 68 years, IQR 60–74 years, and 84·6% were reported as white (non-Hispanic), 9·1% as black (non-Hispanic), 2·0% as Hispanic, 0·9% as Asian, and 0·6% as being from other ethnic backgrounds. Ethnic background was not reported for 2·8%. Median baseline NIHSS score was 11, and median OTT 243 min. 1847 patients (67%) were treated for longer than 3

Discussion

Our results confirm that rapid treatment is associated with better outcomes at 3 months. Previously, NINDS Stroke Study investigators reported that the probability of benefit from intravenous rt-PA in the combined data from the two NINDS trials diminishes as time elapses during the first 3 h after onset of the stroke.6 Our results confirm and expand on this finding. For example, the odds ratio of a favourable outcome for patients treated with rt-PA compared with controls was 2·81 (1·75–4·50)

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