Thrombolysis for acute ischaemic stroke

Joanna M Wardlaw, Veronica Murray, Eivind Berge, Gregory J del Zoppo, Joanna M Wardlaw, Veronica Murray, Eivind Berge, Gregory J del Zoppo

Abstract

Background: Most strokes are due to blockage of an artery in the brain by a blood clot. Prompt treatment with thrombolytic drugs can restore blood flow before major brain damage has occurred and improve recovery after stroke in some people. Thrombolytic drugs, however, can also cause serious bleeding in the brain, which can be fatal. One drug, recombinant tissue plasminogen activator (rt-PA), is licensed for use in selected patients within 4.5 hours of stroke in Europe and within three hours in the USA. There is an upper age limit of 80 years in some countries, and a limitation to mainly non-severe stroke in others. Forty per cent more data are available since this review was last updated in 2009.

Objectives: To determine whether, and in what circumstances, thrombolytic therapy might be an effective and safe treatment for acute ischaemic stroke.

Search methods: We searched the Cochrane Stroke Group Trials Register (last searched November 2013), MEDLINE (1966 to November 2013) and EMBASE (1980 to November 2013). We also handsearched conference proceedings and journals, searched reference lists and contacted pharmaceutical companies and trialists.

Selection criteria: Randomised trials of any thrombolytic agent compared with control in people with definite ischaemic stroke.

Data collection and analysis: Two review authors applied the inclusion criteria, extracted data and assessed trial quality. We verified the extracted data with investigators of all major trials, obtaining additional unpublished data if available.

Main results: We included 27 trials, involving 10,187 participants, testing urokinase, streptokinase, rt-PA, recombinant pro-urokinase or desmoteplase. Four trials used intra-arterial administration, while the rest used the intravenous route. Most data come from trials that started treatment up to six hours after stroke. About 44% of the trials (about 70% of the participants) were testing intravenous rt-PA. In earlier studies very few of the participants (0.5%) were aged over 80 years; in this update, 16% of participants are over 80 years of age due to the inclusion of IST-3 (53% of participants in this trial were aged over 80 years). Trials published more recently utilised computerised randomisation, so there are less likely to be baseline imbalances than in previous versions of the review. More than 50% of trials fulfilled criteria for high-grade concealment; there were few losses to follow-up for the main outcomes.Thrombolytic therapy, mostly administered up to six hours after ischaemic stroke, significantly reduced the proportion of participants who were dead or dependent (modified Rankin 3 to 6) at three to six months after stroke (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.78 to 0.93). Thrombolytic therapy increased the risk of symptomatic intracranial haemorrhage (OR 3.75, 95% CI 3.11 to 4.51), early death (OR 1.69, 95% CI 1.44 to 1.98; 13 trials, 7458 participants) and death by three to six months after stroke (OR 1.18, 95% CI 1.06 to 1.30). Early death after thrombolysis was mostly attributable to intracranial haemorrhage. Treatment within three hours of stroke was more effective in reducing death or dependency (OR 0.66, 95% CI 0.56 to 0.79) without any increase in death (OR 0.99, 95% CI 0.82 to 1.21; 11 trials, 2187 participants). There was heterogeneity between the trials. Contemporaneous antithrombotic drugs increased the risk of death. Trials testing rt-PA showed a significant reduction in death or dependency with treatment up to six hours (OR 0.84, 95% CI 0.77 to 0.93, P = 0.0006; 8 trials, 6729 participants) with significant heterogeneity; treatment within three hours was more beneficial (OR 0.65, 95% CI 0.54 to 0.80, P < 0.0001; 6 trials, 1779 participants) without heterogeneity. Participants aged over 80 years benefited equally to those aged under 80 years, particularly if treated within three hours of stroke.

Authors' conclusions: Thrombolytic therapy given up to six hours after stroke reduces the proportion of dead or dependent people. Those treated within the first three hours derive substantially more benefit than with later treatment. This overall benefit was apparent despite an increase in symptomatic intracranial haemorrhage, deaths at seven to 10 days, and deaths at final follow-up (except for trials testing rt-PA, which had no effect on death at final follow-up). Further trials are needed to identify the latest time window, whether people with mild stroke benefit from thrombolysis, to find ways of reducing symptomatic intracranial haemorrhage and deaths, and to identify the environment in which thrombolysis may best be given in routine practice.

Conflict of interest statement

The Division of Clinical Neurosciences at the University of Edinburgh had a collaborative project with Boehringer Ingelheim (UK) to establish a research magnetic resonance scanner, through the UK Research Councils Joint Research Equipment Initiative in 1997. For this, the Division received a grant from Boehringer Ingelheim, manufacturers of rt‐PA in Europe, towards the purchase of the scanner. Further details of competing interests are listed on the Division's web site (www.dcn.ed.ac.uk).

The Division of Clinical Neurosciences at the University of Edinburgh are co‐ordinating the Third International Stroke Trial (IST3 2012) of intravenous tissue Plasminogen Activator within six hours of acute ischaemic stroke. Prof Joanna Wardlaw is the Imaging Principal Investigator of this trial, Dr Veronica Murray is the Swedish National Co‐ordinator and Dr Eivind Berge is the Norwegian National Co‐ordinator for IST‐3. The start‐up phase was funded by the UK Stroke Association and PPP Foundation, with a limited supply of drug and placebo for the first part of the start‐up phase from Boehringer Ingelheim; the main trial is funded by the UK Medical Research Council.

Prof Joanna Wardlaw received payment from Boehringer Ingelheim for reading scans for ECASS 3 on a cost‐per‐scan basis up to 2008. She was/is on the Steering Committees of MAST‐I 1995, IST3 2012, and contributed to the design of ECASS 3 2008 (first Steering Committee meeting and design of scan reading). Boehringer Ingelheim applied for an extension to the licence for rt‐PA from three to 4.5 hours on the basis of the ECASS 3 2008 result and supporting data, such as individual patient data analyses and the Cochrane review.

The review was assembled, analysed and reported independent of any sponsor or pharmaceutical company.