Thrombolysis for Acute Ischemic Stroke, Update August 2014
We analyzed all available data from randomized trials testing any thrombolytic agent versus control ≤6 hours after acute ischemic stroke to determine safety, efficacy, and effect-modifying factors.
We searched the Cochrane Stroke Group Trials Register (last searched November 2013), MEDLINE (1966 to November 2013), EMBASE (1980 to November 2013), stroke journals, conference proceedings, ongoing clinical trials registers, contacted trial authors, and pharmaceutical companies.
We included 27 trials,1 involving 10 187 participants (16% aged >80 years), testing urokinase, streptokinase, recombinant tissue-type plasminogen activator (r-tPA), recombinant prourokinase or desmoteplase. Four trials used intra-arterial, the rest intravenous administration. Most trials tested treatment ≤6 hours after stroke, 44% of trials (70% of participants) tested intravenous r-tPA, >50% of trials had high-grade concealment, with few losses to follow-up; 19 of 27 trials were conducted independently of pharmaceutical companies.
Thrombolytic therapy significantly reduced the proportion of participants who were dead or dependent (modified Rankin Scale, 3–6; odds ratio [OR], 0.86; 95% confidence interval [CI], 0.78–0.93; Figure 1), and increased the proportion who were alive with a favorable outcome (modified Rankin Scale, 0–1; OR, 1.33; 95% CI, 1.21–1.46; Figure 2), at 3 to 6 months after stroke.
These late benefits occurred despite thrombolytic therapy increasing the risk of symptomatic intracranial hemorrhage (OR, 3.75; 95% CI, 3.11–4.51) and early death (OR, 1.69; 95% CI, 1.44–1.98), most being attributable to intracranial hemorrhage. In participants surviving the first 7 days, the risk of death was similar in thrombolysis-treated to control patients (OR, 0.88; 95% CI, 0.76–1.02) but by 3 to 6 months after stroke; there was still a modest excess of deaths in thrombolysis-treated patients (OR, 1.18; 95% CI, 1.06–1.30) although not among those treated with r-tPA (OR, 1.06; 95% CI, 0.94–1.20).
Sensitivity analyses identified several factors influencing outcome after thrombolysis:
Thrombolysis treatment <3 hours after stroke significantly reduced death or dependency at 3 to 6 months (OR, 0.66; 95% CI, 0.56–0.79) with no increase in death (OR, 0.99; 95% CI, 0.82–1.21); at progressively later times to treatment, the benefit decreased, disappearing between 4.5 and 6 hours.
Trials testing r-tPA (n=7012) showed a significant reduction in death or dependency with treatment <6 hours (OR, 0.84; 95% CI, 0.77–0.93) with significant between-trial heterogeneity. r-tPA treatment <3 hours was more beneficial (OR, 0.65; 95% CI, 0.54–0.80), without heterogeneity.
Participants aged >80 years benefited equally to those aged <80 years, particularly if treated <3 hours of stroke. There was no evidence of less benefit in patients with severe stroke.
There was no difference in treatment effect between participants randomized after plain computed tomographic versus MR diffusion-perfusion imaging, or with no/small versus large early visible infarct on computed tomography.
Administration of antithrombotic agents contemporaneously with thrombolysis increased the risk of death.
Thrombolytic therapy within 6 hours reduces the proportion of dead or dependent patients after stroke, but most benefit occurs in patients treated within the first 3 hours and declines with later treatment. Most data are available for r-tPA. The benefits of treatment apply to older and younger patients, and regardless of the type of imaging assessment or extent of early visible infarction. This overall benefit was apparent despite an increase in symptomatic intracranial hemorrhage and early deaths.
Services should aim to deliver intravenous r-tPA as fast as possible. Additional trials are needed to identify which patients may still benefit at later times, clarify the effect in mild stroke, and how to reduce risks of symptomatic intracranial hemorrhage and death.
This article is based on a Cochrane Review published in The Cochrane Library 2014, Issue 7 (see http://www.thecochranelibrary.com for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and The Cochrane Library should be consulted for the most recent version of the review. We thank Hazel Fraser and Brenda Thomas of the Cochrane Stroke Group, Edinburgh/Glasgow, for their assistance with literature searching.
Sources of Funding
The update was supported by a grant from the United Kingdom National Institutes of Health Research Cochrane Review Incentive Scheme 2013. The review was assembled, analyzed, and reported independently of any sponsor or pharmaceutical company.
Full disclosures are given in Wardlaw et al.1 Drs Wardlaw, Murray, Berge were investigators in The Third International Stroke Trial (IST-3). The authors hold academic grants administered by their institutions for research in stroke. Dr del Zoppo received research funding from Boehringer Ingelheim GmbH.
- Received September 5, 2014.
- Revision received September 5, 2014.
- Accepted September 11, 2014.
- © 2014 American Heart Association, Inc.
- Wardlaw JM,
- Murray V,
- Berge E,
- del Zoppo GJ