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Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials
Open accessAbstract
BACKGROUND: Alteplase is effective for treatment of acute ischaemic stroke but debate continues about its use after longer times since stroke onset, in older patients, and among patients who have had the least or most severe strokes. We assessed the role of these factors in affecting good stroke outcome in patients given alteplase. METHODS: We did a pre-specified meta-analysis of individual patient data from 6756 patients in nine randomised trials comparing alteplase with placebo or open control. We included all completed randomised phase 3 trials of intravenous alteplase for treatment of acute ischaemic stroke for which data were available. Retrospective checks confirmed that no eligible trials had been omitted. We defined a good stroke outcome as no significant disability at 3-6 months, defined by a modified Rankin Score of 0 or 1. Additional outcomes included symptomatic intracranial haemorrhage (defined by type 2 parenchymal haemorrhage within 7 days and, separately, by the SITS-MOST definition of parenchymal type 2 haemorrhage within 36 h), fatal intracranial haemorrhage within 7 days, and 90-day mortality. FINDINGS: Alteplase increased the odds of a good stroke outcome, with earlier treatment associated with bigger proportional benefit. Treatment within 3·0 h resulted in a good outcome for 259 (32·9%) of 787 patients who received alteplase versus 176 (23·1%) of 762 who received control (OR 1·75, 95% CI 1·35-2·27); delay of greater than 3·0 h, up to 4·5 h, resulted in good outcome for 485 (35·3%) of 1375 versus 432 (30·1%) of 1437 (OR 1·26, 95% CI 1·05-1·51); and delay of more than 4·5 h resulted in good outcome for 401 (32·6%) of 1229 versus 357 (30·6%) of 1166 (OR 1·15, 95% CI 0·95-1·40). Proportional treatment benefits were similar irrespective of age or stroke severity. Alteplase significantly increased the odds of symptomatic intracranial haemorrhage (type 2 parenchymal haemorrhage definition 231 [6·8%] of 3391 vs 44 [1·3%] of 3365, OR 5·55, 95% CI 4·01-7·70, p<0·0001; SITS-MOST definition 124 [3·7%] vs 19 [0·6%], OR 6·67, 95% CI 4·11-10·84, p<0·0001) and of fatal intracranial haemorrhage within 7 days (91 [2·7%] vs 13 [0·4%]; OR 7·14, 95% CI 3·98-12·79, p<0·0001). The relative increase in fatal intracranial haemorrhage from alteplase was similar irrespective of treatment delay, age, or stroke severity, but the absolute excess risk attributable to alteplase was bigger among patients who had more severe strokes. There was no excess in other early causes of death and no significant effect on later causes of death. Consequently, mortality at 90 days was 608 (17·9%) in the alteplase group versus 556 (16·5%) in the control group (hazard ratio 1·11, 95% CI 0·99-1·25, p=0·07). Taken together, therefore, despite an average absolute increased risk of early death from intracranial haemorrhage of about 2%, by 3-6 months this risk was offset by an average absolute increase in disability-free survival of about 10% for patients treated within 3·0 h and about 5% for patients treated after 3·0 h, up to 4·5 h. INTERPRETATION: Irrespective of age or stroke severity, and despite an increased risk of fatal intracranial haemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4·5 h of stroke onset, with earlier treatment associated with bigger proportional benefits. FUNDING: UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.
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“The atrial and systemic activation of the coagulation system can partially explain why short episodes of AF convey a longterm stroke risk.471”
From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [471]
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“Systemic thrombolysis with recombinant tissue plasminogen activator (rtPA) is an effective and approved medical treatment for acute ischaemic stroke in patients presenting within 4.5 hours of symptom onset.471”
From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [471]
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Metadata
- Authors
- Emberson, J., Lees, K. R., Lyden, P., Blackwell, L., Albers, G., Bluhmki, E., Brott, T., Cohen, G., Davis, S., Donnan, G., Grotta, J., Howard, G., Kaste, M., Koga, M., von Kummer, R., Lansberg, M., Lindley, R. I., Murray, G., Olivot, J. M., Parsons, M., Tilley, B., Toni, D., Toyoda, K., Wahlgren, N., Wardlaw, J., Whiteley, W., del Zoppo, G. J., Baigent, C., Sandercock, P., & Hacke, W.
- Affiliations
- University of Oxford (GB)
- University of Glasgow (GB)
- Cedars-Sinai Medical Center (US)
- Stanford University (US)
- Boehringer Ingelheim (Germany) (DE)
- Mayo Clinic in Florida (US)
- University of Edinburgh (GB)
- The University of Melbourne (AU)
- Florey Institute of Neuroscience and Mental Health (AU)
- The University of Texas Health Science Center at Houston (US)
- University of Alabama at Birmingham (US)
- Helsinki University Hospital (FI)
- National Cerebral and Cardiovascular Center (JP)
- The University of Sydney (AU)
- University of Newcastle Australia (AU)
- Sapienza University of Rome (IT)
- Karolinska Institutet (SE)
- Heidelberg University (DE)
- Corresponding author
- Baigent, Colin
- ORCID
- Emberson, Jonathan
- Lees, Kennedy R
- Lyden, Patrick
- Albers, Gregory
- Bluhmki, Erich
- Davis, Stephen
- Donnan, Geoffrey
- Grotta, James
- Howard, George
- Kaste, Markku
- Koga, Masatoshi
- Lansberg, Maarten
- Lindley, Richard I
- Murray, Gordon
- Olivot, Jean Marc
- Parsons, Mark
- Tilley, Barbara
- Toni, Danilo
- Wahlgren, Nils
- Wardlaw, Joanna
- Whiteley, William
- Baigent, Colin
- Sandercock, Peter
- Hacke, Werner
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 384
- Issue
- 9958
- Pages
- 1929-1935
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC4441266
- OpenAlex
- W2165568749
- Cited by
- 2,737
- References
- 32
- Citations by year
- 2026: 187 · 2025: 239 · 2024: 289 · 2023: 236 · 2022: 249 · 2021: 291 · 2020: 243 · 2019: 232 · 2018: 201 · 2017: 182 · 2016: 190 · 2015: 162 · 2014: 31
- FWCI
- 25.13
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The Lancet (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Figshare (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- NOVA (University of Newcastle Australia) (submittedVersion)
- Funders
- Medical Research Council
- British Heart Foundation
- Topics
- Health Sciences › Medicine › Clinical Neurology › Acute Ischemic Stroke Management
- Health Sciences › Medicine › Clinical Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
- Keywords
- alteplase, intravenous thrombolysis, acute ischemic stroke, treatment delay, age, stroke severity, modified Rankin Scale, symptomatic intracranial hemorrhage, 90-day mortality, individual patient data, elderly patients, severe stroke, subgroup analysis, prognostic factors
- MeSH terms
- Acute Disease, Age Factors, Aged, Aged, 80 and over, Female, Fibrinolytic Agents, Humans, Infusions, Intravenous, Male, Middle Aged, Tissue Plasminogen Activator, Randomized Controlled Trials as Topic, Treatment Outcome, Clinical Trials, Phase III as Topic, Intracranial Hemorrhages, Stroke, Time-to-Treatment
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