William N Whiteley1, Jonathan Emberson2, Kennedy R Lees3, Lisa Blackwell2, Gregory Albers4, Erich Bluhmki5, Thomas Brott6, Geoff Cohen1, Stephen Davis7, Geoffrey Donnan8, James Grotta9, George Howard10, Markku Kaste11, Masatoshi Koga12, Rüdiger von Kummer13, Maarten G Lansberg4, Richard I Lindley14, Patrick Lyden15, Jean Marc Olivot16, Mark Parsons17, Danilo Toni18, Kazunori Toyoda12, Nils Wahlgren19, Joanna Wardlaw1, Gregory J Del Zoppo20, Peter Sandercock1, Werner Hacke21, Colin Baigent22. 1. University of Edinburgh, Edinburgh, UK. 2. Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford, Oxford, UK. 3. University of Glasgow, Glasgow, UK. 4. Stanford University, Stanford, CA, USA. 5. Boehringer Ingelheim, Ingelheim, Germany. 6. Mayo Clinic, Jacksonville, FL, USA. 7. University of Melbourne, Melbourne, VIC, Australia. 8. Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia. 9. Memorial Hermann Hospital, Houston, TX, USA. 10. University of Alabama, Birmingham, AL, USA. 11. Clinical Neurosciences, Neurology, University of Helsinki, Helsinki, Finland; Department of Neurology, Helsinki University Hospital, Helsinki, Finland. 12. National Cerebral and Cardiovascular Centre, Suita, Japan. 13. Technische Universität, Dresden, Germany. 14. The George Institute for Global Health, University of Sydney, Sydney, NSW, Australia. 15. Department of Neurology, Cedars-Sinai, Los Angeles, CA, USA. 16. Centre Hospitalier Universitaire de Toulouse, France. 17. University of Newcastle, Newcastle, NSW, Australia. 18. Sapienza University, Rome, Italy. 19. Karolinska Institutet, Clinical Neuroscience, Stockholm, Sweden. 20. University of Washington, Seattle, WA, USA. 21. University of Heidelberg, Heidelberg, Germany. 22. Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford, Oxford, UK. Electronic address: STT@ctsu.ox.ac.uk.
Abstract
BACKGROUND: Randomised trials have shown that alteplase improves the odds of a good outcome when delivered within 4·5 h of acute ischaemic stroke. However, alteplase also increases the risk of intracerebral haemorrhage; we aimed to determine the proportional and absolute effects of alteplase on the risks of intracerebral haemorrhage, mortality, and functional impairment in different types of patients. METHODS: We used individual patient data from the Stroke Thrombolysis Trialists' (STT) meta-analysis of randomised trials of alteplase versus placebo (or untreated control) in patients with acute ischaemic stroke. We prespecified assessment of three classifications of intracerebral haemorrhage: type 2 parenchymal haemorrhage within 7 days; Safe Implementation of Thrombolysis in Stroke Monitoring Study's (SITS-MOST) haemorrhage within 24-36 h (type 2 parenchymal haemorrhage with a deterioration of at least 4 points on National Institutes of Health Stroke Scale [NIHSS]); and fatal intracerebral haemorrhage within 7 days. We used logistic regression, stratified by trial, to model the log odds of intracerebral haemorrhage on allocation to alteplase, treatment delay, age, and stroke severity. We did exploratory analyses to assess mortality after intracerebral haemorrhage and examine the absolute risks of intracerebral haemorrhage in the context of functional outcome at 90-180 days. FINDINGS: Data were available from 6756 participants in the nine trials of intravenous alteplase versus control. Alteplase increased the odds of type 2 parenchymal haemorrhage (occurring in 231 [6·8%] of 3391 patients allocated alteplase vs 44 [1·3%] of 3365 patients allocated control; odds ratio [OR] 5·55 [95% CI 4·01-7·70]; absolute excess 5·5% [4·6-6·4]); of SITS-MOST haemorrhage (124 [3·7%] of 3391 vs 19 [0·6%] of 3365; OR 6·67 [4·11-10·84]; absolute excess 3·1% [2·4-3·8]); and of fatal intracerebral haemorrhage (91 [2·7%] of 3391 vs 13 [0·4%] of 3365; OR 7·14 [3·98-12·79]; absolute excess 2·3% [1·7-2·9]). However defined, the proportional increase in intracerebral haemorrhage was similar irrespective of treatment delay, age, or baseline stroke severity, but the absolute excess risk of intracerebral haemorrhage increased with increasing stroke severity: for SITS-MOST intracerebral haemorrhage the absolute excess risk ranged from 1·5% (0·8-2·6%) for strokes with NIHSS 0-4 to 3·7% (2·1-6·3%) for NIHSS 22 or more (p=0·0101). For patients treated within 4·5 h, the absolute increase in the proportion (6·8% [4·0% to 9·5%]) achieving a modified Rankin Scale of 0 or 1 (excellent outcome) exceeded the absolute increase in risk of fatal intracerebral haemorrhage (2·2% [1·5% to 3·0%]) and the increased risk of any death within 90 days (0·9% [-1·4% to 3·2%]). INTERPRETATION: Among patients given alteplase, the net outcome is predicted both by time to treatment (with faster time increasing the proportion achieving an excellent outcome) and stroke severity (with a more severe stroke increasing the absolute risk of intracerebral haemorrhage). Although, within 4·5 h of stroke, the probability of achieving an excellent outcome with alteplase treatment exceeds the risk of death, early treatment is especially important for patients with severe stroke. FUNDING: UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.
BACKGROUND: Randomised trials have shown that alteplase improves the odds of a good outcome when delivered within 4·5 h of acute ischaemic stroke. However, alteplase also increases the risk of intracerebral haemorrhage; we aimed to determine the proportional and absolute effects of alteplase on the risks of intracerebral haemorrhage, mortality, and functional impairment in different types of patients. METHODS: We used individual patient data from the Stroke Thrombolysis Trialists' (STT) meta-analysis of randomised trials of alteplase versus placebo (or untreated control) in patients with acute ischaemic stroke. We prespecified assessment of three classifications of intracerebral haemorrhage: type 2 parenchymal haemorrhage within 7 days; Safe Implementation of Thrombolysis in Stroke Monitoring Study's (SITS-MOST) haemorrhage within 24-36 h (type 2 parenchymal haemorrhage with a deterioration of at least 4 points on National Institutes of Health Stroke Scale [NIHSS]); and fatal intracerebral haemorrhage within 7 days. We used logistic regression, stratified by trial, to model the log odds of intracerebral haemorrhage on allocation to alteplase, treatment delay, age, and stroke severity. We did exploratory analyses to assess mortality after intracerebral haemorrhage and examine the absolute risks of intracerebral haemorrhage in the context of functional outcome at 90-180 days. FINDINGS: Data were available from 6756 participants in the nine trials of intravenous alteplase versus control. Alteplase increased the odds of type 2 parenchymal haemorrhage (occurring in 231 [6·8%] of 3391 patients allocated alteplase vs 44 [1·3%] of 3365 patients allocated control; odds ratio [OR] 5·55 [95% CI 4·01-7·70]; absolute excess 5·5% [4·6-6·4]); of SITS-MOST haemorrhage (124 [3·7%] of 3391 vs 19 [0·6%] of 3365; OR 6·67 [4·11-10·84]; absolute excess 3·1% [2·4-3·8]); and of fatal intracerebral haemorrhage (91 [2·7%] of 3391 vs 13 [0·4%] of 3365; OR 7·14 [3·98-12·79]; absolute excess 2·3% [1·7-2·9]). However defined, the proportional increase in intracerebral haemorrhage was similar irrespective of treatment delay, age, or baseline stroke severity, but the absolute excess risk of intracerebral haemorrhage increased with increasing stroke severity: for SITS-MOST intracerebral haemorrhage the absolute excess risk ranged from 1·5% (0·8-2·6%) for strokes with NIHSS 0-4 to 3·7% (2·1-6·3%) for NIHSS 22 or more (p=0·0101). For patients treated within 4·5 h, the absolute increase in the proportion (6·8% [4·0% to 9·5%]) achieving a modified Rankin Scale of 0 or 1 (excellent outcome) exceeded the absolute increase in risk of fatal intracerebral haemorrhage (2·2% [1·5% to 3·0%]) and the increased risk of any death within 90 days (0·9% [-1·4% to 3·2%]). INTERPRETATION: Among patients given alteplase, the net outcome is predicted both by time to treatment (with faster time increasing the proportion achieving an excellent outcome) and stroke severity (with a more severe stroke increasing the absolute risk of intracerebral haemorrhage). Although, within 4·5 h of stroke, the probability of achieving an excellent outcome with alteplase treatment exceeds the risk of death, early treatment is especially important for patients with severe stroke. FUNDING: UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.
Authors: Andrew D Barreto; Gary A Ford; Loren Shen; Claudia Pedroza; Jon Tyson; Chunyan Cai; Mohammad H Rahbar; James C Grotta Journal: Stroke Date: 2017-05-15 Impact factor: 7.914
Authors: Shahram Majidi; Marie Luby; John K Lynch; Amie W Hsia; Richard T Benson; Chandni P Kalaria; Zurab Nadareishvili; Lawrence L Latour; Richard Leigh Journal: Neurology Date: 2019-09-13 Impact factor: 9.910
Authors: Anuska V Andjelkovic; Jianming Xiang; Svetlana M Stamatovic; Ya Hua; Guohua Xi; Michael M Wang; Richard F Keep Journal: Arterioscler Thromb Vasc Biol Date: 2019-09-12 Impact factor: 8.311
Authors: Babikir Kheiri; Mohammed Osman; Ahmed Abdalla; Tarek Haykal; Sahar Ahmed; Mustafa Hassan; Ghassan Bachuwa; Mohammed Al Qasmi; Deepak L Bhatt Journal: J Thromb Thrombolysis Date: 2018-11 Impact factor: 2.300
Authors: Xia Wang; Thompson G Robinson; Tsong-Hai Lee; Qiang Li; Hisatomi Arima; Philip M Bath; Laurent Billot; Joseph Broderick; Andrew M Demchuk; Geoffrey Donnan; Jong S Kim; Pablo Lavados; Richard I Lindley; Sheila O Martins; Veronica V Olavarria; Jeyaraj D Pandian; Mark W Parsons; Octavio M Pontes-Neto; Stefano Ricci; Vijay K Sharma; Nguyen H Thang; Ji-Guang Wang; Mark Woodward; Craig S Anderson; John Chalmers Journal: JAMA Neurol Date: 2017-11-01 Impact factor: 18.302