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Title: Association of Reperfusion After Thrombolysis With Clinical Outcome Across the 4.5- to 9-Hours and Wake-Up Stroke Time Window: A Meta-Analysis of the EXTEND and EPITHET Randomized Clinical Trials.
Austin Authors: Campbell, Bruce C V;Ma, Henry;Parsons, Mark W;Churilov, Leonid ;Yassi, Nawaf;Kleinig, Timothy J;Hsu, Chung Y;Dewey, Helen M;Butcher, Kenneth S;Yan, Bernard;Desmond, Patricia M;Wijeratne, Tissa;Curtze, Sami;Barber, P Alan;De Silva, Deidre A;Thijs, Vincent N ;Levi, Christopher R;Bladin, Christopher F;Sharma, Gagan;Bivard, Andrew;Donnan, Geoffrey A ;Davis, Stephen M
Affiliation: Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Department of Neurology, Priority Research Centre for Stroke and Brain Injury, John Hunter Hospital, University of Newcastle, Newcastle, Australia
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
Department of Medicine, Melbourne Medical School, University of Melbourne and Western Health, Sunshine Hospital, St Albans, Victoria, Australia
Ambulance Victoria, Melbourne, Victoria, Australia
Department of Neurology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
Medicine (University of Melbourne)
Department of Medicine, School of Clinical Science, Monash University, Clayton, Victoria, Australia
Department of Radiology, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
Prince of Wales Clinical School, University of New South Wales, Randwick, New South Wales, Australia
Department of Neurosciences, Eastern Health and Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia
New South Wales and Maridulu Budyari Gumal, The Sydney Partnership for Health, Education Research and Enterprise (SPHERE), University of New South Wales, Sydney, Australia
Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
Department of Neurology, Helsinki University Hospital, Helsinki, Finland
Department of Medicine, University of Auckland, Auckland, New Zealand
Department of Neurology, Singapore General Hospital Campus, National Neuroscience Institute, Singapore
Issue Date: 2-Nov-2020 2020-11-02
Publication information: JAMA Neurology 2020; online first: 2 November
Abstract: Intravenous alteplase reduces disability after ischemic stroke in patients 4.5 to 9 hours after onset and with wake-up onset stroke selected using perfusion imaging mismatch. However, whether the benefit is consistent across the 4.5- to 6-hours, 6- to 9-hours, and wake-up stroke epochs is uncertain. To examine the association of reperfusion with reduced disability, including by onset-to-randomization time strata in the Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) and Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) randomized clinical trials. Individual patient meta-analysis of randomized clinical trials performed from August 2001 to June 2018 with 3-month follow-up. Patients had acute ischemic stroke with 4.5-to 9-hours poststroke onset or with wake-up stroke were randomized to alteplase or placebo after perfusion mismatch imaging. Analysis began July 2019 and ended May 2020. Reperfusion was defined as more than 90% reduction in time to maximum of more than 6 seconds' lesion volume at 24- to 72-hour follow-up. Ordinal logistic regression adjusted for baseline age and National Institutes of Health Stroke Scale score was used to analyze functional improvement in day 90 modified Rankin Scale score overall, including a reperfusion × time-to-randomization multiplicative interaction term, and in the 4.5- to 6-hours, 6- to 9-hours, and wake-up time strata. Symptomatic hemorrhage was defined as large parenchymal hematoma with a National Institutes of Health Stroke Scale score increase of 4 points or more. Reperfusion was assessable in 270 of 295 patients (92%), 68 of 133 (51%) in the alteplase group, and 38 of 137 (28%) in the placebo reperfused group (P < .001). The median (interquartile range) age was 76 (66-81) years in the reperfusion group vs 74 (64.5-81.0) years in the group with no reperfusion. The median (interquartile range) baseline National Institutes of Health Stroke Scale score was 10 (7-15) in the reperfusion group vs 12 (8.0-17.5) in the no reperfusion group. Overall, reperfusion was associated with improved functional outcome (common odds ratio, 7.7; 95% CI, 4.6-12.8; P < .001). Reperfusion was associated with significantly improved functional outcome in each of the 4.5- to 6-hours, 6- to 9-hours, and wake-up time strata, with no evidence of association between time to randomization and beneficial effect of reperfusion (P = .63). Symptomatic hemorrhage, assessed in all 294 patients, occurred in 3 of 51 (5.9%) in the 4.5- to 6-hours group, 2 of 28 (7.1%) in the 6- to 9-hours group, and 4 of 73 (5.5%) in the wake-up stroke in patients treated with alteplase (Fisher P = .91). Strong benefits of reperfusion in all time strata without differential risk in symptomatic hemorrhage support the consistent treatment effect of alteplase in perfusion mismatch-selected patients throughout the 4.5- to 9-hours and wake-up stroke time window.
DOI: 10.1001/jamaneurol.2020.4123
PubMed URL: 33137171
Type: Journal Article
Appears in Collections:Journal articles

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