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Brief Report
November 2, 2020

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

Author Affiliations
  • 1Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
  • 2Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
  • 3Department of Medicine, School of Clinical Science, Monash University, Clayton, Victoria, Australia
  • 4Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia
  • 5Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  • 6Department of Neurology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
  • 7Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
  • 8Department of Neurosciences, Eastern Health and Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia
  • 9Prince of Wales Clinical School, University of New South Wales, Randwick, New South Wales, Australia
  • 10Department of Radiology, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
  • 11Department of Medicine, Melbourne Medical School, University of Melbourne and Western Health, Sunshine Hospital, St Albans, Victoria, Australia
  • 12New South Wales and Maridulu Budyari Gumal, The Sydney Partnership for Health, Education Research and Enterprise (SPHERE), University of New South Wales, Sydney, Australia
  • 13Department of Neurology, Helsinki University Hospital, Helsinki, Finland
  • 14Department of Medicine, University of Auckland, Auckland, New Zealand
  • 15Department of Neurology, Singapore General Hospital Campus, National Neuroscience Institute, Singapore
  • 16Department of Neurology, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia
  • 17Department of Neurology, Priority Research Centre for Stroke and Brain Injury, John Hunter Hospital, University of Newcastle, Newcastle, Australia
  • 18Ambulance Victoria, Melbourne, Victoria, Australia
JAMA Neurol. 2021;78(2):236-240. doi:10.1001/jamaneurol.2020.4123
Key Points

Question  Does the benefit of reperfusion in patients with ischemic stroke with perfusion imaging mismatch vary in trials of intravenous thrombolysis beyond 4.5 hours?

Finding  In this meta-analysis of 2 randomized clinical trials that included 295 patients, reperfusion was strongly associated with improved functional outcomes in 4.5- to 6-hours, 6- to 9-hours, and wake-up stroke time epochs with no heterogeneity in the beneficial association of reperfusion with outcomes by time to randomization and similar risk of symptomatic intracerebral hemorrhage.

Meaning  These data provide reassurance that the benefits and risks of thrombolysis-induced reperfusion are consistent across the 4.5- to 6-hours, 6- to 9-hours, and wake-up stroke patient groups selected using perfusion mismatch.


Importance  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.

Objective  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.

Design, Setting, and Participants  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.

Exposures  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.

Main Outcomes and Measures  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.

Results  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).

Conclusions and Relevance  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.

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