Association of Reperfusion After Thrombolysis With Clinical Outcome Across the 4.5- to 9-Hours and Wake-up Stroke Time Window
Authors: Bruce C. V. Campbell, Henry Ma, Mark W. Parsons, Leonid Churilov, Nawaf Yassi, Timothy J. Kleinig, Chung Y. Hsu, Helen M. Dewey, Kenneth S. Butcher, Bernard Yan, Patricia M. Desmond, Tissa Wijeratne, Sami Curtze, P. Alan Barber, Deidre A. De Silva, Vincent Thijs, Christopher R. Levi, Christopher F. Bladin, Gagan Sharma, Andrew Bivard, Geoffrey A. Donnan, Stephen M. Davis
Journal: JAMA Neurology (2020)

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.