Extending thrombolysis to 4·5–9 h and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data
Bruce Campbell, Henry Ma, Peter A. Ringleb, Mark Parsons, Leonid Churilov, Martin Bendszus, Christopher Levi, Chung Hsu, Timothy Kleinig, Marc Fatar, Didier Leys, Carlos A. Molina, Tissa Wijeratne, Sami Curtze, Helen M. Dewey, P. Alan Barber, Kenneth Butcher, Deidre Anne De Silva, Christopher F. Bladin, Nawaf Yassi, Johannes Pfaff, Gagan Sharma, Andrew Bivard, Patricia Desmond, Stefan Schwab, Peter D. Schellinger, Bernard Yan, Peter Mitchell, Joaquı́n Serena, Danilo Toni, Vincent Thijs, Werner Hacke, Stephen M. Davis, Geoffrey A. Donnan, Geoffrey A. Donnan, Stephen M. Davis, Henry Ma, Bruce Campbell, Leonid Churilov, Mark Parsons, Bernard Yan, Peter Mitchell, Nawaf Yassi, Gagan Sharma, Patricia Desmond, Thomas J. Oxley, Teddy Y. Wu, Darshan Shah, Henry Zhao, Edrich Rodrigues, Patrick Salvaris, Fana Alemseged, Felix Ng, Cameron Williams, Jo-Lyn Ng, Hans T.H. Tu, Amy McDonald, David M. Jackson, Jessica Tsoleridis, Rachael McCoy, Lauren Pesavento, Louise Weir, Andrew Bivard, Timothy Kleinig, Sanjay R. Patel, Jackson Harvey, Jeyaledchumy Mahadevan, EunSun Cheong, Anna Balabanski, Michael F. Waters, Roy Drew, Jennifer Cranefield, Tissa Wijeratne, Elizabeth A. Mackey, Sherisse Celestino, Essie Low, Helen M. Dewey, Christopher F. Bladin, Poh Sien Loh, Philip Choi, Skye Coote, Tanya Frost, Kyla B. Hogan, Cheng Ding, S. McModie, W.W. Zhang, Christopher Kyndt, Alan Moore, Zofia Ross, Jack Edward Liu, Ferdinand Miteff, Christopher Levi, Timothy Ang, Neil J. Spratt, Carlos García-Esperón, Lara Kaauwai, Thanh G. Phan, John Ly, Shaloo Singhal, Benjamin Clissold
Abstract
BACKGROUND: Stroke thrombolysis with alteplase is currently recommended 0-4·5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4·5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis. METHODS: In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials.gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged ≥18 years) with ischaemic stroke treated more than 4·5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0-1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036. FINDINGS: We identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1·86, 95% CI 1·15-2·99, p=0·011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [<1%] of 201 patients in the placebo group; adjusted OR 9·7, 95% CI 1·23-76·55, p=0·031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1·55, 0·81-2·96, p=0·66). INTERPRETATION: Patients with ischaemic stroke 4·5-9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis. FUNDING: None.