Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4·5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial
Mark Parsons, Vignan Yogendrakumar, Leonid Churilov, Carlos García-Esperón, Bruce Campbell, Michelle Russell, Gagan Sharma, Chushuang Chen, Longting Lin, Beng Lim Chew, Felix Ng, Akshay Deepak, Philip Choi, Timothy Kleinig, Dennis Cordato, Teddy Y. Wu, John Fink, Henry Ma, Thanh G. Phan, Hugh S Markus, Carlos A. Molina, Chon‐Haw Tsai, Jiunn‐Tay Lee, Jiann‐Shing Jeng, Daniel Strbian, Atte Meretoja, Juan F. Arenillas, Brian Buck, Michael J. Devlin, Helen Brown, Kenneth Butcher, Billy O'Brien, Arman Sabet, Tissa Wijeratne, Andrew Bivard, Rohan Grimley, Smriti Agarwal, Sunil K Munshi, Geoffrey A. Donnan, Stephen M. Davis, Ferdinand Miteff, Neil J. Spratt, Christopher Levi, Timmy Phan, Christine Selmes, Kennedy Lees, Markku Kaste, Rachael MacIsaac, Tom Wellings, Andre Loiselle, Elizabeth Pepper, Ferdi Miteff, Venkatesh Krishnamurthy, Timothy Ang, Khaled Alanati, Shyam Gangadharan, Hossein Zareie, Rita Starling, Sophie Dunkerton, Jiacheng He, Raka Datta, Angela Royan, Erin Kerr, Lara Kaauwai, Linda Belevski, Sally Ormond, Annalese Johnson, Malcolm Evans, Nicole Lachapelle, Fouke Ombelet, Chris Bladin, Helen Dewey, Joseph Wong, Peter Park, Ross Cody, Peter Tan, Edward Callaly, Channa Senanayake, Grace Thomas, Jennifer Liu, Tessa Busch, Narelle Stuart, Malcohm Chung, Nawaf Yassi, Michael Valente, Angelos Sharobeam, Regan Cooley, Henry Zhao, Fana Alemseged, Cameron Williams, Jo Lyn Ng, Anna Balabanski, Angela dos Santos, John Williamson, Davor Pavlin-Premrl, James Beharry, Margaret Ma, Ashley Park, Bernard Yan, Peter Hand
Abstract
Background Intravenous tenecteplase increases reperfusion in patients with salvageable brain tissue on perfusion imaging and might have advantages over alteplase as a thrombolytic for ischaemic stroke. We aimed to assess the non-inferiority of tenecteplase versus alteplase on clinical outcomes in patients selected by use of perfusion imaging. Methods This international, multicentre, open-label, parallel-group, randomised, clinical non-inferiority trial enrolled patients from 35 hospitals in eight countries. Participants were aged 18 years or older, within 4·5 h of ischaemic stroke onset or last known well, were not being considered for endovascular thrombectomy, and met target mismatch criteria on brain perfusion imaging. Patients were randomly assigned (1:1) by use of a centralised web server with randomly permuted blocks to intravenous tenecteplase (0·25 mg/kg) or alteplase (0·90 mg/kg). The primary outcome was the proportion of patients without disability (modified Rankin Scale 0–1) at 3 months, assessed via masked review in both the intention-to-treat and per-protocol populations. We aimed to recruit 832 participants to yield 90% power (one-sided alpha=0·025) to detect a risk difference of 0·08, with an absolute non-inferiority margin of −0·03. The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000243718, and the European Union Clinical Trials Register, EudraCT Number 2015-002657-36, and it is completed. Findings Recruitment ceased early following the announcement of other trial results showing non-inferiority of tenecteplase versus alteplase. Between March 21, 2014, and Oct 20, 2023, 680 patients were enrolled and randomly assigned to tenecteplase (n=339) and alteplase (n=341), all of whom were included in the intention-to-treat analysis (multiple imputation was used to account for missing primary outcome data for five patients). Protocol violations occurred in 74 participants, thus the per-protocol population comprised 601 people (295 in the tenecteplase group and 306 in the alteplase group). Participants had a median age of 74 years (IQR 63–82), baseline National Institutes of Health Stroke Scale score of 7 (4–11), and 260 (38%) were female. In the intention-to-treat analysis, the primary outcome occurred in 191 (57%) of 335 participants allocated to tenecteplase and 188 (55%) of 340 participants allocated to alteplase (standardised risk difference [SRD]=0·03 [95% CI −0·033 to 0·10], one-tailed p non-inferiority =0·031). In the per-protocol analysis, the primary outcome occurred in 173 (59%) of 295 participants allocated to tenecteplase and 171 (56%) of 306 participants allocated to alteplase (SRD 0·05 [−0·02 to 0·12], one-tailed p non-inferiority =0·01). Nine (3%) of 337 patients in the tenecteplase group and six (2%) of 340 in the alteplase group had symptomatic intracranial haemorrhage (unadjusted risk difference=0·01 [95% CI −0·01 to 0·03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0·02 [95% CI −0·02 to 0·05]). Interpretation The findings in our study provide further evidence to strengthen the assertion of the non-inferiority of tenecteplase to alteplase, specifically when perfusion imaging has been used to identify reperfusion-eligible stroke patients. Although non-inferiority was achieved in the per-protocol population, it was not reached in the intention-to-treat analysis, possibly due to sample size limtations. Nonetheless, large-scale implementation of perfusion CT to assist in patient selection for intravenous thrombolysis in the early time window was shown to be feasible. Funding Australian National Health Medical Research Council; Boehringer Ingelheim.