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<middle dot>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<middle dot>25 mg/kg) or alteplase (0<middle dot>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<middle dot>025) to detect a risk difference of 0<middle dot>08, with an absolute non-inferiority margin of -0<middle dot>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<middle dot>03 [95% CI -0<middle dot>033 to 0<middle dot>10], one-tailed p non-inferiority =0<middle dot>031). In the perprotocol 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<middle dot>05 [-0<middle dot>02 to 0<middle dot>12], one-tailed p non-inferiority =0<middle dot>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<middle dot>01 [95% CI -0<middle dot>01 to 0<middle dot>03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0<middle dot>02 [95% CI -0<middle dot>02 to 0<middle dot>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-totreat 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.