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 pnon-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 pnon-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.
