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.

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. 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. 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]). 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. Australian National Health Medical Research Council; Boehringer Ingelheim.

Parsons MW ，Yogendrakumar V ，Churilov L ，Garcia-Esperon C ，Campbell BCV ，Russell ML ，Sharma G ，Chen C ，Lin L ，Chew BL ，Ng FC ，Deepak A ，Choi PMC ，Kleinig TJ ，Cordato DJ ，Wu TY ，Fink JN ，Ma H ，Phan TG ，Markus HS ，Molina CA ，Tsai CH ，Lee JT ，Jeng JS ，Strbian D ，Meretoja A ，Arenillas JF ，Buck BH ，Devlin MJ ，Brown H ，Butcher KS ，O'Brien B ，Sabet A ，Wijeratne T ，Bivard A ，Grimley RS ，Agarwal S ，Munshi SK ，Donnan GA ，Davis SM ，Miteff F ，Spratt NJ ，Levi CR ，TASTE investigators ... -  《-》

Safety and efficacy of intravenous recombinant human prourokinase for acute ischaemic stroke within 4·5 h after stroke onset (PROST-2): a phase 3, open-label, non-inferiority, randomised controlled trial.

Intra-arterial prourokinase has been shown to be a promising thrombolytic agent in patients with acute ischaemic stroke. Given the global shortage of thrombolytics, we aimed to assess the non-inferiority of intravenous recombinant human prourokinase compared with alteplase in patients with acute ischaemic stroke who were ineligible for or who refused endovascular thrombectomy. PROST-2 was a phase 3, open-label, non-inferiority, randomised controlled trial conducted at 61 hospitals in China. Patients older than 18 years with acute ischaemic stroke, who were ineligible for or who refused endovascular thrombectomy, were randomly assigned in a 1:1 ratio within 4·5 h of stroke onset to receive intravenous recombinant human prourokinase (15 mg bolus followed by 20 mg infusion within 30 min) or intravenous alteplase (0·9 mg per kg, maximum dose 90 mg; 10% bolus followed by remainder as infusion over 60 min). The primary efficacy outcome was the proportion of patients with a modified Rankin Scale score of 0 or 1 at 90 days, assessed via masked review in the intention-to-treat population, with a non-inferiority margin for the risk ratio of 0·93. The primary safety outcome was the incidence of symptomatic intracranial haemorrhage within 36 h. This trial is registered with ClinicalTrials.gov (NCT05700591) and is now completed. Between Jan 29, 2023, and March 14, 2024, 1552 patients were randomly assigned: 775 received recombinant human prourokinase and 777 received alteplase. The primary outcome of a modified Rankin Scale score of 0 or 1 at 90 days was reached by 558 (72·0%) of 775 patients in the recombinant human prourokinase group versus 534 (68·7%) of 777 in the alteplase group (risk ratio 1·04 [95% CI 0·98 to 1·10]; p<0·0001 for non-inferiority). The frequency of symptomatic intracranial haemorrhage within 36 h was lower in the recombinant human prourokinase group than in the alteplase group (two [0·3%] of 770 patients vs ten [1·3%] of 775, risk difference -1·0 percentage points [95% CI -2·1 to -0·1]; p=0·021), as was the incidence of major bleeding at 7 days (four [0·5%] vs 16 [2·1%]; -1·5 percentage points (-2·8 to -0·4); p=0·0072). All-cause mortality within 7 days did not differ between groups (five [0·6%] deaths in the recombinant human prourokinase group vs 13 [1·7%] in the alteplase group; risk difference -1·0 percentage points; 95% CI -2·3 to 0·1]; p=0·060). In our trial, recombinant human prourokinase was shown to be non-inferior to alteplase for achieving excellent functional outcome, with no difference between groups in safety endpoints. These findings support the use of recombinant human prourokinase as a viable alternative to alteplase for patients with ischaemic stroke who are eligible for intravenous thrombolysis therapy but ineligible for or who have refused endovascular thrombectomy. Tasly Biopharmaceuticals, National Key R&D Program of China, National Natural Science Foundation of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and Beijing Municipal Science & Technology Commission. For the Chinese translation of the abstract see Supplementary Materials section.

Li S ，Gu HQ ，Feng B ，Li H ，Wang X ，Dong Q ，Fan D ，Xu Y ，Zhu S ，Dai H ，Wei Y ，Wang Z ，Lu G ，Ma Y ，Li Z ，Wang Y ，Meng X ，Zhao X ，Liu L ，Wang Y ，PROST-2 investigators ... -  《-》

Lamotrigine versus levetiracetam or zonisamide for focal epilepsy and valproate versus levetiracetam for generalised and unclassified epilepsy: two SANAD II non-inferiority RCTs.

Marson AG ，Burnside G ，Appleton R ，Smith D ，Leach JP ，Sills G ，Tudur-Smith C ，Plumpton CO ，Hughes DA ，Williamson PR ，Baker G ，Balabanova S ，Taylor C ，Brown R ，Hindley D ，Howell S ，Maguire M ，Mohanraj R ，Smith PE ... -  《-》

Safety and efficacy of active blood-pressure reduction to the recommended thresholds for intravenous thrombolysis in patients with acute ischaemic stroke in the Netherlands (TRUTH): a prospective, observational, cluster-based, parallel-group study.

Intravenous thrombolysis is contraindicated in patients with ischaemic stroke with blood pressure higher than 185/110 mm Hg. Prevailing guidelines recommend to actively lower blood pressure with intravenous antihypertensive agents to allow for thrombolysis; however, there is no robust evidence for this strategy. Because rapid declines in blood pressure can also adversely affect clinical outcomes, several Dutch stroke centres use a conservative strategy that does not involve the reduction of blood pressure. We aimed to compare the clinical outcomes of both strategies. Thrombolysis and Uncontrolled Hypertension (TRUTH) was a prospective, observational, cluster-based, parallel-group study conducted across 37 stroke centres in the Netherlands. Participating centres had to strictly adhere to an active blood-pressure-lowering strategy or to a non-lowering strategy. Eligible participants were adults (≥18 years) with ischaemic stroke who had blood pressure higher than 185/110 mm Hg but were otherwise eligible for intravenous thrombolysis. The primary outcome was functional status at 90 days, measured using the modified Rankin Scale and assessed through telephone interviews by trained research nurses. Secondary outcomes were symptomatic intracranial haemorrhage, the proportion of patients treated with intravenous thrombolysis, and door-to-needle time. All ordinal logistic regression analyses were adjusted for age, sex, stroke severity, endovascular thrombectomy, and baseline imbalances as fixed-effect variables and centre as a random-effect variable to account for the clustered design. Analyses were done according to the intention-to-treat principle, whereby all patients were analysed according to the treatment strategy of the participating centre at which they were treated. Recruitment began on Jan 1, 2015, and was prematurely halted because of a declining inclusion rate and insufficient funding on Jan 5, 2022. Between these dates, we recruited 853 patients from 27 centres that followed an active blood-pressure-lowering strategy and 199 patients from ten centres that followed a non-lowering strategy. Baseline characteristics of participants from the two groups were similar. The 90-day mRS score was missing for 15 patients. The adjusted odds ratio (aOR) for a shift towards a worse 90-day functional outcome was 1·27 (95% CI 0·96-1·68) for active blood-pressure reduction compared with no active blood-pressure reduction. 798 (94%) of 853 patients in the active blood-pressure-lowering group were treated with intravenous thrombolysis, with a median door-to-needle time of 35 min (IQR 25-52), compared with 104 (52%) of 199 patients treated in the non-lowering group with a median time of 47 min (29-78). 42 (5%) of 852 patients in the active blood-pressure-lowering group had a symptomatic intracranial haemorrhage compared with six (3%) of 199 of those in the non-lowering group (aOR 1·28 [95% CI 0·62-2·62]). Insufficient evidence was available to establish a difference between an active blood-pressure-lowering strategy-in which antihypertensive agents were administered to reduce blood pressure below 185/110 mm Hg-and a non-lowering strategy for the functional outcomes of patients with ischaemic stroke, despite higher intravenous thrombolysis rates and shorter door-to-needle times among those in the active blood-pressure-lowering group. Randomised controlled trials are needed to inform the use of an active blood-pressure-lowering strategy. Fonds NutsOhra.

Zonneveld TP ，Vermeer SE ，van Zwet EW ，Groot AED ，Algra A ，Aerden LAM ，Alblas KCL ，de Beer F ，Brouwers PJAM ，de Gans K ，van Gemert HMA ，van Ginneken BCAM ，Grooters GS ，Halkes PHA ，van der Heijden-Montfroy TAMHG ，Jellema K ，de Jong SW ，Lövenich-Ciccarello H ，van der Meulen WDM ，Peters EW ，van der Ree TC ，Remmers MJM ，Richard E ，Rovers JMP ，Saxena R ，van Schaik SM ，Schonewille WJ ，Schreuder TAHCML ，de Schryver ELLM ，Schuiling WJ ，Spaander FH ，van Tuijl JH ，Visser MC ，Zinkstok SM ，Zock E ，Dippel DWJ ，Kappelle LJ ，van Oostenbrugge RJ ，Roos YBWEM ，Vermeij FH ，Wermer MJH ，van der Worp HB ，Nederkoorn PJ ，Kruyt ND ... -  《-》

Collagenase injection versus limited fasciectomy surgery to treat Dupuytren's contracture in adult patients in the UK: DISC, a non-inferiority RCT and economic evaluation.

Dias J ，Tharmanathan P ，Arundel C ，Welch C ，Wu Q ，Leighton P ，Armaou M ，Corbacho B ，Johnson N ，James S ，Cooke J ，Bainbridge C ，Craigen M ，Warwick D ，Brady S ，Flett L ，Jones J ，Knowlson C ，Watson M ，Keding A ，Hewitt C ，Torgerson D ... -  《-》