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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., Competing Interests: Declaration of interests MWP is on a Boehringer-Ingelheim Advisory Board for metalyse in stroke. FCN has received grants from the National Health and Medical Research Council of Australia and the National Heart Foundation of Australia. AM participates on an advisory board for Boehringer Ingelheim and is a World Stroke Organisation board member. HSM reports grants from the British Heart Foundation, the Medical Research Council, the Alzheimer's Society, and the Stroke Association UK, and is the editor-in-chief of the World Stroke Organisation journal, International Journal of Stroke. HM has received speaking fees from the Indonesian Stroke Society and reports travel support for investigator meetings. TGP has received speaking fees from Bayer, Boehringer Ingelheim, Pfizer, and BMS. JFA reports consulting fees from Amgen, Medtronic, and BMS-Pfizer, reports speaking fees from Medtronic and BMS–Pfizer, reports travel support from Daiichi–Sankyo, participates on the advisory board for the WE-TRUST trial, and reports research grants from the Spanish Ministry of Science, the European Commission, and Astra Zeneca. RSG has received travel support from Boehringer Ingelheim. SA has received funding from the UK Stroke Clinical Research Network. KSB is in a spousal relationship with an employee of Boehringer Ingelheim and has received speaking fees from Boehringer Ingelheim and AstraZeneca. All other authors report no disclosures., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Importance: Pediatric large vessel occlusion (LVO) stroke has a poor natural history. However, uptake of mechanical thrombectomy is hindered by a lack of clinical trial data in children. A randomized clinical trial is not feasible due to small sample sizes and absence of equipoise., Objective: To evaluate whether pediatric patients with acute LVO stroke who undergo thrombectomy have better clinical outcomes than matched patients managed conservatively., Design, Setting, and Participants: This matched case-control study used pooled stroke registry data from 5 tertiary referral hospitals in Australia and Canada from January 2011 to April 2022. Patients were aged 1 month to younger than 18 years with acute LVO stroke. Pooled data identified 31 thrombectomy patients and 46 control patients. Five patients undergoing thrombectomy with basilar artery occlusion were excluded due to insufficient controls. Using a hierarchal matching system (site of occlusion, age group, side of occlusion, and sex), deidentified consensus matching of patients and controls was undertaken while blinded to clinical outcome. Data were analyzed from July to November 2022., Exposure: In the case cohort, mechanical thrombectomy was undertaken for management of acute LVO stroke. The control cohort received medical treatment only., Main Outcomes and Measures: The primary outcome was the functional clinical status 3 months following stroke, measured by the pediatric modified Rankin Scale (mRS). Clinical outcomes were compared between groups using ordinal regression analysis., Results: Of 52 included patients, 31 (60%) were male, and the mean (SD) age was 10.3 (4.4) years. Matching was achieved for 26 children undergoing thrombectomy with 26 controls. There was no significant difference between groups for site or side of occlusion, age, sex, etiology, thrombolysis status, baseline Alberta Stroke Programme Early CT Score, or time since last seen well to presentation. Patients undergoing thrombectomy had superior clinical outcomes than control patients at 3 months on the pediatric mRS (odds ratio, 3.76; 95% CI, 1.32-10.67; P = .01). These superior outcomes were maintained at final follow-up (odds ratio, 3.65; 95% CI, 1.25-10.68; P = .02)., Conclusions and Relevance: In the absence of a randomized clinical trial, this case-control study demonstrates better clinical outcomes with thrombectomy than medical management alone for pediatric patients aged 2 to 18 years with anterior circulation LVO stroke.

Introduction: The very elderly (⩾80 years) are under-represented in randomised endovascular thrombectomy (EVT) clinical trials for acute ischaemic stroke. Rates of independent outcome in this group are generally lower than the less-old patients but the comparisons may be biased by an imbalance of non-age related baseline characteristics, treatment related metrics and medical risk factors., Patients and Methods: We compared outcomes between very elderly (⩾80) and the less-old (<80 years) using retrospective data from consecutive patients receiving EVT from four comprehensive stroke centres in New Zealand and Australia. We used propensity score matching or multivariable logistic regression to account for confounders., Results: We included 600 patients (300 in each age cohort) after propensity score matching from an initial group of 1270 patients. The median baseline National Institutes of Health Stroke Scale was 16 (11-21), with 455 (75.8%) having symptom free pre-stroke independent function, and 268 (44.7%) receiving intravenous thrombolysis. Good functional outcome (90-day modified Rankin Scale 0-2) was achieved in 282 (46.8%), with very elderly patients having less proportion of good outcome compared to the less-old (118 (39.3%) vs 163 (54.3%), p  < 0.01). There was no difference between the very elderly and the less-old in the proportion of patients who returned to baseline function at 90 days (56 (18.7%) vs 62 (20.7%), p  = 0.54). All-cause 90-day mortality was higher in the very elderly (75 (25%) vs 49 (16.3%), p  < 0.01), without a difference in symptomatic haemorrhage (very elderly 11 (3.7%) vs 6 (2.0%), p  = 0.33). In the multivariable logistic regression models, the very elderly were significantly associated with reduced odds of good 90-day outcome (OR 0.49, 95% CI 0.34-0.69, p  < 0.01) but not with return to baseline function (OR 0.85, 90% CI 0.54-1.29, p  = 0.45) after adjusting for confounders., Conclusion: Endovascular thrombectomy can be successfully and safely performed in the very elderly. Despite an increase in all-cause 90-day mortality, selected very elderly patients are as likely as younger patients with similar baseline characteristics to return to baseline function following EVT., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© European Stroke Organisation 2022.)

Background: Endovascular thrombectomy (EVT) access in remote areas is limited. Preliminary data suggest that long distance transfers for EVT may be beneficial; however, the magnitude and best imaging strategy at the referring center remains uncertain. We hypothesized that patients transferred >300 miles would benefit from EVT, achieving rates of functional independence (modified Rankin Scale [mRS] score of 0-2) at 3 months similar to those patients treated at the comprehensive stroke center in the randomized EVT extended window trials and that the selection of patients with computed tomography perfusion (CTP) at the referring site would be associated with ordinal shift toward better outcomes on the mRS., Methods: This is a retrospective analysis of patients transferred from 31 referring hospitals >300 miles (measured by the most direct road distance) to 9 comprehensive stroke centers in Australia and New Zealand for EVT consideration (April 2016 through May 2021)., Results: There were 131 patients; the median age was 64 [53-74] years and the median baseline National Institutes of Health Stroke Scale score was 16 [12-22]. At baseline, 79 patients (60.3%) had noncontrast CT+CT angiography, 52 (39.7%) also had CTP. At the comprehensive stroke center, 114 (87%) patients underwent cerebral angiography, and 96 (73.3%) proceeded to EVT. At 3 months, 62 patients (48.4%) had an mRS score of 0 to 2 and 81 (63.3%) mRS score of 0 to 3. CTP selection at the referring site was not associated with better ordinal scores on the mRS at 3 months (mRS median of 2 [1-3] versus 3 [1-6] in the patients selected with noncontrast CT+CT angiography, P =0.1). Nevertheless, patients selected with CTP were less likely to have an mRS score of 5 to 6 (odds ratio 0.03 [0.01-0.19]; P <0.01)., Conclusions: In selected patients transferred >300 miles, there was a benefit for EVT, with outcomes similar to those treated in the comprehensive stroke center in the EVT extended window trials. Remote hospital CTP selection was not associated with ordinal mRS improvement, but was associated with fewer very poor 3-month outcomes.

Background and Objectives: Endovascular thrombectomy (EVT) is effective for patients with large vessel occlusion (LVO) stroke with smaller volumes of CT perfusion (CTP)-defined ischemic core. However, the benefit of EVT is unclear in those with a core volume >70 mL. We aimed to compare outcomes of EVT and non-EVT patients with an ischemic core volume ≥70 mL, hypothesizing that there would be a benefit from EVT for fair outcome (3-month modified Rankin scale [mRS] 0-3) after stroke., Methods: A retrospective analysis of patients enrolled into a multicenter (Australia, China, and Canada) registry (2012-2020) who underwent CTP within 24 hours of stroke onset and had a baseline ischemic core volume ≥70 mL was performed. The primary outcome was the estimation of the association of EVT in patients with core volume ≥70 mL and within 70-100 and ≥100 mL subgroups with fair outcome., Results: Of the 3,283 patients in the registry, 299 had CTP core volume ≥70 mL and 269 complete data (135 had core volume between 70 and 100 mL and 134 had core volume ≥100 mL). EVT was performed in 121 (45%) patients. EVT-treated patients were younger (median 69 vs 75 years; p = 0.011), had lower prestroke mRS, and smaller median core volumes (92 [79-116.5] mL vs 105.5 [85.75-138] mL, p = 0.004). EVT-treated patients had higher odds of achieving fair outcome in adjusted analysis (30% vs 13.9% in the non-EVT group; adjusted odds ratio [aOR] 2.1, 95% CI 1-4.2, p = 0.038). The benefit was seen predominantly in those with 70-100 mL core volume (71/135 [52.6%] EVT-treated), with 54.3% in the EVT-treated vs 21% in the non-EVT group achieving a fair outcome (aOR 2.5, 95% CI 1-6.2, p = 0.005). Of those with a core volume ≥100 mL, 50 of the 134 (37.3%) underwent EVT. Proportions of fair outcome were very low in both groups (8.1% vs 8.7%; p = 0.908)., Discussion: We found a positive association of EVT with the 3-month outcome after stroke in patients with a baseline CTP ischemic core volume 70-100 mL but not in those with core volume ≥100 mL. Randomized data to confirm these findings are required., Classification of Evidence: This study provides Class III evidence that EVT is associated with better motor outcomes 3 months after CTP-defined ischemic stroke with a core volume of 70-100 mL., (© 2022 American Academy of Neurology.)

Background: The benefit of combined treatment with intravenous thrombolysis before endovascular thrombectomy in patients with acute ischaemic stroke caused by large vessel occlusion remains unclear. We hypothesised that the clinical outcomes of patients with stroke with large vessel occlusion treated with direct endovascular thrombectomy within 4·5 h would be non-inferior compared with the outcomes of those treated with standard bridging therapy (intravenous thrombolysis before endovascular thrombectomy)., Methods: DIRECT-SAFE was an international, multicentre, prospective, randomised, open-label, blinded-endpoint trial. Adult patients with stroke and large vessel occlusion in the intracranial internal carotid artery, middle cerebral artery (M1 or M2), or basilar artery, confirmed by non-contrast CT and vascular imaging, and who presented within 4·5 h of stroke onset were recruited from 25 acute-care hospitals in Australia, New Zealand, China, and Vietnam. Eligible patients were randomly assigned (1:1) via a web-based, computer-generated randomisation procedure stratified by site of baseline arterial occlusion and by geographic region to direct endovascular thrombectomy or bridging therapy. Patients assigned to bridging therapy received intravenous thrombolytic (alteplase or tenecteplase) as per standard care at each site; endovascular thrombectomy was also per standard of care, using the Trevo device (Stryker Neurovascular, Fremont, CA, USA) as first-line intervention. Personnel assessing outcomes were masked to group allocation; patients and treating physicians were not. The primary efficacy endpoint was functional independence defined as modified Rankin Scale score 0-2 or return to baseline at 90 days, with a non-inferiority margin of -0·1, analysed by intention to treat (including all randomly assigned and consenting patients) and per protocol. The intention-to-treat population was included in the safety analyses. The trial is registered with ClinicalTrials.gov, NCT03494920, and is closed to new participants., Findings: Between June 2, 2018, and July 8, 2021, 295 patients were randomly assigned to direct endovascular thrombectomy (n=148) or bridging therapy (n=147). Functional independence occurred in 80 (55%) of 146 patients in the direct thrombectomy group and 89 (61%) of 147 patients in the bridging therapy group (intention-to-treat risk difference -0·051, two-sided 95% CI -0·160 to 0·059; per-protocol risk difference -0·062, two-sided 95% CI -0·173 to 0·049). Safety outcomes were similar between groups, with symptomatic intracerebral haemorrhage occurring in two (1%) of 146 patients in the direct group and one (1%) of 147 patients in the bridging group (adjusted odds ratio 1·70, 95% CI 0·22-13·04) and death in 22 (15%) of 146 patients in the direct group and 24 (16%) of 147 patients in the bridging group (adjusted odds ratio 0·92, 95% CI 0·46-1·84)., Interpretation: We did not show non-inferiority of direct endovascular thrombectomy compared with bridging therapy. The additional information from our study should inform guidelines to recommend bridging therapy as standard treatment., Funding: Australian National Health and Medical Research Council and Stryker USA., Competing Interests: Declaration of interests AKC received webinar honoraria from Medtronic and educational honoraria from Stryker. BY received conference honoraria and institutional research grants from Medtronic and Stryker. BS was an unpaid member on the New South Wales Medical Board. GAD received grants from the Australian Medical Research Future Fund by the Australian National Health and Medical Research Council. GAD was on the advisory boards of Allergan and Argenica; received honoraria from Amgen; was on the data safety monitoring board of the STOP-MSU and EXTEND group of trials; was on the steering committee of DIRECT-SAFE; was shareholder in Argenica Therapeutics; and was on the board or committee of the Australian Stroke Alliance, Menzies Research Institute, Argenica Therapeutics, and the Colonial Foundation. MWP received payment to attend meetings by Boehringer Ingelheim. PJM received conference honoraria and institutional research grants from Medtronic and Stryker. SMD received grants from the Australian Medical Research Future Fund by the Australian National Health and Medical Research Council; received payment for participating on advisory boards of Boehringer Ingelheim, Medtronic, and CSL Behring; received speaker's honoraria from Amgen; was a member of the data safety monitoring board of the SELECT-2 trial; was on the steering committee of the DIRECT-SAFE trial and EXTEND group of trials; and was an unpaid cochair of the Australian Stroke Alliance and unpaid trustee of the RMH Neuroscience Foundation. TJK received honoraria from Boehringer Ingelheim. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Importance: The incidence and natural history of large vessel occlusion (LVO) stroke in children is largely unknown. These knowledge gaps limit the uptake of reperfusion therapies and reduce the efficiency of pediatric acute stroke pathways., Objective: To determine the incidence and natural history of pediatric LVO stroke., Design, Setting, and Participants: This retrospective population-based cohort study was conducted between January 2010 and December 2019, with a mean (SD) follow-up of 37.0 (28.8) months. Admissions from all pediatric hospitals in the state of New South Wales, Australia, with a final diagnosis of arterial ischemic stroke (AIS) in patients 1 month to younger than 17 years were included. A total of 85 of 251 identified cases were excluded based on selection criteria. Data were analyzed from July 2020 to June 2021., Exposures: One-third of patients with LVO received mechanical thrombectomy with or without intravenous thrombolysis while the remainder were treated conservatively., Main Outcomes and Measures: The primary outcome was the pediatric modified Rankin Scale (ped-mRS) score 3 months after stroke. Ordinal logistic regression was used to compare non-LVO, LVO without thrombectomy, and LVO with thrombectomy groups., Results: Of 161 included patients, 56 (34.8%) were female, and the mean (SD) age was 6.1 (5.4) years. A total of 166 AIS admissions were studied, and clinical follow-up was available for 164 of 166 admissions. LVO was present in 39 admissions (23.5%). The incidence of LVO stroke was 0.24 per 100 000 patients per year (95% CI, 0.13-0.35). Patients with LVO who did not receive thrombectomy (n = 26) had poor neurological outcomes, with 19 (73.1%) experiencing moderate to severe disability or death (ped-mRS score of 3 to 6) at 3 months (6 of 12 patients receiving thrombectomy [50.0%]; 25 of 38 patients with LVO [65.8%]). Patients with LVO without thrombectomy had significantly worse clinical outcomes than patients with non-LVO at 3 months (odds ratio, 3.64; 95% CI, 1.68-7.87; P = .001). Most patients with LVO presented within time windows suitable for thrombectomy (27 of 39 [69.2%] within 6 hours; 35 of 39 [89.7%] within 24 hours)., Conclusions and Relevance: In this population-based cohort study, the natural history of pediatric patients with LVO stroke treated conservatively was poor, with most experiencing lifelong disability or death. Nearly 90% of pediatric patients with LVO presented within time windows suitable for thrombectomy.

Concurrent epistaxis, embolic stroke and a ruptured internal carotid artery are rare but life-threatening delayed complications of cured nasopharyngeal squamous cell carcinoma. A timely diagnosis and effective management can be problematic. We report a case that highlights the unique diagnostic features of this presentation and contemporary endovascular treatment options available., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To compare the cost-effectiveness of providing endovascular thrombectomy (EVT) for patients with ischemic stroke in the >4.5 h time window between patient groups who met and did not meet the perfusion imaging trial criteria. Methods: A discrete event simulation (DES) model was developed to simulate the long-term outcome post EVT in patients meeting or not meeting the extended time window clinical trial perfusion imaging criteria at presentation, vs. medical treatment alone (including intravenous thrombolysis). The effectiveness of thrombectomy in patients meeting the landmark trial criteria (DEFUSE 3 and DAWN) was derived from a prospective cohort study of Australian patients who received EVT for ischemic stroke, between 2015 and 2019, in the extended time window (>4.5 h). Results: Endovascular thrombectomy was shown to be a cost-effective treatment for patients satisfying the clinical trial criteria in our prospective cohort [incremental cost-effectiveness ratio (ICER) of $11,608/quality-adjusted life year (QALY) for DEFUSE 3-postive or $34,416/QALY for DAWN-positive]. However, offering EVT to patients outside of clinical trial criteria was associated with reduced benefit (-1.02 QALY for DEFUSE 3; -1.43 QALY for DAWN) and higher long-term patient costs ($8,955 for DEFUSE 3; $9,271 for DAWN), thereby making it unlikely to be cost-effective in Australia. Conclusions: Treating patients not meeting the DAWN or DEFUSE 3 clinical trial criteria in the extended time window for EVT was associated with less gain in QALYs and higher cost. Caution should be exercised when considering this procedure for patients not satisfying the trial perfusion imaging criteria for EVT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gao, Bivard, Parsons, Spratt, Levi, Butcher, Kleinig, Yan, Dong, Cheng, Lou, Yin, Chen, Wang, Lin, Choi, Miteff and Moodie.)