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Background: In the ESCAPE-NA1 trial, treatment with nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, was associated with improved functional outcome among patients with acute ischaemic stroke due to large vessel occlusion undergoing endovascular thrombectomy without co-treatment with an intravenous thrombolytic agent. There was no benefit when intravenous thrombolytic agent co-treatment was used. We sought to confirm the clinical benefit of nerinetide in the absence of previous intravenous thrombolytic drug treatment., Methods: In this multicentre, randomised, double-blind, placebo-controlled study, done in 77 centres in Canada (16), the USA (16), Germany (21), Italy (four), the Netherlands (three), Norway (four), Switzerland (three), Australia (eight), and Singapore (two), we enrolled patients with acute ischaemic stroke due to anterior circulation large vessel occlusion within 12 h from onset. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation (baseline National Institutes of Health Stroke Scale [NIHSS] score >5), who had been functioning independently in the community (Barthel Index score >90) before the stroke, had Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and who were not treated with a plasminogen activator. Patients were randomly allocated (1:1) to receive intravenous infusion of nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, based upon estimated or actual weight (if known) or saline placebo using a real-time, dynamic, internet-based, stratified randomised minimisation procedure. All patients underwent endovascular thrombectomy. The primary outcome was a favourable functional outcome 90 days from randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. The analysis was by intention to treat and adjusted for time from stroke onset to randomisation (≤4·5 h [yes or no]), age, sex, baseline NIHSS score, occlusion location, time from qualifying imaging to randomisation, baseline ASPECTS, and region. Secondary outcomes were measures of mortality, worsening of stroke, improved functional independence, and measures of neurological disability. This trial is registered with ClinicalTrials.gov, NCT04462536., Findings: From Dec 6, 2020, to Jan 31, 2023, 850 patients were assigned to receive nerinetide (n=454) or placebo (n=396). 206 (45%) participants in the nerinetide group and 181 (46%) participants in the placebo group achieved an mRS score of 0-2 at 90 days (odds ratio 0·97, 95% CI 0·72-1·30; p=0·82). Serious adverse events occurred equally between groups., Interpretation: While nerinetide did not improve outcomes in patients with acute ischaemic stroke, it was not associated with excess adverse events. Further study is needed to identify the ideal timing of treatment and the sub-population of stroke patients who might benefit from treatment combined with current reperfusion therapies., Funding: Canadian Institutes for Health Research and NoNO., Competing Interests: Declaration of interests AHA reports an unrestricted grant from Boehringer-Ingelheim for the TenCRAOS trial. DJG reports share ownership in NoNO. MAA reports Advisory Board membership for Fluid Biomed and Palmera Medical. NA reports salary support from the American Heart Association for her role as section editor in Stroke and from the Florida Stroke Registry. JMC reports grants from Bayer and AstraZeneca and is a co-founder and shareholder of TrianecT. AMD reports a grant from Medtronic, DSMC membership for the WE TRUST study (sponsored by Phillips), DSMC chairman for the LT 3001-203 and LT3001-205 studies (sponsored by Lumosa), and board chairmanship for the Canadian Stroke Consortium (non-profit sector). DWJD reports grants from Stryker Neurovascular, Medtronic, Cerenovus, Penumbra, and Thrombolytic Science, DSMC chairmanship for the ACT-Global and LATE-MT studies, and past chairmanship of the CONTRAST Consortium. AE reports board membership of the Norwegian Stroke Organization. TSF reports payment for advisory board roles for Bayer, Novartis, HLS Therapeutics, and AstraZeneca and board membership for Destine Health and the Vancouver General Hospital–University of British Columbia Foundation. SF reports consulting fees and honoria from Microvention, Rapid Medical,and Stryker Neurovascular. DG reports grants from Microvention and consulting fees from Navigantis. MG reports grants from Medtronic and Cerenovus; consulting fees from Microvention, Stryker Neurovascular, Medronic, Mentice, Phillips, and Penumbra; and stock ownership in Circle Neurovascular. JG reports consulting fees from Medtronic and Johnson & Johnson/Cerenovus. AEH reports grants from GE Healthcare and Viz.ai, consulting fees or honoraria from Medtronic, Microvention, Stryker Neurovascular, Penumbra, Cerevonus, Xcath, Imperative Care, Perfuze, Route 92, Genentech, GE Healthcare, Scientia, Balt, Viz.ai, Insera Therapeutics, Proximie, NovaSignal, and Vesalio, DSMC membership for the COMMAND study, and is the past-president of the Society of Vascular and Interventional Neurology. KJH reports share ownership in NoNO. VH reports grants and consulting fees from Wallaby/Phenox. MDH reports grants from NoNO and Canadian Institutes of Health Research (CIHR) which directly supported the ESCAPE-NEXT study, past grants from NoNO, Medtronic, Boehringer-Ingelheim, CIHR, and Heart & Stroke Foundation; consulting fees from Sun Pharma and Brainsgate, patents licensed to Circle Neurovascular, DSMC charimanship for the DUMAS and Oncover Hiltonel trials, DSMC membership for the ARTESIA, BRAIN-AF and LAAOS-4 trials, stock ownership in Circle Neurovascular, and is the current president of the Canadian Neurological Sciences Federation (non-profit sector). MH reports consulting fees or honoraria from Balt, Medtronic, Stryker Neurovascular, Microvention, Phenox, Cerenovus, Siemens, and Rapid Medical. MEK reports consulting fees from Medtronic and Penumbra and stock or stock options from Basecamp Vascular, Radical Catheter Technology, and Endostream. TL reports grants from Cerus, Stryker Neurovascular, and Phenox and DSMC membership in the CLOT OUT study. NL reports consulting fees from Medtronic and honoraria from Medtronic, Penumbra, Balt, Cerenovus, Microvention, and Stryker Neurovascular. JLM reports advisory board membership for the SECRET study and board membership for the Canadian Stroke Consortium (non-profit sector). BKM reports grants for the CIHR. MM reports consulting fees from Stryker Neurovascular. MP reports grants from German Research Foundation and honoraria from Merck. SP reports grants from BMS/Pfizer, Boehringer-Ingelheim, Danichi-Sankyo, EU, German Federal Joint Committee Innovation Fund, German Federal Ministry of Education of Research, Helena Laboratories, and Werfen; consulting fees from Alexion, AstraZeneca, Daichi-Sankyo, and Werfen; and honoraria from Alexion, Bayer, Boehringer-Ingelheim, BMS/Pfizer, and Portola. AYP reports grants from Brain Canada, Heart & Stroke Foundation Canada, and CIHR, honoraria from Roche Canada, safety committee chairmanship for the ACT trial, and fellowship certification committee chairmanship for the Canadian Stroke Consortium (non-profit sector). M-NP reports grants from Swiss National Science Foundation, Bangerter-Rhyner Stiftung, Stryker Neurovascular, Phenox, Medtronic, Penumbra, and Siemens Healthineers and honoraria from Stryker Neurovascular, Medtronic, Pneumbra, Acandis, and Siemens Healthineers. ASP reports DSMC membership for Cerevasc and Keep, stock or stock options in NTI, Galaxy, Agile, and Perfuse, and a consultancy role for Cerenovus, Agile, Arsenal, Route 92, Stryker Neurovascular, Rapid, and Spryte. MR reports grants from the National Institutes of Health (NIH). RHS reports grants from the NIH, CIHR, and Ontario Brain Institute, DSMC membership for Hoffman La Roche, and stock or stock options in FollowMD. JWT reports consulting fees from Medtronic, Stryker Neurovascular, and Qure.ai. MT reports stock and CEO role in NoNO. PJvD reports consulting fees from Stryker Neurovascular, Phillips, Medtronic, and Siemens. WvZ reports consulting fees or honoraria from Phillips, Bayer, Stryker Neurovascular, Medtronic, Nico Lab, Cerenovus, and DSMC membership in the WeTrust, Athena, and InExtremis trials. MW reports grants from Ab medica, Acandis, Cerenovus, Kaneka Pharmaceuticals, Medtronic, Microvention, Phenox, Siemens Healthcare, and Stryker Neurovascular, consulting fees from Stryker Neurovascular, honoraria from Bracco Imaging, Medtronic, Siemens Healthcare, and Stryker Neurovascular. LLLY reports grants from National Medical Research Council (Singapore) and the Ministry of Education, advisory board membership for AstraZeneca, vice-president role for the Society of Neurointerventional Surgery, stock or stock options in Cereflo and medical advisor roles for Sunbird-bio, Cortirio, and See-mode. All other authors declare no competing interests., (Copyright © 2025 The Author(s). Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies. Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: Mechanical thrombectomy (MT) along with emergent carotid stent placement (eCAS) has been suggested to have a greater benefit in patients with tandem lesions (TL), compared with other strategies of treatment. Nonetheless, there is no agreement on whether the intracranial occlusion should be treated before the cervical ICA lesion, or vice versa. In this retrospective multicenter study, we sought to compare clinical and procedural outcomes of the 2 different treatment approaches in patients with TL., Materials and Methods: The prospective databases of 17 comprehensive stroke centers were screened for consecutive patients with TL who received MT and eCAS. Patients were divided in 2 groups based on whether they received MT before eCAS (MT-first approach) or eCAS before MT (eCAS-first approach). Propensity score matching was used to estimate the effect of the retrograde-versus-anterograde approach on procedure-related and clinical outcome measures. These included the modified TICI score 2b-3, other procedure-related parameters and adverse events after the endovascular procedure, and the ordinal distribution of the 90-day mRS scores., Results: A total of 295 consecutive patients were initially enrolled. Among them, 208 (70%) received MT before eCAS. After propensity score matching, 56 pairs of patients were available for analysis. In the matched population, the MT-first approach resulted in a higher rate of successful intracranial recanalization (91% versus 73% in the eCAS-first approach, P  = .025) and a mean shorter groin-to-reperfusion time (72 [SD, 38] minutes versus 93 [SD, 50] minutes in the anterograde approach, P  = .017). Despite a higher rate of efficient recanalization in the MT-first group, we did not observe a significant difference regarding the ordinal distribution of the 90-day mRS scores. Rates of procedure-related adverse events and the occurrence of both parenchymal hemorrhage types 1 and 2 were comparable., Conclusions: Our study demonstrates that in patients with TL undergoing endovascular treatment, prioritizing the intracranial occlusion is associated with an increased rate of efficient MT and faster recanalization time. However, this strategy does not have an advantage in long-term clinical outcome. Future controlled studies are needed to determine the optimal treatment technique., (© 2025 by American Journal of Neuroradiology.)