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Purpose: Recombinant human interleukin-1 receptor antagonist (anakinra) is an anti-inflammatory with efficacy in animal models of stroke. We tested the effect of anakinra on perihaematomal oedema in acute intracerebral haemorrhage (ICH) and explored effects on inflammatory markers., Methods: We conducted a multicentre, randomised, double-blind, placebo-controlled trial in patients with acute, spontaneous, supratentorial ICH between May 2019 and February 2021. Patients were randomised to 100 mg subcutaneous anakinra within 8 h of onset, followed by five, 12-hourly, 100 mg subcutaneous injections, or matched placebo. Primary outcome was oedema extension distance (OED) on a 72 h CT scan. Secondary outcomes included plasma C-reactive protein (CRP) and interleukin-6 (IL-6)., Findings: 25 patients (target = 80) were recruited, 14 randomised to anakinra, 11 to placebo. Mean age was 67 and 52% were male. The anakinra group had higher median baseline ICH volume (12.6 ml, interquartile range[IQR]:4.8-17.9) versus placebo (5.5 ml, IQR:2.1-10.9). Adjusting for baseline, 72 h OED was not significantly different between groups (mean difference OED anakinra vs placebo -0.05 cm, 95% confidence interval [CI]: -0.17-0.06, p  = 0.336). There was no significant difference in area-under-the-curve to Day 4 for IL-6 and CRP, but a post-hoc analysis demonstrated IL-6 was 56% (95% CI: 2%-80%) lower at Day 2 with anakinra. There were 10 and 2 serious adverse events in anakinra and placebo groups, respectively, none attributed to anakinra., Conclusion: We describe feasibility for delivering anakinra in acute ICH and provide preliminary safety data. We lacked power to test for effects on oedema thus further trials will be required.

Introduction: To assess the association between 24 h blood pressure variability (BPV) on functional outcome and treatment effect of intravenous alteplase in acute ischaemic stroke., Patients and Methods: In all patients with acute ischaemic stroke of unknown onset randomised in the WAKE-UP (Efficacy and Safety of magnetic resonance imaging [MRI]-based Thrombolysis in Wake-Up Stroke) trial, blood pressure (BP) was measured before randomisation and after initiation of treatment at regular intervals up to 24 hours. Individual BPV was measured by coefficient of variation (CV) of all BP values. Primary outcome measure was favourable outcome defined by a modified Rankin Scale (mRS) score 0 or 1 at 90 days after stroke., Results: BP measurements were available for 498 of 503 patients randomised (177 women [35.5%], mean age [SD] of 65.2 [11.5] years). Systolic BPV was not associated with the treatment effect of thrombolysis (test for interaction, p = 0.46). The adjusted odds ratio (aOR) for favourable outcome with alteplase, adjusted for age, stroke severity and baseline BP on admission, did not show an association across the quintiles of increasing systolic BPV with an aOR 1.89 (95% confidence interval [CI], 0.76-4.70) in the lowest quintile to aOR 1.05 (95% CI, 0.43-2.56) in the highest quintile. Higher mean systolic BP was associated with a smaller treatment effect of thrombolysis with a significant interaction (p = 0.033). The aOR for favourable outcome with alteplase decreased with quintiles of increasing mean systolic BP from aOR 3.16 (95% CI, 1.26-7.93) in the lowest quintile to aOR 0.84 (95% CI, 0.34-2.10) in in the highest quintile., Conclusions: There was a significant interaction between mean systolic BP and treatment effect of thrombolysis with higher mean systolic BP being associated with poorer outcome. BPV was not associated with outcome after thrombolysis.ClinicalTrials.gov identifier NCT01525290., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: EB, BC, ME, MEn, JBF, AN, VT, KWM, PR, SP, CG and GT report grants from European Union 7th Framework Program during the conduct of the study. FB reports grants from University Medical Center Hamburg-Eppendorf during the conduct of the study. MEn reports grants from Bayer and fees paid to the Charité from Bayer, Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo, Amgen, GlaxoSmithKlineGSK, Sanofi, Covidien, Novartis, all outside the submitted work. JBF reports personal fees from Bioclinica, Artemida, Cerevast, and Nicolab outside the submitted work. RL reports fees paid to VIB/KU Leuven from Bayer, Boehringer Ingelheim, Medtronic, Ischemiaview and Genentec all outside the submitted work. VT reports personal fees and non-financial support from Boehringer Ingelheim, Pfizer/BMS, Bayer, Sygnis, Amgen and Allergan outside the submitted work. KWM reports personal fees and non-financial support from Boehringer Ingelheim outside the submitted work. CZS reports grants from Novo Nordisk Foundation and personal fees from Bayer outside the submitted work. CG reports personal fees from AMGEN, Bayer Vital, BMS, Boehringer Ingelheim, Sanofi Aventis, Abbott, and Prediction Biosciences outside the submitted work. GT reports personal fees from Acandis, Boehringer Ingelheim, BMS/Pfizer, Stryker, Daiichi Sankyo, grants and personal fees from Bayer, grants from Corona Foundation, German Innovation Fonds and Else Kroener Fresenius Foundation outside the submitted work. All remaining authors declare no competing interests., (© European Stroke Organisation 2021.)

Introduction: Hyperintense acute reperfusion marker (HARM) is an indicator of early disruption of the blood-brain-barrier. Our aim was to investigate the incidence of HARM in patients with a diffusion weighted imaging (DWI) - fluid attenuated inversion recovery (FLAIR) mismatch and determine the association between this marker and hemorrhagic complications as well as clinical outcome., Patients and Methods: We included patients from the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial who underwent baseline perfusion weighted imaging (PWI). HARM was defined as a hyperintense signal in the cerebrospinal fluid space on FLAIR imaging at 24 h after baseline imaging. We compared baseline characteristics in patients with and without HARM and investigated the association between HARM and any hemorrhagic transformation (HT) and parenchymal hematoma (PH) in a multivariate logistic regression. We also explored HARM as an independent predictor of poor outcome, defined as a modified Rankin Scale of 3-6 at 90 days., Results: HARM was present in 14 of 223 (6%) patients with a DWI-FLAIR mismatch and baseline characteristics were similar in patients with vs without HARM. HARM showed an independent relationship with any HT (OR 6.67; 95%CI 1.72-26.58) and any PH (OR 6.92; 95%CI 1.34-29.49). The rate of HARM was similar in patients with good and poor outcome (5%, p = 0.90)., Conclusion: In the WAKE-UP trial, the incidence of HARM was only 6% at 24 h. An association was present between HARM and hemorrhagic complications, but no relationship with functional outcome was observed., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: GT received Consulting fees from Acandis, grant support and lecture fees from Bayer, lecture fees from Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and Daiichi Sankyo, and consulting fees and lecture fees from Stryker. CG received funding from German Research Council (DFG), European Union, Federal Ministry of Education and Research (BMBF), German Statutory Pension Insurance Scheme (RV Nord), National Innovation Fond, Wegener Foundation, and Schilling Foundation; he received honoraria as speaker or consultant from Abbott, Amgen, Bayer Vital, Bristol-Myers-Squibb, Boehringer Ingelheim, Sanofi Aventis, and Prediction Biosciences. JF reports consulting and advisory board fees from BioClinica, Cerevast, Artemida, Brainomix, Biogen, BMS, and EISAI, outside the submitted work. KM has participated in advisory boards for Bayer, Boehringer-Ingelheim and Daiichi-Sankyo; and receives research support from Boehringer-Ingelheim for the ATTEST-2 trial. ME reports grant support from Bayer, and fees paid to the Charité from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Daiichi Sankyo, Amgen, GlaxoSmithKline, Sanofi, Covidien, Novartis, all outside the submitted work., (© European Stroke Organisation 2021.)

Background: Allopurinol, a xanthine oxidase inhibitor, reduced progression of carotid-intima media thickness and lowered blood pressure in a small clinical trial in people with ischaemic stroke. Xanthine oxidase inhibition for improvement of long-term outcomes following ischaemic stroke and transient ischaemic attack (XILO-FIST) aims to assess the effect of allopurinol treatment on white matter hyperintensity progression and blood pressure after stroke. This paper describes the XILO-FIST protocol., Methods: XILO-FIST is a multicentre randomised double-blind, placebo-controlled, parallel group clinical trial funded by the British Heart Foundation and the Stroke Association. The trial has been adopted by the Scottish Stroke Research Network and the UK Clinical Research Network. The trial is registered in clinicaltrials.gov (registration number NCT02122718). XILO-FIST will randomise 464 participants, aged greater than 50 years, with ischaemic stroke within the past month, on a 1:1 basis, to two years treatment with allopurinol 300 mg twice daily or placebo. Participants will undergo brain magnetic resonance imaging, cognitive assessment, ambulatory blood pressure monitoring and blood sampling at baseline and after two years treatment. The primary outcome will be white matter hyperintensity progression, measured using the Rotterdam progression scale. Secondary outcomes will include change in white matter hyperintensity volume, mean day-time systolic blood pressure and measures of cognitive function. Up to 100 will undergo additional cardiac magnetic resonance imaging in a sub-study of left ventricular mass., Discussion: If white matter hyperintensity progression is reduced, allopurinol could be an effective preventative treatment for patients with ischaemic stroke and clinical endpoint studies would be needed. If allopurinol reduces blood pressure after stroke, then it could be used to help patients reach blood pressure targets.

Introduction: Lacunes are defined morphologically by size and location, but radiological characteristics alone may be unable to distinguish small vessel disease aetiology from alternative mechanisms. We investigated the branching order of arterial vessels associated with basal ganglia lacunes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), in order to improve the understanding of their pathogenesis in pure cerebral small vessel disease., Patients and Methods: Adults with a confirmed diagnosis of CADASIL were included. A pilot study was conducted in a Scottish CADASIL cohort. The Paris-Munich CADASIL cohort was used for independent validation. Lacunes identified on T1-weighted magnetic resonance imaging scans were registered to a standard brain template. A microangiographic template of the basal ganglia vasculature was automatically overlaid onto coronal slices, and raters estimated the vessel branching order related to each lacune., Results: Of 179 lacunes, 150 (84%) were associated with third-order vessels. In 14 incident lacunes, 11 (79%) were associated with third-order vessels. In the pilot study, lacune volume was significantly lower in lacunes associated with third-order vessels (0.04 ml ± 0.04 ml) compared to second-order vessels (0.48 ± 0.16 ml; p  < 0.001)., Discussion: In this study of CADASIL patients, most lacunes were small and associated with third-order vessel disease. This suggests that these are the vessels primarily affected in cerebral small vessel disease. Microangiographic template techniques could be used to further investigate in a general stroke population whether finding large lacunes originating from higher order vessels indicates an alternative cause of stroke., Conclusion: Lacunes in pure small vessel disease are associated with the smallest vessels in the basal ganglia.

Introduction: Recent studies showed improved patient outcomes with endovascular treatment of acute stroke compared to medical care, including IV rtPA, alone. Seven trials have reported results, each using different clinical and imaging criteria for patient selection. We compared eligibility for different trial protocols to estimate the number of patients eligible for treatment., Patients and Methods: Patient data were extracted from a single centre database that combined patients recruited to three clinical studies, each of which obtained both CTA and CTP within 6 h of stroke onset. The published inclusion and exclusion criteria of seven intervention trials (MR CLEAN, EXTEND-IA, ESCAPE, SWIFT-PRIME, REVASCAT, THERAPY and THRACE) were applied to determine the proportion that would be eligible for each of these studies., Results: A total of 263 patients was included. Eligibility for IAT in individual trials ranged from 53% to 3% of patients; 17% were eligible for four trials and under 10% for two trials. Only three patients (1%) were eligible for all studies. The most common cause of exclusion was absence of large artery occlusion (LAO) on CTA. When applying simplified criteria requiring an ASPECT score > 6, 16% were eligible for IAT, but potentially 40% of these patients were excluded by perfusion criteria and more than half by common NIHSS thresholds., Conclusion: Around 15% of patients presenting within 6 h of stroke onset were potentially eligible for IAT, but clinical trial eligibility criteria have much more limited overlap than is commonly assumed and only 1% of patients fulfilled criteria for all recent trials., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Cognard: Consultancies: Medtronic, Sequent, Codman, Microvention, Stryker. No other conflicts of interest reported. Fiehler: Jens Fiehler has received fees as consultant or lecturer from Acandis, Bayer, Boehringer-Ingelheim, Codman, Covidien, MicroVention, Penumbra, Philips, Sequent, Siemens and Stryker. Consultant for Codman, MicroVention. Lectures for Boehringer-Ingelheim, Covidien, and Penumbra. Funding to institution: MicroVention. Unrelated: Consultant for Acandis, Sequent, Stryker. Lectures for Bayer, Philips, Siemens. Funding to Institution: DFG, BMBF, BMWi. Gallitelli: None. Jansen: Olav Jansen was a co-author of SWIFT-Prime, and is a steering committee member of SITS Open. Kobayashi: Employment, consultancies, stock ownership: none. Honoraria: Procardia Medical sp. Z o.o./Microvention, Travel grants: ev3/Covidien/Medtronic, Balt Extrusion. Mazighi: Consultancies: Servier, Boehringer Ingelheim; travel or speaker honoraria: Covidien, Boehringer Ingelheim, Aztra Zeneca and Bayer. Muir: No personal conflicts of interest. Institutional conflicts of interest: Grants to support the PISTE trial from the Stroke Association, National Institute of Health Research Health Technology Assessment programme, and unrestricted grants from Covidien (Medtronic) and Codman, to the University of Glasgow. Intellectual conflict of interest: Co-PI of the PISTE trial. Schaller: None. Schellinger: Employment: none, consultancies: Boehringer Ingelheim, Bayer, Daiichi Sankyo, Pfizer, Cerevast, Photothera, Covidien, stock ownership: none, honoraria Boehringer Ingelheim, Bayer, Daiichi Sankyo, Pfizer, Cerevast, Photothera, Covidien, paid expert testimony: expert witness at German courts, patents or patent applications: none, travel grants: Biogen, Novartis, Genzyme, Boehringer Ingelheim, Bayer, Daiichi Sankyo, Serono.

Background: Embolic strokes of undetermined source comprise up to 20% of ischemic strokes. The stroke recurrence rate is substantial with aspirin, widely used for secondary prevention. The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source international trial will compare the efficacy and safety of rivaroxaban, an oral factor Xa inhibitor, versus aspirin for secondary prevention in patients with recent embolic strokes of undetermined source., Main Hypothesis: In patients with recent embolic strokes of undetermined source, rivaroxaban 15 mg once daily will reduce the risk of recurrent stroke (both ischemic and hemorrhagic) and systemic embolism (primary efficacy outcome) compared with aspirin 100 mg once daily., Design: Double-blind, randomized trial in patients with embolic strokes of undetermined source, defined as nonlacunar cryptogenic ischemic stroke, enrolled between seven days and six months from the qualifying stroke. The planned sample size of 7000 participants will be recruited from approximately 480 sites in 31 countries between 2014 and 2017 and followed for a mean of about two years until at least 450 primary efficacy outcome events have occurred. The primary safety outcome is major bleeding. Two substudies assess (1) the relative effect of treatments on MRI-determined covert brain infarcts and (2) the biological underpinnings of embolic strokes of undetermined source using genomic and biomarker approaches., Summary: The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source trial is evaluating the benefits and risks of rivaroxaban for secondary stroke prevention in embolic strokes of undetermined source patients. Main results are anticipated in 2018., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: All of the coauthors have received financial remuneration from Bayer Pharma AG for service on the Steering Committee except H. Mundl, S. Berkowitz, C. Pater, G. Peters, and B. Kirsch who are all employees of the sponsors. All coauthors receive stipend and research support for participation in NAVIGATE ESUS from the industry sponsors.