INTRODUCTION:Genetic deficiency of factor XI is associated with a reduced risk of ischemic stroke. Asundexian is a direct inhibitor of activated factor XIa (FXIa) with a low risk of bleeding in early trials. We seek to determine its efficacy and safety combined with antiplatelet therapy for prevention of ischemic stroke. PATIENTS AND METHODS:Oral faCtor Eleven A iNhibitor asundexian as novel antithrombotiC (OCEANIC-STROKE) is a placebo-controlled, double-blind, event-driven randomised trial including participants with stroke (NIHSS ≤ 15) or high-risk TIA (ABCD2 6 or 7) within 72 h of onset. Participants had at least one of the following: atherosclerosis of extra- or intracranial vessels, a medical history of atherosclerosis or an imaged acute non-lacunar infarct. We excluded sources of stroke requiring anticoagulation and active non-trivial bleeding other than hemorrhagic infarction (HI 1 or 2). Participants received asundexian 50 mg daily or placebo stratified by planned concurrent antiplatelet therapy (single vs dual). The primary endpoint is time to ischemic stroke. We present baseline characteristics as of 5 June 2025. RESULTS:Between January 2023 and February 2025, we randomised 12,327 participants. Participants were 67% male with a mean (SD) age of 68 (11) years. Ischemic stroke was the index event for 95% of whom 27.4% had thrombolysis and/or mechanical thrombectomy. By TOAST classification, 43% of index strokes were LAA, 22% small vessel disease, 30% undetermined and 2% cardioembolic. Dual antiplatelets were planned in 63% as standard initial treatment. Trial completion is anticipated in October 2025. CONCLUSION:OCEANIC-STROKE will be the first completed trial of FXIa inhibition for prevention of stroke after non-cardioembolic stroke or TIA. TRIAL REGISTRATION:ClinicalTrials.gov (NCT05686070).
Recent research demonstrated activation of the innate immune system in ALS models. This pathway can be activated by cGAS-STING sensing of cytosolic DNA that accumulates as a result of chronic DNA damage and defective mitochondria, both of which was identified as pathology in FUS-ALS. Therefore, we analyzed innate immune pathways in FUS-ALS, which revealed upregulation of interferon-stimulated genes (ISGs) and activation of the TBK1-IRF3 pathway in FUSmut iPSC-derived spinal motor neurons (sMNs). Accumulation of cytosolic dsRNA and its sensor RIG-I, but not MDA5, was found to be significantly upregulated in FUSmut sMNs, which was abolished upon siRNA-mediated knockdown of RIG-I. RIG-I was highly expressed in FUS-ALS post-mortem α-MNs. IFN treatment of FUSwt sMNs phenocopied the axonal degeneration of FUSmut sMNs. Mitochondrial transcription, a known source of dsRNA, was found to be upregulated in compartmental axonal RNAseq analysis and its inhibition reduced ISGs in FUS-ALS sMNs. The JAK-STAT inhibitor ruxolitinib alleviated the upregulated ISG expression and reversed the axonal degeneration of sMNs. Finally, we analyzed ISG expression in peripheral blood from 18 FUS-ALS patients, eight of whom had a significantly elevated interferon signature. RIG-I-mediated innate immune activation in sMNs may be an interesting novel individualized biomarker-driven therapeutic target in (FUS-) ALS. A one-sentence summary of your paper: RIG-I-mediated innate immune activation is found in FUS-ALS spinal motor neurons caused by cytosolic dsRNA accumulation due to mitochondrial transcriptional activation and is amenable to JAK-STAT inhibition and might thus be an interesting novel individualized biomarker-driven therapeutic approach in (FUS-) ALS.
Abstract Background and aims The mechanisms underlying breakthrough strokes are incompletely understood. The association between carotid atherosclerosis and breakthrough strokes has not been sufficiently assessed. We aimed to determine the prevalence and potential contribution of carotid atherosclerosis to breakthrough strokes. Methods We analyzed data from the prospective, multicenter, observational RASUNOA-Prime study (ClinicalTrials.gov NCT02533960). Eligible patients had AF and an acute ischemic stroke. Patients were grouped by pre-stroke anticoagulation: direct oral anticoagulant (DOAC), vitamin K antagonist (VKA), or no oral anticoagulation. Stenosing and non-stenosing atherosclerosis including vulnerable plaques was assessed by core laboratory CTA readings. Associations of atherosclerotic manifestations with ipsilateral carotid-territory ischemia were examined using a generalized linear mixed model. Results Of 2,737 patients, CT angiography (CTA) was available for 1,464 (53.5%). Any carotid atherosclerosis was present in 81% of the 1,464 patients with available CTA. Overall, 17% had extracranial carotid stenosis ≥50% (NASCET) or carotid occlusion. Among 792 patients with unilateral carotid-territory ischemia and no stenosis, ipsilateral vulnerable carotid plaques were detected in 34% (28% non-OAC, 38% DOAC, 38% VKA), including bilateral plaques, whereas 5% had vulnerable plaques on the contralateral side only. In DOAC patients, the odds of ipsilateral vulnerable plaques were higher than in non-anticoagulated patients (OR = 4.4, 95% CI 1.6-11.8, P = 0.004). Conclusions Stenosing and non-stenosing carotid atherosclerosis with vulnerable plaques is an underestimated comorbidity in patients with breakthrough strokes which may contribute to the high risk of recurrence. Longitudinal studies including advanced vascular imaging are needed to better understand the impact of atherosclerosis to stroke recurrence after breakthrough strokes. Conflict of interest This was an investigator-initiated study funded by an unrestricted research grant to the Heidelberg University Hospital, Heidelberg, Germany. The RASUNOA-Prime study was supported by unrestricted grants to the Universitätsklinikum Heidelberg, Germany from Bayer Vital GmbH, Germany, Bristol-Myers Squibb/Pfizer Alliance, Boehringer Ingelheim Pharma GmbH & Co. KG, and Daiichi Sankyo Europe GmbH. The funding sources had no role in the design of the study, data collection, data analysis, or manuscript preparation, and no influence on the decision to submit the manuscript for publication. Alexander W Veltkamp: nothing to disclose. David Kinzler: nothing to disclose. Birte Hellwig: nothing to disclose. Adrian Heeger: nothing to disclose. Anika Huesing: nothing to disclose. Peter U. Heuschmann: research grants from, University Hospital Heidelberg (within RASUNOA-prime; supported by an unrestricted research grant to the University Hospital Heidelberg from Bayer, BMS, Boehringer-Ingelheim, Daiichi Sankyo); as well as from the German Ministry of Research and Education, Federal Joint Committee (G-BA), European Union, German Heart Foundation, German Research Foundation, Bavarian State, German Cancer Aid, Robert-Koch-Institute, outside the submitted work. Jan Purrucker: consultation fees and travel expenses from Abbott, Akcea, Bayer, Boehringer Ingelheim, Daiichi Sankyo, and BMS/Pfizer, and he reports grants from the Federal Joint Committee within the Innovation Fund. Roland Veltkamp: research support from European Union’s Horizon 2020 research and innovation program under grant agreement No 754517, and from Bayer, BMS-Pfizer, Boehringer Ingelheim, Daiichi Sankyo, Medtronic, Biogen. Honoraria for consultancies and lectures for Astra Zeneca, Bayer, BMS-Pfizer, Javelin, Portola, and he is an investigator of the Imperial BRC.
