BACKGROUND:Tenecteplase has been previously evaluated in large- and medium-sized vessel occlusion subgroups, but its effectiveness in more distal occlusions, particularly those involving the distal middle cerebral artery branches or the anterior cerebral artery and posterior cerebral artery territories, and across varying ischemic core and perfusion profiles, remains uncertain. METHODS:We performed a secondary analysis of TASTE (Tenecteplase Versus Alteplase for Stroke Thrombolysis Evaluation), a randomized clinical trial comparing tenecteplase and alteplase in patients presenting within 4.5 hours of symptom onset with perfusion imaging-confirmed stroke and evidence of target mismatch (penumbra/core ratio >1.8 and an absolute difference >15 mL). The primary outcome was the modified Rankin Scale (mRS) score of 0 to 1 at 90 days. We compared the effect of tenecteplase versus alteplase in subgroups based on occlusion site (proximal M2, distal M2, M3 and beyond, anterior cerebral artery, and posterior cerebral artery), ischemic core, core growth rate, and penumbra. The treatment effect of tenecteplase and alteplase was compared stratifying by the subgroup of interest, adjusting for age, baseline National Institutes of Health Stroke Scale score, and premorbid mRS score in modified Poisson regression models. RESULTS:Of the 680 patients enrolled, 492 were included in the primary analysis (median age, 73 [interquartile range, 63-82] years; male sex: 306/492 [62%]). Two hundred forty-two (49%) received tenecteplase, and 250 (51%) received alteplase. Tenecteplase was associated with a higher proportion of mRS score of 0 to 1 with distal (M3 and beyond) occlusions (tenecteplase: 62/81 [77%] versus alteplase: 59/93 [63%]; adjusted risk ratio, 1.23 [95% CI, 1.04-1.46]). Numerically higher rates of mRS score of 0 to 1 were observed with distal M2 (tenecteplase: 30/46 [65%] versus alteplase 28/48 [58%]; adjusted risk ratio, 1.14 [95% CI, 0.84-1.54]) and anterior cerebral artery occlusions (tenecteplase: 12/21 [57%] versus alteplase 5/13 [38%]; adjusted risk ratio, 1.46 [95% CI, 0.71-3.00]). No treatment differences were seen for proximal M2 or posterior cerebral artery occlusions (Pinteraction across all occlusion sites: 0.89). Across ischemic core, penumbra, and core growth rate subgroups, no difference in treatment effect was observed. CONCLUSIONS:Patients with distal middle cerebral artery occlusions who are treated with tenecteplase are more likely to achieve an mRS score of 0 to 1 at 90 days than those treated with alteplase. REGISTRATION:URL: https://www.anzctr.org.au; Unique identifier: ACTRN12613000243718.

Stroke remains a leading cause of death and disability worldwide. In response, many governments have developed stroke policies emphasizing prevention, early detection, timely treatment, and rehabilitation. However, the implementation of those strategies remains uneven, challenged by fragmented health systems, unequal access to care, and resource constraints. Digital health tools provide robust solutions to enhance national and regional stroke policies by improving data collection, care access and coordination, monitoring, education, and public engagement. This review explores how digital health can strengthen stroke care systems across different contexts, highlighting real-world applications, policy integration, and strategic enablers for equitable implementation.

Abstract Background and aims Clonal Hematopoiesis of Indeterminate Potential (CHIP) is an age-related condition from somatic hematopoietic mutations associated with increased cardiovascular and cerebrovascular risk. However, its prevalence, etiological distribution, and prognostic impact in acute ischemic stroke remain unclear. This study investigated these aspects in a stroke cohort. Methods In this prospective observational study, consecutive patients >60 years with a non-lacunar first ischemic stroke were enrolled and underwent complete etiological evaluation and targeted sequencing of 13 CHIP-associated genes during hospitalization. CHIP was defined by presence of ≥1 mutation with Variant Allele Frequency (VAF)≥2%. Outcomes included NIHSS at onset and discharge, infarct volume at 24–72 hours and 3-months mRS. Results Seventy-eight patients (50% female; median age 72) were included. Stroke subtypes were cardioembolic 46%, atherothrombotic 44%, and cryptogenic 10%. CHIP was identified in 21 (27%) patients with the most frequent mutations DNMT3A (48%), TET2 (19%), and SRSF2 (9.5%). Cardioembolic stroke was associated with CHIP (p=0.031), and TET2 mutations were detected only in this etiological subgroup. CHIP with VAF>4%, multiple CHIP mutations and presence of TET2 were associated with higher infarct volume (p=0.07, 0.02 and 0.02). Additionally, there was a trend toward higher NIHSS and poorer 3-months mRS in CHIP patients. However, in multivariable regression analysis, cardioembolic stroke subtype was the main predictor of NIHSS at onset, infarct volume and 3-months mRS. Conclusions CHIP was frequent, particularly in cardioembolic stroke. CHIP with VAF>4%, TET2 and multiple CHIP mutations were associated with larger infarcts, but cardioembolic stroke remained the main predictor of clinical outcomes. Conflict of interest All authors declare no conflicts of interest

Abstract Background and aims Despite anticoagulation with direct oral anticoagulants (DOACs), some atrial fibrillation (AF) patients still experience ischemic stroke. Understanding whether breakthrough stroke (BS) represents therapeutic failure or identifies higher-risk phenotypes is essential for optimizing secondary prevention. We compared outcomes between breakthrough stroke patients on DOACs versus newly discovered AF patients. Methods Retrospective cohort study using Vall d'Hebron University Hospital stroke registry (2020-2025). Patients with acute ischemic stroke and AF were classified as breakthrough stroke (known AF on DOACs) or newly discovered AF. Propensity score matching (1:1) adjusted for age, sex, pre-stroke modified Rankin Scale, baseline NIHSS, and reperfusion therapies. Primary outcomes: 90-day mRS shift and functional independence (mRS 0-2). Secondary outcomes: mortality and 1-year recurrence using Fine-Gray competing risk regression. Results Among 9,000 stroke admissions, 778 had AF-related stroke. After matching, 229 pairs were analyzed. Breakthrough stroke patients showed significantly worse mRS distribution (common OR 1.72; 95% CI 1.24-2.39; p=0.001) and lower functional independence (39.7% vs 54.1%; RR 0.73; 95% CI 0.60-0.90; p<0.001). Breakthrough patients had higher 90-day mortality (7.9% vs 3.1%; RR 3.60; 95% CI 1.36-9.53; p=0.011) and five-fold increased 1-year recurrence risk (HR 3.59; 95% CI 1.19-10.86; p=0.024). All primary outcomes survived multiple testing corrections. Conclusions Breakthrough stroke patients on DOACs have significantly worse functional outcomes, higher mortality, and increased recurrence compared to newly discovered AF patients. These findings identify breakthrough stroke as a high-risk phenotype requiring intensified secondary prevention strategies. Conflict of interest Giulio Fiore: Nothing to disclose, Marta Olive: Nothing to disclose, Federica Rizzo: Nothing to disclose, Claudia Patricia Meza Burgos: Nothing to disclose, David Rodriguez-Luna: Nothing to disclose, Noelia Rodriguez-Villatoro: Nothing to disclose, Alvaro Garcia-Tornel: Nothing to disclose, Adriano Bonura: Nothing to disclose, Marián Muchada: Nothing to disclose, Carlos A. Molina: Nothing to disclose, Marta Rubiera: Nothing to disclose, Jorge Pagola: Nothing to disclose Figure 1 - belongs to Results Table 1 - belongs to Conclusions

Abstract Background and aims Early differentiation between intracerebral hemorrhage (ICH) and ischemic stroke is critical, as management strategies differ substantially, yet this distinction is unavailable in prehospital and hyper-acute settings. This study assessed the feasibility and diagnostic performance of HYPER-AI-SCAN, an AI-assisted transcranial ultrasound framework for ICH detection. Methods In this single-centre prospective pilot study, 100 patients with acute stroke (33 ICH), confirmed by non-contrast CT, underwent portable transtemporal transcranial B-mode ultrasound using a strictly standardized 5-second sweep protocol applied by three operators with different neurosonology experience; infratentorial hemorrhages were excluded. Baseline characteristics were comparable between groups. Ultrasound videos were preprocessed and sampled using a first-pass policy (20 frames from first 2.5 s). A deep-learning pipeline combined a pre-trained ultrasound foundation model with attention-based multiple-instance learning for patient-level ICH classification. Ultrasound-only and cross-modal (NCCT-guided knowledge distillation) training strategies were evaluated, preserving ultrasound-only inference. Performance was assessed using 5-fold patient-disjoint cross-validation. Results In the ultrasound-only cohort (n = 100), balanced accuracy was 0.74 (95% CI 0.60–0.88), sensitivity 0.59 (0.39–0.79), specificity 0.87 (0.71–1.00), AUROC 0.85 (0.68–1.00), and F1 score 0.64 (0.47–0.81). In patients with paired ultrasound–CT data (n = 89), cross-modal training yielded balanced accuracy 0.80 (0.74–0.86), sensitivity 0.69 (0.58–0.80), specificity 0.91 (0.85–0.97), AUROC 0.89 (0.83–0.95), and F1 score 0.72 (0.63–0.81). Conclusions HYPER-AI-SCAN demonstrates the feasibility of AI-assisted, standardized transcranial ultrasound for reliable ICH detection in a real-world, multi-operator pilot setting, supporting scalable ultra-early and prehospital stroke triage. Conflict of interest nothing to disclose. Figure 1 - belongs to Methods

Background Rapid identification of large vessel occlusion (LVO) in acute ischemic stroke (AIS) is essential for reperfusion therapy. Screening tools, including Artificial Intelligence (AI) based algorithms, have been developed to accelerate detection but rely heavily on pre-test LVO prevalence. This study aimed to review LVO prevalence across clinical contexts and analyze its impact on AI-algorithm performance.Methods We systematically reviewed studies reporting consecutive suspected AIS cohorts. Cohorts were grouped into four clinical scenarios based on patient selection criteria: (a) high suspicion of LVO by stroke specialists (direct-to-angiosuite candidates), (b) high suspicion of LVO according to pre-hospital scales, (c) and (d) any suspected AIS without considering severity cut-off in a hospital or pre-hospital setting, respectively. We analyzed LVO prevalence in each scenario and assessed the false discovery rate (FDR) - number of positive studies needed to encounter a false positive, if applying eight commercially available LVO-detecting algorithms.Results We included 87 cohorts from 80 studies. Median LVO prevalence was: (a) 84% (77-87%), (b) 35% (26-42%), (c) 19% (14-25%), and (d) 14% (8-22%). At high prevalence levels: (a) FDR ranged between 0.007 (1 false positive in 142 positives) and 0.023 (1 in 43), whereas in low prevalence scenarios (Ccand d), FDR ranged between 0.168 (1 in 6) and 0.543 (over 1 in 2).Conclusion To ensure meaningful clinical impact, AI algorithms must be evaluated within the specific populations and care pathways where they are applied.

Abstract Background and aims Our objective is to identify thrombus composition and other factors associated with severe clinical outcomes after successful mechanical thrombectomy (SMT). Methods Tandem occlusions were excluded. SMT cases with final mTICI > 2b were included . Each thrombus was analyzed by Flow Cytometry for main leukocyte composition and leukocyte-platelet subpopulations: platelets-Lymphocytes, platelets-monocytes and platelets-granulocytes aggregates. Thrombus analysis, baseline variables, antithrombotic treatment, etiology, neuroimaging and reperfusion treatment were analyzed to evaluate associations with severe outcomes defined as mRs 4, 5 or 6 at 3 months. Results Almost 50% of patients developed severe outcomes (22/45). Higher NIHSS score (20 vs 13, p=0.07) and passes (2 vs 1 p=0.09), hyperglycemia (116 mg vs 111mg p=0.018), slower procedures (46 vs 38 minutes of groin-to-recanalization p 0.026), worse ASPECTS (8 vs 10 p=0.014), cardioembolic etiology [ 19 (86%) vs 12 (57%) ], no-chronic antiplatelet treatment [ 4(18%) vs10 (47%) p =0.39], higher monocyte-to-lymphocyte ratio [ 4% ( 2-8) vs. 2% (1-5); p=0.039] and higher platelets-lymphocytes aggregates [34% (18- 61) vs 21% (9-34); p= 0.046 ] in thrombus analysis were associated with severe outcomes at 3 months. In the logistic regression analysis adjusted by age, intravenous fibrinolysis and significative features from univariate analysis, the only independent predictor of severe outcomes was the proportion of platelets-lymphocytes aggregates in intracranial thrombus (aOR 1.062, 95% CI 1.009- 1.119). Conclusions Rich platelets-lymphocytes thrombus is an independent predictor of severe outcomes at 3 months from stroke and a potential therapeutic target to improve the benefits of succesfull endovascular treatments. Conflict of interest nothing to disclose

INTRODUCTION:Patients with a CTA spot sign could benefit more from interventions to limit ICH expansion. We evaluated whether its presence modifies the association between systolic blood pressure (SBP) reduction and ICH outcomes. PATIENTS AND METHODS:A prospective study of patients with ICH < 6 hours and SBP ≥ 150 mmHg at 2 Comprehensive Stroke Centers in Barcelona over 4.5 years. Patients underwent multiphase CTA (arterial, peak venous and late venous phases) and received treatment targeting SBP ≤ 140 mmHg ≤ 60 minutes. We assessed independent associations and interaction of achieving SBP target ≤ 60 minutes and spot sign status (arterial, or secondarily any phase) with hematoma expansion (>6 mL or > 33%) at 24 hours (primary outcome) and 90-day mRS. RESULTS:Among 207 patients (mean age 71 ± 13.2 years, 134 [64.7%] male), 67 (32.4%) presented an arterial spot sign and 122 (58.9%) achieved SBP target ≤ 60 minutes. Target rates were similar with and without arterial spot sign (38 [56.7%] vs 84 [60.0%], P = .653). Hematoma expansion occurred in 46/177 (26.0%), and median 90-day mRS was 4 (2-5). Arterial spot sign and SBP target ≤ 60 minutes were independently associated with hematoma expansion (adjusted odds ratio [aOR] 4.07; 95% CI, 1.74-9.89 and aOR 0.27; 95% CI, 0.11-0.64) and 90-day mRS (aOR 2.23; 95% CI, 1.23-4.07 and aOR 0.43; 95% CI, 0.24-0.76), with no interaction between them (P = .575 and P = .187, respectively). Similar results were observed considering spot sign in any multiphase CTA phase. CONCLUSION:The association between rapidly achieving SBP reduction and ICH outcomes appears neither dependent on nor modified by spot sign status.

Abstract Background and aims Breakthrough stroke (BT) in patients with atrial fibrillation (AF) receiving anticoagulation (ACO) are at risk of left atrial appendage thrombosis (LAAT). We evaluated the usefulness of delayed venous-phase cardiac CT to detect cardiac thrombus. Methods We conducted a retrospective analysis of consecutive BT patients who underwent a modified CT protocol for hyperacute stroke, including venous-phase non–ECG-gated cardiac CT (CCT) without additional contrast injection. Detection of LAAT, quality of left atrial appendage (LAA) contrast filling in hounsfield units (HU), thrombus location, and factors associated with thrombus detection. Results 127 patients were included (mean age 81 years; 55.9% women; baseline NIHSS 6 [IQR 3–15]). LAAT was detected in 15% (n=19), predominantly in the LAA (84.2%), and was associated with lower attenuation values (HU) compared with patients without LAAT (63 HU [IQR 58–79] vs 151 HU [IQR 133–178]; p<0.001). Median injection-to-scan delay was 186 seconds (IQR 172–226). LAA contrast filling was optimal, with no difference between aortic and LAA attenuation (165±46 HU vs 170±38 HU; p=0.098). Patients with LAAT had a larger left atrial (LA) area on cardiac CT (37.6 cm2 [IQR 31–46] vs 32 cm2 [IQR 28–37]; p=0.007) adjusted by age. A ROC showed LA area on cardiac CT < 30cm2 to rule out LAAT (sensitivity 89%, specificity 33%) and LA area > 38cm2 to suspect LAAT (sensitivity 47%, specificity 80%). Conclusions Venous-phase cardiac CT facilitates thrombus detection with minimal delay and without additional contrast administration. LA enlargement appears to be a risk marker for LAAT. Conflict of interest Jorge Pagola: nothing to disclose, Fabian Andres: nothing to disclose, Claudia Meza: nothing to disclose, Giulio Giulio: nothing to disclose, Jesus Juega: nothing to disclose, Federica Rizzo: nothing to disclose, Georgina Figueras: nothing to disclose, Carlos A. Molina: nothing to disclose, Hug Cuellarhug: nothing to disclose

BACKGROUND:Intracranial hemorrhage (ICH) negatively impacts functional outcomes after ischemic stroke, with potentially disproportionate impacts in patients with minor stroke. This study aimed to evaluate the effect of ICH on outcomes in minor ischemic stroke and to identify predictors associated with ICH. METHODS:This was a secondary analysis of the TEMPO-2 (A Randomized Controlled Trial of Tenecteplase Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion) multicenter, randomized trial, which compared tenecteplase with nonthrombolytic standard care in patients within 12 hours of symptom onset with minor stroke (National Institutes of Health Stroke Scale score ≤5) and a visible vessel occlusion or perfusion mismatch. Follow-up imaging was assessed for hemorrhage using the Heidelberg classification. Symptomatic ICH was defined as any hemorrhage associated with neurological deterioration. The primary outcome was return to premorbid functional status at 90 days, measured using the modified Rankin Scale. Mixed-effects regression was used to assess the effect of ICH status on outcomes, adjusting for treatment, age, sex, baseline stroke severity, and onset-to-randomization time, with region included as a random effect. RESULTS:Among 884 participants, 865 had complete 24-hour imaging and follow-up. Using complete case analysis (n=865), any ICH occurred in 102 participants (11.8%). Patients with any ICH (median age, 70 years; 35.3% females) more frequently had premorbid hypertension (71.6% versus 57.7%) and atrial fibrillation (28.4% versus 18.1%). Any ICH was not associated with reduced odds of returning to baseline neurological function (adjusted odds ratio, 0.93 [95% CI, 0.87-1.00]) but was associated with higher 90-day mortality (9.8% versus 1.8%; adjusted hazard ratio, 3.71 [95% CI, 1.54-8.95]). Rates of any ICH were higher in tenecteplase than standard care (14.4% versus 9.2%; P=0.02), although most were petechial hemorrhagic transformations. Symptomatic ICH rates, although numerically higher, were not significantly different between the tenecteplase versus control arms (8 [1.9%] versus 2 [0.5%]; P=0.06). CONCLUSIONS:Although most hemorrhages were minor, the presence of any ICH was strongly associated with increased mortality, highlighting that even minor hemorrhagic transformation may be prognostically significant in patients with minor ischemic stroke.

The temporal evolution of non-contrast CT (NCCT) markers of intracerebral hemorrhage (ICH) expansion during the dynamics of acute ICH is understudied. We aimed to evaluate the temporal evolution of these markers and its relationship with ICH dynamics. Single-center, prospective, observational cohort study on 271 ICH patients < 6 h. Patients underwent baseline NCCT and multiphase CTA, and 24-hour NCCT. NCCT markers included: irregular shape, satellite sign, and island sign (shape markers); heterogeneous density, hypodensities, swirl sign, black hole sign, blend sign, and fluid level (qualitative density markers); and mean, standard deviation, and coefficient of variation hematoma density (quantitative density markers). The spot sign in first phase of multiphase CTA was considered marker of active hemorrhage. Primary outcome was the change in frequency or values of NCCT markers from baseline to follow-up NCCT. Other outcomes included associations of active hemorrhage with NCCT markers at baseline and with the magnitude of their change at follow-up NCCT. Heterogeneous density predicted active hemorrhage with the highest accuracy (66.4

Background and Purpose Embolic stroke of undetermined source (ESUS) emains a major diagnostic challenge in vascular neurology, as a substantial proportion of patients lack an identifiable embolic source despite standardized diagnostic workup. The failure of empiric anticoagulation strategies highlights the need for individualized, mechanism-oriented risk stratification. We aimed to develop a machine learning?based framework to estimate the most likely embolic source in ESUS using routinely available clinical data. Methods We retrospectively analyzed consecutive ESUS patients admitted to the Stroke Unit of Vall d?Hebron Hospital between 2020 and 2024. Three supervised machine learning models (XGBoost, Random Forest, and regularized logistic regression) were trained to independently predict the presence of left atrial enlargement (LAE), left ventricular dysfunction or akinesia (LVD), and complex aortic plaques (AP), based on demographic, clinical, laboratory, and imaging variables available at diagnosis. Model interpretability was assessed using permutation importance and SHAP analyses. Results Among 1,741 ESUS patients (mean age 71.5±14.6 years; 48.3% women), LAE was present in 40.5%, AP in 11.0%, and LVD in 6.5%. XGBoost achieved the best overall performance across targets (PR-AUC: 0.71 for LAE, 0.29 for AP, 0.44 for LVD). Distinct and biologically coherent risk profiles emerged. LAE was driven by older age, elevated NT-proBNP, higher stroke severity, and a non-linear association with cholesterol. AP was associated with advanced age and traditional vascular risk factors. LVD showed a cardiomyopathic pattern characterized by elevated NT-proBNP, younger age, male sex, and severe strokes. Conclusions A machine learning?based approach can provide probabilistic, mechanism-oriented stratification in ESUS, capturing non-linear interactions among routinely available variables. This framework may support clinicians in prioritizing targeted diagnostic pathways and tailoring secondary prevention strategies. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement None ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was exempt from Institutional Review Board approval, as it was a retrospective observational analysis based on routinely collected, fully anonymized data and involved no intervention or deviation from standard clinical care. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data will be shared upon request

Introduction The increasing number of stroke survivors underscores the need for coordinated post-discharge care and systematic outcome monitoring. HARMONICS aimed to provide standardised follow-up, integrating clinician-reported (CROMs) and patient-reported outcomes (PROMs) into a value-based care model.Patients and methods Using lean methodology, post-stroke care pathways were mapped, and a harmonised workflow was implemented across 6 comprehensive stroke centres (CSCs) in Spain and Portugal. Consecutive patients discharged home or to socio-rehabilitation facilities with an mRS < 5 were offered participation. Follow-up was conducted via a smartphone app or telephone, enabling bidirectional communication with a case manager for health education, vital sign monitoring and PROMs collection. Feasibility required meeting 4 predefined indicators: inclusion > 60%, 3-month retention > 75%, PROMs completion > 60% and satisfaction > 70% measured by patient-reported experience measurement (PREM). Secondary analyses compared outcomes with historical cohorts.Results Between 2022 and 2024, 4209 patients were recruited (40.2% women; median age 73 [IQR 62-81]; 75.6% ischaemic; median admission NIHSS 3 [1-6]; median discharge mRS 2 [1-3]). App use occurred in 59.9% (56% independently). Feasibility was achieved for inclusion (82.8%), retention (84.6%) and satisfaction (72.9%), but PROMs completion was 53.7% at 90 days. Despite mild severity, many reported suboptimal PROMs at 3 months, improving modestly by 1 year. Compared with historical controls, HARMONICS patients showed a better 3-month mRS distribution (OR 1.124; 95% CI, 1.042-1.213; P = .0026) and improved PROMs (P < .05).Discussion and Conclusion HARMONICS is a feasible multicentre value-based follow-up model that promotes education, engagement and self-responsibility, with high rates of healthcare satisfaction reported by stroke survivors.

BACKGROUND AND OBJECTIVES:There are few high-quality data on thrombolysis outcomes in the oldest patients, especially for minor stroke. We examined safety and efficacy outcomes of thrombolysis in patients older than 80 years, compared with those ≤80 years, in the Tenecteplase Versus Standard of care for Minor Ischaemic Stroke With Proven Occlusion (TEMPO-2) trial. METHODS:In this post hoc analysis of the TEMPO-2 randomized controlled trial, we compared outcomes and adverse events in patients with minor stroke and symptomatic intracranial occlusion or focal perfusion lesion within 12 hours of symptom onset, assigned to tenecteplase vs nonthrombolytic standard of care, in those >80 years and ≤80 years. The primary outcome was responder analysis of the 90-day modified Rankin Scale (responder was mRS = 0-1 if premorbid mRS = 0-1, 0-2 if premorbid mRS = 2). Secondary outcomes included neurologic recovery according to the NIH Stroke Scale (NIHSS) at 5 days/discharge, vessel recanalization, Lawton Instrumental Activities of Daily Living Scale, EuroQol-5 Dimension (EQ-5D), and adverse events. We used mixed-effects Poisson, ordinal logistic, and quantile regression as appropriate, adjusted for sex, baseline NIHSS, and treatment assignment as fixed-effects and enrolling site as random effects. RESULTS:Among 884 patients in the intention-to-treat analysis (208 [23.5%] >80 years, 365 [41.6%] female). Significant interactions between age and treatment were observed for mRS responder, mRS 0-1, return to baseline function, EQ-5D index, and vessel recanalization. Patients >80 years generally fared worse with tenecteplase for mRS outcomes (mRS 0-1 in 49 [46.2%] vs 61 [59.8%] with control, adjusted risk ratio [aRR] 0.83, 95% CI 0.72-0.97), while among patients ≤80 years, there was no significant difference (249 [76.4%] vs 260 [74.7%], aRR 1.01, 95% CI 0.98-1.03). However, in both age groups, patients were more likely to achieve recanalization of visible occlusions (aRR ≤80 years 2.06, 95% CI 1.60-2.65, >80 years 2.77, 95% CI 2.21-3.47) and NIHSS = 0 at 5 days/discharge when assigned to tenecteplase (aRR ≤80 years 1.14, 95% CI 1.04-1.26, >80 years 1.21, 95% CI 1.10-1.33). Serious adverse events (SAEs) were more frequent with tenecteplase among patients >80 years (risk ratio 2.29, 95% CI 1.27-4.13), particularly hemorrhages and stroke progression/recurrence (any extra/intracranial hemorrhage in 5 [4.7%] vs 0 with standard of care, p = 0.026). DISCUSSION:Older patients (>80 years) with minor stroke and visible occlusion or perfusion lesion assigned to tenecteplase were more likely to achieve recanalization of occlusions and short-term neurologic recovery, as were younger patients, but they experienced worse 90-day outcomes with more frequent hemorrhagic and stroke progression/recurrence-related SAEs. Overall, these results, while post hoc, do not support thrombolysis for minor strokes in older patients. TRIAL REGISTRATION INFORMATION:ClinicalTrials.gov: NCT02398656. CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that in patients >80 years with minor stroke and visible occlusion or perfusion lesion, IV thrombolysis with tenecteplase is associated with worse functional outcomes at 90 days compared with nonthrombolytic standard of care therapies.

Abstract Background and aims Breakthrough stroke occurs despite treatment with direct oral anticoagulants (DOACs), yet the clinical implications of DOAC plasma levels at stroke onset remain unclear. We investigated the association between DOAC plasma levels, acute ischemic stroke features, and 3-month functional outcome. Methods Between January 2024 and September 2025, we prospectively collected data from consecutive stroke code activations at our comprehensive stroke center. Patients with acute ischemic stroke and available DOAC plasma levels at admission were included. DOAC levels were categorized as therapeutic (≥50 ng/mL, tDOAC) or non-therapeutic (<50 ng/mL, ntDOAC). Associations with vessel occlusion, baseline stroke severity (NIHSS), and functional outcome at 3 months (mRS) were analyzed. Results Ninety-six patients had complete acute laboratory, clinical, and imaging data. DOAC plasma levels were not associated with LVO presence (p=0.63). Baseline stroke severity, LVO rates, and acute reperfusion treatments were similar between the both group. Patients with tDOAC levels had significantly lower rates of functional independence (mRS 0–2: 17.9% vs 42.4%; OD 0.30, 95% [0.11–0.78];p=0.012). A consistent trend toward fewer excellent outcomes (mRS 0–1) was observed (p=0.051). Patients with tDOAC levels had higher premorbid disability, and a trend toward greater vascular comorbidity burden, including hypertension, diabetes and heart failure, indicating greater baseline vulnerability. Conclusions In breakthrough AIS, tDOAC levels were not associated with reduced acute stroke severity or LVO occurrence but were linked to poorer functional outcome at 3 months. This dissociation may reflect increased frailty, comorbidity burden, and competing non-cardioembolic mechanisms in patients experiencing stroke despite adequate anticoagulation. Conflict of interest Federica Rizzo is supported by the Instituto de Salud Carlos III (CM24/00105), Marta Olive Gadea: is supported by the Instituto de Salud Carlos III (CM23/00280), Jorge Pagola is supported by Instituto de Salud Carlos III (FIS n.° PI24/00333), Carlos Molina, PI of two projects funded by the European Commission (TRUSTROKE_HE-HLTH-STAYHLTH2022 and UMBRELLA_HE_IHI2024). Giulio Fiore: nothing to disclose, Claudia Meza: nothing to disclose, Jesus Juega: nothing to disclose, Marta Rubiera: nothing to disclose. Marian Muchada: nothing to disclose.

BACKGROUND:The best revascularization strategy for acute ischemic stroke from isolated vertebral artery occlusion remains unclear. METHODS:This retrospective, international, multicenter cohort study included patients from 30 comprehensive stroke centers across Europe (n=23), North America (n=5), and Asia (n=2) between 2016 and 2022. Eligible patients presented with acute ischemic stroke within 24 hours of last seen well and had imaging-confirmed isolated vertebral artery occlusion. Two treatment comparisons were analyzed: intravenous thrombolysis (IVT)-only versus conservative treatment (Cx), and endovascular treatment (EVT)±IVT versus medical management (Cx and IVT). The primary outcome was the shift in 3-month modified Rankin Scale (mRS) score; secondary outcomes included early neurological improvement (24-hour-delta National Institutes of Health Stroke Scale score), recanalization, early neurological deterioration of ischemic origin, symptomatic intracerebral hemorrhage, and 3-month mortality. Analyses were adjusted using inverse probability of treatment weighting (IPTW). RESULTS:Among 494 patients, 143 (29%) received Cx, 218 (44%) IVT-only, and 133 (27%) EVT±IVT. Compared with Cx, IVT-only showed similar 3-month mRS score (IPTW-adjusted odds ratio [aOR] mRS shift score, 1.32 [95% CI, 0.80-2.18]), greater early neurological improvement (IPTW-adjusted-β coefficient, -1 [95% CI, -2.05 to 0.05]), and higher recanalization rates (IPTW-aOR, 4.33 [95% CI, 1.36-13.78]). Compared with MM (=IVT+Cx), EVT±IVT was associated with an unfavorable mRS shift score (IPTW-aOR mRS shift score, 0.51 [95% CI, 0.35-0.74]), higher early neurological deterioration of ischemic origin (IPTW-aOR, 9.06 [95% CI, 2.86-28.67]), and symptomatic intracerebral hemorrhage (IPTW-aOR, 6.05 [95% CI, 1.14-32.1]) though recanalization was over 4-fold higher (OR, 4.64 [95% CI, 1.90-11.33]). Patients with National Institutes of Health Stroke Scale score ≥10 showed point estimates favoring EVT+IVT (Pinteraction=0.025). CONCLUSIONS:IVT-only appeared safe and was associated with better early recovery and recanalization. EVT±IVT showed overall worse outcomes, potentially due to increased early neurological deterioration of ischemic origin and symptomatic intracerebral hemorrhage rates, but may confer benefit in moderate-to-severe strokes, warranting prospective trials in symptomatic isolated vertebral artery occlusion.

BACKGROUND:Glenzocimab, a platelet glycoprotein VI antagonist, is a novel agent that inhibits platelet activation and aggregation. Its safety was demonstrated in the ACTIMIS trial (Acute Ischemic Stroke Interventional Study; URL: https://www.clinicaltrials.gov; Unique identifier: NCT03803007) for patients with stroke receiving thrombolysis, with or without mechanical thrombectomy, and results suggested a reduction in intracranial hemorrhages and mortality. The ACTISAVE trial was designed as a confirmatory study to evaluate the efficacy and safety of glenzocimab in acute ischemic stroke.METHODS:ACTISAVE (Acute Ischemic Stroke Study Evaluating Glenzocimab Used as Add-On Therapy Versus Placebo) was an international, randomized, double-blind, placebo-controlled phase 2/3 study in patients with stroke, treated by thrombolysis within 4.5 hours of symptoms onset with or without mechanical thrombectomy. The study was conducted at 54 primary and comprehensive stroke centers located in 10 countries. Patients were randomized 1:1 to glenzocimab (1000 mg-IV) or placebo. The primary outcome was the modified Rankin Scale (mRS) score of 4 to 6 at day 90. Key secondary outcome was the mRS score of 0 to 2 at day 90. Mortality, mRS shift, National Institutes of Health Stroke Scale score, quality of life, and safety outcomes were assessed.RESULTS:Between September 2021 and October 2023, 438 patients were randomized, 421 treated, and included as randomized in the primary analysis set. Median age was 73 (63-80) years, and 43% were female. Thrombolysis was performed 2.3 hours (median) after symptom onset and followed by mechanical thrombectomy in 36% of patients. The assigned treatment began a median of 1.2 (interquartile range, 0.8-1.6) hours after thrombolysis initiation. Prethrombolysis National Institutes of Health Stroke Scale score median was 9 (6-15). At day 90, there was no statistically significant difference in the primary outcome between the treatment groups: the incidence of poor outcome (mRS score 4-6 versus 0-3) was 21.6% in the glenzocimab group compared with 15.3% placebo group (odds ratio, 1.51 [95% CI, 0.90-2.54]; P=0.120). No statistically significant difference in secondary outcomes was observed. There were no major safety signals with any intracerebral hemorrhage occurring respectively in 60 (28.6%) and 63 (29.9%) patients in glenzocimab and placebo arms.CONCLUSIONS:ACTISAVE failed to confirm a beneficial effect of glenzocimab on mRS in patients with acute ischemic stroke treated by thrombolysis.REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT05070260.

Abstract Background and aims Within the international CERES-TANDEM cohort, emergent carotid stenting (eCAS) during thrombectomy improved 90-day outcomes for anterior circulation tandem lesions overall. Whether this benefit extends to the subgroup with cervical carotid dissection remains uncertain. Methods This is a predefined CERES-TANDEM substudy including consecutive patients with extracranial carotid dissection–related tandem occlusions treated with endovascular thrombectomy at 49 comprehensive stroke centres worldwide (2018–2024). Patients were classified as eCAS (n=288) or no-stenting (n=194); IPTW balanced >20 baseline and procedural covariates, and the primary estimand was 90-day mRS shift. Secondary outcomes were good functional outcome (mRS 0–2), mortality, and safety; we also provide a meta-analysis of eCAS in dissection-related tandem occlusions, including multicentre studies with n>100 patients. Results Patients were middle-aged (median 55 years) with severe stroke at baseline (NIHSS 15–17) and similar imaging profiles across strategies. After IPTW, eCAS was associated with a non-significant trend toward lower disability (common OR 1.10, 95% CI 0.80–1.51) and no excess in sICH or mortality versus no-stenting. Distribution of 90-day mRS suggested numerically more favourable outcomes with eCAS, but good outcome did not differ significantly between strategies. In the updated meta-analysis (3 studies, 892 patients), eCAS yielded a marginal increase in good functional outcome (pooled OR 1.20, 95% CI 0.92–1.57). Conclusions In this CERES-TANDEM substudy, eCAS in cervical dissection–related tandem lesions conferred only a non-significant benefit on functional outcome after rigorous adjustment. Pooled evidence from our meta-analysis suggests a modest treatment effect that supports RCTs. Conflict of interest

Abstract Background and aims Oral anticoagulant (OAC)–related intracerebral hemorrhage (ICH) carries high mortality. Despite guideline recommendations, anticoagulation reversal is inconsistently used, particularly in severe presentations. We aimed to identify determinants of reversal administration and its association with mortality in real-world practice. Methods We analyzed data from the prospective, multicenter ARICH registry including consecutive OAC-related ICH patients admitted to 18 Spanish stroke centers (2019–2024). Outcomes included reversal administration (primary) and 24-hour and 90-day mortality. Hierarchical mixed-effects regression models with hospital-level random intercepts were used. Post-hoc analyses evaluated mortality in patients with ICH volume >60 mL and/or GCS ≤5, commonly excluded from RCTs. Results Among 891 patients (mean age 79.0±9.3 years, 541 [60.7%] male), 678 (76.1%) received reversal. Independent determinants included baseline mRS (aOR 0.84, 95% CI 0.71-0.99), GCS (aOR 1.24, 95% CI 1.13-1.36), ICH volume (per 10-mL increase, aOR 0.86, 95% CI 0.80-0.93), and time since last DOAC dose (per 60-minute increase, aOR 0.94, 95% CI 0.92-0.97). Overall 24-hour mortality was 159/889 (17.9%) and 90-day mortality was 429/887 (48.6%). Reversal was independently associated with lower 24-hour (aOR 0.32, 95% CI 0.18-0.56) and 90-day (aOR 0.59, 95% CI 0.35-0.99) mortality, and with improved outcomes across clinical severity strata: lower 24-hour mortality (Figure 1A) and higher 90-day survival (Figure 1B) (adjusted log-rank P<0.05 for all pairwise comparisons). Conclusions In real-world practice, anticoagulation reversal is influenced by perceived prognosis and is independently associated with lower 24-hour and 90-day mortality, including among patients with severe ICH presentations. Conflict of interest David Rodriguez-Luna: nothing to disclose. Olalla Pancorbo: nothing to disclose. Ana Núñez: nothing to disclose. Renato Simonetti: nothing to disclose. Laura Sánchez Cirera: nothing to disclose. Marta Serrano Ponz: nothing to disclose. Rocío Vera Lechuga: nothing to disclose. Cristina Pérez: nothing to disclose. Luis Prats-Sanchez: nothing to disclose. Carlos A. Molina: nothing to disclose. Figure 1 - belongs to Results