Over the past 2 decades, transcranial direct current stimulation has attracted substantial interest as an adjunctive strategy to enhance poststroke motor recovery. In addition to its potential neuromodulatory effects on motor cortical networks, transcranial direct current stimulation devices are low-cost, easy to use, and compatible with concurrent rehabilitation. Yet, despite its promise, several barriers hinder translation into routine clinical practice, including neutral results from several recently completed multicenter trials, such as TRANSPORT2 (Transcranial Direct Current Stimulation for Post-Stroke Motor Recovery). Moving forward, progress will depend on addressing issues in 3 broad domains: device-related (stimulation parameters and montage), disease-related (patient characteristics and timing), and trial design (outcomes, analytical approaches, adjunctive therapy, and trial infrastructure). In this topical review, we critically examine these challenges and outline strategies to refine transcranial direct current stimulation application, with the goal of more effectively leveraging its neuromodulation properties to promote neuroplasticity and enhance motor recovery after stroke.

The utility-weighted approach to analyzing the modified Rankin Scale (mRS) is increasingly being utilized in acute stroke clinical trials. This analytic approach assigns a patient-centered utility weight—the desirability or value of a health state to patients—to each level of the mRS. The utility-weighted-mRS analysis converts the mRS from a scale reflecting only the rank order of functional outcome after stroke into one that quantifies the value of each poststroke mRS health state from patients’ perspectives. The ability of the utility-weighted-mRS analysis to capture the unequal difference in patient health-related quality of life between each level of the mRS makes it an appealing patient-centered end point for acute stroke clinical trials. However, several concerns have historically raised skepticism regarding its value as a trial end point. Unfamiliarity with how utility weights are derived and used poses challenges to its use for shared decision-making between patients and clinicians. There are valid concerns that social, geographic, and demographic factors that differ between countries influence the mRS utility weights, so that use of uniform weights across all settings mildly reduces the precision of utility quantification, particularly in multinational stroke clinical trials. This narrative review aims to provide the clinical and research stroke community with a practical overview of key methodology in the utility-weighted-mRS analysis to aid in its interpretation, considers the advantages and challenges of using the utility-weighted-mRS analysis, and suggests future areas of study.

The concept of vascular neurology-specific education was launched nearly 50 years ago in response to a growing understanding of the pathophysiology of stroke. The vascular neurology field, and the training required to support its growth and evolution, has been heavily influenced by a simultaneously increasing breadth of knowledge in approaches to clinical management of stroke. There are increasing numbers of vascular neurology fellows each academic year, yet we continue to experience shortages in clinical coverage for patients with vascular neurological conditions. Here, we review the origins of vascular neurology training and current challenges in sustaining educational programs. We then propose action items to help shape the future of vascular neurology education.

OBJECTIVE:The relative risks of bleeding with apixaban and aspirin remain unclear. We compared bleeding end points on apixaban versus aspirin in the ARCADIA trial. METHODS:ARCADIA was a multicenter, double-blind, randomized trial of apixaban versus aspirin in patients with cryptogenic stroke and evidence of atrial cardiopathy. International Society on Thrombosis and Hemostasis (ISTH) criteria were used to classify bleeding as intracranial, symptomatic intracranial, major non-intracranial hemorrhages, and any major and minor hemorrhages. We calculated annualized incidence rate differences (IRDs) between apixaban and aspirin. Our primary analysis included the safety sample which censored patients who permanently stopped taking the study drug. Sensitivity analyses included the intention-to-treat sample. RESULTS:Among 1,015 patients assigned to apixaban or aspirin and followed for a mean 1.8 (±1.2) years, 115 (11.3%) patients experienced 146 hemorrhages: 27 (18.5%) major and 119 (81.5%) minor hemorrhages. Apixaban resulted in significantly fewer intracranial hemorrhages than aspirin in both the safety sample (IRD = -1.4%, 95% confidence interval [CI] = -2.3% to -0.5%) and intention-to-treat sample (IRD = -1.0%, 95% CI = -1.8% to -0.2%). Findings were similar for the risk of symptomatic intracranial hemorrhage in the safety sample (IRD = -1.1%, 95% CI = -1.8% to -0.3%), although this was not statistically significant in the sensitivity analysis of the intention-to-treat sample (IRD = -0.7%, 95% CI = -1.4% to 0.0%, p = 0.11). Risks of major non-intracranial hemorrhage, any major hemorrhage, and minor hemorrhage did not differ significantly between apixaban and aspirin. INTERPRETATION:We found no increase in any hemorrhage type and a decrease in intracranial hemorrhage with apixaban relative to aspirin in patients with cryptogenic stroke and evidence of atrial cardiopathy. ANN NEUROL 2026;99:1589-1597.

Introduction: Intracranial hemorrhage (ICrH) is an umbrella term that encompasses any bleeding within the skull. The underlying mechanisms, clinical presentations, and management strategies of ICrH vary considerably based on the anatomical location of the blood. However, the current terminology surrounding ICrH is often ambiguous and inadequate for conveying the precise anatomical origins and extent of the bleeding, contributing to confusion and inconsistency in both clinical practice and research. Methods: To address these challenges, we identify six key shortcomings in current usage and propose a harmonized terminology for anatomical classification. Results: We propose the following clarifications: (i) intraparenchymal hemorrhage (IPH) refers to any bleeding within the parenchyma of the brain or the brainstem; (ii) isolated intraventricular hemorrhage (IVH) denotes bleeding within the ventricles, not secondary to intraparenchymal or subarachnoid hemorrhage; (iii) intracerebral hemorrhage (ICH) includes both IPH and IVH; (iv) ICrH encompasses all bleeding within the skull (i.e., intraparenchymal, intraventricular, subarachnoid, subdural and epidural hemorrhages); (v) precise anatomical terminology should be favored over the ambiguous term “hemorrhagic stroke”; and (vi) the term “hemorrhage” indicates an active bleeding process, whereas “hematoma” describes the resulting mass or collection of blood. Conclusion: We invite stroke physicians and researchers to use this harmonized terminology to standardize and facilitate communication, as well as the interpretation and translation of research findings.

BACKGROUND:Infants and toddlers with perinatal arterial ischemic stroke face a high risk for lifelong neuromotor impairments and multiple disabilities. Phase 3 clinical trial evidence is urgently needed to identify efficacious treatment to improve outcomes. METHODS:The I-ACQUIRE Phase 3 trial (Perinatal Arterial Stroke: A Multisite RCT of Intensive Infant Rehabilitation) is a 15-site randomized clinical trial of 2 dosages of I-ACQUIRE, a multicomponent, therapist-delivered intervention including key components of constraint-induced movement therapy compared with usual and customary treatment. The trial recruited children 8 to 36 months old with parent-reported perinatal arterial ischemic stroke, hemiparesis, good health, and no prior botulinum toxin or constraint-induced movement therapy. Central 1:1:1 randomization assigned children to High-dose I-ACQUIRE (6-hour sessions, 5 days/wk, 4 weeks), Moderate-dose I-ACQUIRE (3-hour sessions, 5 days/wk, 4 weeks), and Usual and Customary Treatment. Blinded assessments at baseline, end-of-treatment, and 6-months later include the Emerging Behaviors Scale (success defined as % with gains ≥7 points), the primary outcome for unilateral skills on the paretic arm-and-hand; and the Mini-Assisting Hand Assessment, the secondary outcome for bimanual activities. Parents also rate children's motor skills, treatment responses, and stress. Statistical analyses include 2-sample binomial tests for group differences and linear mixed regression models. The registered trial adheres to international trial reporting guidelines and has a parent council. RESULTS:This study protocol describes intervention components plus training and monitoring of treatment fidelity. The trial recruited N=216 children; 198 completed baseline assessments, and 168 (85 boys and 83 girls) qualified for the modified intent-to-treat sample. The mean age was 18.0 (SD=7.6) months. A majority had right-sided paresis (70%); 51% had seizures/epilepsy. Children varied widely in functional classification levels and parent ratings. CONCLUSIONS:The trial sets a unique high threshold for efficacy and proposes sensitivity and exploratory analyses to consider differential response patterns to treatment. If 1 or both I-ACQUIRE dosages lead to significant improvements, then Phase 3 evidence will assist in infant/toddler rehabilitation decision-making. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03910075.

BACKGROUND:Recombinant factor VIIa has been shown to slow bleeding in patients with intracerebral haemorrhage (ICH), but no haemostatic agent has been shown to improve clinical outcomes. We aimed to evaluate the safety, clinical efficacy, and effect on growth of ICH and intraventricular haemorrhage (IVH) of recombinant factor VIIa in patients with acute spontaneous ICH who were most likely to benefit from treatment with this agent. METHODS:We conducted a multicentre, prospective, double-blind, randomised, placebo-controlled, adaptive, phase 3 trial (FASTEST) at 93 sites across the USA, Japan, Canada, Spain, Germany, and the UK. Adults aged 18-80 years with a spontaneous ICH of 2-60 mL, IVH in less than two-thirds of one lateral ventricle or in less than a third of both lateral ventricles, a Glasgow Coma Scale score of at least 8, no evidence of recent ischaemic stroke or myocardial infarction, no recent use of anticoagulation medication or other structural cause of ICH, and who had been treated with study medication within 2 h of stroke onset or last known well were eligible for inclusion. Patients were randomly assigned (1:1) by a simple randomisation scheme to either 80 μg/kg recombinant factor VIIa (intervention group) or an identical placebo (placebo group), administered intravenously over 2 min. All investigators and participants were masked to allocated group assignment. The primary outcome was functional outcome at 180 days, measured by modified Rankin Scale (mRS; score 0-2, 3, and 4-6) and analysed by intention to treat in all randomly assigned patients. The primary safety outcome was life-threatening thromboembolic events during the first 4 days, assessed in all randomly assigned participants. The secondary aim was change in ICH volume and ICH plus IVH volume between baseline and 24 h of treatment administration. We performed an ordinal logistic regression, adjusted for age, baseline ICH volume, baseline IVH volume, and pre-stroke mRS. Preplanned interim analyses, including adaptive sample size re-estimation and enrichment to a younger subgroup (aged ≤70 years), were also conducted. This trial is registered with ClinicalTrials.gov (NCT03496883) and is closed to new participants. FINDINGS:Between Dec 3, 2021, and Oct 1, 2025, we screened 3288 patients, of whom 626 participants were randomly assigned and included in the intention-to-treat analyses: 298 (48%) in the placebo group and 328 (52%) in the intervention group. 216 (35%) participants were female and 410 (65%) were male, with a mean age of 61 years (SD 12). Mean time from stroke onset to administration of study drug was 100 min (SD 22). The trial met the prespecified stopping criteria for futility at the second interim analysis. There was no differential effect in the primary clinical outcome measure of mRS at 180 days between the intervention group and placebo group (adjusted common odds ratio 1·09 [95% CI 0·79-1·51]; p=0·61). Life-threatening thromboembolic complications within 4 days occurred in 15 (<5%) participants in the intervention group and in four (1%) in the placebo group (relative risk 3·41 [95% CI 1·14-10·15]; p=0·020). Compared with placebo, recombinant factor VIIa was associated with decreased growth of ICH (-3·7 mL [95% CI -5·4 to -1·9]) and of ICH plus IVH growth (-5·2 mL [-7·6 to -2·8]) between baseline and CT scan at 24 h. INTERPRETATION:Recombinant factor VIIa administered within 2 h of ICH onset slowed haematoma growth, but did not improve functional outcomes and showed a small increased risk of life-threatening thromboembolic complications. Further testing of recombinant factor VIIa in patients with the greatest risk of continued bleeding is ongoing. FUNDING:National Institute of Neurological Diseases and Stroke, Japan Agency for Medical Research and Development, and Novo Nordisk.

BACKGROUND:Recent randomized trials showed no benefit of mechanical thrombectomy (MT) for ischemic stroke due to distal medium vessel occlusion (DMVO). We sought to understand the use of MT for DMVO stroke treatment before and after the publication of these trials. METHODS:We conducted an email survey of 47 comprehensive stroke centers across the United States, which are participating in a National Institutes of Health-funded randomized controlled trial (RCT; Unique identifier: NCT05948566). The questionnaire was developed and modified with expert feedback. Site principal investigators were asked to discuss the DMVO RCT results with their local clinical teams and to subsequently respond to survey questions in a manner that reflected team-based decision-making regarding MT for DMVO before and after the publication of the RCTs, considering the location of the vessel occlusion (nondominant M2 versus M3/M4/A1/A2). If the site principal investigator was responsible for >1 site with the same stroke team, only 1 survey response was tallied. RESULTS:Of the 43 site principal investigators surveyed representing 47 unique sites, 40 (93%) representing 44 unique sites completed the survey. Before the DMVO RCTs, 95% of respondents were treating nondominant M2 occlusions with MT. Only 15% will continue to be treated with MT, while 57.5% said that treatment was dependent on at least ≥1 variable following presentation of the DMVO RCTs. For all other anterior circulation DMVOs, 50% were treating DMVOs with MT before RCT results' presentation. Only 7.5% will continue to treat with MT, while 32.5% said that treatment was dependent on at least 1 other variable following presentation of the DMVO RCTs. The most common variable named by survey respondents as important to treatment decision was symptom severity. CONCLUSIONS:In this survey of comprehensive stroke centers, the DMVO RCT results created a significant practice change in how stroke teams approach anterior circulation DMVO stroke with MT.

In 2013, the National Institute of Neurological Disorders and Stroke established National Institutes of Health (NIH) StrokeNet to support multi-site clinical trials focused on stroke prevention, treatment, and recovery. The University of Cincinnati (UC) serves as the National Coordinating Center for StrokeNet. As part of the initiative, the UC StrokeNet Central IRB (SN-CIRB) was established at UC to serve as a single IRB to oversee StrokeNet trials. Since the SN-CIRB approved the first StrokeNet study in 2014, it has reviewed and approved 16 additional studies. Over this period, the UC Human Research Protection Program refined its review processes based on insights from earlier reviews. These improvements have improved efficiency while still ensuring the protection of study participants. The successful implementation and ongoing conduct of the SN-CIRB at UC demonstrate that an academic-based IRB can effectively serve as a Central IRB for a large clinical trial network.

BACKGROUND:The prognostic significance of body weight in patients receiving thrombolysis for acute ischemic stroke remains uncertain. This study aimed to determine whether body weight modifies the comparative effects of low- versus standard-dose intravenous alteplase and to evaluate the associations of body weight and clinical outcomes in patients with acute ischemic stroke. METHODS:A post hoc analysis of the ENCHANTED trial (Enhanced Control of Hypertension and Thrombolysis Stroke Study), an international partial-factorial randomized controlled trial comparing low-dose (0.6 mg/kg) versus standard-dose (0.9 mg/kg) intravenous alteplase and intensive (target systolic blood pressure 130-140 mm Hg) versus guideline-recommended (target systolic blood pressure <180 mm Hg) treatment. The primary outcome was poor functional outcome at 90 days, defined as a modified Rankin Scale score of 2 to 6 (versus 0-1). For the first objective, the exposure was defined as alteplase dose and body weight, whereas for the second objective, body weight alone was considered as the exposure. Logistic regression models were performed to analyze the association between body weight and outcome. The association shape between treatment effect and body weight was evaluated using restricted cubic splines. RESULTS:Among 3206 patients (mean age, 66.6 years; female 37.9%) in the alteplase-dose arm, body weight did not significantly modify the comparative effects of low- versus standard-dose alteplase on functional recovery (Pinteraction=0.60), death (Pinteraction=0.56), or symptomatic intracerebral hemorrhage (Pinteraction=0.46). In the full cohort of 4458 patients (mean age 66.7 years; female 37.8%), a nonlinear relationship was observed between continuous body weight and 90-day modified Rankin Scale score, with an inflection point at ≈74 kg. Patients weighing <74 kg had a significantly higher likelihood of poor functional outcome (odds ratio, 1.41 [95% CI, 1.06-1.87]; P=0.017) and death (1.65 [95% CI, 1.04-2.61]; 0.03), but not an increase in symptomatic intracerebral hemorrhage. CONCLUSIONS:There was no evidence of effect modification by body weight on the effectiveness of low- versus standard-dose intravenous alteplase in patients with acute ischemic stroke. Low body weight predicts a poor outcome but not an increased risk of symptomatic intracerebral hemorrhage after thrombolysis treatment for acute ischemic stroke. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01422616. URL: https://anzctr.org.au; Unique identifier: ACTRN12611000236998.

Importance:In the Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke (ARCADIA) randomized clinical trial, anticoagulation did not prevent recurrent stroke among patients with a recent cryptogenic stroke and atrial cardiopathy. It is unknown whether anticoagulation prevents covert infarcts in this population. Objective:To test the use of apixaban vs aspirin for prevention of nonlacunar covert infarcts after cryptogenic stroke in patients with atrial cardiopathy. Design, Setting, and Participants:ARCADIA-MRI, an ancillary study to the ARCADIA trial with a median follow-up period of 27 months, enrolled participants from 75 sites in the US from November 14, 2019, until December 2, 2022. Participants in ARCADIA were invited to coenroll in ARCADIA-MRI if they had not permanently discontinued the study drug and had no contraindications on magnetic resonance imaging (MRI). A total of 310 (31%) of the 1015 ARCADIA participants enrolled in ARCADIA-MRI and of those 174 (56%) with adequate quality baseline and follow-up MRI were included in the present analyses. Interventions:MRI performed at the time of the index stroke served as the baseline image unless it was unavailable or of insufficient quality, in which case a new research MRI was obtained. A follow-up research MRI was performed upon each participant's completion of participation in the ARCADIA parent study. Main Outcomes and Measures:The primary outcome was incident nonlacunar covert infarct on the follow-up MRI assessed by 2 independent raters who were masked to treatment assignment. Results:Baseline characteristics were balanced between the apixaban (n = 79) and aspirin (n = 95) arms. The mean (SD) age was 66 (10.6) years, and the median (IQR) modified Rankin Scale (mRS) score 1 (0-2). Ninety-one participants (52.3%) were male. During the median (IQR) follow-up of 811 (487-1288) days, the risk of incident nonlacunar covert infarcts was lower in the apixaban group (5.1%) than the aspirin group (17.9%) (weighted relative risk, 0.29; 95% CI, 0.10-0.83). Conclusions and Relevance:Apixaban compared to aspirin was associated with fewer incident nonlacunar covert infarcts among a subset of patients with a recent cryptogenic ischemic stroke and atrial cardiopathy who were enrolled in ARCADIA. Trial Registration:ClinicalTrials.gov Identifier: NCT03192215.

BACKGROUND:The ARCADIA (Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke) trial found no benefit of anticoagulation for preventing recurrent stroke in patients with atrial cardiopathy. Data on AF monitoring across trial sites may provide context for the findings and knowledge about the current standard of care for poststroke monitoring. METHODS:At study visits, sites reported any preceding use of prolonged heart rhythm monitoring, classified as either external ambulatory monitors or implantable loop recorders. We used relative risk regression, least absolute shrinkage and selection operator (LASSO) regression, and survival analysis to explore patient characteristics associated with monitoring, the association between monitoring and AF detection, and the interaction between monitoring and study treatment effect on recurrent stroke. RESULTS:Of 1633 patients with monitoring data, 957 (58.6%) underwent prolonged monitoring: 567 (34.7%) external ambulatory monitor, 479 (29.3%) implantable loop recorder, and 89 (5.5%) both. The strongest predictors of monitoring were Hispanic ethnicity (standardized LASSO coefficient, -0.19 [risk ratio (RR), 0.66]), National Institutes of Health Stroke Scale score (LASSO, -0.15 [RR per point, 0.97]), left atrial diameter (LASSO, 0.13 [RR per cm, 1.09]), and serum hemoglobin (LASSO, -0.12 [RR per g/dL, 0.97]). At the site level, the median proportion of patients who underwent monitoring was 63% (interquartile range, 36%-92%). The site-level proportion of patients with an implantable loop recorder was associated with greater likelihood of AF detection (RR, 3.9 [95% CI, 2.1-7.4]) but did not modify the trial treatment effect (P value for interaction, 0.99). CONCLUSIONS:In the ARCADIA trial, which enrolled patients with cryptogenic stroke across the United States and Canada, nearly 60% of patients underwent prolonged heart rhythm monitoring. Use of implantable loop recorders was associated with greater likelihood of AF detection.

BACKGROUND:Minimally invasive surgical evacuation improved outcomes for patients with acute, spontaneous, lobar intracerebral hemorrhage (ICH) in the ENRICH trial (Early Minimally Invasive Removal of ICH). We determined the percentage of patients with ICH in a US population-based study eligible for minimally invasive surgical evacuation and projected the annual number of patients with ICH in the United States in 2020 eligible for this therapy. METHODS:We ascertained adults (aged ≥18 years) with acute (<24 hours from last known well), spontaneous ICH in Greater Cincinnati/Northern Kentucky in 2015. Cases were identified by the International Classification of Diseases codes, clinical data abstracted, and physician adjudicated. Location and volume of ICH were centrally adjudicated by neuroradiologists. We applied ENRICH trial criteria to calculate conservative and liberal estimates of the percentage of patients with (1) all ICH at any location and (2) lobar ICH eligible for minimally invasive surgical evacuation. We extrapolated our estimates to the 2020 US adult population using 2020 US census data. RESULTS:We identified 196 patients in Greater Cincinnati/Northern Kentucky in 2015 with acute, spontaneous ICH. After applying all criteria, 2.0% (n=5) of all patients with acute ICH (5.1%; n=5 lobar ICH) were eligible for minimally invasive surgical evacuation. The most common exclusion criteria were ICH volume <30 mL (60%) and prestroke modified Rankin Scale score >1 (52%). In liberal estimates, 2.6% to 3.6% (n=4-7) of all patients with acute ICH (4.1%-7.1% of lobar ICH) were eligible. We projected 1066 to 1848 patients of an estimated 72 283 adult patients with ICH in the United States in 2020 met eligibility criteria. CONCLUSIONS:Approximately 2% to 4% of patients with ICH in our population were eligible for minimally invasive surgical evacuation based on ENRICH criteria, which extrapolates to 1066 to 1848 patients with ICH in the United States annually. Future research is needed to determine whether indications for effective surgical therapy for ICH can be expanded.

Background Approximately 50% of strokes in patients with cancer are classified as cryptogenic after standard evaluation. Atrial cardiopathy could explain some cancer‐related cryptogenic strokes. However, the relationship between cancer and atrial cardiopathy is uncertain. Methods AND RESULTS We conducted a post hoc cross‐sectional analysis of baseline data collected from participants enrolled in ARCADIA (Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke), a clinical trial conducted from 2018 to 2023 at 185 sites. The analytical cohort presented herein included patients age ≥45 years with cryptogenic ischemic stroke within the past 180 days, of whom a subset had atrial cardiopathy and were randomized into the trial. Atrial fibrillation before enrollment was exclusionary. Linear regression models examined the associations between history of cancer and the atrial cardiopathy biomarkers analyzed in ARCADIA: serum NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), P‐wave terminal force in ECG lead V1, and left atrial diameter index on echocardiogram. Among 3745 patients with cryptogenic stroke, 506 (13.5%) had history of cancer. History of cancer was associated with higher median values of NT‐proBNP (126 versus 103 pg/mL, P<0.001) and left atrial diameter index (1.9 versus 1.8 cm/m2, P<0.001) but similar median values of P‐wave terminal force in ECG lead V1 (3000 versus 3025, P=0.08). After adjusting for demographics, tobacco use, and body mass index, no significant association remained between history of cancer and log‐transformed NT‐proBNP (standardized β$$ \beta $$, −0.06 [95% CI, −0.15 to 0.02]), P‐wave terminal force in ECG lead V1 (standardized β$$ \beta $$, −0.02 [95% CI, −0.11 to 0.08]), or left atrial diameter index (standardized β$$ \beta $$, 0.06 [95% CI, −0.05 to 0.16]). Conclusions In a multicenter, prospective, cryptogenic stroke cohort, history of cancer was not associated with selected biomarkers for atrial cardiopathy. Registration URL: https://www.ClinicalTrials.gov; Unique Identifier: NCT03192215.

BACKGROUND:The usual antithrombotic treatment for symptomatic intracranial atherosclerotic stenosis (ICAS) consists of dual treatment with clopidogrel and aspirin for 90 days followed by aspirin alone but the risk of recurrent stroke remains high up to 12 months. The Comparison of Anticoagulation and anti-Platelet Therapies for Intracranial Vascular Atherostenosis (CAPTIVA) trial was designed to determine whether other combinations of dual antithrombotic therapy are superior to clopidogrel and aspirin. METHODS:CAPTIVA is an ongoing, prospective, double-blinded, three-arm clinical trial at over 100 sites in the United States and Canada that will randomize 1683 high-risk subjects with a symptomatic infarct attributed to 70-99% stenosis of a major intracranial artery to 12 months of treatment with (1) ticagrelor (180 mg loading dose, then 90 mg twice daily), (2) low-dose rivaroxaban (2.5 mg twice daily), or (3) clopidogrel (600 mg loading dose, then 75 mg daily). All subjects receive aspirin (81 mg daily), intensive risk factor management, and will undergo blinded CYP2C19 genotype analysis. The primary goal of the trial is to determine whether rivaroxaban or ticagrelor or both are superior to clopidogrel for lowering the primary endpoint (ischemic stroke, intracerebral hemorrhage (ICH), or vascular death) within 12 months. A prespecified interim safety analysis will be conducted when the first 450 randomized subjects have been followed for 12 months to evaluate the risk of major hemorrhage in the rivaroxaban and ticagrelor arms. RESULTS:Enrollment began in August 2022 and, as of 26 June 2024, the 450th subject was randomized into the study. CONCLUSION:CAPTIVA is evaluating two alternative dual antithrombotic therapies to clopidogrel and aspirin to maximize the chance of establishing more effective antithrombotic therapy for symptomatic ICAS, one of the most common and high-risk cerebrovascular diseases worldwide.

BACKGROUND:ARCADIA (Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke), a secondary stroke prevention study comparing apixaban versus aspirin for cryptogenic stroke and biomarkers of atrial cardiopathy, ended prematurely for futility. In the ARCADIA-Cognition study we hypothesized that cognitive decline would be slower in the apixaban arm due to less microembolization. METHODS:ARCADIA subjects on study drug and eligible for magnetic resonance imaging participated in ARCADIA-CSI (ARCADIA-Cognition and Silent Infarction). Cognitive tests were administered centrally by telephone ≥3 months after the ARCADIA index stroke and yearly thereafter. Composite Z scores were the means of 5 standardized cognitive tests. Trajectories of the composite Z score and the individual test scores were compared between treatment arms using a mixed-effects model. RESULTS:Of 799 screened patients at 75 sites, 310 were enrolled in ARCADIA-CSI. Of these, 296 completed at least 1 cognitive exam, and 47 subjects were excluded from the primary analysis for baseline dementia. For the 249 subjects included in the analysis, there were 582 cognitive assessments. Baseline characteristics were balanced between the apixaban (n=128) and aspirin (n=121) arms. Mean age was 68 (SD: 10.4) years, median modified Rankin Scale score 1 (interquartile range, 0-2), 52% female, and 19% Black. During median follow-up of 378 (interquartile range, 183-735) days, the annual change in the overall standardized composite score was 0.084 (95% CI, 0.017-0.149) in the aspirin arm and 0.107 (95% CI, 0.041-0.174) in the apixaban arm (P=0.62). CONCLUSIONS:Cognitive trajectories did not differ between apixaban and aspirin. Further studies should address infarct location and volume and concurrent pathology to determine optimal treatment to mitigate cognitive decline with atrial disease. REGISTRATION:URL: http://clinicaltrials.gov; Unique Identifier: NCT03192215.

BACKGROUND:Obtaining timely informed consent is a key barrier in acute ischemic stroke clinical trial recruitment. Electronic consent (eConsent) allows electronic delivery and documentation of the informed consent process, which may optimize recruitment. eConsent in acute ischemic stroke clinical trials, however, is limited and understudied. We conducted a post hoc analysis of eConsent adoption in MOST (Multi-Arm Optimization of Stroke Thrombolysis Trial), a phase III acute ischemic stroke clinical trial, and studied the impact on recruitment. METHODS:From October 10, 2019, to July 5, 2023, MOST enrolled 514 participants at 57 sites in the United States. Study databases were reviewed to determine informed consent modality for each participant: paper-in person, paper-remote, eConsent-in person, and eConsent-remote. Study sites could use paper consent or eConsent for each enrollment. eConsent adoption trends and participant demographic diversity were reported using descriptive statistics. We utilized χ2 and Kruskal-Wallis tests to compare individual site enrollment, remote consent utilization, baseline neuroimaging-to-randomization times, data clarification requests, and reportable consent-related unanticipated events. RESULTS:eConsent was utilized for 173 (33.7%) of 514 participants. Of 57 sites, 32 (56.1%) utilized eConsent at least once: those sites had higher median enrollment over the course of the entire trial than non-eConsent sites (7.5 [interquartile range, 5-17] versus 3 [interquartile range, 2-4]; P<0.001). eConsent was completed remotely more frequently than paper consent (46.2% versus 1.2%; P<0.001). Participant demographic diversity and baseline neuroimaging-to-randomization times were similar between eConsent-in person and paper-in person (median, 58.5 [interquartile range, 46.5-72.5] versus 55 [interquartile range, 39-70] minutes). Consent documentation adherence was superior with eConsent-in person compared with paper-in person including decreased data clarification requests (44 versus 81 per 100 participants) and reportable unanticipated events (6 versus 25 per 100 participants). CONCLUSIONS:eConsent in MOST was associated with higher individual site enrollment, higher remote consent rates, and improved consent documentation adherence over paper consent. Our study outlines the potential advantages of eConsent adoption in future acute ischemic stroke clinical trials and stroke research networks.