Abstract Background and aims Breakthrough stroke despite oral anticoagulation (OAC) for atrial fibrillation (AF) is associated with unfavorable prognosis. We assessed the long-term outcomes and treatment-related prognostic factors of patients with stroke under OAC for AF. Methods Prospective data from consecutive patients with anterior ischemic stroke, AF and carotid imaging from 10 stroke registries were included. Outcomes assessed were stroke recurrence, major adverse cardiovascular events (MACE), and mortality. Multivariable Cox-regression was performed to identify independent predictors for every outcome. Results Among 2,551 patients, 1,725 discharged on OAC. At 5 years, 9.6% experienced a recurrence, 33.4% a MACE and 27.2% died. Patients with breakthrough stroke had higher risk of recurrence at 12 months (HR 2.14; 95%CI 1.17–3.89) and 5 years (HR 2.06; 95%CI 1.32–3.22). At 5 years, breakthrough stroke was independently associated with increased MACE risk (HR 1.37; 1.06–1.79). Compared with vitamin K antagonists, DOACs were associated with lower stroke (HR 0.57; 0.33–1.00) and MACE risk (HR 0.69; 0.50–0.95). Statins were associated with lower risk of stroke (HR 0.68; 0.46–0.99), MACE (HR 0.65; 0.52–0.81), and mortality (HR 0.52; 95%CI 0.39–0.68). Advanced age (HR 1.06/year; 1.04–1.07), diabetes (HR 1.53; 1.16–2.02), coronary artery disease (HR 1.51; 1.11–2.06), and cancer (HR 3.16; 2.12–4.71) were associated with higher mortality. Conclusions Patients with breakthrough stroke despite OAC treatment represent a high-risk population with significantly worse long-term outcomes. DOAC and statin therapy remain the standard of care and warrant emphasis in secondary prevention strategies. Conflict of interest

Background: There are ~4 million annual ED visits for dizziness in the US. While cerebrovascular disease is detected in only a small proportion of these visits, specialist consultation and neuroimaging are often sought. We therefore aimed to describe the use of brain MRI in ED patients presenting with dizziness and to explore associations between its use and subsequent stroke. Methods: We conducted a retrospective study using data from the Healthcare Cost and Utilization Project from 11 states (2016-2021). Only ED visits for dizziness resulting in discharge to home were included. ICD-10-CM codes R42 and H81 in primary discharge position were used to identify dizzy patients and Current Procedural Terminology codes (70551-70552, 70540, and 70543) were used to detect ED brain MRI use. Study variables included patient demographics, comorbidities classified via Charlson Comorbidity Index (CCI), hospital factors (bed size, presence of EM residents and/or medical students, location, and availability of neurological services), and on-hours vs off-hours arrival/discharge. Our primary study outcome was stroke hospitalization within 30 days of index ED visit defined using validated ICD-10-CM codes. We used simple descriptive statistics to report brain MRI use and logistic regression to evaluate associations between its use and subsequent stroke. Results: Among 966,510 dizzy patients with an ED visit, 95,998 (9.9%) had a brain MRI. The proportion of dizzy patients who received brain MRI increased from 7.8% in 2016 to 12.0% in 2021. Mean ED length of stay among those with brain MRI was 621 minutes compared to 273 minutes for those who did not receive brain MRI. There were 1,486 (0.2%) stroke hospitalizations at 30 days. Risk of stroke was lower at 30 days (OR, 0.66; 95% CI, 0.54 - 0.81) in unadjusted analysis when an MRI brain was obtained. After adjusting for patient demographics, CCI, study year, hospital characteristics (teaching status, location, size, presence of neurological services) and presentation timing (on-hours vs off-hours, weekend vs weekday), risk of stroke remained lower at 30 days (aOR, 0.52; 95% CI, 0.36-0.72) among patients receiving brain MRI. Conclusion: In a large, population-based study, short-term stroke risk was halved among ED patients with dizziness discharged to home who received a MRI brain compared to those who did not, highlighting the potential role of MRI for improving the acute assessment of ED patients presenting with dizziness.

Background: Multiple trials have found no difference in stroke prevention comparing anticoagulation to antiplatelet therapy in patients with stroke from a potential occult cardioembolic source. One explanation is the failure to exclude patients with index or subsequent strokes due to hypertensive arteriopathy. We sought to determine whether systemic evidence of high-risk hypertension (HRH) modifies the treatment effect of anticoagulation versus antiplatelet therapy after cryptogenic stroke. Methods: This secondary analysis of the Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy (ARCADIA) trial assessed whether HRH modified the effect of apixaban versus aspirin in patients with cryptogenic stroke and atrial cardiopathy. HRH was defined as systolic blood pressure ≥160 mmHg at enrollment, left ventricular hypertrophy on echocardiography using left ventricular mass index, or both. The primary outcome was recurrent ischemic stroke or systemic embolism. Cox proportional hazards models evaluated treatment effects and interaction with HRH adjusted for 1) CHA 2 DS 2 VASc score and race; 2) individual variables associated with the primary outcome. Unadjusted stratified analyses and cumulative event rate curves were performed. Results: In 945 randomized patients followed over a median of 1.8 years, 351 (37%) had evidence of HRH, and the primary outcome occurred in 67 patients. Among 594 patients without HRH, a lower incidence rate of the primary outcome was observed in patients randomized to apixaban compared to aspirin (21.5 vs 55.1 per 1000 person-years), whereas patients with HRH had higher incidence with apixaban (55.8 vs 31.8 per 1000 person-years). In the crude and fully adjusted models, a significant interaction effect between HRH and antithrombotic treatment arm was observed (p<0.05) (Table 1). Stratified analysis in patients without HRH demonstrated a lower risk for recurrent ischemic stroke or systemic embolism with apixaban (HR 0.40, CI 0.21-0.79, p=0.008). In patients with HRH, there was no evidence for a beneficial effect of apixaban (HR 1.73, CI 0.80-3.72, p=0.164) (Table 2, Figure 1). Conclusion: Evidence of HRH modified the effect of anticoagulation treatment in patients with cryptogenic stroke and atrial cardiopathy. An underappreciated inclusion of strokes due to hypertensive arteriopathy may account for the absent benefit of anticoagulation in prior trials of embolic stroke of unknown source.

BACKGROUND:Studies evaluating direct oral anticoagulant (DOAC) therapy in reducing covert brain infarction (CBI), compared to aspirin monotherapy, have generally been small and yielded inconclusive results. We, therefore, performed a systematic review and meta-analysis to summarize the effect of DOAC use with CBI and ischemic stroke. METHODS:Using PRISMA guidelines, we systematically searched PubMed, Scopus, Embase, and the Cochrane Library from inception to August 1, 2025, for randomized controlled trials or ancillary studies of trials comparing DOACs with aspirin. Studies were included if magnetic resonance imaging (MRI) scans of the brain were performed during follow-up, and rates of CBI were reported. The primary outcome was any ischemic cerebrovascular event defined as a composite of CBI or symptomatic ischemic stroke, while the secondary outcomes were symptomatic ischemic stroke, incident CBI and incident cerebral microbleeds on follow up brain MRI. After assessing study heterogeneity, we performed a meta-analysis using random-effects inverse-variance weighted models to generate log odds ratios (ORs) and evaluate the strength of association between the type of antithrombotic therapy and outcomes. A subgroup analysis was performed stratified by the type of indication for antithrombotic therapy (primary vs. secondary prevention). RESULTS:Six studies, with a total of 3,666 patients, were eligible for inclusion in the meta-analysis. DOAC use was associated with lower odds of any ischemic cerebrovascular event (OR, 0.65; CI, 0.50-0.85; I2 = 0.0%). In secondary analyses, DOAC use was associated with lower odds of symptomatic ischemic stroke (OR, 0.57; CI, 0.35-0.92; I2 = 9.7%), but there was no relationship with CBI (OR, 0.81; CI, 0.61-1.07; I2 = 0.0%), or cerebral microbleeds (OR, 1.10; CI, 0.79-1.52; I2 = 0.0%). CONCLUSIONS:In this hypothesis-generating meta-analysis of patients at risk for ischemic cerebrovascular disease, DOAC therapy, compared with aspirin, suggested a lower risk of ischemic cerebrovascular events, driven by reductions in symptomatic stroke while there was no association with covert brain infarction.

Background: Management of modifiable risk factors is the mainstay for the prevention of recurrent stroke. Our objective was to investigate trends in vascular risk factor (hyperglycemia, hyperlipidemia, hypertension, and smoking) control among community-dwelling U.S. adults with prior stroke. Methods: We performed analyses of 1999-2018 National Health and Nutrition Examination Surveys (NHANES) participants with self-reported history of stroke. Meeting guideline-recommended targets for post-stroke risk factor control was defined as follows: hemoglobin A1c (HbA1c) <6.5% for individuals without history of diabetes or HbA1c <7.0% for individuals with a history of diabetes, low-density lipoprotein (LDL) cholesterol <70mg/dL, blood pressure <130/80mmHg, and non-smoking. Age-standardized mean HbA1c, LDL, and blood pressure and prevalence of meeting each guideline target individually and cumulatively were calculated for each four-year epoch. Results: Age-standardized mean HbA1c and blood pressure were stable over time, while mean LDL decreased from 125.5mg/dL (95%CI=117.9-133.0) in 1999-2002 to 110.7mg/dL (95%CI=104.4-117.0) in 2015-2018. From 1999 through 2018, the age-standardized prevalence of individuals meeting guideline recommendations for glycemic control remained stable above 85% and for blood pressure control and smoking remained stable between 50% and 75%. The age-standardized prevalence of individuals meeting guideline recommendations for lipid control increased from 5.1% (95%CI=0-12.3) in 1999-2002 to 23.4% (95%CI=19.9-27.0) in 2002-2006 and subsequently decreased in 2015-2018 (8.8%, 95%CI=4.3-13.3). Fewer than 5% of individuals met guidelines for all four stroke risk factors over this time period, while the proportion meeting two guidelines increased from 46.7% (95%CI=23.8-69.5) to 62.4% (95%CI=51.7-73.1). Discussion: In this nationally representative sample of U.S. adults with stroke, few stroke survivors met guideline recommendations for all risk factors from 1999 through 2018, with an overall stable trend. Despite a significant decrease in the mean measured LDL during the study period, guideline adherence for lipid control was the lowest among the four risk factors evaluated, while adherence to glycemic guidelines was consistently the highest. Our results suggest that current secondary stroke prevention efforts aimed at targeting improved blood pressure, lipid control, and smoking cessation could be improved to reduce the burden of recurrent stroke.

BACKGROUND:QT interval prolongation is associated with incident stroke in the general population. Whether QT prolongation predicts recurrent stroke is unknown. METHODS:The Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke trial was conducted in North America from 2018 to 2023 and randomised patients with cryptogenic stroke and atrial cardiopathy to apixaban versus aspirin to assess the prevention of recurrent strokes. In this secondary analysis, we excluded patients with missing ECG data and those with prolonged QRS (≥120 ms). The poststroke QT interval was corrected for heart rate (QTc) using a cohort-specific correction formula and the Framingham, Hodges, Bazett and Fridericia formulae. Multivariable Cox proportional hazards models were used to assess the association between QTc and recurrent stroke of any type. RESULTS:Among 881 included patients, 139 (15.8%) had a prolonged cohort-specific QTc. Over a mean of 1.8 years, 62 patients had recurrent strokes of any type (crude rate 7.0%, annualised rate 3.9% per year). After multivariable adjustment, prolongation of cohort-specific QTc was associated with decreased risk of recurrent stroke (HR (95% CI)=0.72 (0.54 to 0.95) per SD and 0.16 (0.04 to 0.64) for prolonged vs normal QTc). These findings were consistent across methods of QT interval correction. Accounting for the timing of baseline ECG, QRS duration, incident atrial fibrillation and the competing risk of death did not change the results. CONCLUSIONS:Among patients with recent cryptogenic stroke and atrial cardiopathy, QTc prolongation was associated with a reduced risk of recurrent stroke. These findings contrast with the association observed between QTc prolongation and first stroke in the general population, which may reflect the unique characteristics of this selected population. If confirmed in broader populations, these findings suggest that electrocardiographic markers such as QTc may have distinct implications for risk stratification in terms of first versus recurrent stroke. TRIAL REGISTRATION NUMBER:NCT03192215.

BACKGROUND AND PURPOSE:Intracranial atherosclerosis (ICAS) is a major cause of stroke worldwide, highly prevalent in Asian populations. While systemic inflammation plays a well-established role in the onset and progression of extracranial atherosclerosis, its relevance to ICAS remains poorly defined. This meta-analysis aimed to evaluate the association between systemic inflammatory markers and ICAS presence and progression. METHODS:The meta-analysis was performed with a comprehensive literature search that identified 292 studies, of which 12 met inclusion criteria, encompassing 19674 patients. After stratification by three biomarkers (hs-CRP, CRP, NLR), the analysis assessed the association with ICAS presence using random-effects models to estimate effect sizes. ICAS progression analysis could not be performed due to insufficient data. RESULTS:A negligible effect size magnitude was found between ICAS presence and both hs-CRP (Cliff's Delta = 0.090, 95% CI: 0.043-0.137) and NLR (Cliff's Delta = 0.151, 95% CI 0.104-0.198). Uncertainty about effect size existence or direction was found for CRP (Cohen's d = 0.145, 95% CI: -0.072-0.361). Heterogeneity was low for NLR (I² = 39.7%), but high for hs-CRP and CRP (I² = 98.5% and 71.9%, respectively). CONCLUSIONS:Increased inflammatory biomarkers do not lead to increased ICAS presence, raising concern about the actual role of systemic inflammation in ICAS pathophysiology. Despite substantial heterogeneity, the direction and magnitude of effect sizes were consistent across biomarkers. Future multicenter, prospective studies are further needed to define the role of inflammation in ICAS progression.

Background Management of modifiable risk factors is key in the prevention of recurrent stroke. We investigated trends in vascular risk factors (hyperglycemia, hyperlipidemia, hypertension, and smoking) control among US adults with stroke. Methods We performed analyses of data from 1999 through 2023 National Health and Nutrition Examination Surveys participants with self‐reported stroke. Meeting guideline‐recommended targets for risk factor control was defined as hemoglobin A1c <6.5% without diabetes or hemoglobin A1c <7.0% with diabetes, low‐density lipoprotein cholesterol <70 mg/dL, blood pressure <130/80 mm Hg, and nonsmoking. Age‐standardized mean hemoglobin A1c, low‐density lipoprotein, and blood pressure and prevalence of meeting each recommended target were calculated for each epoch (1999 through 2002, 2003 through 2006, 2007 through 2010, 2011 through 2014, 2015 through 2020, and 2021 through 2023). Results Mean hemoglobin A1c increased from 5.7% (95% CI, 5.5–5.9) in 1999 through 2002 to 6.0% (95% CI, 5.7–6.3) in 2021 through 2023 (P‐trend=0.04) and LDL decreased from 125.9 mg/dL (95% CI, 119.4–132.4) in 1999 through 2002 to 115.6 mg/dL (95% CI, 107.8–123.5) in 2021 through 2023 (P‐trend<0.001), whereas blood pressure was largely stable. The prevalence of meeting glycemia guidelines decreased from 90.7% (95% CI, 85.9%–95.6%) in 1999 through 2002 to 83.9% (95% CI, 70.2%–97.5%) in 2021–2023 (P‐trend=0.03), whereas the prevalence of meeting lipid guidelines increased from 1999 through 2002 (5.1% [95% CI, 0%–11.0%]) to 2021 through 2023 (13.6% [95% CI, 6.9%–20.4%; P‐trend=0.002). The prevalence of meeting smoking and blood pressure guidelines was stable. Fewer than 10% of individuals met guidelines for all 4 risk factors over the study. Conclusions In this nationally representative sample of US adults with stroke, <10% met guideline recommendations for all risk factors with an overall stable trend. These results suggest that efforts aimed at glycemia, blood pressure, and lipid control and smoking cessation could be improved to reduce the burden of recurrent stroke.

Abstract Background and aims Breakthough ischemic stroke despite oral anticoagulation (OAC) among patients with atrial fibrillation (AF) remains insufficiently characterized. We aimed to identify characteristics associated with ischemic stroke despite OAC treatment. Methods Prospective data from consecutive patients with ischemic stroke and AF who underwent carotid imaging from 10 stroke registries were included. Patients were categorized in those with i)stroke despite OAC, ii) known AF not on OAC, iii) newly diagnosed AF. Multivariable logistic regression was performed to identify clinical characteristics associated with stroke despite OAC. Results Among 2,551 stroke patients, 30.1% experienced a breakthrough stroke, 32.0% were not receiving OAC despite AF history, and 37.9% had newly diagnosed AF. Patients with breakthrough were older, had a higher cardiovascular comorbidity burden, and presented with milder neurological deficits compared to those not on OACs. Ipsilateral atherosclerotic carotid stenosis was more prevalent in the OAC group (p=0.008). Compared to those not treated with OACs, characteristics associated with breakthrough stroke included increasing age (aOR:1.02/year; 95%CI:1.00–1.03), prior stroke/TIA (aOR:1.67; 1.13–2.47), persistent/permanent AF (aOR:1.49; 1.11–2.01), multiterritorial infarcts (aOR:2.04; 1.27–3.25), hyperlipidemia (aOR:1.4; 1.05–1.90), and cancer (aOR:2.73; 1.10–6.76). Mild ipsilateral carotid stenosis was associated with breakthrough stroke (aOR:1.37; 1.00–1.86), even though stenosis >50% were not associated with breakthrough stroke. Conclusions Breakthrough strokes were associated with older age and higher cardiovascular risk burden. These findings suggest the presence of competing stroke mechanisms beyond cardioembolism and underscore the need for comprehensive vascular risk assessment. Conflict of interest

Background: Insertable cardiac monitoring (ICM) detects atrial fibrillation (AF) in substantial proportions of cryptogenic stroke, non-cryptogenic ischemic stroke without known AF, and non-stroke patients who are at risk of underlying AF. Given differences in patient characteristics across studies, there may be differences in AF detection rates on ICM across these subgroups that have not been identified. We investigate whether AF detection rates on ICM are higher in cryptogenic stroke or TIA (C-IS/TIA) patients compared to individuals with non-cryptogenic stroke or without stroke when accounting for differences in study populations. Methods: This is an individual-participant data (IPD) meta-analysis of prospective studies and randomized controlled trials (RCTs) of ICM in C-IS/TIA, non-cryptogenic ischemic stroke, and non-stroke patients. Multi-level multivariable logistic regression models were used to test whether C-IS/TIA is associated with increased AF detection relative to other categories. We performed multiple imputation to derive values for variables with <20% missing data and Rubin’s rules to estimate adjusted odds ratios (aOR) by combining 100 post-imputation datasets. The primary outcome was detection of AF. The attributable risk was derived by application of Bayes Theorem. Results: Two RCTs and 12 prospective studies were included with a total of 1562 C-IS/TIA patients and 474 non C-IS/TIA. In adjusted multi-level logistic regression analyses, AF detection was higher in C-IS/TIA patients (aOR 1.90; 95%CI 1.18-3.06, p=0.009), indicating that 47% of AF detected in C-IS/TIA may be pathogenic. Limiting the comparator group to ischemic stroke or history of stroke yielded similar results (aOR 2.83 95% CI 1.47-5.44, p = 0.002). Days to AF detection was significantly shorter in C-IS/TIA patients (median 65 vs. 169, p<0.001). Conclusion: In this IPD meta-analysis of patients undergoing ICM, AF detection was higher in C-IS/TIA patients, with shorter time to AF detection compared to non-cryptogenic/non-stroke individuals. These findings suggest that nearly 50% of the AF detected in patients with C-IS/TIA may be pathogenic.

BACKGROUND:Acute myocardial infarction (MI) is associated with subsequent cognitive decline. Whether the detection of prior MI using routine ECG and self-reported history can identify different trajectories of cognitive decline is uncertain. We sought to determine the association between prior MI and longitudinal cognitive assessments within a national, biracial cohort study. METHODS:We included participants in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) cohort, enrolled from 2003 to 2007, who had an interpretable ECG and no baseline cognitive impairment. Prior MI at baseline was determined by self-reported history and ECG evidence of MI. Individuals were subdivided into self-reported (no Q-wave with MI history), clinical (Q-wave with MI history), and silent MI (Q-wave without MI history). We examined the interaction between prior MI and longitudinal change in global cognitive function, assessed by annual telephone-based 6-item screener scores, using linear mixed-effects models adjusted for demographics, cardiovascular risk factors, and incident cardiovascular events with censoring for death. RESULTS:The primary analytic cohort consisted of 20 923 individuals followed over a median of 10.1 years with 2183 having evidence of prior MI at baseline (1098 self-reported, 281 clinical, and 804 silent MI). A total of 4884 participants died during follow-up and were censored at the time of death. Prior MI was associated with an excess adjusted annual decline of global cognition (-0.016 points [95% CI, -0.021 to -0.012]; Pinteraction<0.001). Similar trajectories of accelerated annual global cognitive decline were seen with self-reported (-0.016 points [95% CI, -0.022 to -0.010]; Pinteraction<0.001), clinical (-0.020 points [95% CI, -0.032 to -0.008]; Pinteraction=0.001), and silent (-0.015 points [95% CI, -0.022 to -0.008]; Pinteraction<0.001) MI. CONCLUSIONS:Evidence of prior MI, whether clinically recognized or silent, was associated with an accelerated decline in global cognition. Prior MI may identify individuals at risk for future cognitive impairment.

This Viewpoint describes trials of revascularization with medical therapy vs medical therapy alone to prevent stroke in patients with asymptomatic carotid stenosis.

BACKGROUND: Identifying acute ischemic stroke (AIS) etiology guides targeted therapy implementatoin to prevent recurrent stroke. We derive plasma protein signatures of non-cryptogenic AIS etiologies and apply them to cryptogenic strokes to predict etiologies. METHODS: We studied adults at Yale-New Haven Hospital with an AIS from 2015-2020 and stored plasma samples. Proteins were measured with a SomaScan 11K Assay. Etiology was adjudicated by > 2 board-certified vascular neurologists. ANOVA tests identified proteins significantly different among the 4 non-cryptogenic etiologies (large artery atherosclerosis (LAA), cardioembolism (CE), small vessel disease (SVD), and other rare, determined etiologies (ODE)). Proteins with fold change > 1.2 and p-value < 0.05 were selected without multiple testing adjustment in this exploration. We built logistic regression models to classify 4-level and binary etiologies versus not with: A) age, B) age, sex, C) age, sex, hypertension, D) proteins, and E) age, sex, hypertension, proteins selected by stepwise selection for each outcome. We computed 95% confidence intervals for binary models with 2,000 bootstrap replicates. The PheWeb 2019 database was used to link predictive proteins with phenotypes. We applied the 4-level model to cryptogenic strokes to predict non-cryptogenic etiologies. RESULTS: We included 64 patients (median age 69 years [IQR 58-76], 42.2% female, last known well to sample collection time: median 27 hours [IQR 22-68], LAA n=15; CE n=23; SVD n=6; ODE n=7; cryptogenic n=13). Of 11,083 proteins, there were 40 differentially expressed proteins among 4 etiologies ( Figure 1 ). Three proteins (lithostathine-1-beta, transcription factor SOX-21, creatine kinase M- and B-types) classified 4-level etiologies: areas under the curve (AUC) Model A: 0.69, B: 0.70, C: 0.76, D: 0.84, E: 0.88; Table ). AUCs for each etiology were: 0.88 LAA (95% CI 0.78-0.97), 0.89 CE (0.80-0.98), 0.98 SVD (0.94-1.0), and 0.97 ODE (0.94-1.00). Identified proteins are linked with malignancy, varicella zoster, inflammation, hematologic conditions, and atrial fibrillation ( Figure 2) . In the cryptogenic stroke cohort, 7 patients had highest predicted probabilities for LAA (range: 0.55-0.83) and 6 for CE (0.47-0.85). CONCLUSION: We derived plasma proteomic signatures of non-cryptogenic etiologies with biologic plausibility and applied them to predict etiologies in cryptogenic AIS. Further studies are needed to evaluate their generalizability.