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Background: Stroke incidence and case-fatality are reported to decline in high-income countries during the last decades. Epidemiological studies are important for health services to organize prevention and treatment strategies. Aims: The aim of this population-based study was to determine temporal trends of stroke incidence and case-fatality rates of first-ever stroke in Arcadia, a prefecture in southern Greece. Methods: All first-ever stroke cases in the Arcadia prefecture were ascertained using the same standard criteria and multiple overlapping sources in three study periods: from November 1993 to October 1995; 2004; and 2015–2016. Crude and age-adjusted to European population incidence rates were compared using Poisson regression. Twenty-eight days case fatality rates were estimated and compared using the same method. Results: In total, 1315 patients with first-ever stroke were identified. The age-standardized incidence to the European population was 252 per 100,000 person-years (95% CI 231–239) in 1993/1995, 252 (95% CI 223–286) in 2004, and 211 (192–232) in 2015/2016. The overall age- and sex-adjusted incidence rates fell by 16% (incidence rates ratio 0.84, 95% CI: 0.72–0.97). Similarly, 28-day case-fatality rate decreased by 28% (case fatality rate ratio = 0.72, 95% CI: 0.58–0.90). Conclusions: This population-based study reports a significant decline in stroke incidence and mortality rates in southern Greece between 1993 and 2016. © 2021 World Stroke Organization.

The aim of this study was to present the descriptive characteristics of the Stroke Units Necessity for Patients (SUN4P) registry. Methods: The study population derived from the web-based SUN4P registry included 823 patients with first-ever acute stroke. Descriptive statistics were used to present patients' characteristics. Results: The vast majority of patients (80.4%) had an ischemic stroke, whereas 15.4% had a hemorrhagic stroke. Hypertension was the leading risk factor in both patients. The patients with ischemic stroke had higher prevalence of traditional cardiovascular risk factors such as diabetes mellitus, dyslipidemia and smoking and most commonly cryptogenic stroke (39%). National Institutes of Health Stroke Scale (NIHSS) was higher among patients with hemorrhagic in comparison to those with ischemic stroke (10.5 vs 6 respectively). Moreover, all patients had similar rate of disability prior to stroke, as shown by Modified Rankin Scale (mRS=0). Conclusions: These data are in accordance with current evidence and should be thoroughly assessed in order to ensure optimal therapeutic management of stroke patients. © 2022 The authors and IOS Press.

The aim of this study was to calculate the average operational cost per sub-type of stroke patient and to investigate cost drivers (e.g. ALoS, NIHSS score, age) correlated to cost. Methods: Direct medical costs (diagnostic imaging and clinical laboratory exams, overheads/bed cost, pharmaceuticals, ringers and other non-durables and inpatient rehabilitation) per patient were calculated from the providers' (hospitals') perspective. Resource use data derived from the 'SUN4P' web-based registry and unit costs were retrieved from publically available sources and were assigned to resource use. Results: The sample comprised 6,282 inpatient days of 750 patients (mean age: 75.5±13.3 years) admitted from July 2019 to July 2021, in nine public hospitals. Mean length of stay was 8.4±7.6 days and mean total operational cost was calculated to €1,239.4 (from which 45% and 35% related to diagnostic exams and overheads/bed cost respectively). Mean cost related to hemorrhagic stroke patients that were discharged alive was calculated significantly higher compared to mean cost related to ischemic stroke patients who didn't undertake thrombolysis and were also discharged alive from the hospital (€2,155.2 vs. €945.2, p

This document presents the consensus recommendations of the Hellenic Stroke Organization and the Hellenic Atherosclerosis Society for lipid modification in patients with ischemic stroke or transient ischemic attack. This clinical guide summarizes the current literature on lipid management and can be of assistance to the physicians treating stroke patients in clinical practice. © 2020 World Stroke Organization.

Background: Carotid atherosclerosis and likely pathogenic patent foramen ovale (PFO) are two potential embolic sources in patients with embolic stroke of undetermined source (ESUS). The relationship between these two mechanisms among ESUS patients remains unclear. Aim: To investigate the relation between carotid atherosclerosis and likely pathogenic PFO in patients with ESUS. We hypothesized that ipsilateral carotid atherosclerotic plaques are less prevalent in ESUS with likely pathogenic PFO compared to patients with likely incidental PFO or without PFO. Methods: The presence of PFO was assessed with transthoracic echocardiography with microbubble test and, when deemed necessary, through trans-oesophageal echocardiography. The presence of PFO was considered as likely incidental if the RoPE (Risk of Paradoxical Embolism) score was 0–6 and likely pathogenic if 7–10. Results: Among 374 ESUS patients (median age: 61years, 40.4% women), there were 63 (49.6%) with likely incidental PFO, 64 (50.4%) with likely pathogenic PFO and 165 (44.1%) with ipsilateral carotid atherosclerosis. The prevalence of ipsilateral carotid atherosclerosis was lower in patients with likely pathogenic PFO (7.8%) compared to patients with likely incidental PFO (46.0%) or patients without PFO (53.0%) (p

Background and aims: Only a minority of patients with Embolic Stroke of Undetermined Source (ESUS) receive prolonged cardiac monitoring despite current recommendations. The identification of ESUS patients who have low probability of new diagnosis of atrial fibrillation (AF) could potentially support a strategy of more individualized allocation of available resources and hence, increase their diagnostic yield. We aimed to develop a tool that can identify ESUS patients who have low probability of new incident AF. Methods: We performed multivariate stepwise regression in a pooled dataset of consecutive ESUS patients from three prospective stroke registries to identify predictors of new incident AF. The coefficient of each independent covariate of the fitted multivariable model was used to generate an integer-based point scoring system. Results: Among 839 patients (43.1% women, median age 67.0 years) followed-up for a median of 24.3 months (2999 patient-years), 125 (14.9%) had new incident AF. The proposed score assigns 3 points for age ≥ 60 years; 2 points for hypertension; −1 point for left ventricular hypertrophy reported at echocardiography; 2 points for left atrial diameter >40 mm; −3 points for left ventricular ejection fraction 0 (relative risk: 13.7, 95%CI: 5.9--31.5). The area under the curve of the score was 84.8% (95%CI: 79.9--86.9%). The sensitivity and negative predictive value of a score of ≤0 for new incident AF during follow-up were 94.9% (95%CI: 89.3--98.1%) and 98.0% (95%CI: 95.8--99.3%), respectively. Conclusions: The proposed AF-ESUS score has high sensitivity and high negative predictive value to identify ESUS patients who have low probability of new incident AF. Patients with a score of 1 or more may be better candidates for prolonged automated cardiac monitoring. Clinical trial registration: URL: https://www.clinicaltrials.gov/ Unique identifier: NCT02766205. © 2020 World Stroke Organization.

The association of low-density lipoprotein cholesterol lowering with outcomes in embolic stroke of undetermined source (ESUS) patients is unclear. In these patients we aimed to assess the effect of statin on stroke recurrence, major adverse cardiovascular events (MACE) and death rates. Consecutive ESUS patients in the Athens Stroke Registry were prospectively followed-up to 10 years for stroke recurrence, MACE, and death. The Nelson–Aalen estimator was used to estimate the cumulative probability by statin allocation at discharge and cox-regression analyses to investigate whether statin at discharge was a predictor of outcomes. Among 264 ESUS patients who were discharged and followed for 4 years, 89 (33.7%) were treated with statin at discharge. Patients who were discharged on statin had lower rates of stroke recurrence (3.58 vs. 7.23/100 patient-years, HR: 0.48; 95% CI 0.26–0.90), MACE (4.98 vs. 9.89/100 patient-years, HR: 0.49; 95% CI 0.29–0.85), and death (3.93 vs. 8.21/100 patient-years, HR: 0.50; 95% CI: 0.28–0.89). In the multivariate analysis, statin treatment at discharge was an independent predictor of stroke recurrence (adjusted HR: 0.48; 95% CI 0.26–0.91), MACE (adjusted HR: 0.48; 95% CI 0.28–0.82), and death (adjusted HR: 0.50; 95% CI 0.27–0.93). Patients with ESUS discharged on statins have lower rates of stroke recurrence, MACE, and death compared to those not receiving statin therapy. © 2021, Società Italiana di Medicina Interna (SIMI).

The aim of this study was to assess stroke patients' experiences in regards to hospital stay and during discharge. A cross-sectional study with retrospective data collection was conducted including patients (n=135) with first-ever acute stroke, who were admitted in seven Public Hospitals in Greece ('Stroke Units Necessity for Patients, SUN4P' registry). The translated version of the NHS-Stroke Questionnaire in the Greek was used. 48.2% of patients rated their overall experience from the care they received as very good/excellent. 66% of patients reported that they participated in decision making about their care and 21.5% reported not having received help from the hospital's social services regarding any benefits/aids, thus lowering their overall patient experience score (p=0.017). Decision and policymakers must consider factors affecting stroke patients experiences during their hospitalization. The development of a national stroke patients' experiences database can help prioritize relevant actions and draw up a commonly accepted management and services redesign framework for patients. © 2020 The authors and IOS Press.

Background: Controversial evidence suggests that right insular stroke may be associated with worse outcomes compared to the left insular ischemic lesion. Objectives: We investigated whether lateralization of insular stroke is associated with early and late outcome in terms of in-hospital complications, stroke recurrence, cardiovascular events, and death. Methods: Data were prospectively collected from the Athens Stroke Registry. Insular cortex involvement was identified based on brain CT scans or MRI images. Patients were followed up prospectively at 1, 3, 6 months after hospital discharge and yearly thereafter up to 5-years or until death. The assessed outcomes were in-hospital complications, functional outcome assessed by the modified Rankin Scale, stroke recurrence, cardiovascular events, and death. Cox-regression analysis was performed to estimate the cumulative probability of each outcome according to the lateralization of insular strokes. Results: Among the 1212 patients, 650 had left insular stroke involvement and 562 had right. New onset of in-hospital atrial fibrillation was similar between right and left insular strokes (11.6% versus 12.9%, P = .484). During the 5-year follow-up sudden death occurred in 21 (3.7%) patients with right insular compared to 30 (4.6%) with left insular stroke (P = .476). There was no difference between left and right insular strokes regarding mortality (adjusted odds ratio [OR]: .92, 95% confidence interval [CI]: .80-1.06), stroke recurrence (4.3% versus 4.9%; adjusted OR: .81 95% CI: .58-1.13), cardiovascular events, and sudden death (adjusted OR: .99, 95% CI: .76-1.29) and on death and dependency (adjusted OR: .88, 95% CI: .75-1.02) during a 5-year follow up. Conclusions: Lateralization of insular ischemic stroke involvement is not associated with stroke outcomes. © 2019 Elsevier Inc.

OBJECTIVE: To compare the efficacy and safety of oral anticoagulants vs antiplatelets in patients with stroke and atherosclerotic plaques in the aortic arch or cervical or intracranial arteries, collectively described as supracardiac atherosclerosis. METHODS: We searched PubMed and Scopus until August 28, 2019, for randomized trials comparing oral anticoagulants vs antiplatelets in patients with stroke and supracardiac atherosclerosis using the terms "anticoagulant or anticoagulation" and "antiplatelet or aspirin" and "randomized controlled trial or RCT" and "stroke or cerebral ischemia" and "aortic or carotid or vertebrobasilar or intracranial or atherosclerosis or stenosis or arterial." Four outcomes were assessed: recurrent ischemic stroke, major ischemic event or death, major bleeding, and intracranial bleeding. Treatment effects (relative risk [RR] and 95% confidence interval [CI]) were estimated by meta-analysis using random-effects models. RESULTS: Among 1,117 articles identified in the literature search, results from 10 randomized controlled trials involving 6,068 patients with stroke/TIA with supracardiac atherosclerosis were included in the meta-analysis. Recurrent ischemic stroke rates were 2.94 per 100 patient-years in the anticoagulant-assigned patients vs 3.30 per 100 patient-years in the antiplatelet-assigned patients (RR, 0.91; 95% CI, 0.70-1.18 for the SJ estimator, I2 = 26%). Major ischemic event or death rates were 4.39 per 100 patient-years in anticoagulant-assigned patients vs 4.32 in antiplatelet-assigned patients (RR, 1.03; 95% CI, 0.79-1.35; I2 = 54.5%). Major bleeding rates were 2.88 per 100 patient-years in anticoagulant-assigned patients vs 0.82 in antiplatelet-assigned patients (RR, 3.21; 95% CI, 1.96-5.24; I2 = 46%). CONCLUSION: This systematic review and meta-analysis showed that anticoagulant-assigned patients with stroke and supracardiac atherosclerosis were not at different risk of ischemic stroke recurrence and increased risk of major bleeding compared to antiplatelet-assigned patients. © 2020 American Academy of Neurology.

The aim of this study was to evaluate accessibility of stroke patients to optimal healthcare technology in Greece. Methods: The study population consisted of 313 first ever stroke patients derived from the 'Stroke Units Necessity for Patients, SUN4P' registry. Descriptive statistics were used, to present patients' characteristics and resources utilization Results: The vast majority of patients (91.7%) conducted a CT scan during the acute phase (within the first 24hours). Almost, (65%) were admitted to wards of Internal Medicine Departments, whereas only 21% of patients were admitted to a Stroke Unit. Of note, a total of 6.9% of ischemic stroke patients received intravenous thrombolytic therapy with recombinant tissue plasminogen activator (rtPA). Conclusions: Preliminary results from SUN4P underline the urgent necessity for the re-organization of acute stroke care in Greece, as rates of admissions to stroke units and rtPA treatment during the acute phase are currently below optimal. © 2020 The authors and IOS Press.

SUN4Patients is an observational study for the monitoring of patients with first ever acute stroke. For the support of this study, an online platform has been developed which facilitates the collection of various information related to hospital discharge, health services utilization and loss of productivity of the patients. This paper presents the main characteristics of the platform and the methodology followed for its design and implementation. © 2020 The authors and IOS Press.

Background and aims: To reassess the effect of statin-based lipid-lowering therapy on ischemic stroke in primary and secondary prevention trials with regard to achieved levels of low-density lipoprotein-cholesterol in view of the availability of novel potent hypolipidemic agents. Methods: English literature was searched (up to November 2018) for publications restricted to trials with a minimum enrolment of 1000 and 500 subjects for primary and secondary prevention, respectively, meeting the following criteria: adult population, randomized controlled design, and recorded outcome data on ischemic stroke events. Data were meta-analyzed and curve-estimation procedure was applied to estimate regression statistics and produce related plots. Results: Four primary prevention trials and four secondary prevention trials fulfilled the eligibility criteria. Lipid-lowering therapy was associated with a lower risk of ischemic stroke in primary (risk ratio, RR 0.70, 95% confidence interval, CI, 0.60–0.82; p < 0.001) and in the secondary prevention setting (RR 0.80, 95% CI 0.70–0.90; p < 0.001). Curve-estimation procedure revealed a linear relationship between the absolute risk reduction of ischemic stroke and active treatment-achieved low-density lipoprotein-cholesterol levels in secondary prevention (adjusted R-square 0.90) in support of “the lower the better” hypothesis for stroke survivors. On the other hand, the cubic model followed the observed data well in primary prevention (adjusted R-square 0.98), indicating greater absolute risk reduction in high-risk cardiovascular disease-free individuals. Conclusions: Statin-based lipid-lowering is effective both for primary and secondary prevention of ischemic stroke. Most benefit derives from targeting disease-free individuals at high cardiovascular risk, and by achieving low treatment targets for low-density lipoprotein-cholesterol in stroke survivors. © 2019 World Stroke Organization.

ObjectiveA tool to stratify the risk of stroke recurrence in patients with embolic stroke of undetermined source (ESUS) could be useful in research and clinical practice. We aimed to determine whether a score can be developed and externally validated for the identification of patients with ESUS at high risk for stroke recurrence.MethodsWe pooled the data of all consecutive patients with ESUS from 11 prospective stroke registries. We performed multivariable Cox regression analysis to identify predictors of stroke recurrence. Based on the coefficient of each covariate of the fitted multivariable model, we generated an integer-based point scoring system. We validated the score externally assessing its discrimination and calibration.ResultsIn 3 registries (884 patients) that were used as the derivation cohort, age, leukoaraiosis, and multiterritorial infarct were identified as independent predictors of stroke recurrence and were included in the final score, which assigns 1 point per every decade after 35 years of age, 2 points for leukoaraiosis, and 3 points for multiterritorial infarcts (acute or old nonlacunar). The rate of stroke recurrence was 2.1 per 100 patient-years (95% confidence interval [CI] 1.44-3.06) in patients with a score of 0-4 (low risk), 3.74 (95% CI 2.77-5.04) in patients with a score of 5-6 (intermediate risk), and 8.23 (95% CI 5.99-11.3) in patients with a score of 7-12 (high risk). Compared to low-risk patients, the risk of stroke recurrence was significantly higher in intermediate-risk (hazard ratio [HR] 1.78, 95% CI 1.1-2.88) and high-risk patients (HR 4.67, 95% CI 2.83-7.7). The score was well-calibrated in both derivation and external validation cohorts (8 registries, 820 patients) (Hosmer-Lemeshow test χ2: 12.1 [p = 0.357] and χ2: 21.7 [p = 0.753], respectively). The area under the curve of the score was 0.63 (95% CI 0.58-0.68) and 0.60 (95% CI 0.54-0.66), respectively.ConclusionsThe proposed score can assist in the identification of patients with ESUS at high risk for stroke recurrence. © 2019 American Academy of Neurology.

Background and Purpose- It is unclear whether treatment with anticoagulants or antiplatelets is the optimal strategy in patients with stroke or transient ischemic attack of undetermined cause and patent foramen ovale that is not percutaneously closed. We aimed to perform a systematic review and meta-analysis of randomized controlled trials to compare anticoagulant or antiplatelet treatment in this population. Methods- We searched PubMed until July 16, 2019 for trials comparing anticoagulants and antiplatelet treatment in patients with stroke/transient ischemic attack and medically treated patent foramen ovale using the terms: "cryptogenic or embolic stroke of undetermined source" and "stroke or cerebrovascular accident or transient ischemic attack" and "patent foramen ovale or patent foramen ovale or paradoxical embolism" and "trial or study" and "antithrombotic or anticoagulant or antiplatelet." The outcomes assessed were stroke recurrence, major bleeding, and the composite end point of stroke recurrence or major bleeding. We used 3 random-effects models: (1) a reference model based on the inverse variance method with the Sidik and Jonkman heterogeneity estimator; (2) a strict model, implementing the Hartung and Knapp method; and (3) a commonly used Bayesian model with a prior that assumes moderate to large between-study variance. Results- Among 112 articles identified in the literature search, 5 randomized controlled trials were included in the meta-analysis (1720 patients, mean follow-up 2.3±0.5 years). Stroke recurrence occurred at a rate of 1.73 per 100 patient-years in anticoagulant-assigned patients and 2.39 in antiplatelet-assigned patients (hazard ratio, 0.68; 95% CI, 0.32-1.48 for the Sidik and Jonkman estimator). Major bleeding occurred at a rate of 1.16 per 100 patient-years in anticoagulant-assigned patients and 0.68 in antiplatelet-assigned patients (hazard ratio, 1.61; 95% CI, 0.72-3.59 for the Sidik and Jonkman estimator). The composite outcome occurred in 52 anticoagulant-assigned and 54 antiplatelet-assigned patients (odds ratio, 1.05; 95% CI, 0.65-1.70 for the Sidik and Jonkman estimator). Conclusions- We cannot exclude a large reduction of stroke recurrence in anticoagulant-assigned patients compared with antiplatelet-assigned, without significant differences in major bleeding. An adequately powered randomized controlled trial of a non-vitamin K antagonist versus aspirin is warranted.

Background: Stratification of overall vascular risk in patients with ischemic stroke is important as it may guide management decisions. Currently available schemes have only modest prognostic accuracy. The TRA2°P score aids in vascular risk stratification in patients with previous myocardial infarction (MI). Aim: We investigated whether the prognostic performance of TRA2°P can be extended in patients with ischemic stroke and whether it can improve the risk stratification made by CHA2DS2VASc and Essen-Stroke-Risk-Score (ESRS). Methods: We analyzed the Athens Stroke Registry using Kaplan-Meier survival and Cox-regression analyses to assess if TRA2°P (in different categorizations) predicts the composite endpoint of stroke recurrence, MI or cardiovascular death. We compared its incremental predictive value over CHA2DS2-VASc and ESRS and calculated continuous net reclassification indices (cNRI). Results: In 2833 patients (followed for 9278 patient-years) and 776 events, there was decreased survival probability for TRA2°P-based high-risk patients compared to low-risk (log-rank-test P < .001), but the discriminatory power for the occurrence of the composite endpoint was only modest (Harrell's-C:.566, 95% CI:.545-.587). Combined with ESRS, TRA2°P conferred incremental discrimination (Harrell's-C:.544, 95% CI:.513-.574 versus .574, 95% CI:.543-.605 respectively, P = .049) and reclassification value (cNRI = 9.8%, P = .02). Combined with CHA2DS2-VASc, TRA2°P did not improve discrimination (Harell's-C:.578, 95% CI: .547-.608 versus .585, 95% CI:.554-.616, P = .738). Conclusion: The currently available prognostic scores have generally low performance to predict the overall cardiovascular risk in ischemic stroke patients. Further research is needed to improve vascular risk stratification in ischemic stroke patients. © 2019 Elsevier Inc.

OBJECTIVE: To investigate the association between the presence of ipsilateral nonstenotic carotid plaques and the rate of detection of atrial fibrillation (AF) during follow-up in patients with embolic strokes of undetermined source (ESUS). METHODS: We pooled data of all consecutive ESUS patients from 3 prospective stroke registries. Multivariate stepwise regression assessed the association between the presence of nonstenotic carotid plaques and AF detection. The 10-year cumulative probabilities of AF detection were estimated by the Kaplan-Meier product limit method. RESULTS: Among 777 patients followed for 2,642 patient-years, 341 (38.6%) patients had an ipsilateral nonstenotic carotid plaque. AF was detected in 112 (14.4%) patients in the overall population during follow-up. The overall rate of AF detection was 8.5% in patients with nonstenotic carotid plaques (2.9% per 100 patient-years) and 19.0% in patients without (5.0% per 100 patient-years) (unadjusted hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.37-0.84). The presence of ipsilateral nonstenotic carotid plaques was associated with lower probability for AF detection (adjusted HR 0.57, 95% CI 0.34-0.96, p = 0.03). The 10-year cumulative probability of AF detection was lower in patients with ipsilateral nonstenotic carotid plaques compared to those without (34.5%, 95% CI 21.8-47.2 vs 49.0%, 95% CI 40.4-57.6 respectively, log-rank-test: 11.8, p = 0.001). CONCLUSIONS: AF is less frequently detected in ESUS patients with nonstenotic carotid plaques compared to those without. CLINICALTRIALSGOV IDENTIFIER: NCT02766205. © 2019 American Academy of Neurology.

Atrial fibrillation (AF) could be a coincidental finding in certain patients with ischemic stroke and increased burden of underlying cardiovascular disease. Concomitant large-vessel atheromatosis and cerebral small vessel disease may be the actual cause of stroke, and distinguishing between different pathophysiologic mechanisms could impose substantial diagnostic difficulties. Despite routine use of oral anticoagulants (OACs) in patients with AF based on their risk for embolism (ie, CHA 2 DS 2 -Vasc score), antithrombotic agents may exert differential effects depending on stroke etiology and stroke subtyping should be evaluated as an additional component of risk stratification that could facilitate optimal management. In the present study, we summarize the evidence on noncardioembolic (non-CE) stroke and treatment approaches based on different stroke subtypes in patients with AF. In particular, approximately one-third of patients with AF seem to suffer a non-CE stroke. Within this category, 11% to 24% of patients present high-grade carotid stenosis and 9% to 16% of ischemic strokes are classified as lacunar. In terms of secondary prevention, the effectiveness of OACs in preventing non-CE stroke has been disputed. Additional large-scale prospective studies are warranted to assess the pathophysiologic stroke mechanisms in patients with AF and compare the differential efficacy of antithrombotic treatment strategies in non-CE ischemic syndromes. © The Author(s) 2018.

Background and Purpose- The sources of emboli in patients with embolic stroke of undetermined source (ESUS) are multiple and may not respond uniformly to anticoagulation. In this exploratory subgroup analysis of patients with carotid atherosclerosis in the NAVIGATE (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism)-ESUS trial, we assessed whether the treatment effect in this subgroup is consistent with the overall trial population and investigated the association of carotid atherosclerosis with recurrent ischemic stroke. Methods- Carotid atherosclerosis was analyzed either as the presence of mild (ie, 20%-49%) atherosclerotic stenosis or, separately, as the presence of carotid plaque. Primary efficacy outcome was ischemic stroke recurrence. Safety outcomes were major bleeding and symptomatic intracerebral bleeding. Results- Carotid plaque was present in 40% of participants and mild carotid stenosis in 11%. There was no significant difference in ischemic stroke recurrence between rivaroxaban- and aspirin-treated patients among 490 patients with carotid stenosis (5.0 versus 5.9/100 patient-years, respectively, hazard ratio [HR], 0.85; 95% CI, 0.39-1.87; P for interaction of treatment effect with patients without carotid stenosis 0.78) and among 2905 patients with carotid plaques (5.9 versus 4.9/100 patient-years, respectively, HR, 1.20; 95% CI, 0.86-1.68; P for interaction of treatment effect with patients without carotid stenosis 0.2). Among patients with carotid plaque, major bleeding was more frequent in rivaroxaban-treated patients compared with aspirin-treated (2.0 versus 0.5/100 patient-years, HR, 3.75; 95% CI, 1.63-8.65). Patients with carotid stenosis had similar rate of ischemic stroke recurrence compared with those without (5.4 versus 4.9/100 patient-years, respectively, HR, 1.11; 95% CI, 0.73-1.69), but there was a strong trend of higher rate of ischemic stroke recurrence in patients with carotid plaque compared with those without (5.4 versus 4.3/100 patient-years, respectively, HR, 1.23; 95% CI, 0.99-1.54). Conclusions- In ESUS patients with carotid atherosclerosis, we found no difference in efficacy between rivaroxaban and aspirin for prevention of recurrent stroke, but aspirin was safer, consistent with the overall trial results. Carotid plaque was much more often present ipsilateral to the qualifying ischemic stroke than contralateral, supporting an important etiological role of nonstenotic carotid disease in ESUS.