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Background and Purpose: Hierarchical clustering, a common 'unsupervised' machine-learning algorithm, is advantageous for exploring potential underlying aetiology in particularly heterogeneous diseases. We investigated potential embolic sources in embolic stroke of undetermined source (ESUS) using a data-driven machine-learning method, and explored variation in stroke recurrence between clusters., Methods: We used a hierarchical k-means clustering algorithm on patients' baseline data, which assigned each individual into a unique clustering group, using a minimum-variance method to calculate the similarity between ESUS patients based on all baseline features. Potential embolic sources were categorised into atrial cardiopathy, atrial fibrillation, arterial disease, left ventricular disease, cardiac valvulopathy, patent foramen ovale (PFO) and cancer., Results: Among 800 consecutive ESUS patients (43.3% women, median age 67 years), the optimal number of clusters was four. Left ventricular disease was most prevalent in cluster 1 (present in all patients) and perfectly associated with cluster 1. PFO was most prevalent in cluster 2 (38.9% of patients) and associated significantly with increased likelihood of cluster 2 [adjusted odds ratio: 2.69, 95% confidence interval (CI): 1.64-4.41]. Arterial disease was most prevalent in cluster 3 (57.7%) and associated with increased likelihood of cluster 3 (adjusted odds ratio: 2.21, 95% CI: 1.43-3.13). Atrial cardiopathy was most prevalent in cluster 4 (100%) and perfectly associated with cluster 4. Cluster 3 was the largest cluster involving 53.7% of patients. Atrial fibrillation was not significantly associated with any cluster., Conclusions: This data-driven machine-learning analysis identified four clusters of ESUS that were strongly associated with arterial disease, atrial cardiopathy, PFO and left ventricular disease, respectively. More than half of the patients were assigned to the cluster associated with arterial disease., (© 2020 European Academy of Neurology.)

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 <35%; 1 point for the presence of any supraventricular extrasystole recorded during all available 12-lead standard electrocardiograms performed during hospitalization for the ESUS; -2 points for subcortical infarct; -3 points for the presence of non-stenotic carotid plaques. The rate of new incident AF during follow-up was 1.97% among the 42.3% of the cohort who had a score of ≤0, compared to 26.9% in patients with > 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.

Background and Aims: Patients with embolic strokes of undetermined source (ESUS) usually present with mild symptoms. We aimed to compare the baseline characteristics between mild and severe ESUS, identify predictors for severe ESUS, and assess outcomes of patients with severe ESUS., Methods: In the AF-ESUS (AF-ESUS) dataset, we stratified ESUS severity using the median National Institutes of Health Stroke Scale (NIHSS) score on admission as cut-off. We performed multivariable stepwise regression analyses to identify independent predictors of severe ESUS and to assess the association between ESUS severity and stroke recurrence, death, and new incident atrial fibrillation (AF) on follow-up. The 10-year cumulative probabilities of outcome incidence were estimated by the Kaplan-Meier product limit method., Results: In 772 patients (median NIHSS: 6 (interquartile range: 3-12)), 414 (53.6%) patients had severe ESUS (i.e. NIHSS ≥6). Female sex was the only independent predictor for severe ESUS (odds ratio: 1.72 (1.27-2.33)). The rates of recurrence (3.3%/year vs. 3.4%/year, adjusted-hazard ratio: 1.09 (0.73-1.62)) and new incident AF (13.5% vs. 17.0%, adjusted odds ratio: 0.67 (0.44-1.03)) were similar between severe and mild ESUS, but mortality was higher (5.4%/year vs. 3.7%/year, adjusted-hazard ratio: 1.51 (1.05-2.16)) in severe ESUS. The 10-year cumulative probability for stroke recurrence was similar between severe and mild ESUS (38.1% (29.2-48.6) vs. 36.6% (27.8-47.0), log-rank test: 0.01, p  = 0.920). The 10-year cumulative probability of death was higher in patients with severe ESUS compared with mild ESUS (40.5% (32.5-50.0) vs. 34.0% (26.0-43.6) respectively; log-rank test: 4.54, p  = 0.033)., Conclusions: Women have more severe ESUS compared with men. Patients with severe ESUS have similar rates of stroke recurrence and new incident AF, but higher mortality compared with mild ESUS.

Background and Purpose: We analyzed consecutive patients with embolic stroke of undetermined source (ESUS) from three prospective stroke registries to compare the prognostic performance of different LAD thresholds for the prediction of new incident AF., Methods: We calculated the sensitivity, specificity, positive prognostic value (PPV), negative prognostic value (NPV) and Youden's J-statistic of different LAD thresholds to predict new incident AF. We performed multivariate stepwise regression with forward selection of covariates to assess the association between the LAD threshold with the highest Youden's J-statistic and AF detection., Results: Among 675 patients followed for 2437 patient-years, the mean LAD was 38.5 ± 6.8 mm. New incident AF was diagnosed in 115 (17.0%) patients. The LAD threshold of 40mm yielded the highest Youden's J-statistic of 0.35 with sensitivity 0.69, specificity 0.66, PPV 0.27 and NPV 0.92. The likelihood of new incident AF was nearly twice in patients with LAD > 40 mm compared to LAD ≤ 40 mm (HR:1.92, 95%CI:1.24-2.97, p = 0.004). The 10-year cumulative probability of new incident AF was higher in patients with LAD>40 mm compared to LAD ≤ 40 mm (53.5% and 22.4% respectively, log-rank-test: 28.2, p < 0.001). The annualized rate of stroke recurrence of 4.0% in the overall population did not differ significantly in patient above vs. below this LAD threshold (HR:0.96, 95%CI:0.62-1.48, p = 0.85)., Conclusions: The LAD threshold of 40 mm has the best prognostic performance among other LAD values to predict new incident AF after ESUS. The diagnostic yield of prolonged cardiac rhythm monitoring in patients with LAD ≤ 40 mm seems low; therefore, such patients may have lower priority for prolonged cardiac monitoring., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: The diagnosis of covert atrial fibrillation (AF) remains a major challenge to guide secondary prevention of patients with embolic stroke of undetermined source (ESUS)., Aims: We analyzed consecutive ESUS patients from 3 prospective stroke registries to assess whether the presence of supraventricular extrasystoles (SVE) on standard 12-lead electrocardiogram (ECG) is associated with the detection of AF (primary outcome), stroke recurrence and death (secondary outcomes) during follow-up., Methods: We measured the number of SVEs in all available ECGs of patients hospitalized for ESUS. Multivariate stepwise regression with forward selection of covariates assessed the association between SVE (classified in 4 groups according to their number per 10 seconds of ECG: no SVE, >0-1SVEs, >1-2SVEs, and >2SVEs) and outcomes during follow-up. The Kaplan-Meier product limit method estimated the 10-year cumulative probabilities of outcomes in each SVE group. We calculated the negative prognostic value (NPV) of the presence of any SVE to predict new AF, defined as the probability that AF will not be detected during follow-up if there is no SVE., Results: Among 853 ESUS patients followed for 2857 patient-years (median age: 67 years, 43.0% women), 226 (26.5%) patients had at least 1 SVE at the standard 12-lead ECGs performed during hospitalization. AF was detected in 125 (14.7%) of patients in the overall population during follow-up: 8.9%, 22.5%, 28.1%, and 48.3% in patients with no SVE, greater than 0-1SVE, greater than 1-2SVE and greater than 2SVE respectively. In multivariate regression analysis, compared to patients with no SVEs, the corresponding hazard-ratios were 1.80 [95% confidence intervals (95%CI):1.06-3.05], 2.26 (95%CI:1.28-4.01) and 3.19 (95%CI:1.93-5.27). The NPV of the presence of any SVE for the prediction of new AF was 91.4%. There was no statistically significant association of SVE with the risk of ischemic stroke recurrence and death., Conclusions: In ESUS patients without SVEs during hospitalization, the probability that AF will not be detected during a follow-up of 3.4 years is more than 91%., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Purpose- The HAVOC score (hypertension, age, valvular heart disease, peripheral vascular disease, obesity, congestive heart failure, coronary artery disease) was proposed for the prediction of atrial fibrillation (AF) after cryptogenic stroke. It showed good model discrimination (area under the curve, 0.77). Only 2.5% of patients with a low-risk HAVOC score (ie, 0-4) were diagnosed with new incident AF. We aimed to assess its performance in an external cohort of patients with embolic stroke of undetermined source. Methods- In the AF-embolic stroke of undetermined source dataset, we assessed the discriminatory power, calibration, specificity, negative predictive value, and accuracy of the HAVOC score to predict new incident AF. Patients with a HAVOC score of 0 to 4 were considered as low-risk, as proposed in its original publication. Results- In 658 embolic stroke of undetermined source patients (median age, 67 years; 44% women), the median HAVOC score was 2 (interquartile range, 3). There were 540 (82%) patients with a HAVOC score of 0 to 4 and 118 (18%) with a score of ≥5. New incident AF was diagnosed in 95 (14.4%) patients (28.8% among patients with HAVOC score ≥5 and 11.3% among patients with HAVOC score 0-4 [age- and sex-adjusted odds ratio, 2.29 (95% CI, 1.37-3.82)]). The specificity of low-risk HAVOC score to identify patients without new incident AF was 88.7%. The negative predictive value of low-risk HAVOC score was 85.1%. The accuracy was 78.0%, and the area under the curve was 68.7% (95% CI, 62.1%-73.3%). Conclusions- The previously reported low rate of AF among embolic stroke of undetermined source patients with low-risk HAVOC score was not confirmed in our cohort. Further assessment of the HAVOC score is warranted before it is routinely implemented in clinical practice.

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.)

Background and Purpose- We aimed to assess if renal function can aid in risk stratification for ischemic stroke or transient ischemic attack (TIA) recurrence and death in patients with embolic stroke of undetermined source (ESUS). Methods- We pooled 12 ESUS datasets from Europe and America. Renal function was evaluated using the estimated glomerular filtration rate (eGFR) and analyzed in continuous, binary, and categorical way. Cox-regression analyses assessed if renal function was independently associated with the risk for ischemic stroke/TIA recurrence and death. The Kaplan-Meier product limit method estimated the cumulative probability of ischemic stroke/TIA recurrence and death. Results- In 1530 patients with ESUS followed for 3260 patient-years, there were 237 recurrences (15.9%) and 201 deaths (13.4%), corresponding to 7.3 ischemic stroke/TIA recurrences and 5.6 deaths per 100 patient-years, respectively. Renal function was not associated with the risk for ischemic stroke/TIA recurrence when forced into the final multivariate model, regardless if it was analyzed as continuous (hazard ratio, 1.00; 95% CI, 0.99-1.00 for every 1 mL/min), binary (hazard ratio, 1.27; 95% CI, 0.87-1.73) or categorical covariate (likelihood-ratio test 2.59, P=0.63 for stroke recurrence). The probability of ischemic stroke/TIA recurrence across stages of renal function was 11.9% for eGFR ≥90, 16.6% for eGFR 60-89, 21.7% for eGFR 45-59, 19.2% for eGFR 30-44, and 24.9% for eGFR <30 (likelihood-ratio test 2.59, P=0.63). The results were similar for the outcome of death. Conclusions- The present study is the largest pooled individual patient-level ESUS dataset, and does not provide evidence that renal function can be used to stratify the risk of ischemic stroke/TIA recurrence or death in patients with ESUS.