Moving from traditional to more advanced treatments in stroke care is cost-effective: A case study from Greece.

OBJECTIVES: Stroke is the most common cause of disability in high-income countries. Several countries offer a limited range of advanced treatments with implications for outcomes, disability and costs. This study estimates the burden of disability that could have been avoided through the transition from traditional (no intravenous thrombolytic therapy (IVT), or endovascular thrombectomy (EVT)) to modern stroke treatments (treatment in stroke units, IVT and EVT). We perform a cost-effectiveness analysis comparing best practice with traditional stroke care, using Greece as a case study. MATERIALS AND METHODS: A Markov model was used to calculate costs and Quality Adjusted Life Years (QALYs) for each treatment strategy, using a lifetime horizon. Data for model inputs were derived from meta-analyses of trials, and national and international cost databases. Sensitivity analyses were also performed to address potential uncertainty and test the robustness of the findings. RESULTS: Incremental effectiveness comprised 0.22 QALYs per patient and year. Best practice was cost-effective for more than 90% of all iterations (ICER for the baseline scenario: €2,109.25/QALY). Sensitivity analysis demonstrated that the findings remain robust. Considering the stroke incidence in Greece, the annual additional cost to implement best practice was calculated to be between 0.07%-0.15% of the total health expenditure. CONCLUSION: Best practice stroke treatment was cost-effective and affordable in a case study based on Greece. The results could be leveraged by including effects of preventive policies and rehabilitation. They also highlight the importance of adopting modern treatment strategies from a cost-effectiveness perspective, apart from the improved clinical outcomes.

Case-Fatality and Functional Outcome after Subarachnoid Hemorrhage (SAH) in INternational STRoke oUtComes sTudy (INSTRUCT).

BACKGROUND: There are few large population-based studies of outcomes after subarachnoid hemorrhage (SAH) than other stroke types. METHODS: We pooled data from 13 population-based stroke incidence studies (10 studies from the INternational STRroke oUtComes sTudy (INSTRUCT) and 3 new studies; N=657). Primary outcomes were case-fatality and functional outcome (modified Rankin scale score 3-5 [poor] vs. 0-2 [good]). Harmonized patient-level factors included age, sex, health behaviours (e.g. current smoking at baseline), comorbidities (e.g.history of hypertension), baseline stroke severity (e.g. NIHSS >7) and year of stroke. We estimated predictors of case-fatality and functional outcome using Poisson regression and generalized estimating equations using log-binomial models respectively at multiple timepoints. RESULTS: Case-fatality rate was 33% at 1 month, 43% at 1 year, and 47% at 5 years. Poor functional outcome was present in 27% of survivors at 1 month and 15% at 1 year. In multivariable analysis, predictors of death at 1-month were age (per decade increase MRR 1.14 [1.07-1.22]) and SAH severity (MRR 1.87 [1.50-2.33]); at 1 year were age (MRR 1.53 [1.34-1.56]), current smoking (MRR 1.82 [1.20-2.72]) and SAH severity (MRR 3.00 [2.06-4.33]) and; at 5 years were age (MRR 1.63 [1.45-1.84]), current smoking (MRR 2.29 [1.54-3.46]) and severity of SAH (MRR 2.10 [1.44-3.05]). Predictors of poor functional outcome at 1 month were age (per decade increase RR 1.32 [1.11-1.56]) and SAH severity (RR 1.85 [1.06-3.23]), and SAH severity (RR 7.09 [3.17-15.85]) at 1 year. CONCLUSION: Although age is a non-modifiable risk factor for poor outcomes after SAH, however, severity of SAH and smoking are potential targets to improve the outcomes.

Machine-Learning-Derived Model for the Stratification of Cardiovascular risk in Patients with Ischemic Stroke.

Background Stratification of cardiovascular risk in patients with ischemic stroke is important as it may inform management strategies. We aimed to develop a machine-learning-derived prognostic model for the prediction of cardiovascular risk in ischemic stroke patients. MATERIALS AND METHODS: Two prospective stroke registries with consecutive acute ischemic stroke patients were used as training/validation and test datasets. The outcome assessed was major adverse cardiovascular event, defined as non-fatal stroke, non-fatal myocardial infarction, and cardiovascular death during 2-year follow-up. The variables selection was performed with the LASSO technique. The algorithms XGBoost (Extreme Gradient Boosting), Random Forest and Support Vector Machines were selected according to their performance. The evaluation of the classifier was performed by bootstrapping the dataset 1000 times and performing cross-validation by splitting in 60% for the training samples and 40% for the validation samples. RESULTS: The model included age, gender, atrial fibrillation, heart failure, peripheral artery disease, arterial hypertension, statin treatment before stroke onset, prior anticoagulant treatment (in case of atrial fibrillation), creatinine, cervical artery stenosis, anticoagulant treatment at discharge (in case of atrial fibrillation), and statin treatment at discharge. The best accuracy was measured by the XGBoost classifier. In the validation dataset, the area under the curve was 0.648 (95%CI:0.619-0.675) and the balanced accuracy was 0.58 ± 0.14. In the test dataset, the corresponding values were 0.59 and 0.576. CONCLUSIONS: We propose an externally validated machine-learning-derived model which includes readily available parameters and can be used for the estimation of cardiovascular risk in ischemic stroke patients.

Carotid Atherosclerosis and Patent Foramen Ovale in Embolic Stroke of Undetermined Source.

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<0.001). After adjustment for multiple confounders, the prevalence of ipsilateral carotid atherosclerosis remained lower in patients with likely pathogenic PFO compared to patients with likely incidental PFO or without PFO (adjusted OR=0.32, 95%CI:0.104-0.994, p=0.049). CONCLUSIONS: The presence of carotid atherosclerosis is inversely related to the presence of likely pathogenic PFO in patients with ESUS.

External Performance of the HAVOC Score for the Prediction of New Incident Atrial Fibrillation.

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.

Lateralization of Insular Ischemic Stroke is Not Associated With Any Stroke Clinical Outcomes: The Athens Stroke Registry.

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.

Supraventricular Extrasystoles on Standard 12-lead Electrocardiogram Predict New Incident Atrial Fibrillation after Embolic Stroke of Undetermined Source: The AF-ESUS Study.

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%.

Antithrombotic Treatment in Cryptogenic Stroke Patients With Patent Foramen Ovale: Systematic Review and Meta-Analysis.

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.

Efficacy and Safety of Rivaroxaban Versus Aspirin in Embolic Stroke of Undetermined Source and Carotid Atherosclerosis.

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. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

External Validation of the PREMISE Score in the Athens Stroke Registry.

BACKGROUND: A simple score was proposed recently for Predicting Early Mortality from Ischemic Stroke (PREMISE) derived from the Austrian Stroke Unit Registry. This score could be useful in clinical practice and research. However, its generalizability is uncertain, as it was validated internally only. AIMS: We aimed to validate the PREMISE score externally. METHODS: The analysis was performed in the Athens Stroke Registry. The PREMISE score was calculated as described in the original publication. The outcome was death within 7 days after stroke. Logistic regression analysis was used to estimate the relative death risk in different strata of the PREMISE score using the lowest values of the score (ie, 0-4) as the reference category. We assessed the score's calibration by the Hosmer-Lemeshow goodness-of-fit test and its discriminatory power by calculating the area under the receiver operating characteristics curve (AUC). RESULTS: In 2608 consecutive patients (median age 71 years, 38.8% women) with acute ischemic stroke treated in the stroke unit, mortality increased with increasing PREMISE score from .1% (95% confidence intervals [95% CI]: 0%-.2%) in patients with a score of 0-4 to 28.2% (95% CI: 14.1%-42.3%) in patients with a score of ≥10. The risk for death was more than 6 times higher in patients with a PREMISE score of ≥10 compared to patients with 0-4 points (odds ratio [OR]:6.21, 95% CI:4.13-8.29). Τhe PREMISE score showed excellent calibration (Hosmer-Lemeshow χ2: .01, P= .99) and good discriminatory power (AUC .873, 95% CI: .844-.901). CONCLUSIONS: The present study confirms the prognostic accuracy of the PREMISE score in an independent cohort of patients with acute ischemic stroke treated in the stroke unit.

Comparison of Risk Scores for the Prediction of the Overall Cardiovascular Risk in Patients with Ischemic Stroke: The Athens Stroke Registry.

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.

Closure of Patent Foramen Ovale Versus Medical Therapy in Patients With Cryptogenic Stroke or Transient Ischemic Attack: Updated Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Previous systematic reviews and meta-analyses compared the efficacy and safety of patent foramen ovale (PFO) closure versus medical treatment in patients with cryptogenic stroke or transient ischemic attack (TIA). Recently, new evidence from randomized trials became available. METHODS: We searched PubMed until September 24, 2017, for trials comparing PFO closure with medical treatment in patients with cryptogenic stroke/TIA using the items: stroke or cerebrovascular accident or TIA and patent foramen ovale or paradoxical embolism and trial or study. RESULTS: Among 851 identified articles, 5 were eligible. In 3627 patients with 3.7-year mean follow-up, there was significant difference in ischemic stroke recurrence (0.53 versus 1.1 per 100 patient-years, respectively; odds ratio [OR], 0.43; 95% confidence intervals (CI), 0.21-0.90; relative risk reduction, 50.5%; absolute risk reduction, 2.11%; and number needed to treat to prevent 1 event, 46.5 for 3.7 years). There was no significant difference in TIAs (0.78 versus 0.98 per 100 patient-years, respectively; OR, 0.80; 95% CI, 0.53-1.19) and all-cause mortality (0.18 versus 0.23 per 100 patient-years, respectively; OR, 0.73; 95% CI, 0.34-1.56). New-onset atrial fibrillation occurred more frequently in the PFO closure arm (1.3 versus 0.25 per 100 patient-years, respectively; OR, 5.15; 95% CI, 2.18-12.15) and resolved in 72% of cases within 45 days, whereas rates of myocardial infarction (0.12 versus 0.09 per 100 patient-years, respectively; OR, 1.22; 95% CI, 0.25-5.91) and any serious adverse events (7.3 versus 7.3 per 100 patient-years, respectively; OR, 1.07; 95% CI, 0.92-1.25) were similar. CONCLUSIONS: In patients with cryptogenic stroke/TIA and PFO who have their PFO closed, ischemic stroke recurrence is less frequent compared with patients receiving medical treatment. Atrial fibrillation is more frequent but mostly transient. There is no difference in TIA, all-cause mortality, or myocardial infarction.

Renal Function and Risk Stratification of Patients With Embolic Stroke of Undetermined Source.

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.

Real-World Setting Comparison of Nonvitamin-K Antagonist Oral Anticoagulants Versus Vitamin-K Antagonists for Stroke Prevention in Atrial Fibrillation: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Evidence from the real-world setting complements evidence coming from randomized controlled trials. We aimed to summarize all available evidence from high-quality real-world observational studies about efficacy and safety of nonvitamin-K oral anticoagulants compared with vitamin-K antagonists in patients with atrial fibrillation. METHODS: We searched PubMed and Web of Science until January 7, 2017 for observational nationwide or health insurance databases reporting matched or adjusted results comparing nonvitamin-K oral anticoagulants versus vitamin-K antagonists in patients with atrial fibrillation. Outcomes assessed included ischemic stroke, ischemic stroke or systemic embolism, any stroke or systemic embolism, myocardial infarction, intracranial hemorrhage, major hemorrhage, gastrointestinal hemorrhage, and death. RESULTS: In 28 included studies of dabigatran, rivaroxaban, and apixaban compared with vitamin-K antagonists, all 3 nonvitamin-K oral anticoagulants were associated with a large reduction of intracranial hemorrhage (apixaban hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.31-0.63; dabigatran HR, 0.42; 95% CI, 0.37-0.49; rivaroxaban HR, 0.64; 95% CI, 0.47-0.86); similar rates of ischemic stroke and ischemic stroke or systemic embolism (apixaban HR, 1.05; 95% CI, 0.75-1.19 and HR, 1.08; 95% CI, 0.95-1.22 / dabigatran HR, 0.96; 95% CI, 0.80-1.16 and HR, 1.17; 95% CI, 0.92-1.50 / rivaroxaban HR, 0.89; 95% CI, 0.76-1.04 and HR, 0.73; 95% CI, 0.52-1.04, respectively); apixaban and dabigatran with lower mortality (HR, 0.65; 95% CI, 0.56-0.75 and HR, 0.63; 95% CI, 0.53-0.75, respectively); apixaban with fewer gastrointestinal (HR, 0.63; 95% CI, 0.42-0.95) and major hemorrhages (HR, 0.55; 95% CI, 0.48-0.63); dabigatran and rivaroxaban with more gastrointestinal hemorrhages (HR, 1.20; 95% CI, 1.06-1.36 and HR, 1.24; 95% CI, 1.08-1.41, respectively); dabigatran and rivaroxaban with similar rate of myocardial infarction (HR, 0.96; 95% CI, 0.77-1.21 and HR, 1.02; 95% CI, 0.54-1.89, respectively). CONCLUSIONS: This meta-analysis confirms the main findings of the randomized controlled trials of dabigatran, rivaroxaban, and apixaban in the real-world setting and, hence, strengthens their validity.

Aspirin Versus Clopidogrel for Type 2 Diabetic Patients with First-Ever Noncardioembolic Acute Ischemic Stroke: Ten-Year Survival Data from the Athens Stroke Outcome Project.

BACKGROUND AND OBJECTIVE: Diabetes mellitus is associated with an increased risk of stroke and poor outcome following a stroke event. We assessed the impact of discharge treatment with aspirin versus clopidogrel on the 10-year survival of patients with type 2 diabetes after a first-ever noncardioembolic acute ischemic stroke (AIS). METHODS: This was a post hoc analysis of the Athens Stroke Outcome Project. Study outcomes included death, stroke recurrence, and a composite cardiovascular disease (CVD) end point (recurrent stroke, myocardial infarction, unstable angina, coronary revascularization, aortic aneurysm rupture, or sudden death). Kaplan-Meier survival curve and Cox regression analyses were performed. RESULTS: A total of 304 (93 women) diabetic patients receiving either aspirin (n = 197) or clopidogrel (n = 107) were studied. The 10-year survival was better in clopidogrel-treated patients than in aspirin-treated patients (19 deaths [17.7%] for clopidogrel versus 55 deaths [27.9%] for aspirin; log-rank test: 4.91, P = .027). Similarly, clopidogrel was associated with a favorable impact on recurrent stroke (12 events [11.2%] for clopidogrel versus 39 events [19.7%] for aspirin; log-rank test: 4.46, P = .035) and on the composite CVD end point (21 events [19.6%] for clopidogrel versus 54 events [27.4%] for aspirin; log-rank test: 4.17, P = .041). In the multivariable analysis, the beneficial effect of clopidogrel over aspirin on both primary and secondary end points was independent of age, gender, the presence of CVD or CVD risk factors, and stroke severity. CONCLUSIONS: Our findings indicate a favorable effect of clopidogrel at discharge compared with aspirin in preventing death, recurrent stroke, and CVD events in diabetic patients with a first-ever noncardioembolic AIS.

Risk Stratification for Recurrence and Mortality in Embolic Stroke of Undetermined Source.

BACKGROUND AND PURPOSE: The risk of stroke recurrence in patients with Embolic Stroke of Undetermined Source (ESUS) is high, and the optimal antithrombotic strategy for secondary prevention is unclear. We investigated whether congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and stroke or transient ischemic attack (TIA; CHADS2) and CHA2DS2-VASc scores can stratify the long-term risk of ischemic stroke/TIA recurrence and death in ESUS. METHODS: We pooled data sets of 11 stroke registries from Europe and America. ESUS was defined according to the Cryptogenic Stroke/ESUS International Working Group. Cox regression analyses were performed to investigate if prestroke CHADS2 and congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or TIA, vascular disease, age 65-74 years, sex category (CHA2DS2-VASc) scores were independently associated with the risk of ischemic stroke/TIA recurrence or death. The Kaplan-Meier product limit method was used to estimate the cumulative probability of ischemic stroke/TIA recurrence and death in different strata of the CHADS2 and CHA2DS2-VASc scores. RESULTS: One hundred fifty-nine (5.6% per year) ischemic stroke/TIA recurrences and 148 (5.2% per year) deaths occurred in 1095 patients (median age, 68 years) followed-up for a median of 31 months. Compared with CHADS2 score 0, patients with CHADS2 score 1 and CHADS2 score >1 had higher risk of ischemic stroke/TIA recurrence (hazard ratio [HR], 2.38; 95% confidence interval [CI], 1.41-4.00 and HR, 2.72; 95% CI, 1.68-4.40, respectively) and death (HR, 3.58; 95% CI, 1.80-7.12, and HR, 5.45; 95% CI, 2.86-10.40, respectively). Compared with low-risk CHA2DS2-VASc score, patients with high-risk CHA2DS2-VASc score had higher risk of ischemic stroke/TIA recurrence (HR, 3.35; 95% CI, 1.94-5.80) and death (HR, 13.0; 95% CI, 4.7-35.4). CONCLUSIONS: The risk of recurrent ischemic stroke/TIA and death in ESUS is reliably stratified by CHADS2 and CHA2DS2-VASc scores. Compared with the low-risk group, patients in the high-risk CHA2DS2-VASc group have much higher risk of ischemic stroke recurrence/TIA and death, approximately 3-fold and 13-fold, respectively.

Embolic Stroke of Undetermined Source and Detection of Atrial Fibrillation on Follow-Up: How Much Causality Is There?

BACKGROUND: There is increasing debate whether atrial fibrillation (AF) episodes during follow-up in patients with embolic stroke of undetermined source (ESUS) are causally associated with the event. AF-related strokes are more severe than strokes of other etiologies. In this context, we aimed to compare stroke severity between ESUS patients diagnosed with AF during follow-up and those who were not. We hypothesized that, if AF episodes detected during follow-up are indeed causally associated with the index event, stroke severity in the AF group should be higher than the non-AF group. METHODS: Dataset was derived from the Athens Stroke Registry. ESUS was defined by the Cryptogenic Stroke/ESUS International-Working-Group criteria. Stroke severity was assessed by the National Institutes of Health Stroke Scale (NIHSS) score. Cumulative probabilities of recurrent stroke or peripheral embolism in the AF and non-AF ESUS groups were estimated by Kaplan-Meier analyses. RESULTS: Among 275 ESUS patients, AF was detected during follow-up in 80 (29.1%), either during repeated electrocardiogram monitoring (18.2%) or during hospitalization for stroke recurrence (10.9%). NIHSS score was similar between the two groups (5 [2-13] versus 5 [2-14], P = .998). More recurrent strokes or peripheral embolisms occurred in the AF group compared with the non-AF group (42.5% versus 13.3%, P = .001). CONCLUSIONS: Stroke severity is similar between ESUS patients who were diagnosed with AF during follow-up and those who were not. Given that AF-related strokes are more severe than strokes of other etiologies, this finding challenges the assumption that the association between ESUS and AF detected during follow-up is as frequently causal as regarded.

Embolic strokes of undetermined source in the Athens stroke registry: a descriptive analysis.

BACKGROUND AND PURPOSE: A new clinical construct termed embolic stroke of undetermined source (ESUS) was recently introduced, but no such population has been described yet. Our aim is to provide a detailed descriptive analysis of an ESUS population derived from a large prospective ischemic stroke registry using the proposed diagnostic criteria. METHODS: The criteria proposed by the Cryptogenic Stroke/ESUS International Working Group were applied to the Athens Stroke Registry to identify all ESUS patients. ESUS was defined as a radiologically confirmed nonlacunar brain infarct in the absence of (a) extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis in arteries supplying the ischemic area, (b) major-risk cardioembolic source, and (c) any other specific cause of stroke. RESULTS: Among 2735 patients admitted between 1992 and 2011, 275 (10.0%) were classified as ESUS. In the majority of ESUS (74.2%), symptoms were maximal at onset. ESUS were of moderate severity (median National Institute Health Stroke Scale score, 5). The most prevalent risk factor was arterial hypertension (64.7%), and 50.9% of patients were dyslipidemic. Among potential causes of the ESUS, covert atrial fibrillation (AF) was the most prevalent: in 30 (10.9%) patients, AF was diagnosed during hospitalization for stroke recurrence, whereas in 50 (18.2%) patients AF was detected after repeated ECG monitoring during follow-up. Also, covert AF was strongly suggested in 38 patients (13.8%) but never recorded. CONCLUSIONS: About 10% of patients with first-ever ischemic stroke met criteria for ESUS; covert paroxysmal AF seems to be a frequent cause of ESUS.

Embolic Strokes of Undetermined Source in the Athens Stroke Registry: An Outcome Analysis.

BACKGROUND AND PURPOSE: Information about outcomes in Embolic Stroke of Undetermined Source (ESUS) patients is unavailable. This study provides a detailed analysis of outcomes of a large ESUS population. METHODS: Data set was derived from the Athens Stroke Registry. ESUS was defined according to the Cryptogenic Stroke/ESUS International Working Group criteria. End points were mortality, stroke recurrence, functional outcome, and a composite cardiovascular end point comprising recurrent stroke, myocardial infarction, aortic aneurysm rupture, systemic embolism, or sudden cardiac death. We performed Kaplan-Meier analyses to estimate cumulative probabilities of outcomes by stroke type and Cox-regression to investigate whether stroke type was outcome predictor. RESULTS: 2731 patients were followed-up for a mean of 30.5±24.1months. There were 73 (26.5%) deaths, 60 (21.8%) recurrences, and 78 (28.4%) composite cardiovascular end points in the 275 ESUS patients. The cumulative probability of survival in ESUS was 65.6% (95% confidence intervals [CI], 58.9%-72.2%), significantly higher compared with cardioembolic stroke (38.8%, 95% CI, 34.9%-42.7%). The cumulative probability of stroke recurrence in ESUS was 29.0% (95% CI, 22.3%-35.7%), similar to cardioembolic strokes (26.8%, 95% CI, 22.1%-31.5%), but significantly higher compared with all types of noncardioembolic stroke. One hundred seventy-two (62.5%) ESUS patients had favorable functional outcome compared with 280 (32.2%) in cardioembolic and 303 (60.9%) in large-artery atherosclerotic. ESUS patients had similar risk of composite cardiovascular end point as all other stroke types, with the exception of lacunar strokes, which had significantly lower risk (adjusted hazard ratio, 0.70 [95% CI, 0.52-0.94]). CONCLUSIONS: Long-term mortality risk in ESUS is lower compared with cardioembolic strokes, despite similar rates of recurrence and composite cardiovascular end point. Recurrent stroke risk is higher in ESUS than in noncardioembolic strokes.

The Pathophysiological Mechanism Is an Independent Predictor of Long-Term Outcome in Stroke Patients with Large Vessel Atherosclerosis.

BACKGROUND: Etiopathological mechanisms underlying ischemic stroke play a crucial role in long-term prognosis. We aimed to investigate the association between the mechanism of stroke due to large vessel disease, and long-term outcome. METHODS: All consecutive patients registered in the Athens Stroke Registry with atherosclerotic stroke between 1993 and 2010 were included in the analysis. The patients were subdivided into 3 groups according to the presumed underlying mechanism: low-flow infarcts, artery-to-artery embolism, and intrinsic atherosclerosis. They were followed up for up to 10 years or until death. The end points of the study were 10-year all-cause mortality, stroke recurrence, and composite cardiovascular events. RESULTS: Five hundred two patients were classified as follows: 156 (31%) as low-flow (watershed) strokes, 256 (51%) as artery-to-artery embolic strokes, and 90 (18%) as intrinsic atherosclerotic strokes. The cumulative probability of 10-year mortality rate was similar between groups of patients with different stroke mechanisms: 49.9% (95% confidence interval [CI], 38.5-61.3) for patients with low-flow mechanism, 47.6% (95% CI, 39.4-55.8) for patients with artery-to-artery embolism, and 48.5% (95% CI, 34.0-63.0) for patients with intrinsic atherosclerosis. Patients in the intrinsic atherosclerosis group had significantly higher risks of recurrence (adjusted hazard ratio [HR] = 2.1; 95% CI, 1.19-3.73) compared with those in the artery-to-artery embolism group. Moreover, patients in the intrinsic atherosclerosis and low-flow groups had significantly higher risks of composite cardiovascular events compared with those in the artery-to-artery embolism group (adjusted HR = 1.94; 95% CI, 1.26-3.00; and adjusted HR = 1.64; 95% CI, 1.13-2.38, respectively). CONCLUSION: Low-flow and intrinsic atherosclerosis strokes are associated with a high risk for future cardiovascular events and stroke recurrence. However, long-term mortality is similar across different subgroups.