Vasileios Papavasileiou

Nonvitamin-K-Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Previous Stroke or Transient Ischemic Attack A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background and Purpose— To assess whether the combined analysis of all phase III trials of nonvitamin-K-antagonist (non-VKA) oral anticoagulants in patients with atrial fibrillation and previous stroke or transient ischemic attack shows a significant difference in efficacy or safety compared with warfarin. Methods— We searched PubMed until May 31, 2012, for randomized clinical trials using the following search items: atrial fibrillation, anticoagulation, warfarin, and previous stroke or transient ischemic attack. Studies had to be phase III trials in atrial fibrillation patients comparing warfarin with a non-VKA currently on the market or with the intention to be brought to the market in North America or Europe. Analysis was performed on intention-to-treat basis. A fixed-effects model was used as more appropriate than a random-effects model when combining a small number of studies. Results— Among 47 potentially eligible articles, 3 were included in the meta-analysis. In 14 527 patients, non-VKAs were associated with a significant reduction of stroke/systemic embolism (odds ratios, 0.85 [95% CI, 074–0.99]; relative risk reduction, 14%; absolute risk reduction, 0.7%; number needed to treat, 134 over 1.8–2.0 years) compared with warfarin. Non-VKAs were also associated with a significant reduction of major bleeding compared with warfarin (odds ratios, 0.86 [95% CI, 075–0.99]; relative risk reduction, 13%; absolute risk reduction, 0.8%; number needed to treat, 125), mainly driven by the significant reduction of hemorrhagic stroke (odds ratios, 0.44 [95% CI, 032–0.62]; relative risk reduction, 57.9%; absolute risk reduction, 0.7%; number needed to treat, 139). Conclusions— In the context of the significant limitations of combining the results of disparate trials of different agents, non-VKAs seem to be associated with a significant reduction in rates of stroke or systemic embolism, hemorrhagic stroke, and major bleeding when compared with warfarin in patients with previous stroke or transient ischemic attack.

CHADS2, CHA2DS2-VASc, and long-term stroke outcome in patients without atrial fibrillation

Objective: CHADS2 and CHA2DS2-VASc scores are used to assess stroke risk in patients with atrial fibrillation (AF). We investigated whether these scores are associated with stroke outcome in non-AF stroke patients. Methods: Consecutive patients with acute first-ever ischemic stroke but without AF were classified into subgroups according to prestroke CHADS2 and CHA2DS2-VASc scores and followed up for 5 years. The end points were death, stroke recurrence, and a composite of major cardiovascular events. Results: Among 1,756 patients (aged 67.2 ± 12.3 years, 68.2% males), there were 258 (14.7%), 617 (35.3%), and 878 (50.0%) patients with low, intermediate, and high CHADS2 score, respectively. The corresponding figures for CHA2DS2-VASc subgroups were 110 (6.3%), 255 (14.5%), and 1,391 (79.2%). There were significant differences between CHADS2 subgroups in 5-year mortality (log-rank test = 74.5, p < 0.0001), stroke recurrence (log-rank test = 12.3, p = 0.002), and cardiovascular events (log-rank test = 19.4, p < 0.001). Similarly, there were significant differences between CHA2DS2-VASc subgroups in 5-year mortality (log-rank test = 74.5, p < 0.0001), stroke recurrence (log-rank test = 10.6, p = 0.005), and cardiovascular events (log-rank test = 16.4, p < 0.001). Compared with the low-risk group, patients in intermediate- and high-risk CHADS2 subgroups had higher 5-year mortality (hazard ratio [HR]: 2.22 [95% confidence interval {CI}: 1.78–2.77] and 3.66 [95% CI: 2.38–5.62], respectively), stroke recurrence (HR: 1.74 [95% CI: 1.09–2.79] and 1.71 [95% CI: 1.08–2.71], respectively), and cardiovascular events (HR: 1.78 [95% CI: 1.23–2.57] and 1.86 [95% CI: 1.30–2.67], respectively). Compared with the low-risk group, patients in the high-risk CHA2DS2-VASc subgroup also had higher 5-year mortality (HR: 3.56, 95% CI: 1.89–6.70), stroke recurrence (HR: 2.93, 95% CI: 1.30–6.61), and cardiovascular events (HR: 2.71, 95% CI: 1.49–4.95). Conclusions: Prestroke CHADS2 and CHA2DS2-VASc scores predict long-term stroke outcomes in non-AF patients with acute ischemic stroke. These scores may provide a simple way of stroke prognostic risk stratification among non-AF stroke patients.

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.

ASTRAL Score Predicts 5-Year Dependence and Mortality in Acute Ischemic Stroke

Background and Purpose— The ASTRAL score was externally validated showing remarkable consistency on 3-month outcome prognosis in patients with acute ischemic stroke. The present study aimed to evaluate ASTRAL score’s prognostic accuracy to predict 5-year outcome. Methods— All consecutive patients with acute ischemic stroke registered in the Athens Stroke Registry between January 1, 1998, and December 31, 2010, were included. Patients were excluded if admitted >24 hours after symptom onset or if any ASTRAL score component was missing. End points were 5-year unfavorable functional outcome, defined as modified Rankin Scale 3 to 6, and 5-year mortality. For each outcome, the area under the receiver operating characteristics curve was calculated; also, a multivariate Cox proportional hazards analysis was performed to investigate whether the ASTRAL score was an independent predictor of outcome. The Kaplan–Meier product limit method was used to estimate the probability of 5-year survival for each ASTRAL score quartile. Results— The area under the receiver operating characteristics curve of the score to predict 5-year unfavorable functional outcome was 0.89, 95% confidence interval 0.88 to 0.91. In multivariate Cox proportional hazards analysis, the ASTRAL score was independently associated with 5-year unfavorable functional outcome (hazard ratio, 1.09; 95% confidence interval, 1.08–1.10). The area under the receiver operating characteristics curve for the ASTRAL score’s discriminatory power to predict 5-year mortality was 0.81 (95% confidence interval, 0.78–0.83). In multivariate analysis, the ASTRAL score was independently associated with 5-year mortality (hazard ratio, 1.09, 95% confidence interval, 1.08–1.10). During the 5-year follow-up, the probability of survival was significantly lower with increasing ASTRAL score quartiles (log-rank test <0.001). Conclusions— The ASTRAL score reliably predicts 5-year functional outcome and mortality in patients with acute ischemic stroke.

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.

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.

Leukoaraiosis and stroke recurrence risk in patients with and without atrial fibrillation

Objective: We aimed to investigate the association between leukoaraiosis and long-term risk of stroke recurrence adjusting for clinical scores developed and validated for the prediction of stroke risk, such as CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and stroke or TIA) and CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or TIA, vascular disease, age 65–74 years, sex category). Methods: Study population was derived from the Athens Stroke Registry and was categorized in 2 subgroups according to the presence of atrial fibrillation (AF). Cox proportional hazards analysis was performed to assess the independent predictors of stroke recurrence. To investigate whether leukoaraiosis adds to the prognostic accuracy of CHADS2 and CHA2DS2-VASc scores, we used the likelihood ratio test. Overall model assessment was performed with Nagelkerke R2 and Harrell C statistic. Kaplan–Meier analyses were also performed. Results: Among 1,892 patients, there were 320 (16.9%) with leukoaraiosis and 670 (35.4%) with AF. In the Kaplan–Meier analysis, there was significant difference in cumulative probability of stroke recurrence between patients with and without leukoaraiosis in the non-AF group (p < 0.01), but not in the AF group (p = 0.46). On Cox multivariate analysis, leukoaraiosis was found to be a significant independent predictor of stroke recurrence only in the non-AF group, in the models adjusting for CHADS2 (hazard ratio: 1.86, 95% confidence interval: 1.35–2.56) and CHA2DS2-VASc (hazard ratio: 1.82, 95% confidence interval: 1.32–2.51) scores. Leukoaraiosis was not a predictor of stroke recurrence in the AF group. Leukoaraiosis did not improve the predictive accuracy of the 2 scores, whether in the non-AF group (Harrell C statistic: 0.56 vs 0.59 [p = 0.31] for the model including CHADS2; 0.56 vs 0.59 [p = 0.44] for the model including CHA2DS2-VASc) or the AF group (Harrell C statistic: 0.63 vs 0.62 for the model including CHADS2; 0.64 vs 0.64 for the model including CHA2DS2-VASc). Conclusions: Leukoaraiosis is an independent predictor of stroke recurrence in non-AF stroke patients. However, leukoaraiosis did not increase the accuracy of the CHADS2 and CHA2DS2-VASc scores to predict stroke recurrence in AF or non-AF stroke patients.

European Stroke Organisation (ESO) Guidelines for the Management of Temperature in Patients with Acute Ischemic Stroke

Background Hyperthermia is a frequent complication in patients with acute ischemic stroke. On the other hand, therapeutically induced hypothermia has shown promising potential in animal models of focal cerebral ischemia. This Guideline Document presents the European Stroke Organisation guidelines for the management of temperature in patients with acute ischemic stroke. Methods A multidisciplinary group identified related questions and developed its recommendations based on evidence from randomized controlled trials elaborating the Grading of Recommendations Assessment, Development, and Evaluation approach. This Guideline Document was reviewed within the European Stroke Organisation and externally and was approved by the European Stroke Organisation Guidelines Committee and the European Stroke Organisation Executive Committee. Results We found low-quality evidence, and therefore, we cannot make any recommendation for treating hyperthermia as a means to improve functional outcome and/or survival in patients with acute ischemic stroke and hyperthermia; moderate evidence to suggest against routine prevention of hyperthermia with antipyretics as a means to improve functional outcome and/or survival in patients with acute ischemic stroke and normothermia; very low-quality evidence to suggest against routine induction of hypothermia as a means to improve functional outcome and/or survival in patients with acute ischemic stroke. Conclusions The currently available data about the management of temperature in patients with acute ischemic stroke are limited, and the strengths of the recommendations are therefore weak. We call for new randomized controlled trials as well as recruitment of eligible patients to ongoing randomized controlled trials to allow for better-informed recommendations in the future.

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.