Konstantinos Makaritsis

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.

Adipokines as mediators of endothelial function and atherosclerosis

For many decades, adipose tissue was considered as an inactive body compartment that was only used as an energy store. During the recent years, an increasing amount of data has revealed that adipose tissue is a major endocrine and paracrine organ producing numerous enzymes, hormones and growth factors which are collectively termed as adipokines. Several experimental and clinical studies showed that adipokines modulate insulin sensitivity and have an influence on glucose/fat metabolism and obesity. Apart from these properties, recent research revealed several direct actions of adipokines on endothelial function, vascular homeostasis and atherogenesis which are independent of their effects on glucose and fat metabolism. The present review focuses on the direct effects of adipokines on vascular/endothelial function and atherosclerosis and summarizes the experimental and clinical data which suggest a role for these molecules as potential diagnostic and prognostic cardiovascular markers as well as potential therapeutic target to reduce cardiovascular risk.

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.

Spontaneous spondylodiscitis: presentation, risk factors, diagnosis, management, and outcome.

BACKGROUND Spontaneous spondylodiscitis is an uncommon disease, which may result in serious complications with potentially high morbidity and mortality. We conducted a prospective case study over a 2-year period in order to analyze the clinical features, approaches to management, and outcome of spondylodiscitis. METHODS Eight consecutive patients (four men, four women; age range 53-82 years) suffering from spondylodiscitis were identified during the study period. Parameters recorded included: demographics, past medical history, predisposing factors, presenting signs and symptoms, spinal level and extension of the infection, laboratory indices of inflammation, microbiological testing, radiological assessment, kind and duration of treatment, follow-up magnetic resonance imaging (MRI) studies, and outcome. RESULTS Duration of symptoms varied from 14 to 90 days. All patients had back pain; fever>or=38 degrees C was present in 5/8 (62.5%) and neurological findings in 6/8 (75%). Diabetes mellitus was identified in six (75%). Most of the patients had elevated laboratory markers of inflammation. At the initial MRI, 12 anatomical levels were found. The microorganism was identified in 7/8 by blood or bone marrow cultures (50% Staphylococcus aureus). None of the patients underwent surgical intervention. Seven patients (87.5%) recovered to full activity; follow-up MRI study results were not always in parallel with the clinical improvement of patients. CONCLUSIONS Spontaneous spondylodiscitis should be considered in every patient with back pain accompanied by fever and laboratory markers of inflammation. The major predisposing risk factor seems to be uncontrolled diabetes. MRI appears to be the method of choice for confirming diagnosis. Timely and accurate diagnosis along with prompt administration of antibiotics appears mandatory for a favorable outcome and avoidance of surgical intervention.

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.

Adiponectin: a key playmaker adipocytokine in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and can progress to cirrhosis, liver failure, and hepatocellular carcinoma. In the last two decades, the prevalence of NAFLD has been growing in most developed countries, mainly as a consequence of its close association with obesity and diabetes mellitus. The exact pathogenesis of NAFLD and especially the mechanisms leading to disease progression have not been completely understood. Adipocytes produce and secrete several bioactive substances known as adipocytokines which are implicated in the pathogenesis of the disease. Among them, adiponectin is an insulin-sensitizing adipocytokine possessing multiple beneficial effects on obesity-related medical complication. This review focuses on the role of adiponectin in NAFLD pathogenesis and its potential use as a diagnostic tool but also as therapeutic target for NAFLD management.

Hematogenous spinal infection in central Greece.

Study Design. We retrospectively analyzed spinal infection (SpI), in a teaching Hospital, in Central Greece. Objective. To study presentation, etiology, and outcome of SpI in Central Greece. Summary of Background Data. SpI most frequently involves the intervertebral disc and adjacent vertebral bodies and can cause neurologic impairment. Methods. Thirty three patients (23 men; age [mean ± standard deviation], 60.6 ± 11.3 years; disease duration, 44.5 [±54.7] days) hospitalized with SpI between January 2000 and December 2007 were included in the study. All patients had magnetic resonance imaging of the spine. Results. Nineteen patients had pyogenic SpI (57.6%) and 14 patients had granulomatous SpI, 11 due to Brucella spp (34.4%), 3 due to Mycobacterium tuberculosis (9.4%). Staphylococcus aureus was the most frequent cause of pyogenic SpI, and spondylodiscitis (SpD) was the most frequent localization. Epidural entension was found in 8 of 17 pyogenic SpD and in 2 of 11 brucellar SpD patients. Subdural extension was detected in 3 patients with pyogenic SpD. Blood cultures were positive in 17 of 19 patients with pyogenic SpI. Two patients had concomitant endocarditis (staphylococcal 1, enterococcal 1). The most common associated disease was diabetes mellitus. All but 2 patients received medical treatment alone. Two patients died of uncontrollable sepsis. Conclusion. Back pain in presence of fever, constitutional symptoms, and/or high inflammation markers should alert physicians for spinal infection. In endemic areas, Brucella is a frequent cause of SpI.

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.