Right drug, wrong dosage: insights from the PAVE-AF antithrombotic study in older patients with atrial fibrillation.

Optimal antithrombotic treatment of older patients is usually impeded by several prevailing misconceptions. The aim of our study was to assess the type, dosage and predictors of antithrombotic therapy in older patients with non-valvular atrial fibrillation (NVAF). PAVE-AF was a prospective, cross-sectional study, including NVAF patients ≥ 80 years from 30 participating centers. Demographic data, comorbidities and treatment patterns were documented in a single visit. Patients treated with non-vitamin K oral anticoagulants (NOACs) were further classified into three dosing categories (recommended, underdosing and overdosing). Among 1018 patients (85.4±4.0 years), 88.4% received anticoagulants (AC), 8% antiplatelets (AP) and 3.6% no treatment. The primary reason for AP administration was physician concern of bleeding followed by patient denial. Patients ≥90 years had two times greater probability to receive AP therapy compared to patients < 90 years. Among patients treated with AC, one third received vitamin K antagonists, while two thirds received NOACs [34.6% apixaban, 9.5% dabigatran and 22.6% rivaroxaban]. Independent predictors of AC prescription over AP or no treatment were low HAS-BLED score, hypertension, labile INR, permanent AF, absence of uncontrolled hypertension, prior stroke/systemic embolism, age and male gender. In total, 37% of NOAC recipients received inappropriate dosage, while the number of patients receiving recommended dosing differed significantly among NOAC subgroups (p < 0.001). In our study, a minority of older NVAF patients received AP or no therapy for stroke prevention. Among patients treated with anticoagulants, two thirds were on NOAC treatment, though with a considerable proportion of inappropriate dosing.

Increased detection of suspected atrial fibrillation in elderly and female hypertensive patients through home blood pressure monitoring: the HOME-AF study.

BACKGROUND: Episodes of suspected atrial fibrillation are particularly frequent in essential hypertension. This study aimed to investigate the incidence of new suspected atrial fibrillation cases detected through home blood pressure (BP) screening among hypertensive patients. Association of new suspected atrial fibrillation cases with arterial hypertension (AH) phenotypes and the CHA2DS2-VASc score was also investigated. METHODS: The prospective study recruited hypertensive patients at least 50 years old from private and hospital hypertensive clinics. An ECG was performed during the first visit. Microlife BP A6 PC was used to measure office and home BP for at least 3 and preferably 7 consecutive days. RESULTS: A total of 2408 AH patients were recruited. Suspected atrial fibrillation was detected by BP monitor in 12.5% of patients. CHA2DS2-VASc was greater in hypertensive patients with suspected atrial fibrillation detection, as compared with all other hypertensive patients (3.3 ±â€Š1.4 vs. 2.8 ±â€Š1.4, P < 0.0001). Suspected atrial fibrillation detection was associated with advanced age (≥ 75 years, P < 0.0001) and female sex (P = 0.01). A nonsignificant association between suspected atrial fibrillation detection and history of chronic heart failure/left ventricular dysfunction was observed (P = 0.06). In the multivariate analysis, age and sex were the only independent risk factors with patients at least 75 years old having more than twice the risk of suspected atrial fibrillation compared with patients less than 64 years old. No differences between new suspected atrial fibrillation cases and AH phenotype (white coat/uncontrolled/masked hypertension) were identified. CONCLUSION: In our cohort of hypertensive patients, suspected atrial fibrillation was common particularly among elderly and female patients. These results underline the need for early suspected atrial fibrillation detection to minimize the increased thromboembolic risk associated with hypertension.

Cost Effectiveness of Apixaban versus Warfarin or Aspirin for Stroke Prevention in Patients with Atrial Fibrillation: A Greek Perspective.

BACKGROUND: Strokes attributed to atrial fibrillation (AF) represent a major cause of adult disability and a great burden to society and healthcare systems. OBJECTIVES: Our objective was to assess the cost effectiveness of apixaban, a direct acting oral anticoagulant (DOAC), versus warfarin or aspirin for patients with AF in the Greek healthcare setting. METHODS: We used a previously published Markov model to simulate clinical events for patients with AF treated with apixaban, the vitamin K antagonist (VKA) warfarin, or aspirin. Clinical events (ischemic and hemorrhagic stroke, intracranial hemorrhage, other major bleed, clinically relevant non-major bleed, myocardial infarction, and cardiovascular [CV] hospitalizations) were modeled using efficacy data from the ARISTOTLE and AVERROES clinical trials. The cohort's baseline characteristics also sourced from these trials. Among VKA-suitable patients, 64.7% were men with a mean age of 70 years and average CHADS2 (cardiac failure, hypertension, age, diabetes, stroke2) score of 2.1, whereas 58.5% of VKA-unsuitable patients were men with a mean age of 70 years and a CHADS2 score of 2.0. A panel of experts (cardiologists and internists) provided information on the resource use associated with the management of AF. Cost calculations reflect the local clinical setting and a third-party payer perspective (€, discounted at 3%). RESULTS: Based on a simulation of 1000 VKA-suitable patients over a lifetime horizon, the use of apixaban versus warfarin resulted in 26 fewer strokes and systemic embolisms in total, 65 fewer bleeds, 41 fewer myocardial infarctions, and 29 fewer CV-related deaths, with an incremental cost-effectiveness ratio (ICER) of €14,478/quality-adjusted life-year (QALY). For VKA-unsuitable patients, apixaban versus aspirin resulted in 72 fewer strokes and systemic embolisms and 57 fewer CV-related deaths, with an ICER of €7104/QALY. Sensitivity analyses indicated that results were robust. CONCLUSIONS: Based on the present analysis, apixaban represents a cost-effective treatment option versus warfarin and aspirin for the prevention of stroke in patients with AF from a Greek healthcare payer perspective over a lifetime horizon.

Linezolid is associated with serotonin syndrome in a patient receiving amitriptyline, and fentanyl: a case report and review of the literature.

We report a unique case of an adverse interaction between the oxazolidinone antibiotic linezolid, the tricyclic antidepressant amitriptyline and the opioid analgesic fentanyl in a 68-year-old woman with advanced ischemic peripheral arterial disease and sepsis, under empirical antibiotic treatment. We also summarize the current relevant literature as identified via PubMed, EMBASE, and PsycINFO as well as reference sections of selected articles.

CHADS2, CHA2S2DS2-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.

Prevalence of atrial fibrillation in Greece: the Arcadia Rural Study on Atrial Fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is a major factor for stroke and stroke-associated mortality, and its incidence is increasing during the last decades. There are only scarce data about its prevalence in Greece. We designed an epidemiological cross-sectional study to estimate the prevalence of AF in Greece and evaluate the adequacy of anticoagulant treatment in AF patients. SUBJECTS AND METHODS: The Arcadia Rural Study on Atrial Fibrillation (ARSAF) was conducted between 2002-2003 in five rural villages of the Arcadia province (Greece) with a permanent population of 1312 individuals. Patients had a thorough medical examination and electrocardiogram, and information was collected about their medical history and comorbidities. CHADS2 score was used to determine stroke risk for participants with AF. RESULTS: 1155 subjects (88% of the entire population) participated in the study. The overall prevalence of AF was 3.9% showing an increasing trend with increasing age ranging from 0.4% in patients <55 years to 10.7% in patients > 84 years. Among patients with AF, 14 (32%) had paroxysmal AF. The presence of AF was associated with increasing age (OR: 1.67 for every 10 years increase, 95% CI: 1.26-2.15), hypertension (OR: 2.12, 95% CI: 1.02-4.14), heart failure (OR: 11.85, 95% CI: 4.92-28.56) and prior cerebrovascular disease (OR: 4.17, 95% CI: 1.44-12.06). Among these subjects with AF, 12 (26.6%) were considered as low-risk (CHADS2 = 0), 18 (40.0%) as intermediate-risk (CHADS2 = 1), and 15 (33.3%) as high-risk (CHADS2 > 1) patients for stroke. 25 (55.5%) patients with AF did not receive appropriate antithrombotic treatment. CONCLUSION: The prevalence of AF in Greece is similar to other countries and increases with increasing age.

Stroke aetiology and predictors of outcome in patients with heart failure and acute stroke: a 10-year follow-up study.

AIMS: The aim of this study was to investigate stroke aetiology and assess the predictors of early and late outcome in patients with heart failure (HF) and acute stroke. METHODS AND RESULTS: A total of 2904 patients, admitted between 1993 and 2010, were regularly followed up at months 1, 3, and 6, and yearly thereafter up to 10 years. There were 283 (9.7%) stroke patients with HF; atrial fibrillation (AF) was present in 144 (50.9%) of them. Stroke aetiology in patients with HF and AF was mainly cardioembolism (82%) regardless of HF aetiology. In contrast, in the 139 non-AF patients with HF, the stroke mechanism was associated with the aetiology of HF: valvular heart disease and dilated cardiomyopathy were related to cardioembolism in 60% and 66.7% of patients, respectively, whereas HF due to coronary artery disease or hypertension was associated with atherosclerotic and lacunar stroke in 40.8% and 61.5%, respectively. In the overall population, HF was an independent predictor of 10-year mortality [hazard ratio = 1.54, 95% confidence interval (CI) 1.29-1.83; P < 0.001]. Probability of 10-year survival was 19.4% (95% CI 14.5-23.5) for HF patients and 44.1% (95% CI 41.4-46.8) for non-HF patients (P < 0.0001). Ten-year mortality in HF patients was associated with functional class of HF, age, diabetes, stroke severity, and in-hospital aspirin use. The presence of AF in HF stroke patients did not influence 10-year survival and composite cardiovascular events (P = 0.429 and P = 0.406, respectively). CONCLUSIONS: In patients with HF, stroke aetiology is influenced by the presence of AF and the underlying cause of HF. Early and late stroke outcome is associated with HF severity but not with the presence of AF.

Association between obesity and mortality after acute first-ever stroke: the obesity-stroke paradox.

BACKGROUND AND PURPOSE: limited data exist concerning obesity and survival in patients after acute stroke. The objective of this study was to investigate the association between obesity and survival in patients with acute first-ever stroke. METHODS: patients were prospectively investigated based on a standard diagnostic protocol over a period of 16 years. Evaluation was performed on admission, at 7 days, at 1, 3, and 6 months after discharge, and yearly thereafter for up to 10 years after stroke. The study patients were divided into 3 groups according to body mass index (BMI): normal weight (<25 kg/m(2)), overweight (25-29.9 kg/m(2)), and obese (≥ 30 kg/m(2)). Overall survival during follow-up was the primary end point. The secondary end point was the overall composite cardiovascular events over the study period. RESULTS: based on our inclusion criteria, 2785 patients were recruited. According to BMI, 1138 (40.9%) patients were of normal weight, 1113 (41.0%) were overweight, and 504 (18.1%) were obese. NIHSS score on admission (mean, 11.28 ± 8.65) was not different among the study groups. Early (first week) survival in obese (96.4%; 95% CI, 94.8%-97.9%) and overweight patients (92.8%; 95% CI, 91.2%-94.4%) was significantly higher compared to that of normal-weight patients (90.2%; 95% CI, 88.4%-92.0%). Similarly, 10-year survival was 52.5% (95% CI, 46.4%-58.6%) in obese, 47.4% (95% CI, 43.5%-51.3%) in overweight, and 41.5% (95% CI, 39.7%-45.0%) in normal-weight patients (log-rank test=17.7; P<0.0001). Overweight (HR, 0.82; 95% CI, 0.71-0.94) and obese patients (HR, 0.71; 95% CI, 0.59-0.86) had a significantly lower risk of 10-year mortality compared to normal-weight patients after adjusting for all confounding variables. CONCLUSIONS: based on BMI estimation, obese and overweight stroke patients have significantly better early and long-term survival rates compared to those with normal BMI.

Burkitt's lymphoma in pregnancy with bilateral breast involvement: case report with review of the literature.

BACKGROUND: Burkitt's lymphoma (BL) in pregnancy presenting with breast involvement is a rare clinical entity, and only 13 cases have been reported so far. CASE REPORT: We describe the case of a 28-year-old postpartum woman who presented with markedly enlarged breasts caused by BL. She was treated with 8 cycles of the CALGB 10002 regimen, as well as with irradiation to both breasts. After achieving a complete objective response, the patient received consolidation with high dose BEAM followed by autologous stem cell transplantation. 20 months after the initial diagnosis, our patient remains alive and relapse-free. Data extracted from the published case reports include information regarding demographic details, type of treatment, sites of disease, and survival. The clinical outcome of the reviewed cases was very unfavorable. CONCLUSIONS: BL affecting breasts during pregnancy or lactation is a rare entity that requires a prompt diagnosis and an aggressive therapeutic approach.

Increased expression of bFGF is associated with carotid atherosclerotic plaques instability engaging the NF-κB pathway.

Unstable atherosclerotic plaques of the carotid arteries are at great risk for the development of ischemic cerebrovascular events. The degradation of the extracellular matrix by matrix metalloproteinases (MMPs) and NO-induced apoptosis of vascular smooth muscle cells (VSMCs) contribute to the vulnerability of the atherosclerotic plaques. Basic fibroblast growth factor (bFGF) through its mitogenic and angiogenic properties has already been implicated in the pathogenesis of atherosclerosis. However, its role in plaque stability remains elusive. To address this issue, a panel of human carotid atherosclerotic plaques was analyzed for bFGF, FGF-receptors-1 and -2 (FGFR-1/-2), inducible nitric oxide synthase (iNOS) and MMP-9 expression. Our data revealed increased expression of bFGF and FGFR-1 in VSMCs of unstable plaques, implying the existence of an autocrine loop, which significantly correlated with high iNOS and MMP-9 levels. These results were recapitulated in vitro by treatment of VSMCs with bFGF. bFGF administration led to up-regulation of both iNOS and MMP-9 that was specifically mediated by nuclear factor-kappaB (NF-kappaB) activation. Collectively, our data demonstrate a novel NF-kappaB-mediated pathway linking bFGF with iNOS and MMP-9 expression that is associated with carotid plaque vulnerability.

Paraneoplastic humorally mediated hypercalcemia induced by parathyroid hormone-related protein in gynecologic malignancies: a systematic review.

Humoral hypercalcemia of malignancy (HHM) is a metabolic phenomenon that is mediated by the paraneoplastic secretion of parathyroid hormone-related peptide (PTHrP). Gynecologic malignant neoplasms complicated by HHM have been reported for organs such as the uterus, cervix, ovary, vulva and the vagina. The purpose of our study was to perform a review of the published cases in the literature and, further, to identify parameters with effect on outcome. Among 34 women with gynecologic neoplasms, 22 suffered from ovarian and 6 from uterine malignancies, while 3 had vulvar and another 3 cervical cancer. Furthermore, clear cell carcinoma was the predominant histology associated with PTH-rP expression. A significant correlation was found between serum calcium and PTH-rP levels. Treatment of hypercalcemia was successful in all cases; pamidronate was utilized in 8 patients. Ovarian cancer patients with severe hypercalcemia and high PTH-rP serum levels had shorter survival compared to their counterparts with mild hypercalcemia or moderately elevated PTH-rP serum levels, but the differences were not statistically significant.

Hypomethylation of retrotransposable elements correlates with genomic instability in non-small cell lung cancer.

LINE-1 and Alu elements are non-LTR retrotransposons, constituting together over 30% of the human genome and they are frequently hypomethylated in human tumors. A relationship between global hypomethylation and genomic instability has been shown, however, there is little evidence to suggest active role for hypomethylation-mediated reactivation of retroelements in human cancer. In our study, we examined by Pyrosequencing the methylation levels of LINE-1 and Alu sequences in 48 primary nonsmall cell carcinomas and their paired adjacent tissues. We demonstrate a significant reduction of the methylation levels of both elements (p = 7.7 x 10(-14) and 9.6 x 10(-7), respectively). The methylation indices of the 2 elements correlated (p = 0.006), suggesting a possible common mechanism for their methylation maintenance. Genomic instability was measured utilizing 11 fluorescent microsatellite markers located on lung cancer hot-spot regions such as 3p, 5q 9p, 13q and 17p. Hypomethylation of both transposable elements was associated with increased genomic instability (LINE, p = 7.1 x 10(-5); Alu, p = 0.008). The reduction of the methylation index of LINE-1 and Alu following treatment of 3 lung cell lines with 5-aza-2'-deoxycitidine, consistently resulted in increased expression of both elements. Our study demonstrates the strong link between hypomethylation of transposable elements with genomic instability in non-small cell lung cancer and provides early evidence for a potential active role of these elements in lung neoplasia. As demethylating agents are now entering lung cancer trials, it is imperative to gain a greater insight into the potential reactivation of silent retrotransposons in order to advance for the clinical utilization of epigenetics in cancer therapy.

Acute doxorubicin cardiotoxicity is successfully treated with the phytochemical oleuropein through suppression of oxidative and nitrosative stress.

Oleuropein (oleu) is a natural phenolic antioxidant, which is present in elevated concentration in olives, olive oil and olive tree leaves. Doxorubicin (DXR) induced cardiotoxicity is mainly induced by oxidative stress but the precise mechanism remains obscure. However, there is evidence that high concentration of nitric oxide (NO) occurring as a result of iNOS induction and peroxynitrite formation may be involved in DXR cardiotoxicity. The aim of the present study was to evaluate a possible protective role of oleu in DXR induced cardiotoxicity in vivo. Fifty rats were divided into 6 groups and treated as follows: control group with a single injection of 2 ml normal saline intraperitoneally (i.p.), DXR group with a single dose of 20 mg/kg i.p, and DXR plus oleu groups with 20 mg/kg DXR i.p. and 100 or 200 mg/kg/BW of oleu i.p. for 5 or 3 consecutive days starting either 2 days before or on the day of DXR administration. Seventy-two hours after DXR treatment blood samples were collected for creatine phosphokinase (CPK), creatine phosphokinase-MB (CPK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) assessments and the rats were then sacrificed. Hearts were used for general histology, iNOS immunohistochemical and Western blot analysis, and for determination of tissue concentrations of lipid peroxidation products, protein carbonyls (PCs), and nitrotyrosine (NT). DXR treated animals demonstrated very extensive cytoplasmic vacuolisation whereas much less vacuolisation was found in oleu treated groups. They also revealed a significant elevation of cardiac enzymes release into systemic circulation (P<0.05 vs saline). Both doses of Oleu tested and both treatment protocols reduced DXR elevated serum levels of CPK, CPK-MB, LDH, AST and ALT (P<0.05). Furthermore, it reduced DXR induced lipid peroxidation, PCs content, NT concentration and iNOS induction in myocardial tissue (P<0.05). Oleu exerts a protective effect by eliminating DXR induced cardiotoxicity expressed by the alteration of intracellular and peripheral markers. Combined oleu and DXR treatment improves the therapeutic outcome by preventing undesirable toxicity.