Efficacy and safety of prophylactic anticoagulation in patients with primary nephrotic syndrome: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Nephrotic syndrome (NS) is associated with an increased incidence of venous thromboembolism (VTE), approximately 10%. We performed a systematic review to evaluate the efficacy and safety of prophylactic anticoagulation in patients with NS. METHODS: Studies evaluating prophylactic anticoagulation in NS were identified by an electronic search of MEDLINE and EMBASE databases until December 2021. Weighted mean proportion and 95% confidence intervals (CIs) of thromboembolic and haemorrhagic events were calculated using a fixed-effects and a random-effects model. The differences in the outcomes among groups were estimated as pooled odds ratio (OR) and corresponding 95% CI. Statistical heterogeneity was evaluated using the I2 statistic. RESULTS: Five cohort studies, for a total of 414 adult patients, were included. Only two studies had a control group. The weighted mean incidence of pulmonary embolism (PE) and deep vein thrombosis in patients who received VTE prophylaxis was 1.8% (95% CI: 0.6-3.5%; I2 : 4.4%) and 0.9% (95% CI: 0.2-2.2%; I2 : 43.4%) respectively. The weighted mean incidence of major bleeding in patients who received VTE prophylaxis was 2.3% (95% CI: 1-4.2%; I2 : 25.4%). Patients with NS that received VTE prophylaxis had a non-significant reduced risk of PE (OR: 0.63 (95% CI: 0.03-14.8; I2 : 64.4%)) and an increased risk of major bleeding (OR: 2.08 (95% CI: 0.41-10.45; I2 : 0%)) compared to patients with NS that did not receive VTE prophylaxis. CONCLUSIONS: Our findings suggest that prophylactic anticoagulation in adult patients with primary NS may reduce the risk of VTE, even if it may be associated with a not negligible bleeding risk.

Venous and arterial thromboembolic risk of Janus kinase inhibitors: a systematic review with meta-analysis.

OBJECTIVE: Preliminary data led licencing authorities to alert clinicians of an increased venous thrombotic risk associated to the use of Janus kinase (JAK) inhibitors (JAKi). We performed a systematic review to estimate the risk of venous and arterial thrombosis associated to JAKi for the treatment of immune-mediated inflammatory diseases (IMIDs). METHODS: Randomized controlled trials (RCTs) on JAKi in patients with IMIDs were identified by the MEDLINE and EMBASE databases until October 2021. Risk of bias was assessed according to Cochrane criteria. The beta-binomial model was applied to calculate pooled odds ratio (OR) and corresponding 95% CI. The PROSPERO registration number is CRD42022324143. RESULTS: We have included one phase I, 21 phase II, three phase II-III and 36 phase III RCTs for a total of 19 443 patients in the JAKi group and 6354 in the control group. Thirty-one (unweighted rate 0.16%; 95% CI: 0.10, 0.21) events were reported in the JAKi group and 20 (unweighted rate 0.22%; 95% CI: 0.12, 0.32) in the control group in a mean follow-up of 16.8 weeks. IMID patients treated with JAKi did not have an increased thromboembolic risk compared with those treated with placebo (OR 0.82; 95% CI: 0.43, 1.56). No statistically different results were seen in subanalyses for each investigated IMID, drug and dosage. CONCLUSION: JAKi do not increase thromboembolic risk compared with placebo in IMID patients enrolled in selected RCTs.

Incidence Rates and Case-Fatality Rates of Cerebral Vein Thrombosis: A Population-Based Study.

Background and Purpose: Cerebral vein thrombosis (CVT) incidence is estimated to be >10 per 1 000 000 per year. Few population-based studies investigating case-fatality rates (CFRs) and pyogenic/nonpyogenic CVT incidence are available. We assessed trends in CVT incidence between 2002 and 2012, as well as adjusted in-hospital CFRs and incidence of hospital admissions for pyogenic/nonpyogenic CVT in a large Northwestern Italian epidemiological study. Methods: Primary and secondary discharge diagnoses of pyogenic/nonpyogenic CVT were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes 325, 671.5, and 437.6. Age, sex, vital status at discharge, length of hospital stay, and up to 5 secondary discharge diagnoses were collected. Concomitant presence of intracerebral hemorrhage (ICH) was registered, and comorbidities were assessed through the Charlson comorbidity index. Results: A total of 1718 patients were hospitalized for CVT (1147 females­66.8%; 810 pyogenic and 908 nonpyogenic CVT, 47.1% and 52.9%, respectively), with 134 patients (7.8%) experiencing a concomitant ICH. The overall incidence rate for CVT was 11.6 per 1 000 000 inhabitants with a sex-specific rate of 15.1 and 7.8 per 1 000 000 in females and males, respectively. CVT incidence significantly increased in women during time of observation (P=0.007), with the highest incidence being at 40 to 44 years (27.0 cases per 1 000 000). In-hospital CFR was 3%, with no difference between pyogenic/nonpyogenic CVT. Patients with concomitant ICH had a higher in-hospital CFR compared with patients without ICH (7.5% versus 2.7%; odds ratio, 2.96 [95% CI, 1.45­6.04]). In-hospital CFR progressively increased with increasing Charlson comorbidity index (P=0.003). Age (odds ratio, 1.03 [95% CI, 1.02­1.05]), Charlson comorbidity index ≥4 (odds ratio, 4.33 [95% CI, 1.29­14.52]), and ICH (odds ratio, 3.05 [95% CI, 1.40­6.62]) were independent predictors of in-hospital mortality. Conclusions: In a large epidemiological study, CVT incidence was found to be comparable to the one registered in population-based studies reported after the year 2000. CVT incidence increased among women over time. In-hospital CFR was low, but not negligible, in patients with concomitant ICH. Age, ICH, and a high number of comorbidities were independent predictors of in-hospital mortality. Pyogenic CVT was not a predictor of in-hospital CFR, although its high proportion was not confirmed by internal validation.

Preoperative bleeding risk assessment with ISTH-BAT and laboratory tests in patients undergoing elective surgery: A prospective cohort study.

BACKGROUND: Patients with inherited haemorrhagic disorders may bleed during surgery. No questionnaire on bleeding diathesis has been yet validated for the preoperative period and current guidelines provide conflicting recommendations. AIM: We aimed to assess if preoperative assessment with ISTH-BAT (International Society on Thrombosis and Haemostasis Bleeding Assesment Tool) and laboratory screening tests is useful to identify mild previously undiagnosed bleeding disorders (BDs) and to predict bleeding complications in selected patients undergoing elective surgery. METHODS: Consecutive patients undergoing elective surgery received ISTH-BAT evaluation and laboratory screening for platelet count, Prothrombin Time (PT) and activated Partial Thromboplastin Time (aPTT). Subjects with an abnormal ISTH-BAT and/or laboratory results underwent further testing, and they were compared with a 1:1 random gender-, age- and type of surgery- matched control group. RESULTS: Overall, 1502 consecutive surgical patients (1186 adults, 316 children) were enrolled. Of these, 83 (5.5%, 95% confidence interval 4.4-6.8) patients (37 adults and 46 children) had an abnormal ISTH-BAT, and/or prolonged PT and/or prolonged aPTT and/or low platelet count; of them, one subject had low von Willebrand factor level, three Factor XII deficiency and four anticardiolipin and/or antiB2GPI antibodies. No major bleeding was reported in these 83 patients and their controls. CONCLUSION: ISTH-BAT and laboratory screening tests do not accurately detect mild BDs in selected patients undergoing elective surgery.

Baseline PET as prognostic index in diffuse large B-cell lymphoma and grade IIIb follicular lymphoma: a retrospective study of a single-center experience.

BACKGROUND: International guidelines support performing baseline positron emission tomography (PET) in lymphoma. Metabolic tumor volume (MTV) measurement has been proposed as a good measurement of disease burden. We investigated if MTV at baseline PET can be predictive of complete response (CR) to first line standard chemotherapy in diffuse large B-cell lymphoma (DLBCL) and in follicular lymphoma (FL) grade IIIb. METHODS: We retrospectively analyzed data on 54 consecutive patients with DLBCL and FL grade IIIb treated in our institution. Dedicated software automatically estimated the SUVmax of the most active lesion and the MTV of the entire lesion burden using an isocontour threshold method set at 42% (MTV42) and 28% (MTV28) of the SUVmax. In addition, the ratio value (MTV28/MTV42) was calculated. Every group of lesions was evaluated separately. All patients were treated with R-CHOP-21. We performed a univariate and a multivariate logistic regression analysis to explore any possible association between PET parameters and CR. RESULTS: At the univariate logistic regression analysis, patients with a MTV28 lower than the median value (173.1) had an odds ratio (OR) of 4 (95% CI: 0.94-16.9) of obtaining a CR in comparison to patients with a MTV 28 higher than the median value; patients with a MTV42 lower than the median value (i.e. 85.6) had an OR of 3.63 (95% CI: 0.85-15.34) of obtaining a CR in comparison to patients with a MTV 42 equal or higher than the median value. Using MTV28/MTV42 value with median as cut-off instead of MTV28, patients with a MTV28/MTV42 lower than the median value (i.e. 1.81) had an OR of 4.26 (95% CI: 0.72-25.07) and of 7.54 (95% CI: 0.70-80.91) of obtaining a CR in comparison to patients with a MTV28/MTV42 equal or higher than the median value in the two models, respectively. CONCLUSIONS: The results of our study suggest that MTV could be a useful tool to predict response to R-CHOP in patients affected with DLBCL and FL grade IIIb and that a multi-parameters evaluation should be considered.

Diagnostic accuracy of inferior vena cava ultrasound for heart failure in patients with acute dyspnoea: a systematic review and meta-analysis.

BACKGROUND: Dyspnoea is the most common sign of heart failure (HF). Patients accessing the ED for HF-related symptoms require fast diagnosis and early treatment. Transthoracic echocardiography has a crucial role in HF diagnosis, but requires qualified staff and adequate time for execution. The measurement of inferior vena cava (IVC) diameter has been recently proposed as a rapid, simple and reliable marker of volume overload. The aim of this systematic review was to assess the accuracy of IVC-ultrasound as a stand-alone test for HF diagnosis in patients presenting to the ED with acute dyspnoea. METHODS: Studies evaluating the diagnostic accuracy of the inferior vena cava collapsibility index (IVC-CIx) for HF diagnosis were systematically searched in the EMBASE and MEDLINE databases (up to January 2018). Quality Assessment of Diagnostic Accuracy Studies 2 tool was used for the quality assessment of the primary studies. A bivariate random-effects regression approach was used for summary estimates of both sensitivity and specificity. RESULTS: Seven studies, for a total of 591 patients, were included. Three studies were at low-risk of bias. All studies used a proper reference test. Weighted mean prevalence of HF was 49.3% at random-effect model (I2 index for heterogeneity=74.7%). IVC-CIx bivariate weighted mean sensitivity was 79.1% (95% CI 68.5% to 86.8%) and bivariate weighted mean specificity was 81.8% (95% CI 75.0% to 87.0%). CONCLUSIONS: Our findings suggest that the sensitivity and specificity of IVC-CIx are suboptimal to rule in or rule out HF diagnosis in patients with acute dyspnoea in the ED setting. Therefore, IVC-CIx is not advisable as a stand-alone test, but may be useful when integrated in a specific diagnostic algorithm for the differential diagnosis of acute dyspnoea.

Comparison of statins for secondary prevention in patients with ischemic stroke or transient ischemic attack: a systematic review and network meta-analysis.

BACKGROUND: Statins may prevent recurrent ischemic events after ischemic stroke. Determining which statin to use remains controversial. We aimed to summarize the evidence for the use of statins in secondary prevention for patients with ischemic stroke by comparing benefits and harms of various statins. METHODS: We searched for randomized controlled trials (RCTs) assessing statins in patients with ischemic stroke or transient ischemic attack (TIA) in MEDLINE, EMBASE, and CENTRAL up to July 2017. Two authors extracted data and appraised risks of bias. We performed pairwise meta-analyses and trial sequential analyses (TSA) to compare statins versus placebo/no statin, and network meta-analyses using frequentist random-effects models to compare statins through indirect evidence. We used GRADE to rate the overall certainty of evidence. Primary outcomes were all-cause mortality and all strokes. Secondary outcomes were different types of strokes, cardiovascular events, and adverse events. RESULTS: We identified nine trials (10,741 patients). No head-to-head RCTs were found. The median follow-up period was 2.5 years. Statins did not seem to modify all stroke and all-cause mortality outcomes; they were associated with a decreased risk of ischemic stroke (odds ratio, OR, 0.81 [95% CI, 0.70 to 0.93]; absolute risk difference, ARD, - 1.6% [95% CI, - 2.6 to - 0.6%]), ischemic stroke or TIA (OR, 0.75 [95% CI, 0.64 to 0.87]; ARD, - 4.2% [95% CI, - 6.2 to - 2.1%]), and cardiovascular event (OR, 0.75 [95% CI, 0.69 to 0.83]; ARD, - 5.4% [95% CI, - 6.8 to - 3.6%]), and did not seem to modify rhabdomyolysis, myalgia, or rise in creatine kinase. In the comparison of different statins, moderate- to high-quality evidence indicated that differences between pharmaceutical products seemed modest, with high doses (e.g., atorvastatin 80 mg/day and simvastatin 40 mg/day) associated with the greatest benefits. TSA excluded random error as a cause of the findings for ischemic stroke and cardiovascular event outcomes. Evidence for increased risk of hemorrhagic stroke was sensitive to the exclusion of the SPARCL trial. CONCLUSIONS: Evidence strongly suggests that statins are associated with a reduction in the absolute risk of ischemic strokes and cardiovascular events. Differences in effects among statins were modest, signaling potential therapeutic equivalence. TRIAL REGISTRATION: PROSPERO CRD42018079112.

sRAGE and early signs of cardiac target organ damage in mild hypertensives.

BACKGROUND: Soluble Receptor for Advanced Glycation End Products (sRAGE) may be considered a marker inversely related to inflammation and its participation has been established in patients with advanced atherosclerotic vascular diseases. However, it is still unknown whether sRAGE reduction could be early metabolic change in the first stage of hypertension and initial hypertension-associated cardiac damage. We sought to determine the sRAGE values in otherwise healthy, untreated and recently diagnosed mild hypertensives and evaluate their association with blood pressure (BP) values, metabolic parameters, and with subclinical initial signs of cardiac target organ damage (TOD). METHODS: sRAGE were measured in 100 hypertensive and 100 normotensive subjects matched for age, gender and body mass index (BMI), submitted to a clinic visit and both ambulatory BP monitoring and echocardiography to determine the presence of initial cardiac TOD (presence of signs of left ventricular hypertrophy: left ventricular mass indexed for height2.7 (LVMi) > 48 g/m2.7 for men and > 44 g/m2.7 for women and/or increased left atrial volume 4-chamber indexed for body surface area (LAVi) > 34 ml/m2). RESULTS: sRAGE levels were similar between hypertensive and normotensive subjects and were not significantly correlated with office and 24-h BPs values. However, when subgrouping the hypertensive patients in Hyp-TOD and Hyp-withoutTOD, sRAGE was found to be different among the three groups (p = 0.030), being lower in the Hyp-TOD group than the values of both Hyp-withoutTOD (p = 0.038) and normotensives (p = 0.038). In hypertensive patients sRAGE was negatively related with both LVMi (r = - 0.239, p = 0.034) and LAVi (r = - 0.315, p = 0.005) and was independently related to cardiac TOD also in multivariable analysis. CONCLUSIONS: In this population of mild hypertensives, low circulating sRAGE may be a very early marker of initial TOD, suggesting the possible participation of oxidative stress in initial cardiac changes in human hypertension.

What Quality and Safety of Care for Patients Admitted to Clinically Inappropriate Wards: a Systematic Review.

BACKGROUND: In countries with public health system, hospital bed reductions and increasing social and medical frailty have led to the phenomenon of "outliers" or "outlying hospital in-patients." They are often medical patients who, because of unavailability of beds in their clinically appropriate ward, are admitted wherever unoccupied beds are. The present work is aimed to systematically review literature about quality and safety of care for patients admitted to clinically inappropriate wards. METHODS: We performed a systematic review of studies investigating outliers, published in peer-reviewed journals with no time restrictions. Search and screening were conducted by two independent researchers (MLR and ER). Studies were considered potentially eligible for this systematic review if aimed to assess the quality and/or the safety of care for patients admitted to clinically inappropriate units. Our search was supplemented by a hand search of references of included studies. Given the heterogeneity of studies, results were analyzed thematically. We used PRISMA guidelines to report our findings. RESULTS: We collected 17 eligible papers and grouped them into six thematic categories. Despite their methodological limits, the included studies show increased trends in mortality and readmissions among outliers. Quality of care and patient safety are compromised as patients and health professionals declare and risk analysis displays. Reported solutions are often multicomponent, stress early discharge but have not been investigated in the control group. CONCLUSIONS: Published literature cannot definitely conclude on the quality and safety of care for patients admitted to clinically inappropriate wards. As they may represent a serious threat for quality and safety, and moreover often neglected and under valued, well-designed and powered prospective studies are urgently needed.

Balloon Pulmonary Angioplasty in Patients With Chronic Thromboembolic Pulmonary Hypertension　- A Systematic Review and Meta-Analysis.

BACKGROUND: Balloon pulmonary angioplasty (BPA) is a percutaneous treatment option for patients affected by chronic thromboembolic pulmonary hypertension (CTEPH) and either judged inoperable or with persistent symptoms after pulmonary endoarteriectomy. Current data regarding BPA are sparse and results vary according to local center experience. A systematic review of the literature was performed to better understand the effectiveness and safety of BPA in the treatment of CTEPH.Methods and Results:PubMed and EMBASE were searched for studies reporting BPA results in patients with CTEPH. Differences in clinical and hemodynamic parameters before and after the procedure were analyzed. Weighted mean proportion and 95% confidence intervals (CIs) of adverse events were calculated. In total, 14 studies were included (725 patients). BPA was associated with a reduction in mean pulmonary artery pressure (from 43 to 32.5 mmHg), reduction in pulmonary vascular resistance (from 9.94 to 5.06 Woods units), increase in cardiac index (from 2.35 to 2.62 L/min/m2), and improvement of 6-minute walking distance (from 345 to 442 m). Periprocedural mortality occurred in 2.1% of patients (95% CoI 0.8-4.1) while reperfusion and pulmonary vessel injuries occurred in 9.3% (95% CoI 3.1-18.4) and 2.3% (95% CoI 0.9-4.5) of total BPA sessions, respectively. CONCLUSIONS: Our systematic review suggested that BPA for CTEPH patients was an effective and relatively safe treatment option.

Epidemiology and secondary prevention of ischemic stroke in patients on antiplatelet drug: a retrospective cohort study.

One-third to one-half of ischemic strokes occurred in patients taking antiplatelet drugs. The optimal therapeutic strategy for antithrombotic drugs remains uncertain and guidelines provide scarse recommendation. Therefore, aims of our study were to: (i) estimate the prevalence of patients who develop an ischemic stroke while on antiplatelet drugs, (ii) investigate potential factors associated with this phenomenon, (iii) describe management strategies in daily clinical practice. Consecutive adult patients admitted for acute ischemic stroke at the academic hospital of Varese, Italy, from January 2010 till December 2011 were included. Patients were retrospectively identified by searching the administrative database of the hospital. Odds ratios (ORs) and their 95% confidence intervals (CI) for identifying factors associated with dependent variable were estimated using univariate logistic regression. Any variable with a p value < 0.2 at univariate analysis was included in a multivariate model. A total of 419 patients were included. Patients with ischemic stroke while on antiplatelet drugs were 49.6%. The following baseline characteristics were associated with the occurrence of ischemic stroke in patients taking antiplatelet drugs: diabetes mellitus (DM), history of ischemic heart disease (IHD), age > 65 years and previous stroke or transient ischemic stroke (TIA). The following variables were significantly associated with a change of antithrombotic therapy at discharge: DM, history of IHD and previous stroke or TIA. Our study confirms that the occurrence of ischemic stroke during antiplatelet treatment is common and management of antithrombotic therapy is heterogeneous. Factors that may explain therapeutic failure include undetected cardioembolic sources, drug resistance, poor compliance, or the presence of diabetes, atherothrombotic disease, and advanced age. Randomized controlled trials are warranted to assess the optimal antithrombotic strategy for ischemic stroke occurred in patients taking antiplatelet drugs.

Thyroid Disorders and Hemostasis.

Lower levels of free thyroxine (whether this is endogenous or exogenous) lead to a hypocoagulable state, and higher levels of free thyroxine lead to a hypercoagulable state. In this narrative review, the effects of different levels of thyroid hormones on clinical end points are described. Hypothyroidism is associated with an increased bleeding risk, whereas hyperthyroidism leads to an increased risk of venous thrombosis. Besides, effects of thyroid hormone on the heart may indirectly influence hemostasis. Hyperthyroidism leads to a higher incidence of atrial fibrillation and atrial flutter, and, at least partly by that mechanism, a higher risk of cerebral arterial thrombosis. In addition, compression effects of goiter on developing venous thrombosis are described. This is caused by local stasis of blood due to tumor expansion.

Ruxolitinib-associated infections: A systematic review and meta-analysis.

Ruxolitinib exerts immunosuppressive activity that may increase the risk of infectious complications. We performed a systematic review of the literature with the aim of estimating the risk of infections in patients treated with ruxolitinib. Studies were identified by electronic search of MEDLINE and EMBASE database. Differences in the incidence of infectious events between ruxolitinib and comparison groups were expressed as odds ratios (ORs) and 95% confidence intervals (95% CI). Five phase III randomized clinical trials (RCTs) (3 phase IIIa with their extended phase and 2 phase IIIb), 6 phase IV studies and 28 case reports were included in this systematic review. Ruxolitinib was associated with a statistically significant increased risk of herpes zoster infection compared to control group in 3 RCTs including patients with polycythemia vera (OR 7.39 [1.33, 41.07]) and in a pooled analysis of the extended phase IIIa RCTs (OR 5.20 [95%CI 1.27, 21.18]). In the larger phase IV post-marketing study, the incidence of the most frequent infections was 8% for herpes zoster, 6.1% for bronchitis and 6% for urinary tract infections. In the published case reports, the most frequent infections were tuberculosis (N = 10), hepatitis B reactivation (N = 5) and pneumocystis jeroveci infection (N = 2). Evidence is not solid enough to accurately estimate the risk of infection in ruxolitinib-treated patients. However, published data clearly suggest that the infection risk may be clinically relevant. Well-designed studies are warranted to evaluate the risk of ruxolitinib-associated infection, in order to identify the most appropriate antimicrobial prophylactic strategy.

Aspirin Plus Clopidogrel vs Aspirin Alone for Preventing Cardiovascular Events Among Patients at High Risk for Cardiovascular Events.

Clinical Question: Among patients at high risk for or with established cardiovascular disease (ie, history of peripheral artery disease, stroke, or coronary artery disease without a coronary stent), is the addition of clopidogrel to aspirin associated with lower risk of mortality and cardiovascular events compared with aspirin alone? Bottom Line: Clopidogrel plus aspirin is associated with a reduced risk for myocardial infarction and ischemic stroke and an increased risk for major bleeding compared with aspirin alone among patients at high risk for or with an established cardiovascular disease but without a coronary stent. However, combined therapy is not associated with lower mortality.

Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular events.

BACKGROUND: Aspirin is the prophylactic antiplatelet drug of choice for people with cardiovascular disease. Adding a second antiplatelet drug to aspirin may produce additional benefit for people at high risk and people with established cardiovascular disease. This is an update to a previously published review from 2011. OBJECTIVES: To review the benefit and harm of adding clopidogrel to aspirin therapy for preventing cardiovascular events in people who have coronary disease, ischaemic cerebrovascular disease, peripheral arterial disease, or were at high risk of atherothrombotic disease, but did not have a coronary stent. SEARCH METHODS: We updated the searches of CENTRAL (2017, Issue 6), MEDLINE (Ovid, 1946 to 4 July 2017) and Embase (Ovid, 1947 to 3 July 2017) on 4 July 2017. We also searched ClinicalTrials.gov and the WHO ICTRP portal, and handsearched reference lists. We applied no language restrictions. SELECTION CRITERIA: We included all randomised controlled trials comparing over 30 days use of aspirin plus clopidogrel with aspirin plus placebo or aspirin alone in people with coronary disease, ischaemic cerebrovascular disease, peripheral arterial disease, or at high risk of atherothrombotic disease. We excluded studies including only people with coronary drug-eluting stent (DES) or non-DES, or both. DATA COLLECTION AND ANALYSIS: We collected data on mortality from cardiovascular causes, all-cause mortality, fatal and non-fatal myocardial infarction, fatal and non-fatal ischaemic stroke, major and minor bleeding. The overall treatment effect was estimated by the pooled risk ratio (RR) with 95% confidence interval (CI), using a fixed-effect model (Mantel-Haenszel); we used a random-effects model in cases of moderate or severe heterogeneity (I2 ≥ 30%). We assessed the quality of the evidence using the GRADE approach. We used GRADE profiler (GRADE Pro) to import data from Review Manager to create a 'Summary of findings' table. MAIN RESULTS: The search identified 13 studies in addition to the two studies in the previous version of our systematic review. Overall, we included data from 15 trials with 33,970 people. We completed a 'Risk of bias' assessment for all studies. The risk of bias was low in four trials because they were at low risk of bias for all key domains (random sequence generation, allocation concealment, blinding, selective outcome reporting and incomplete outcome data), even if some of them were funded by the pharmaceutical industry.Analysis showed no difference in the effectiveness of aspirin plus clopidogrel in preventing cardiovascular mortality (RR 0.98, 95% CI 0.88 to 1.10; participants = 31,903; studies = 7; moderate quality evidence), and no evidence of a difference in all-cause mortality (RR 1.05, 95% CI 0.87 to 1.25; participants = 32,908; studies = 9; low quality evidence).There was a lower risk of fatal and non-fatal myocardial infarction with clopidogrel plus aspirin compared with aspirin plus placebo or aspirin alone (RR 0.78, 95% CI 0.69 to 0.90; participants = 16,175; studies = 6; moderate quality evidence). There was a reduction in the risk of fatal and non-fatal ischaemic stroke (RR 0.73, 95% CI 0.59 to 0.91; participants = 4006; studies = 5; moderate quality evidence).However, there was a higher risk of major bleeding with clopidogrel plus aspirin compared with aspirin plus placebo or aspirin alone (RR 1.44, 95% CI 1.25 to 1.64; participants = 33,300; studies = 10; moderate quality evidence) and of minor bleeding (RR 2.03, 95% CI 1.75 to 2.36; participants = 14,731; studies = 8; moderate quality evidence).Overall, we would expect 13 myocardial infarctions and 23 ischaemic strokes be prevented for every 1000 patients treated with the combination in a median follow-up period of 12 months, but 9 major bleeds and 33 minor bleeds would be caused during a median follow-up period of 10.5 and 6 months, respectively. AUTHORS' CONCLUSIONS: The available evidence demonstrates that the use of clopidogrel plus aspirin in people at high risk of cardiovascular disease and people with established cardiovascular disease without a coronary stent is associated with a reduction in the risk of myocardial infarction and ischaemic stroke, and an increased risk of major and minor bleeding compared with aspirin alone. According to GRADE criteria, the quality of evidence was moderate for all outcomes except all-cause mortality (low quality evidence) and adverse events (very low quality evidence).

How I treat splanchnic vein thrombosis.

Antithrombotic treatment of splanchnic vein thrombosis (SVT) is a clinical challenge. Depending on the site of thrombosis, patients are at risk of developing liver insufficiency, portal hypertension, or bowel infarction and may experience recurrence in both the splanchnic veins and other vein segments. To prevent recurrence, anticoagulant therapy should be started as soon as possible after diagnosis and is often continued for an indefinite period of time. However, active bleeding is not infrequent at the time of SVT diagnosis, and major risk factors for bleeding, such as esophageal varices or a low platelet count, are frequently present in these patients. In real-world clinical practice, a proportion of SVT patients are left untreated because the risks associated with anticoagulant therapy are felt to exceed its benefits. However, the majority of patients receive anticoagulant drugs, with heterogeneous timing of initiation, drug choice, and dosages. Evidence to drive treatment decisions is limited because no randomized controlled trials have been carried out in these patients. This review provides practical guidance for the use of anticoagulant drugs in patients presenting with SVT, including symptomatic as well as incidentally detected events.

Relationship between regulatory T cells subsets and lipid profile in dyslipidemic patients: a longitudinal study during atorvastatin treatment.

BACKGROUND: The CD4+ T-lymphocytes and their subtype CD4 + CD25(high)FoxP3+ regulatory T cells are receiving growing interest as major regulators of atherogenesis. We sought to investigate 1) whether the CD4 + cell subsets were expressed differently in dyslipidemic patients (Pts) and healthy subjects (HS) and 2) whether atorvastatin treatment could be associated in-vivo and in-vitro with cell changes in expression and functional response. METHODS: CD4+ subsets frequency (CD4 + CD25(high)FoxP3+, CD4 + CD25-FoxP3+) and mRNA expression for FoxP3, IL-10 and TGF-ß were evaluated in 30 consecutive Pts at baseline and after a 3-month atorvastatin therapy, and in 17 HS. RESULTS: The % of CD4 + cells did not differ between HS and Pts. The % of CD4 + CD25(high)FoxP3+ was higher in Pts than HS and did not change during treatment. The CD4 + CD25-FoxP3+ cells were similar between the two groups and were lower in Pts at visit 2. Cytokine expression and FoxP3 did not differ in HS and Pts and no substantial change was observed during treatment. At visit 1, CD4 + CD25(high)FoxP3+ cells were significantly correlated with both total-cholesterol (r = 0.570, P = 0.0002), LDL-cholesterol (r = 0.715, P = 0.0001), Apolipoprotein B (r = 0.590, P = 0.0001). In-vitro atorvastatin (up to 5 µM) failed to induce any significant modulation of cell functions. CONCLUSION: CD4 + CD25(high)FoxP3+ regulatory cells seem to be over-stimulated in the early pre-clinical phase of atherosclerosis and a relationship exists between their frequency and circulating lipids. A potential immuno-modulation by statin treatment is not achieved through a normalization in peripheral CD4 + cell subsets.

Gender Difference in Efficacy and Safety of Nonvitamin K Antagonist Oral Anticoagulants in Patients with Nonvalvular Atrial Fibrillation or Venous Thromboembolism: A Systematic Review and a Meta-Analysis of the Literature.

INTRODUCTION: Limited information exists on gender-related differences in the safety and efficacy of non-vitamin K antagonist oral anticoagulants (NOACs). AIM OF THE STUDY: To assess the safety and efficacy of direct oral anticoagulants (DOACs)/NOACs in men and women pooling data from randomized controlled trials on the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF) and on the acute and extended treatment of venous thromboembolism (VTE). METHODS: MEDLINE and EMBASE databases were searched up to June 2014. The efficacy outcome was defined as the prevention of stroke and systemic embolism (AF studies), or as the prevention of recurrent VTE or VTE-related death (VTE studies). The safety outcome was defined as the occurrence of major and/or clinically relevant non-major bleeding. Differences in the efficacy and safety outcomes were expressed as risk ratio (RR) with pertinent 95% confidence intervals (95% CI). RESULTS: A total of 13 studies (> 100,000 patients) were included. DOACs appeared to have a similar efficacy and safety compared with vitamin K antagonists in female and male patients treated for nonvalvular AF and acute VTE. In the extended treatment of VTE NOACs had a RR of bleeding of 4.97 (95% CI 1.06, 23.41) in males and 1.33 (95% CI 0.63, 2.83) in females compared with placebo (subgroup difference chi-square test: 2.25, p = 0.13). CONCLUSIONS: No gender-related difference in the efficacy and safety of NOACs in patients with AF or acute VTE was found. A trend toward an increased risk of bleeding in male patients as compared with female patients was detected in the extended treatment of VTE.

Association between the metabolic syndrome, its individual components, and unprovoked venous thromboembolism: results of a patient-level meta-analysis.

OBJECTIVE: The metabolic syndrome (MetS) may contribute to the pathogenesis of venous thromboembolism (VTE), but this association requires additional investigation. APPROACH AND RESULTS: We performed a patient-level meta-analysis of case-control and cohort studies that evaluated the role of MetS and risk of unprovoked VTE. For case-control studies, odds ratios and 95% confidence intervals were calculated using logistic regression analysis to estimate the influence of individual variables on the risk of VTE; χ(2) tests for trend were used to investigate the effect of increasing number of components of MetS on the risk of VTE and to explore the influence of abdominal obesity on this relationship. For cohort studies, hazard ratios and 95% confidence interval were calculated using multivariable Cox regression analysis. Six case-control studies were included (908 cases with unprovoked VTE and 1794 controls): in multivariate analysis, MetS was independently associated with VTE (odds ratio, 1.91; 95% confidence interval, 1.57-2.33), and both MetS and abdominal obesity were better predictors of unprovoked VTE than obesity defined by the body mass index. Two prospective cohort studies were included (26,531 subjects and 289 unprovoked VTE events): age, obesity, and abdominal obesity, but not MetS were associated with VTE. CONCLUSIONS: Case-control but not prospective cohort studies support an association between MetS and VTE. Abdominal adiposity is a strong risk factor for VTE.