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Non-vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Patients with Atrial Fibrillation and Liver Disease: A Meta-Analysis and Systematic Review.
Fu, Y, Zhu, W, Zhou, Y, Chen, H, Yan, L, He, W
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2020;(2):139-147
Abstract
BACKGROUND The effect of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) and liver disease remains largely unresolved. Therefore, we performed a meta-analysis to compare the efficacy and safety of NOACs with warfarin in this population. METHODS We systematically searched the Cochrane Library, PubMed, and Embase databases for studies reporting the comparisons of NOACs with warfarin in patients with AF and liver disease. A random-effects model was selected to pool the risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS A total of six studies with 41,954 participants were included in this meta-analysis. In AF patients with liver disease, compared with warfarin use, the use of NOACs was associated with reduced risks of all-cause death (RR 0.78, 95% CI 0.66-0.93), major bleeding (RR 0.68, 95% CI 0.53-0.88), and intracranial hemorrhage (RR 0.49, 95% CI 0.41-0.59), but had comparable risks of stroke or system embolism (RR 0.80, 95% CI 0.57-1.12) and gastrointestinal bleeding (RR 0.90, 95% CI 0.61-1.34). In AF patients with cirrhosis, NOACs significantly reduced the risks of major bleeding (RR 0.53, 95% CI 0.37-0.76), gastrointestinal bleeding (RR 0.57, 95% CI 0.38-0.84), and intracranial hemorrhage (RR 0.55, 95% CI 0.31-0.97) compared with warfarin. CONCLUSIONS Based on current publications, the use of NOACs is at least non-inferior to warfarin in patients with AF and liver disease.
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Real-world use of nonvitamin K antagonist oral anticoagulant in atrial fibrillation patients with liver disease: A meta-analysis.
Dai, Q, Deng, X, Zhou, L, Zhang, L, Xiao, X, Liao, Y
Clinical cardiology. 2020;(7):676-683
Abstract
Several studies have investigated the effectiveness and safety of nonvitamin K antagonist oral anticoagulants (NOACs) vs vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and liver disease. Herein, we conducted a meta-analysis to compare the effect of NOACs with VKAs in patients with AF and liver disease. We also conducted a subsidiary analysis to compare the risk of liver injury between NOACs and VKA in AF patients. We systematically searched the PubMed and Embase databases from January 2009 to May 2020 for the relevant studies. Hazard ratios (HRs) with 95% confidence intervals (CIs) were selected and pooled using a random-effects model. A total of six cohorts were included. Compared with VKA use, the use of NOACs was associated with reduced risks of stroke or systemic embolism (HR 0.68, 95% CI 0.49-0.93), all-cause death (HR 0.69, 95% CI 0.63-0.75), and intracranial bleeding (HR 0.49, 95% CI 0.40-0.59), whereas the outcomes of major bleeding (HR 0.72, 95% CI 0.51-1.01) and gastrointestinal bleeding (HR 0.84, 95% CI 0.51-1.36) were not significantly different between groups in AF patients with liver disease. Moreover, compared with VKA use, the use of NOACs was associated with a reduced risk of liver injury (HR 0.72, 95% CI 0.61-0.84) in AF patients. Compared with VKAs, the use of NOACs was associated with reduced risks of stroke or systemic embolism, all-cause death, and intracranial bleeding in AF patients with liver disease, and associated with a reduced risk of liver injury in AF patients.
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Platelet count, spleen length, and platelet count-to-spleen length ratio for the diagnosis of oesophageal varices in people with chronic liver disease or portal vein thrombosis.
Colli, A, Gana, JC, Yap, J, Adams-Webber, T, Rashkovan, N, Ling, SC, Casazza, G
The Cochrane database of systematic reviews. 2017;(4):CD008759
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Abstract
BACKGROUND Current guidelines recommend screening of people with oesophageal varices via oesophago-gastro-duodenoscopy at the time of diagnosis of hepatic cirrhosis. This requires that people repeatedly undergo unpleasant invasive procedures with their attendant risks, although half of these people have no identifiable oesophageal varices 10 years after the initial diagnosis of cirrhosis. Platelet count, spleen length, and platelet count-to-spleen length ratio are non-invasive tests proposed as triage tests for the diagnosis of oesophageal varices. OBJECTIVES Primary objectives To determine the diagnostic accuracy of platelet count, spleen length, and platelet count-to-spleen length ratio for the diagnosis of oesophageal varices of any size in paediatric or adult patients with chronic liver disease or portal vein thrombosis, irrespective of aetiology. To investigate the accuracy of these non-invasive tests as triage or replacement of oesophago-gastro-duodenoscopy. Secondary objectives To compare the diagnostic accuracy of these same tests for the diagnosis of high-risk oesophageal varices in paediatric or adult patients with chronic liver disease or portal vein thrombosis, irrespective of aetiology.We aimed to perform pair-wise comparisons between the three index tests, while considering predefined cut-off values.We investigated sources of heterogeneity. SEARCH METHODS The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic Test Accuracy Studies Register, the Cochrane Library, MEDLINE (OvidSP), Embase (OvidSP), and Science Citation Index - Expanded (Web of Science) (14 June 2016). We applied no language or document-type restrictions. SELECTION CRITERIA Studies evaluating the diagnostic accuracy of platelet count, spleen length, and platelet count-to-spleen length ratio for the diagnosis of oesophageal varices via oesophago-gastro-duodenoscopy as the reference standard in children or adults of any age with chronic liver disease or portal vein thrombosis, who did not have variceal bleeding. DATA COLLECTION AND ANALYSIS Standard Cochrane methods as outlined in the Cochrane Handbook for Diagnostic Test of Accuracy Reviews. MAIN RESULTS We included 71 studies, 67 of which enrolled only adults and four only children. All included studies were cross-sectional and were undertaken at a tertiary care centre. Eight studies reported study results in abstracts or letters. We considered all but one of the included studies to be at high risk of bias. We had major concerns about defining the cut-off value for the three index tests; most included studies derived the best cut-off values a posteriori, thus overestimating accuracy; 16 studies were designed to validate the 909 (n/mm3)/mm cut-off value for platelet count-to-spleen length ratio. Enrolment of participants was not consecutive in six studies and was unclear in 31 studies. Thirty-four studies assessed enrolment consecutively. Eleven studies excluded some included participants from the analyses, and in only one study, the time interval between index tests and the reference standard was longer than three months. Diagnosis of varices of any size. Platelet count showed sensitivity of 0.71 (95% confidence interval (CI) 0.63 to 0.77) and specificity of 0.80 (95% CI 0.69 to 0.88) (cut-off value of around 150,000/mm3 from 140,000 to 150,000/mm3; 10 studies, 2054 participants). When examining potential sources of heterogeneity, we found that of all predefined factors, only aetiology had a role: studies including participants with chronic hepatitis C reported different results when compared with studies including participants with mixed aetiologies (P = 0.036). Spleen length showed sensitivity of 0.85 (95% CI 0.75 to 0.91) and specificity of 0.54 (95% CI 0.46 to 0.62) (cut-off values of around 110 mm, from 110 to 112.5 mm; 13 studies, 1489 participants). Summary estimates for detection of varices of any size showed sensitivity of 0.93 (95% CI 0.83 to 0.97) and specificity of 0.84 (95% CI 0.75 to 0.91) in 17 studies, and 2637 participants had a cut-off value for platelet count-to-spleen length ratio of 909 (n/mm3)/mm. We found no effect of predefined sources of heterogeneity. An overall indirect comparison of the HSROCs of the three index tests showed that platelet count-to-spleen length ratio was the most accurate index test when compared with platelet count (P < 0.001) and spleen length (P < 0.001). Diagnosis of varices at high risk of bleeding. Platelet count showed sensitivity of 0.80 (95% CI 0.73 to 0.85) and specificity of 0.68 (95% CI 0.57 to 0.77) (cut-off value of around 150,000/mm3 from 140,000 to 160,000/mm3; seven studies, 1671 participants). For spleen length, we obtained only a summary ROC curve as we found no common cut-off between studies (six studies, 883 participants). Platelet count-to-spleen length ratio showed sensitivity of 0.85 (95% CI 0.72 to 0.93) and specificity of 0.66 (95% CI 0.52 to 0.77) (cut-off value of around 909 (n/mm3)/mm; from 897 to 921 (n/mm3)/mm; seven studies, 642 participants). An overall indirect comparison of the HSROCs of the three index tests showed that platelet count-to-spleen length ratio was the most accurate index test when compared with platelet count (P = 0.003) and spleen length (P < 0.001). DIagnosis of varices of any size in children. We found four studies including 277 children with different liver diseases and or portal vein thrombosis. Platelet count showed sensitivity of 0.71 (95% CI 0.60 to 0.80) and specificity of 0.83 (95% CI 0.70 to 0.91) (cut-off value of around 115,000/mm3; four studies, 277 participants). Platelet count-to-spleen length z-score ratio showed sensitivity of 0.74 (95% CI 0.65 to 0.81) and specificity of 0.64 (95% CI 0.36 to 0.84) (cut-off value of 25; two studies, 197 participants). AUTHORS' CONCLUSIONS Platelet count-to-spleen length ratio could be used to stratify the risk of oesophageal varices. This test can be used as a triage test before endoscopy, thus ruling out adults without varices. In the case of a ratio > 909 (n/mm3)/mm, the presence of oesophageal varices of any size can be excluded and only 7% of adults with varices of any size would be missed, allowing investigators to spare the number of oesophago-gastro-duodenoscopy examinations. This test is not accurate enough for identification of oesophageal varices at high risk of bleeding that require primary prophylaxis. Future studies should assess the diagnostic accuracy of this test in specific subgroups of patients, as well as its ability to predict variceal bleeding. New non-invasive tests should be examined.
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Nutritional support for liver disease.
Koretz, RL, Avenell, A, Lipman, TO
The Cochrane database of systematic reviews. 2012;(5):CD008344
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Abstract
BACKGROUND Weight loss and muscle wasting are commonly found in patients with end-stage liver disease. Since there is an association between malnutrition and poor clinical outcome, such patients (or those at risk of becoming malnourished) are often given parenteral nutrition, enteral nutrition, or oral nutritional supplements. These interventions have costs and adverse effects, so it is important to prove that their use results in improved morbidity or mortality, or both. OBJECTIVES To assess the beneficial and harmful effects of parenteral nutrition, enteral nutrition, and oral nutritional supplements on the mortality and morbidity of patients with underlying liver disease. SEARCH METHODS The following computerised databases were searched: the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, and Science Citation Index Expanded (January 2012). In addition, reference lists of identified trials and review articles and Clinicaltrials.gov were searched. Trials identified in a previous systematic handsearch of Index Medicus were also considered. Handsearches of a number of medical journals, including abstracts from annual meetings, were done. Experts in the field and manufacturers of nutrient formulations were contacted for potential references. SELECTION CRITERIA Randomised clinical trials (parallel or cross-over design) comparing groups of patients with any underlying liver disease who received, or did not receive, enteral or parenteral nutrition or oral nutritional supplements were identified without restriction on date, language, or publication status. Six categories of trials were separately considered: medical or surgical patients receiving parenteral nutrition, enteral nutrition, or supplements. DATA COLLECTION AND ANALYSIS The following data were sought in each report: date of publication; geographical location; inclusion and exclusion criteria; the type of nutritional support and constitution of the nutrient formulation; duration of treatment; any nutrition provided to the controls; other interventions provided to the patients; number, sex, age of the study participants; hospital or outpatient status; underlying liver disease; risks of bias (sequence generation, allocation concealment, blinding, incomplete outcome reporting, intention-to-treat analysis, selective outcome reporting, others (vested interests, baseline imbalance, early stopping)); mortality; hepatic morbidity (development or resolution of ascites or hepatic encephalopathy, occurrence of gastrointestinal bleeding); quality of life scores; adverse events; infections; lengths of stay in the hospital or intensive care unit; costs; serum bilirubin; postoperative complications (surgical trials only); and nutritional outcomes (nitrogen balance, anthropometric measurements, body weight). The primary outcomes of this review were mortality, hepatic morbidity, quality of life, and adverse events. Data were extracted in duplicate; differences were resolved by consensus.Data for each outcome were combined in a meta-analysis (RevMan 5.1). Estimates were reported using risk ratios or mean differences, along with the 95% confidence intervals (CI). Both fixed-effect and random-effects models were employed; fixed-effect models were reported unless one model, but not the other, found a significant difference (in which case both were reported). Heterogeneity was assessed by the Chi(2) test and I(2) statistic. Subgroup analyses were planned to assess specific liver diseases (alcoholic hepatitis, cirrhosis, hepatocellular carcinoma), acute or chronic liver diseases, and trials employing standard or branched-chain amino acid formulations (for the hepatic encephalopathy outcomes). Sensitivity analyses were planned to compare trials at low and high risk of bias and trials reported as full papers. The following exploratory analyses were undertaken: 1) medical and surgical trials were combined for each nutritional intervention; 2) intention-to-treat analyses in which missing dichotomous data were imputed as best- and worst-case scenarios; 3) all trials were combined to assess mortality; 4) effects were estimated by absolute risk reductions. MAIN RESULTS Thirty-seven trials were identified; only one was at low risk of bias. Most of the analyses failed to find any significant differences. The significant findings that were found were the following: 1) icteric medical patients receiving parenteral nutrition had a reduced serum bilirubin (mean difference (MD) -2.86 mg%, 95% CI -3.82 mg% to -1.89 mg%, 3 trials) and better nitrogen balance (MD 3.60 g/day, 95% CI 0.86 g/day to 6.34 g/day, 1 trial); 2) surgical patients receiving parenteral nutrition had a reduced incidence of postoperative ascites only in the fixed-effect model (RR 0.65, 95% CI 0.48 to 0.87, 2 trials, I(2) = 70%) and one trial demonstrated a reduction in postoperative complications, especially infections (pneumonia in particular); 3) enteral nutrition may have improved nitrogen balance in medical patients (although a combination of the three trials was not possible); 4) one surgical trial of enteral nutrition found a reduction in postoperative complications; and 5) oral nutritional supplements had several effects in medical patients (reduced occurrence of ascites (RR 0.57, 95% CI 0.37 to 0.88, 3 trials), possibly (significant differences only seen in the fixed-effect model) reduced rates of infection (RR 0.49, 95% CI 0.24 to 0.99, 3 trials, I(2) = 14%), and improved resolution of hepatic encephalopathy (RR 3.75, 95% CI 1.15 to 12.18, 2 trials, I(2) = 79%). While there was no overall effect of the supplements on mortality in medical patients, the one low risk of bias trial found an increased risk of death in the recipients of the supplements. Three trials of supplements in surgical patients failed to show any significant differences. No new information was derived from the various subgroup or sensitivity analyses. The exploratory analyses were also unrevealing except for a logical conundrum. There was no difference in mortality when all of the trials were combined, but the trials of parenteral nutrition found that those recipients had better survival (RR 0.53, 95% CI 0.29 to 0.98, 10 trials). Either the former observation represents a type II error or the latter one a type I error. AUTHORS' CONCLUSIONS The data do not compellingly justify the routine use of parenteral nutrition, enteral nutrition, or oral nutritional supplements in patients with liver disease. The fact that all but one of these trials were at high risks of bias even casts doubt on the few benefits that were demonstrated. Data from well-designed and executed randomised trials that include an untreated control group are needed before any such recommendation can be made. Future trials have to be powered adequately to see small, but clinically important, differences.
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5.
Meta-analysis: Coeliac disease and hypertransaminasaemia.
Sainsbury, A, Sanders, DS, Ford, AC
Alimentary pharmacology & therapeutics. 2011;(1):33-40
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Abstract
BACKGROUND There may be a positive association between coeliac disease and serum hypertransaminasaemia but evidence is conflicting. AIMS To conduct a systematic review and meta-analysis to determine the prevalence of coeliac disease in adults presenting with cryptogenic serum hypertransaminasaemia and the prevalence of hypertransaminasaemia in patients with newly diagnosed coeliac disease. METHODS MEDLINE and EMBASE were searched up to August 2010. Case series and case-control studies recruiting adults with either cryptogenic hypertransaminasaemia that applied serological tests for coeliac disease and/or distal duodenal biopsy to participants or newly diagnosed biopsy-proven coeliac disease that assessed serum transaminases were eligible. The pooled prevalence of coeliac disease in individuals presenting with abnormal serum transaminases and the pooled prevalence of hypertransaminasaemia in newly diagnosed coeliac disease were calculated with 95% confidence intervals (CI). RESULTS Eleven eligible studies were identified. Pooled prevalences of positive coeliac serology and biopsy-proven coeliac disease in cryptogenic hypertransaminasaemia were 6% (95% CI 3% to 10%) and 4% (95% CI 1% to 7%) respectively. Pooled prevalence of abnormal serum transaminases in newly diagnosed coeliac disease was 27% (95% CI 13% to 44%). Exclusion of gluten led to normalisation of serum transaminase levels in 63% to 90% of patients within 1 year. CONCLUSIONS Undetected coeliac disease is a potential cause for cryptogenic hypertransaminasaemia in 3% to 4% of cases. More than 20% of individuals with newly diagnosed coeliac disease may have abnormal serum transaminases and these normalise on a gluten-free diet in the majority of cases.
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Meta-analysis: antioxidant supplements for liver diseases - the Cochrane Hepato-Biliary Group.
Bjelakovic, G, Gluud, LL, Nikolova, D, Bjelakovic, M, Nagorni, A, Gluud, C
Alimentary pharmacology & therapeutics. 2010;(3):356-67
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Abstract
BACKGROUND Several liver diseases have been associated with oxidative stress. Accordingly, antioxidants have been suggested as potential therapeutics for various liver diseases. The evidence supporting these suggestions is equivocal. AIM: To assess the benefits and harms of antioxidant supplements for patients with liver diseases. METHODS We identified trials through electronic and manual searches until August 2009. We included randomized trials comparing antioxidant supplements (beta-carotene, vitamin A, C, E and selenium) vs. placebo or no intervention for autoimmune liver diseases, viral hepatitis, alcoholic liver disease and cirrhosis (any aetiology). Random-effects and fixed-effect meta-analyses were conducted. Results were presented as relative risks (RR), or mean difference (MD), both with 95% confidence intervals (CI). RESULTS Twenty randomized trials with 1225 participants were included. The trials assessed beta-carotene (3 trials), vitamin A (2 trials), vitamin C (9 trials), vitamin E (15 trials) and selenium (8 trials). The majority of the trials had high risk of bias and showed heterogeneity. Overall, the assessed antioxidant supplements had no significant effect on all-cause mortality [relative risk (RR) 0.84, 95% confidence interval (CI) 0.60-1.19, I(2) = 0%] or liver-related mortality (RR 0.89, 95% CI 0.39-2.05, I(2) = 37%). Stratification according to the type of liver disease assessed did not affect the conclusions. Antioxidant supplements significantly increased the activity of gamma glutamyl transpeptidase (MD 24.21 IU/L, 95% CI 6.67-41.75, I(2) = 0%). CONCLUSIONS We found no evidence to support or refute antioxidant supplements in patients with liver disease. Antioxidant supplements may increase liver enzymes.
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Safety and efficacy of Mangafodipir trisodium in patients with liver lesions and cirrhosis.
Martí-Bonmatí, L, Fog, AF, de Beeck, BO, Kane, P, Fagertun, H
European radiology. 2003;(7):1685-92
Abstract
Mangafodipir trisodium (Mn-DPDP, Teslascan) is a well-tolerated liver contrast agent. Although the enhancement characteristics of the cirrhotic liver after Mangafodipir trisodium administration have been studied, at present there is no published data on the impact that cirrhosis might have on the safety and efficacy profiles of this agent. Our objective is to evaluate by means of a retrospective comparison the safety and efficacy of Mangafodipir trisodium in patients with underlying cirrhosis who were examined for suspicion of focal liver lesions. A total of 923 patients received Mangafodipir trisodium (5 micromol/kg) in 11 prospective randomized European clinical trials. Adverse events and discomfort were recorded and graded in all patients. The efficacy analyses were performed on the subsets consisting of 617 patients with independent lesion counts (detection), and on the subset with 399 patients with independent and onsite final lesion diagnosis (characterization). Of the 399 patients, 149 had histologic confirmation. One hundred eighty of 923 patients (19.5%) had cirrhosis. There were no main differences between cirrhotic and non-cirrhotic patients. Adverse events were observed in 64 patients (6.9%), 6.7% in the cirrhotic group and 7.0% in the non-cirrhotic group, a non-significant difference. Adverse events in most patients were mild or moderate. The presence and intensity of the events did not differ between groups. Discomfort was recorded in 79 patients (8.6%), equally distributed in cirrhotic (6.1%) and non-cirrhotic (9.2%) patients. Regarding lesion count, significantly more lesions were found in the post- than in the precontrast images in both the cirrhotic and non-cirrhotic groups ( p<0.0001). This increase was not influenced by the presence of liver cirrhosis ( p=0.94). Lesion characterization was significantly improved in cirrhotic patients after administration of Mangafodipir trisodium ( p=0.002) but not in non-cirrhotic patients ( p=0.13). Mangafodipir trisodium is a safe and well-tolerated useful contrast agent in patients with cirrhosis.