Effect of the EndoBarrier Gastrointestinal Liner on obesity and type 2 diabetes: a systematic review and meta-analysis.

Compared with bariatric surgery, less invasive and reversible techniques to counteract obesity and type 2 diabetes (T2D) have been developed, including the EndoBarrier Gastrointestinal Liner [duodenal-jejunal bypass sleeve (DJBS)]. We conducted a systematic review and meta-analyses of eligible trials to evaluate the efficacy and safety of the DJBS. Five randomized controlled trials (RCTs; 235 subjects) and 10 observational studies (211 subjects) were included. The risk of bias was evaluated as high in all studies. The mean body mass index ranged from 30 to 49.2 kg/m(2) and 10-100% of the subjects had T2D. Meta-analysis showed that the DJBS was associated with significant mean differences in body weight and excess weight loss of -5.1 kg [95% confidence interval (CI) -7.3, -3.0; four trials; n = 151; I(2) = 37%] and 12.6% (95% CI 9.0, 16.2; four trials; n = 166; I(2) = 24%), respectively, compared with diet modification. The mean differences in glycated haemoglobin (-0.9%; 95% CI -1.8, 0.0) and fasting plasma glucose (-3.7 mM; 95% CI -8.2, 0.8) among subjects with T2D did not reach statistical significance. Adverse events consisted mainly of abdominal pain, nausea and vomiting. No deaths occurred. Future high-quality long-term RCTs are needed to further assess efficacy and safety.

The single-dose pharmacokinetics of alitretinoin and its metabolites are not significantly altered in patients with cirrhosis.

BACKGROUND: Alitretinoin (9-cis-retinoic acid, Toctino(®) ) has been marketed recently for oral therapy for chronic hyperkeratotic hand eczema. As alitretinoin is highly lipophilic and metabolized mainly in the liver, it is currently considered to be contraindicated in patients with liver disease. However, the pharmacokinetics and metabolism of alitretinoin have not been studied in these patients. OBJECTIVES: To study the single-dose pharmacokinetics and metabolism of alitretinoin and its metabolites in patients with cirrhosis following oral administration. METHODS: Eight patients with cirrhosis and eight matched volunteer healthy controls were given a single 30-mg oral dose of alitretinoin. Blood and urine samples were collected during the following 24-h study period. Samples were analysed for alitretinoin and for known metabolites using reverse-phase high-performance liquid chromatography. The pharmacokinetics were then evaluated using standard noncompartmental models. RESULTS: No significant differences were found between healthy controls and patients with cirrhosis when analysing the pharmacokinetic parameters of alitretinoin and its metabolites. Thus, the mean half-lives of alitretinoin were 5·3 and 5·6 h (P = 0.733) and the oral clearances were 1·92 and 1·39 L h(-1) kg(-1) (P = 0·243) in the patient group and the healthy control group, respectively. CONCLUSIONS: The metabolism and pharmacokinetics of alitretinoin following oral administration of the recommended dose of 30 mg for the treatment of severe hand eczema were similar in patients with cirrhosis and in healthy controls. If indicated, alitretinoin can be used in these patients with careful and close monitoring.

Secretion of glucagon-like peptide-1 in patients with type 2 diabetes mellitus: systematic review and meta-analyses of clinical studies.

AIMS/HYPOTHESIS: We carried out a systematic review of clinical studies investigating glucagon-like peptide-1 (GLP-1) secretion in patients with type 2 diabetes and non-diabetic controls and performed meta-analyses of plasma total GLP-1 concentrations during an OGTT and/or meal test. METHODS: Random effects models for the primary meta-analysis and random effects meta-regression, subgroup and regression analyses were applied. RESULTS: Random effects meta-analysis of GLP-1 responses in 22 trials during 29 different stimulation tests showed that patients with type 2 diabetes (n = 275) and controls without type 2 diabetes (n = 279) exhibited similar responses of total GLP-1 (p = NS) as evaluated from peak plasma concentrations (weighted mean difference [95% CI] 1.09 pmol/l [-2.50, 4.67]), total AUC (tAUC) (159 pmol/l × min [-270, 589]), time-corrected tAUC (tAUC min⁻¹) (0.99 pmol/l [-1.28, 3.27]), incremental AUC (iAUC) (-122 pmol/l × min [-410, 165]) and time-corrected iAUC (iAUC min⁻¹) (-0.49 pmol/l [-2.16, 1.17]). Fixed effects meta-analysis revealed higher peak plasma GLP-1 concentrations in patients with type 2 diabetes. Subgroup analysis showed increased responses after a liquid mixed meal test (peak, tAUC and tAUC min⁻¹) and after a 50 g OGTT (AUC and tAUC min⁻¹), and reduced responses after a solid mixed meal test (tAUC min⁻¹) among patients with type 2 diabetes. Meta-regression analyses showed that HbA1c and fasting plasma glucose predicted the outcomes iAUC and iAUC min⁻¹, respectively. CONCLUSIONS/INTERPRETATION: The present analysis suggests that patients with type 2 diabetes, in general, do not exhibit reduced GLP-1 secretion in response to an OGTT or meal test, and that deteriorating glycaemic control may be associated with reduced GLP-1 secretion.

Umbilical hernia repair in patients with cirrhosis: systematic review of mortality and complications.

BACKGROUND: Umbilical hernia is a common and potential serious condition in patients with cirrhosis. This systematic review evaluated the risks associated with emergency and elective hernia repair in patients with cirrhosis. METHODS: Systematic review of clinical trials identified through manual and electronic searches in several databases (last update November 2021). The primary random-effects meta-analyses evaluated mortality in patients with or without cirrhosis or following emergency versus elective repair. The quality of the evidence was assessed using GRADE and Newcastle Ottawa Scale. RESULTS: Thirteen prospective and 10 retrospective studies including a total of 3229 patients were included. The evidence was graded as very low quality for all outcomes (mortality and postoperative complications within 90 days). In total 191 patients (6%) died after undergoing umbilical hernia repair. Patients with cirrhosis were more than eight times as likely to die after surgery compared with patients without cirrhosis [OR = 8.50, 95% CI (1.91-37.86)] corresponding to 69 more deaths/1000 patients. Among patients with cirrhosis, mortality was higher after emergency versus elective repair [OR = 2.67, 95% CI (1.87-3.97)] corresponding to 52 more deaths/1000 patients. Postoperative complications were more common in patients with cirrhosis compared with patients without cirrhosis. CONCLUSION: Patients with cirrhosis undergoing emergency umbilical hernia repair have a considerably increased risk of death and severe complications. Accordingly, additional evidence is needed to evaluate methods that would allow elective umbilical hernia repair in patients with cirrhosis.

Lower Risk of Recurrence After Mesh Repair Versus Non-Mesh Sutured Repair in Open Umbilical Hernia Repair: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND AIMS: The use of mesh repair in a small- or middle-sized umbilical hernia remains controversial, and evidence is based on only few and small heterogeneous randomized trials. The primary aim was to assess differences, if any, in recurrence (clinical and reoperation), and secondary aim was to assess differences in infections, seroma formation, hematomas, chronic pain, cosmetic result, and quality of life. METHOD: A systematic review (predefined search strategy) and meta-analyses were conducted based on pre-study strict and well-defined methodology. The literature search was completed on 1 January 2018. The study protocol was registered in PROSPERO. RESULTS: Five randomized controlled trials were identified (mesh repair, n = 326 versus non-mesh sutured repair, n = 330) and 602 records were excluded. Randomized controlled trials included patients with defect diameters of ⩾1 to 4 cm. Mesh repair reduced the risk of recurrence compared with sutured repair with a relative risk of 0.28 (95% confidence interval = 0.13-0.58, I2 = 0%, number needed to treat = 13 patients). Additional analyses found no differences between the two surgical techniques regarding infection (relative risk = 0.80, 95% confidence interval = 0.36-1.79), seroma formation (relative risk = 1.38, 95% confidence interval = 0.57-3.32), or hematomas (relative risk = 0.55, 95% confidence interval = 0.23-1.30). Lack of sufficient data precluded meta-analysis evaluating risk of seroma formation, hematomas, chronic pain, cosmetic result, and quality of life. CONCLUSION: Mesh repair is recommended for umbilical hernia of ⩾1 to 4 cm. More evidence is needed for the optimal placement of the mesh (sublay or onlay) and the role of mesh in patients with an umbilical hernia <1 cm.

Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases.

BACKGROUND: Animal and physiological research as well as observational studies suggest that antioxidant supplements may improve survival. OBJECTIVES: To assess the effect of antioxidant supplements on mortality in primary or secondary prevention randomised clinical trials. SEARCH STRATEGY: We searched The Cochrane Library (Issue 3, 2005), MEDLINE (1966 to October 2005), EMBASE (1985 to October 2005), and the Science Citation Index Expanded (1945 to October 2005). We scanned bibliographies of relevant publications and wrote to pharmaceutical companies for additional trials. SELECTION CRITERIA: We included all primary and secondary prevention randomised clinical trials on antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention. Included participants were either healthy (primary prevention trials) or had any disease (secondary prevention trials). DATA COLLECTION AND ANALYSIS: Three authors extracted data. Trials with adequate randomisation, blinding, and follow-up were classified as having a low risk of bias. Random-effects and fixed-effect meta-analyses were performed. Random-effects meta-regression analyses were performed to assess sources of intertrial heterogeneity. MAIN RESULTS: Sixty-seven randomised trials with 232,550 participants were included. Forty-seven trials including 180,938 participants had low risk of bias. Twenty-one trials included 164,439 healthy participants. Forty-six trials included 68111 participants with various diseases (gastrointestinal, cardiovascular, neurological, ocular, dermatological, rheumatoid, renal, endocrinological, or unspecified). Overall, the antioxidant supplements had no significant effect on mortality in a random-effects meta-analysis (relative risk [RR] 1.02, 95% confidence interval [CI] 0.99 to 1.06), but significantly increased mortality in a fixed-effect model (RR 1.04, 95% CI 1.02 to 1.06). In meta-regression analysis, the risk of bias and type of antioxidant supplement were the only significant predictors of intertrial heterogeneity. In the trials with a low risk of bias, the antioxidant supplements significantly increased mortality (RR 1.05, 95% CI 1.02 to 1.08). When the different antioxidants were assessed separately, analyses including trials with a low risk of bias and excluding selenium trials found significantly increased mortality by vitamin A (RR 1.16, 95% CI 1.10 to 1.24), beta-carotene (RR 1.07, 95% CI 1.02 to 1.11), and vitamin E (RR 1.04, 95% CI 1.01 to 1.07), but no significant detrimental effect of vitamin C (RR 1.06, 95% CI 0.94 to 1.20). Low-bias risk trials on selenium found no significant effect on mortality (RR 0.91, 95% CI 0.76 to 1.09). AUTHORS' CONCLUSIONS: We found no evidence to support antioxidant supplements for primary or secondary prevention. Vitamin A, beta-carotene, and vitamin E may increase mortality. Future randomised trials could evaluate the potential effects of vitamin C and selenium for primary and secondary prevention. Such trials should be closely monitored for potential harmful effects. Antioxidant supplements need to be considered medicinal products and should undergo sufficient evaluation before marketing.

Systematic review and meta-analysis: assessment of factors affecting disability in inflammatory bowel disease and the reliability of the inflammatory bowel disease disability index.

BACKGROUND: The Inflammatory Bowel Disease Disability Index (IBD-DI) has recently been developed for patients with Crohn's disease (CD) and ulcerative colitis (UC). AIM: To assess the severity of disability and associated factors using the IBD-DI, and review the validity of the IBD-DI as a tool. METHOD: Systematic review of cross-sectional studies. Patients included had UC or CD and were classified as active, in remission, or needing surgery, biological and/or steroid treatment. We included studies assessing disability using the IBD-DI and that were captured by electronic and manual searches (January 2017). The possibility of bias was evaluated with the Newcastle-Ottawa Scale. RESULTS: Nine studies were included with 3167 patients. Comparatively, patients with active disease had higher disability rates than those in remission (SMD [CI95] = 1.49[1.11, 1.88], I2  = 94%, P<.01), while patients on biological treatment had lower disability rates than those receiving corticosteroid treatment (SMD [CI95] = -0.22[-0.36, -0.08], I2  = 0%, P<.01). Disease activity and unemployment were found to be associated factors. The IBD-DI scored "good" for internal consistency, "fair" to "excellent" for intra-rater reliability and "excellent" for inter-rater reliability. Construct validity was "moderately strong" to "very strong" and structural validity was found to be mainly unidimensional. The IBD-DI had excellent responsiveness, while its interpretability was only useful on a group level. CONCLUSIONS: This systematic review and meta-analysis found a significant association between disease activity, treatment received and disability; although significant heterogeneity was found. The IBD-DI is reliable and valid, but further studies are needed to measure its interpretability.

Cochrane systematic review: pegylated interferon plus ribavirin vs. interferon plus ribavirin for chronic hepatitis C.

BACKGROUND: About 170 million patients worldwide have chronic hepatitis C. Pegylated interferon plus ribavirin is currently the recommended therapy. AIM: To evaluate the beneficial and harmful effects of pegylated interferon plus ribavirin vs. interferon plus ribavirin for chronic hepatitis C infection. METHODS: We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, Science Citation Index Expanded and contacted pharmaceutical companies and authors of trials (to March 2005). RESULTS: We included 18 randomized clinical trials with 4811 patients. Eleven trials (61%) had allocation bias risks and all had assessment bias risk because of lack of blinding. Compared with interferon plus ribavirin, pegylated interferon plus ribavirin had significant beneficial effects on sustained virological response [risk ratio (RR): 0.80; 95% CI: 0.74-0.88]. Data were insufficient to determine impact on long-term outcomes. Pegylated interferon plus ribavirin significantly increased dose reductions (RR: 1.44; 95% CI: 1.14-1.82) and adverse events including neutropenia (RR: 2.25; 95% CI: 1.58-3.21), thrombocytopenia (RR: 2.28; 95% CI: 1.14-4.54), arthralgia (RR: 1.19; 95% CI: 1.05-1.35), and injection-site reaction (RR: 2.56; 95% CI: 1.06-6.22). CONCLUSIONS: Pegylated interferon plus ribavirin compared with interferon plus ribavirin increased the proportion of patients with sustained virological response, but at the cost of more adverse events.

WITHDRAWN: Ribavirin with or without alpha interferon for chronic hepatitis C.

BACKGROUND: Hepatitis C is a major cause of liver-related morbidity and mortality. Ribavirin plus interferon combination therapy is presently considered the optimal treatment of interferon naive patients with chronic hepatitis C, but its role in relapsers and non-responders to previous interferon therapy is not established. OBJECTIVES: To assess the efficacy and safety of ribavirin alone or in combination with alpha interferon in interferon naive patients, relapsers, and non-responders with chronic hepatitis C. SEARCH STRATEGY: Eligible trials were identified through searches on electronic databases: The Cochrane Hepato-Biliary Group Controlled Trials Register (August 2001), The Cochrane Controlled Trials Register on The Cochrane Library Issue 3, 2001, MEDLINE (1966 - August 2001), and EMBASE (1985 - August 2001). Manual searches of bibliographies and journals were done as well as authors of trials and pharmaceutical companies producing ribavirin or interferon were contacted. SELECTION CRITERIA: We included all randomised trials comparing ribavirin with or without alpha interferon versus no intervention, placebo, or alpha interferon for chronic hepatitis C. DATA COLLECTION AND ANALYSIS: The primary outcome measures were the 'sustained' (six months after treatment) virological response, and morbidity plus mortality. The secondary outcome measures were the 'end of treatment' and 'sustained' biochemical response, the 'end of treatment' virologic response, histology, quality of life, and adverse events. MAIN RESULTS: We included eight trials in which 271 patients were randomised to ribavirin versus placebo or no intervention and 48 trials in which 6585 patients were randomised to interferon with or without ribavirin. Compared with placebo or no intervention, ribavirin monotherapy had no significant effect on the virological response or histology and only a transient effect on the biochemical response. Compared with interferon, combination therapy reduced the risk of not having a sustained virological response by 26% in naive patients (relative risk (RR) 0.74; 95% confidence interval (CI) 0.70-0.78), 33% in relapsers (RR 0.67; 95% CI 0.57-0.78), and 11% in non-responders (RR 0.89; 95% CI 0.83-0.96). There was no significant effect on morbidity plus mortality (Peto odds ratio 0.45; 95% CI 0.19-1.06). Irrespective of previous therapy, combination therapy significantly reduced the risk of not having a sustained biochemical response (RR 0.76; 95% CI 0.59-0.84) or improved histology (RR 0.67; 95% CI 0.56-0.81). Combination therapy also significantly increased the risk of treatment discontinuation (RR 1.28; 95% CI 1.07-1.52) and several types of adverse events. AUTHORS' CONCLUSIONS: Combination therapy increased the number of naive patients, relapsers, and non-responders with a sustained virological, biochemical, or histological response, but also the occurrence of adverse events.

Terlipressin for hepatorenal syndrome.

BACKGROUND: Terlipressin may reverse some of the circulatory changes associated with hepatorenal syndrome. OBJECTIVES: To assess the beneficial and harmful effects of terlipressin for hepatorenal syndrome. SEARCH STRATEGY: Electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Renal Group Register, the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, and EMBASE were combined with scanning of bibliographies and conference proceedings, and correspondence with experts and pharmaceutical companies. Last search update was July 2006. SELECTION CRITERIA: Randomised clinical trials were included irrespective of dose or treatment duration. Included patients had type 1 or type 2 hepatorenal syndrome. Co-interventions were allowed if administered equally to both treatment and control groups. DATA COLLECTION AND ANALYSIS: Data were retrieved from trial reports and correspondence with the authors of included trials. Mortality was the primary outcome. Meta-analyses were performed to calculate risk differences (RD) for binary outcomes and weighted mean differences (WMD) for continuous outcomes. Both were presented with 95% confidence intervals (CI). Due to the limited number of trials, no subgroup analyses were performed. MAIN RESULTS: The initial searches identified 645 potentially relevant references. Six randomised trials were eligible for inclusion. Three trials are still ongoing. Three trials with a total of 51 patients assessed terlipressin 1 mg bid for 2 to 15 days. Co-interventions included albumin, fresh frozen plasma, and cimetidine 800 mg daily. One trial reported adequate bias control assessed by randomisation and blinding. All trials reported mortality. Terlipressin reduced mortality rates by 34% (RD -0.34, 95% CI -0.56 to -0.12). The control group mortality rate was 65%. Terlipressin improved renal function assessed by creatinine clearance (WMD 21 ml/min, 95% CI 17 to 26), serum creatinine (WMD -219 micromol/l, 95% CI -244 to -194), and urine output (WMD 707 ml/day, 95% CI -212 to 1625). Adverse events included headache, abdominal pain, cardiac arrhythmia, and hypertension. AUTHORS' CONCLUSIONS: Additional evidence on terlipressin for hepatorenal syndrome is needed before reliable treatment recommendations can be made. The dose and duration of therapy, and the influence of co-interventions remain to be established.

Cyclosporin versus tacrolimus for liver transplanted patients.

BACKGROUND: Most liver transplant recipients receive either cyclosporin or tacrolimus to prevent rejection. Both drugs inhibit calcineurin phosphatase which is thought to be the mechanism of their anti-rejection effect and principle toxicities. The drugs have different pharmacokinetic profiles and potencies. Several randomised clinical trials have compared cyclosporin and tacrolimus in liver transplant recipients, but it remains unclear which is superior. OBJECTIVES: To evaluate the beneficial and harmful effects of immunosuppression with cyclosporin versus tacrolimus for liver transplanted patients. SEARCH STRATEGY: The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded, and conference proceedings were searched (August 2005) to identify relevant randomised clinical trials. Our search included scanning of reference lists in relevant articles and correspondence with investigators and pharmaceutical companies. SELECTION CRITERIA: All randomised clinical trials where tacrolimus was compared with cyclosporin for the initial treatment of first-time liver transplant recipients. We included randomised trials irrespective of blinding, language, and publication status. DATA COLLECTION AND ANALYSIS: The primary outcome measure was all-cause mortality. Data were synthesised (fixed-effect model) and results expressed as relative risk (RR), values less than 1.0 favouring tacrolimus, with 95% confidence intervals (CI). Two authors assessed trials for eligibility, quality, and extracted data independently. MAIN RESULTS: We included 16 randomised trials. The number of deaths was 254 in the tacrolimus group (1899 patients) and 302 in the cyclosporin group (1914 patients). At one year, mortality (RR 0.85, 95% CI 0.73 to 0.99) and graft loss (RR 0.73, 95% CI 0.61 to 0.86) were significantly reduced in tacrolimus-treated recipients. Tacrolimus reduced the number of recipients with acute rejection (RR 0.81, 95% CI 0.75 to 0.88), and steroid-resistant rejection (RR 0.54, 95% CI 0.47 to 0.74) in the first year. Differences were not seen with respect to lymphoproliferative disorder or de-novo dialysis rates, but more de-novo insulin-requiring diabetes mellitus (RR 1.38, 95% CI 1.01 to 1.86) occurred in the tacrolimus group. More patients were withdrawn from cyclosporin therapy than from tacrolimus (RR 0.57, 95% CI 0.49 to 0.66). AUTHORS' CONCLUSIONS: Tacrolimus is superior to cyclosporin in improving survival (patient and graft) and preventing acute rejection after liver transplantation, but it increases the risk of post-transplant diabetes. Treating 100 recipients with tacrolimus instead of cyclosporin would avoid acute rejection and steroid-resistant rejection in nine and seven patients, respectively, and graft loss and death in five and two patients, respectively, but four additional patients would develop diabetes after liver transplantation.

Ribavirin plus interferon versus interferon for chronic hepatitis C.

BACKGROUND: Hepatitis C is a major cause of liver-related morbidity and mortality. The disease progresses without symptoms for several decades and most patients are diagnosed based on the presence of hepatitis C virus ribonucleic acid and elevated transaminases. OBJECTIVES: To assess the beneficial and harmful effects of ribavirin and interferon combination therapy versus interferon monotherapy for chronic hepatitis C. SEARCH STRATEGY: We identified trials through electronic databases, manual searches of bibliographies and journals, approaching authors of trials and pharmaceutical companies, until May 2004. SELECTION CRITERIA: We included randomised trials, irrespective of blinding, language, or publication status, comparing ribavirin plus interferon versus interferon alone for treatment of chronic hepatitis C. DATA COLLECTION AND ANALYSIS: The primary outcome measures were the sustained loss of hepatitis C virus and liver-related morbidity plus all-cause mortality. We separately analysed patients who were naive, relapsers, or non-responders to previous antiviral treatment. Random-effects and fixed-effect model meta-analyses were performed for all outcomes. We used Peto odds ratios (OR) with 95% confidence intervals (CI) for analysis of morbidity plus mortality. The remaining outcomes were presented as relative risks (RR). MAIN RESULTS: We included 72 randomised trials with 9991 patients. Most trials had low methodological quality but we did not find any significant influence of quality on our results. Compared with interferon, combination therapy had a significant beneficial effect on sustained virological response (RR 0.73, 95% CI 0.71 to 0.75) and in subgroups of naive patients (RR 0.72, 95% CI 0.68 to 0.76), relapsers (RR 0.63, 95% CI 0.54 to 0.73), and non-responders (RR 0.89, 95% CI 0.84 to 0.94) individually. Combination therapy significantly reduced morbidity plus mortality (Peto OR 0.46, 95% CI 0.22 to 0.96), but not in naive, relapsers, or non-responders individually. Combination therapy also had a significant beneficial effect on the histological response. Combination therapy significantly increased the risk of anaemia (RR 10.48, 95% CI 5.34 to 20.55), which occurred in 22% of patients on combination therapy. Combination therapy also significantly increased the risk of dermatological, gastrointestinal, infectious, and miscellaneous (cough, dyspnea, fatigue) adverse events. Accordingly, combination therapy significantly increased the risk of treatment discontinuation (RR 1.19, 95% CI 1.01 to 1.39). AUTHORS' CONCLUSIONS: Compared with interferon alone, ribavirin plus interferon is more effective in clearing hepatitis C virus and improving liver histology. This may lead to reduced morbidity and mortality. However, combination therapy significantly increased the risk of several adverse events.

Ribavirin monotherapy for chronic hepatitis C.

BACKGROUND: Hepatitis C is a major cause of liver-related morbidity and mortality. The disease progresses without symptoms for several decades. Ribavirin monotherapy may represent a treatment for some patients. OBJECTIVES: To assess the beneficial and harmful effect of ribavirin monotherapy for patients with chronic hepatitis C. SEARCH STRATEGY: We identified trials through electronic databases, manual searches of bibliographies and journals, authors of trials, and pharmaceutical companies until May 2005. SELECTION CRITERIA: We included all randomised trials irrespective of blinding, language, or publication status comparing ribavirin versus no intervention, placebo, or interferon for chronic hepatitis C. DATA COLLECTION AND ANALYSIS: The primary outcome measures were the six months sustained loss of hepatitis C virus RNA in blood after end of treatment and liver-related morbidity plus all-cause mortality. Secondary outcome measures were end of treatment virological response, biochemical response, histological response, and adverse events. Random- and fixed-effects meta-analyses with 95% confidence intervals (CI) were performed for all outcomes. We used Peto odds ratios (OR) for analysis of morbidity plus mortality and relative risks (RR) for the remaining outcomes. MAIN RESULTS: We identified 13 randomised trials including 594 patients with chronic hepatitis C. Most trials had low methodological quality. Compared with placebo/no intervention, ribavirin had no significant effect on sustained (RR 1.01, 95% CI 0.96 to 1.07, five trials) or end of treatment virological response (RR 1.00, 95% CI 0.94 to 1.07, ten trials). Ribavirin had no significant effect on liver-related morbidity plus mortality (Peto OR 1.96, 95% CI 0.20 to 19.0, eleven trials). Ribavirin significantly improved end of treatment biochemical and histological response but not sustained biochemical response. Further, ribavirin significantly increased the risk of anaemia. Ribavirin was significantly inferior to interferon regarding virological and biochemical response (four trials). AUTHORS' CONCLUSIONS: We found that ribavirin versus placebo/no intervention had no significant beneficial effect on virological response and liver morbidity, but may improve biochemical and histological response transiently. Ribavirin increased the risk of anaemia. Therefore, we cannot recommend ribavirin monotherapy for patients with chronic hepatitis C outside randomised trials.

Dopaminergic agonists for hepatic encephalopathy.

BACKGROUND: Hepatic encephalopathy may be associated with an impairment of the dopaminergic neurotransmission. Dopaminergic agonists may therefore have a beneficial effect on patients with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of dopaminergic agonists for patients with hepatic encephalopathy. SEARCH STRATEGY: Trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register (July 2004), The Cochrane Central Register of Controlled Trials (Issue 3, 2004), MEDLINE (1966-2004/07), EMBASE (1980-2004/07), manual searches of bibliographies and journals, authors of trials, and pharmaceutical companies. SELECTION CRITERIA: All randomised trials comparing dopaminergic agonists versus placebo or no intervention for hepatic encephalopathy. DATA COLLECTION AND ANALYSIS: Trial inclusion and data extraction were made independently by two reviewers. Binary outcomes are reported as odds ratios (OR) with 95% confidence intervals (CI) based on a random effects model. The presence of statistical heterogeneity was explored by the chi-squared test with significance set at P < 0.1. Potential sources of heterogeneity were explored through subgroup analyses with regard to the type of hepatic encephalopathy and type of dopaminergic agonist. MAIN RESULTS: Five trials were included. Four trials had low methodological quality. Compared with placebo or no treatment, dopaminergic agonists had no significant effect on the risk of no improvement (OR 0.33, 95% CI 0.01 to 11.25, two trials, 80 patients) or mortality (OR 1.11, 95% CI 0.34 to 3.54, four trials, 139 patients). There was significant heterogeneity (P = 0.09) among trial results on the risk of no improvement, but not on mortality (P = 0.19). The treatment response was not significantly different with regard to the type of hepatic encephalopathy or dopaminergic agonist, but the analyses had very low power to detect potential differences. There was a nonsignificant trend that dopaminergic agonists may be associated with adverse events (OR 8.33, 95% CI 0.37 to 187.74, 2 trials, 13 patients). All adverse events (n = 7) occurred in the experimental group. REVIEWERS' CONCLUSIONS: This review does not provide evidence that dopaminergic agonists are of benefit to patients with acute or chronic hepatic encephalopathy, or fulminant hepatic failure. The review is limited by the small number of trials performed within this field, the low number of patients randomised in each trial, and the low methodological quality of included trials. Accordingly, there is also insufficient evidence to exclude a potential beneficial effect. Dopaminergic agonists should not be used for hepatic encephalopathy, but may be assessed in future randomised clinical trials.

Benzodiazepine receptor antagonists for hepatic encephalopathy.

BACKGROUND: Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of benzodiazepine receptor antagonists for patients with hepatic encephalopathy. SEARCH STRATEGY: Eligible trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Controlled Trials Register on The Cochrane Library, MEDLINE and EMBASE (last search: January 2004), reference lists of relevant articles, authors of trials, and pharmaceutical companies. SELECTION CRITERIA: Randomised trials comparing any benzodiazepine receptor antagonist versus placebo or no intervention for hepatic encephalopathy. DATA COLLECTION AND ANALYSIS: Two reviewers independently included trials and extracted data. Binary outcomes are reported as risk difference (RD) with 95% confidence intervals (CI) based on a random effects model. Statistical heterogeneity was explored by a chi-squared test with significance set at P < 0.1. The inconsistency across trials was assessed by I(2). Potential sources of heterogeneity were explored through subgroup analyses. MAIN RESULTS: Thirteen randomised trials with 805 patients were included. Eight trials used a crossover design. All trials were double-blind and assessed flumazenil versus placebo. Data on all outcomes could not be extracted from all trials. The included patients had a favourable prognosis (361/390 [93%] survived in the flumazenil group versus 345/376 [92%] in the placebo group). Flumazenil had a significant beneficial effect on improvement of hepatic encephalopathy at the end of treatment (RD 0.28; 95% CI 0.20 to 0.37, eight trials). Flumazenil had no significant effect on recovery (RD 0.13; 95% CI -0.09 to 0.36, two trials) or mortality RD 0.01; 95% CI -0.05 to 0.07, 10 trials). Flumazenil may be associated with adverse events, but trial results were heterogeneous. REVIEWERS' CONCLUSIONS: Flumazenil had a significant beneficial effect on short-term improvement of hepatic encephalopathy in patients with cirrhosis and a highly favourable prognosis. Flumazenil had no significant effect on recovery or survival. Considering the fluctuating nature of hepatic encephalopathy, future trials should use a parallel design and assess if treatment with flumazenil leads to a sustained improvement or increased recovery and survival. Until this has been demonstrated, flumazenil may be considered for patients with chronic liver disease and hepatic encephalopathy, but cannot be recommended for routine clinical use.

Nonabsorbable disaccharides for hepatic encephalopathy.

BACKGROUND: Nonabsorbable disaccharides (lactulose or lactitol) are considered the treatment of choice for hepatic encephalopathy. OBJECTIVES: To assess the beneficial and harmful effects of nonabsorbable disaccharides for patients with hepatic encephalopathy. SEARCH STRATEGY: Trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register (March 2003), The Cochrane Central Register of Controlled Trials (Issue 1, 2003), MEDLINE (1966 to 2003/03), EMBASE (1980 to 2003/03), manual searches of bibliographies and journals, authors of trials, and pharmaceutical companies. SELECTION CRITERIA: Randomised trials comparing lactulose or lactitol versus no intervention, placebo, or antibiotics and trials comparing lactulose versus lactitol for hepatic encephalopathy. DATA COLLECTION AND ANALYSIS: The primary outcome measures included no improvement of hepatic encephalopathy and all-cause mortality. Binary outcomes are reported as relative risks (RR) based on a random effects model. Subgroup analyses were performed with regard to methodological quality and form of hepatic encephalopathy. MAIN RESULTS: Thirty trials assessed nonabsorbable disaccharides versus placebo, no intervention, or antibiotics or assessed lactulose versus lactitol. We could not extract data from all trials. Compared with placebo or no intervention, nonabsorbable disaccharides had no statistically significant effect on mortality (RR 0.41, 95% CI 0.02 to 8.68, four trials), but appeared to reduce the risk of no improvement of hepatic encephalopathy (RR 0.62, 95% CI 0.46 to 0.84, six trials). However, this result may reflect bias due to low methodological quality of the majority of included trials. Trials of high methodological quality found no significant effect of nonabsorbable disaccharides on the risk of no improvement (RR 0.92, 95% CI 0.42 to 2.04, two trials). We found no statistically significant difference between lactulose and lactitol on mortality (two trials) or risk of no improvement (four trials). However, our meta-analyses were underpowered to establish whether these treatments have comparable effect. Nonabsorbable disaccharides appeared to be inferior to antibiotics on reducing the risk of no improvement (RR 1.24, 95% CI 1.02 to 1.50, 10 trials). REVIEWERS' CONCLUSIONS: This systematic review questions the beneficial effects of nonabsorbable disaccharides and highlights that there is insufficient high-quality evidence to support this treatment. We found that antibiotics appeared to be superior to nonabsorbable disaccharides in improving hepatic encephalopathy, but it is unclear whether this difference in treatment effect is clinically important to patients. Nonabsorbable disaccharides should not serve as comparator in randomised trials on hepatic encephalopathy.

Artificial and bioartificial support systems for liver failure.

BACKGROUND: Artificial and bioartificial liver support systems may 'bridge' patients with acute or acute-on-chronic liver failure to liver transplantation or recovery. OBJECTIVES: To evaluate beneficial and harmful effects of artificial and bioartificial support systems for acute and acute-on-chronic liver failure. SEARCH STRATEGY: Trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register (September 2002), The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 3, 2002), MEDLINE (1966 - September 2002), EMBASE (1985 - September 2002), and The Chinese Biomedical Database (September 2002), manual searches of bibliographies and journals, authors of trials, and pharmaceutical companies. SELECTION CRITERIA: Randomised clinical trials on artificial or bioartificial support systems for acute or acute on-chronic liver failure were included irrespective of blinding, publication status, or language. Non-randomised studies were included in explorative analyses. DATA COLLECTION AND ANALYSIS: Data were extracted independently by three reviewers. Results were presented as relative risks (RR) with 95% confidence intervals (CI). Sources of heterogeneity were explored through sensitivity analyses and meta-regression. The primary outcome was mortality. MAIN RESULTS: Twelve trials on artificial or bioartificial support systems versus standard medical therapy (483 patients) and two trials comparing different artificial support systems (105 patients) were included. Most trials had unclear methodological quality. Compared to standard medical therapy, support systems had no significant effect on mortality (RR 0.86; 95% CI 0.65-1.12) or bridging to liver transplantation (RR 0.87; 95% CI 0.73-1.05), but a significant beneficial effect on hepatic encephalopathy (RR 0.67; 95% CI 0.52-0.86). Meta-regression indicated that the effect of support systems depended on the type of liver failure (P = 0.03). In subgroup analyses, artificial support systems appeared to reduce mortality by 33% in acute-on-chronic liver failure (RR 0.67; 95% CI 0.51-0.90), but not in acute liver failure (RR 0.95; 95% CI 0.71-1.29). Two trials comparing artificial support systems showed significant mortality reductions with intermittent versus continuous haemofiltration (RR 0.58; 95% CI 0.36-0.94) and no significant difference between five versus ten hours of charcoal haemoperfusion (RR 1.03; 95% CI 0.65-1.62). The incidence of adverse events was inconsistently reported. REVIEWER'S CONCLUSIONS: This Review indicates that artificial support systems may reduce mortality in acute-on-chronic liver failure. Artificial and bioartificial support systems did not appear to affect mortality in acute liver failure. However, considering the strength of the evidence additional randomised clinical trials are needed before any support system can be recommended for routine use.

Systematic review with meta-analysis: the effects of rifaximin in hepatic encephalopathy.

BACKGROUND: Rifaximin is recommended for prevention of hepatic encephalopathy (HE). The effects of rifaximin on overt and minimal HE are debated. AIM: To perform a systematic review and meta-analysis of randomised controlled trials (RCTs) on rifaximin for HE. METHODS: We performed electronic and manual searches, gathered information from the U.S. Food and Drug Administration Home Page, and obtained unpublished information on trial design and outcome measures from authors and pharmaceutical companies. Meta-analyses were performed and results presented as risk ratios (RR) with 95% confidence intervals (CI) and the number needed to treat. Subgroup, sensitivity, regression and sequential analyses were performed to evaluate the risk of bias and sources of heterogeneity. RESULTS: We included 19 RCTs with 1370 patients. Outcomes were recalculated based on unpublished information of 11 trials. Overall, rifaximin had a beneficial effect on secondary prevention of HE (RR: 1.32; 95% CI 1.06-1.65), but not in a sensitivity analysis on rifaximin after TIPSS (RR: 1.27; 95% CI 1.00-1.53). Rifaximin increased the proportion of patients who recovered from HE (RR: 0.59; 95% CI: 0.46-0.76) and reduced mortality (RR: 0.68, 95% CI 0.48-0.97). The results were robust to adjustments for bias control. No small study effects were identified. The sequential analyses only confirmed the results of the analysis on HE recovery. CONCLUSIONS: Rifaximin has a beneficial effect on hepatic encephalopathy and may reduce mortality. The combined evidence suggests that rifaximin may be considered in the evidence-based management of hepatic encephalopathy.

Meta-analysis: banding ligation and medical interventions for the prevention of rebleeding from oesophageal varices.

BACKGROUND: In patients with oesophageal varices, the combination of endoscopic variceal ligation (EVL) and medical therapy is recommended as standard of care for prevention of rebleeding. The results of previous meta-analyses on this topic are equivocal. AIM: To assess the effects of EVL plus medical therapy vs. monotherapy (EVL or medical therapy alone) for secondary prevention in oesophageal varices. METHODS: Electronic and manual searches were combined. The primary outcome measures were overall rebleeding (variceal and nonvariceal) and mortality. Random-effects meta-analyses were performed with subgroup, sensitivity, regression and sequential analyses to identify sources of intertrial heterogeneity and the robustness of the results. RESULTS: Nine randomised trials were included. In total, 442 patients were randomised to combination therapy and 513 to monotherapy. Combination therapy reduced rebleeding (RR = 0.68; 95% CI = 0.54-0.85; number needed to treat eight patients). The result was confirmed in sequential and regression analyses, but not when limiting the analysis to trials with adequate selection bias control. No effect on overall mortality was identified (RR = 0.89; 95% CI = 0.65-1.21). Combination therapy reduced bleeding-related mortality (RR = 0.52; 95% CI 0.27-0.99; number needed to treat 33 patients) and the risk of rebleeding from oesophageal varices. Combination therapy increased the risk of serious adverse events in fixed, but not in random-effects meta-analyses. CONCLUSIONS: The combination of endoscopic variceal ligation and medical therapy reduce the risk of rebleeding, but not overall mortality. Additional research is needed to determine why reduced rebleeding rates do not lead to reduced mortality.