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.

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.

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.

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.

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.

Meta-analysis: the safety and efficacy of vaptans (tolvaptan, satavaptan and lixivaptan) in cirrhosis with ascites or hyponatraemia.

BACKGROUND: Vaptans may correct hyponatraemia and mobilise ascites through an increased excretion of water. The effect on clinical outcomes is debated. AIM: To determine the effects of vaptans (tolvaptan, satavaptan and lixivaptan) on patients with cirrhosis and hyponatraemia or ascites. METHODS: Systematic review of randomised controlled trials. The primary outcome measure was mortality. Electronic and manual searches were combined (April 2012). Data were extracted from published reports, online information from the Food and Drug Administration website or obtained through correspondence with authors and pharmaceutical companies. The primary meta-analyses were performed using random effects models due to an expected clinical diversity. RESULTS: Twelve trials with a total of 2266 patients were included. Randomisation was adequate in all trials. Eight trials were double-blind. Random effects meta-analyses found no clear differences between vaptans and control groups regarding mortality (RR = 1.06, 95% CI = 0.90-1.26, I(2) = 0%), variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, or renal failure. Vaptans increased serum sodium levels (WMD = 1.8 mmol/L, 95% CI = 0.79-2.96) and lead to reductions in weight and the time to the first paracentesis. Vaptans increased the risk of adverse events (RR = 3.97, 95% CI = 1.78-8.83), including an excessive urine volume (RR = 9.96, 95% CI = 1.38-71.68). CONCLUSIONS: Vaptans have a small beneficial effect on hyponatraemia and ascites, but do not affect mortality, complications to cirrhosis or renal failure. The data do not support the routine use of vaptans in cirrhosis.

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.

Meta-analysis: ribavirin plus interferon vs. interferon monotherapy for chronic hepatitic C - an updated Cochrane review.

BACKGROUND: Multiple randomized trials have been published on antiviral treatment for chronic hepatitis C. AIM: To meta-analyse the effect of adding ribavirin to interferon for chronic hepatitis C. METHODS: The results of randomized trials were combined in cumulative meta-analyses. Trial sequential analyses were used to adjust for spurious results because of random errors and multiplicity. The outcome measures were undetectable hepatitis C virus RNA in serum (sustained virological response) and liver-related morbidity plus all-cause mortality. RESULTS: We included 82 randomized trials with 12 615 patients. Trial sequential analysis established clear beneficial effect of interferon plus ribavirin vs. interferon on the sustained virological response in 1998 after nine trials (RR: 0.74; 95% CI: 0.64-0.85, P < 0.0001, 1734 patients). Subsequently, additional 73 trials were published just narrowing the confidence interval and decreasing the P-value. By contrast, trial sequential analysis found that additional evidence is needed to convincingly detect a beneficial effect of interferon plus ribavirin vs. interferon monotherapy on clinical outcomes. CONCLUSIONS: The rationale behind several recent trials on adding ribavirin to interferon for chronic hepatitis C is debatable as the effect on virological response is established. More evidence is needed to assess if adding ribavirin to interferon improves clinical outcomes.

Meta-analysis: isosorbide-mononitrate alone or with either beta-blockers or endoscopic therapy for the management of oesophageal varices.

BACKGROUND: The evidence concerning the use of isosorbide-mononitrate (IsMn) for oesophageal varices is equivocal. AIM: To assess the effects of IsMn for patients with oesophageal varices and no previous bleeding (primary prevention) or previous variceal bleeding (secondary prevention). METHODS: Systematic review with meta-analyses of randomized trials on IsMn alone or with beta-blockers or endoscopic therapy for oesophageal varices. Electronic and manual searches were combined. Randomized trials on primary and secondary prevention were included. The primary outcome measure was mortality. Intention-to-treat random effects meta-analyses were performed. The robustness of the results was assessed in trial sequential analyses. RESULTS: Ten randomized trials on primary and 17 on secondary prevention were included. Evidence of bias was identified. No apparent effect of IsMn on mortality compared with placebo or beta-blockers or IsMn plus beta-blockers vs. beta-blockers was identified. Compared with endoscopic therapy, IsMn plus beta-blockers had no apparent effect on bleeding, but did seem to reduce mortality in secondary prevention (RR 0.73, 95% CI 0.59-0.89), but not in primary prevention. The effect of IsMn plus beta-blockers on mortality in secondary prevention was not confirmed in trial sequential analysis. CONCLUSIONS: Isosorbide-mononitrate used alone or in combination with beta blockers does not seem to offer any reduction in bleeding in the primary or secondary prevention of oesophageal varices. Compared with endoscopic therapy, there may be a survival advantage in using IsMn and beta-blockers, but additional large multicentre trials are needed to verify this finding.

Meta-analysis: antioxidant supplements for liver diseases - the Cochrane Hepato-Biliary Group.

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.

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: tranexamic acid for upper gastrointestinal bleeding.

BACKGROUND: Tranexamic acid may reduce upper gastrointestinal bleeding and stabilize patients before endoscopic treatments. AIM: To review randomized trials on tranexamic acid for upper gastrointestinal bleeding. METHODS: Manual and electronic searches of The Cochrane Library, MEDLINE, EMBASE and Science Citation Index were combined. Intention-to-treat random effect meta-analyses were performed and results presented as RRs with 95% confidence intervals. RESULTS: Seven double-blind randomized trials on tranexamic acid vs. placebo were included. Of 1754 patients randomized, 21% were excluded. Only one trial included endoscopic treatments or proton pump inhibitors. Five per cent of patients on tranexamic acid and 8% of controls died (RR: 0.61, 95% CI: 0.42-0.89). No significant differences were found on bleeding, bleeding-related mortality, surgery or transfusion requirements. Adverse events were unclearly reported. Data from three of the included trials suggested that tranexamic acid did not significantly increase the risk of thromboembolic disease. CONCLUSIONS: The present review suggests that tranexamic acid may reduce all-cause mortality. However, because of limitations in the internal and external validity of included trials, additional evidence is needed before treatment recommendations can be made.

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.

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.

Multivariable modelling for meta-epidemiological assessment of the association between trial quality and treatment effects estimated in randomized clinical trials.

Methodological deficiencies are known to affect the results of randomized trials. There are several components of trial quality, which, when inadequately attended to, may bias the treatment effect under study. The extent of this bias, so far only vaguely known, is currently being investigated by 'meta-epidemiological' re-analysis of data collected as part of systematic reviews. As inadequate quality components often co-occur, we maintain that the suspected biases must be evaluated simultaneously. Furthermore, the biases cannot safely be assumed to be homogeneous across systematic reviews. Therefore, a stable multivariable method that allows for heterogeneity is needed for assessing the 'bias coefficients'. We present two general statistical models for analysis of a study of 523 randomized trials from 48 meta-analyses in a random sample of Cochrane reviews: a logistic regression model uses the design of the trials as such to give estimates; a weighted regression model incorporates between-trial variation and thus gives wider confidence intervals, but is computationally lighter and can be used with trials of more general design. In both models, heterogeneity in the bias coefficients can be incorporated in two ways. A stratification approach pools the estimates from models estimated on subgroups of the data. We explore stratification by reviews and by broad trial types, the latter of which gives larger subgroups of the data, circumventing instabilities. A multilevel approach also avoids instabilities and addresses the more fundamental problem of interpretation of the pooled multivariable effect in the presence of heterogeneity.