L. L. Gluud

Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses?

BACKGROUND Results from apparently conclusive meta-analyses may be false. A limited number of events from a few small trials and the associated random error may be under-recognized sources of spurious findings. The information size (IS, i.e. number of participants) required for a reliable and conclusive meta-analysis should be no less rigorous than the sample size of a single, optimally powered randomized clinical trial. If a meta-analysis is conducted before a sufficient IS is reached, it should be evaluated in a manner that accounts for the increased risk that the result might represent a chance finding (i.e. applying trial sequential monitoring boundaries). METHODS We analysed 33 meta-analyses with a sufficient IS to detect a treatment effect of 15% relative risk reduction (RRR). We successively monitored the results of the meta-analyses by generating interim cumulative meta-analyses after each included trial and evaluated their results using a conventional statistical criterion (alpha = 0.05) and two-sided Lan-DeMets monitoring boundaries. We examined the proportion of false positive results and important inaccuracies in estimates of treatment effects that resulted from the two approaches. RESULTS Using the random-effects model and final data, 12 of the meta-analyses yielded P > alpha = 0.05, and 21 yielded P </= alpha = 0.05. False positive interim results were observed in 3 out of 12 meta-analyses with P > alpha = 0.05. The monitoring boundaries eliminated all false positives. Important inaccuracies in estimates were observed in 6 out of 21 meta-analyses using the conventional P </= alpha = 0.05 and 0 out of 21 using the monitoring boundaries. CONCLUSIONS Evaluating statistical inference with trial sequential monitoring boundaries when meta-analyses fall short of a required IS may reduce the risk of false positive results and important inaccurate effect estimates.

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

Rifaximin is recommended for prevention of hepatic encephalopathy (HE). The effects of rifaximin on overt and minimal HE are debated.

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.

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

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.

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

Vaptans may correct hyponatraemia and mobilise ascites through an increased excretion of water. The effect on clinical outcomes is debated.

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

Aliment Pharmacol Ther 2010; 32: 356–367

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

Aliment Pharmacol Ther 2010; 32: 859–871

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

Aliment Pharmacol Ther 2010; 32: 840–850

Letter: the effects of rifaximin in hepatic encephalopathy - authors' reply

jects. However, liver cirrhosis significantly affects the pharmacokinetics of this drug, with systemic absorption markedly increased in these patients compared to controls. Indeed, plasma concentrations as high as 10 ng/mL have been observed in cirrhotics, with levels being even higher in those patients with Child–Pugh C disease, compared to only 1 ng/mL in controls. This could be a cause for concern, particularly when a daily, long-life therapy is proposed for chronic disorders, such as HE prevention. Therefore, a note for caution should be considered before suggesting long-term therapy with rifaximin for the prevention of HE in cirrhotics, and further studies are warranted to assess its actual safety. Of note, a significant increase in serum potassium and sodium concentrations has been reported during rifaximin therapy. This could be a matter for concern in cirrhotic patients with these electrolyte disturbances also being involved in the development of HE. At the same time, some concerns with both possible infection and bacterial resistance induction during rifaximin therapy should be also considered, particularly when long-term treatment is suggested. Following 6 months of rifaximin therapy, two cases of Clostridium difficile infection were found in the rifaximin group, despite this antibiotic being active against such a bacterium, while no case occurred in the placebo group. Therefore, a note of caution should be considered, particularly when long-term antibiotic therapy is suggested. Rifaximin markedly reduced faecal bacterial counts during oral intake, but the effect was short-lasting since the bacterial population recovered within 1–2 week after the end of treatment. Therefore, a rapid disappearance of resistant bacteria was observed after stopping a short course rifaximin treatment but no data are available for long-term therapy. Of note, anaerobic bacteria, especially the Gram-negative rods, regained sensitivity to rifaximin more slowly than aerobic species. Finally, Candida albicans, which has been implicated in the pathogenesis of antibiotic-associated diarrhoea, was isolated from the faecal samples of 20% of patients given 1200 mg of rifaximin daily. Therefore, it has been suggested that rifaximin therapy could be used as a rescue therapy in addition to disaccharides in those cirrhotics who experienced HE during disaccharides therapy. While waiting for further safety data, caution should be used in adding rifaximin therapy in the very short term, disclosing to the patients both the benefit and potential risks.

Letter: vaptans for the treatment of hyponatraemia and ascites in patients with cirrhosis – authors’ reply

temic vasoconstriction, decreased renal blood flow and granular filtration fraction, and sodium and water reabsorption due to an over-active renin–angiotensin– aldosterone system. Thus, patients are locked in a vicious cycle of hyponatraemia and ascites. Deleterious effects on ECV and other adverse effects of vaptans may restrict the use of these agents in patient with advanced cirrhosis. However, short-term use of vaptan with colloid oncotic pressure extenders would be more beneficial than other diuretics in the treatment of acute exacerbation of ascites.