Terlipressin for hepatorenal syndrome

BACKGROUND: Clinical trials suggest that terlipressin improves renal function in hepatorenal syndrome, but the evidence concerning mortality is equivocal. OBJECTIVES: To assess the beneficial and harmful effects of terlipressin alone or with albumin versus placebo, no intervention or albumin for hepatorenal syndrome. SEARCH METHODS: Eligible trials were identified through electronic (The Cochrane Library, MEDLINE, EMBASE and Science Citation Index databases) and manual searches until January 2012. SELECTION CRITERIA: Randomised clinical trials involving patients with type 1 or type 2 hepatorenal syndrome were included irrespective of publication status or language. DATA COLLECTION AND ANALYSIS: The review authors independently extracted data from trial reports and undertook correspondence with the authors. Primary outcome measures included mortality, reversal of hepatorenal syndrome and adverse events. Intention-to-treat, random-effects model meta-analyses were performed and results were expressed as risk ratios (RR) with 95% confidence intervals (CI), and the I2 statistic provided a measure of intertrial heterogeneity. Subgroup, sensitivity, regression and sequential analyses were performed. MAIN RESULTS: We identified six randomised clinical trials. All had high risk of bias. Five trials assessed terlipressin (with albumin in three trials) versus no intervention (with albumin in three trials) and one trial assessed terlipressin versus albumin. Data from five randomised trials on terlipressin alone (one trial) or terlipressin and albumin (four trials) were included in the review. In total, 74 of 155 (47.7%) patients randomised to terlipressin alone or terlipressin with albumin versus 98 of 154 (63.6%) patients randomised to no intervention, placebo or albumin died. Random-effects model meta-analysis found that terlipressin reduced mortality (RR 0.76, 95% CI 0.61 to 0.95). The results were stable when repeated with trials on terlipressin plus albumin, trials on patients with type 2 hepatorenal syndrome, and trials with a low risk of selection bias. No evidence of bias or small study effects were identified in regression analyses. In a trial sequential analysis on mortality, the cumulative Z curve approached but did not cross the monitoring boundary suggesting that the results were not stable to adjustment for sparse data and multiple comparisons. Analyses of the remaining outcome measures found that terlipressin and albumin increased the number of patients with reversal of hepatorenal syndrome as well as adverse events, including cardiovascular and gastrointestinal symptoms. AUTHORS' CONCLUSIONS: Terlipressin may reduce mortality and improve renal function in patients with type 1 hepatorenal syndrome. Whether the evidence is strong enough to support the intervention for clinical practice could be debated due to the results of the trial sequential analyses. However, the outcome measures assessed are objective, which reduces the risk of bias.