Abstract: We included 10 randomised clinical trials with 474 participants. The trials compared terlipressin versus noradrenaline (seven trials), octreotide (one trial), midodrine and octreotide (one trial), or dopamine (one trial). All participants in both groups received albumin as cointervention. We classified two trials at low risk of bias and eight trials at high risk of bias in the assessment of mortality and all trials at high risk of bias for remaining outcomes. In five trials, investigators specifically stated that they did not receive funding from for-profit organisations. We had no information about the funding source from the remaining five trials. Terlipressin was not superior or inferior compared with other vasoactive drugs in regard to mortality when including the two trials with a low risk of bias (RR 0.92, 95% CI 0.63 to 1.36; 94 participants, very low quality evidence) or when including all 10 trials (RR 0.96, 95% CI 0.88 to 1.06; 474 participants; I² = 0%; very low quality evidence). One meta-analysis including nine trials suggested a beneficial effect of terlipressin on hepatorenal syndrome (RR 0.79, 95% CI 0.63 to 0.99; 394 participants; I² = 26%; very low quality evidence). Due to the high mortality of hepatorenal syndrome, the registration of other serious adverse events is uncertain, but comparing terlipressin and other vasoactive drugs we found no significant difference (RR 0.96, 95% CI 0.88 to 1.06; 474 participants; I² = 0%; very low quality evidence). Several trials did not report systematically of adverse events, but terlipressin seemed to increase the risks of diarrhoea or abdominal pain, or both (RR 3.50, 95% CI 1.19 to 10.27; 221 participants; 5 trials, I² = 0%). However, Trial Sequential Analyses found insufficient evidence to support or refute any differences between interventions for all outcomes. Considering reversal of hepatorenal syndrome, subgroup analyses on the type of other vasoactive drugs found that terlipressin was superior compared with midodrine and octreotide (RR 0.47, 95% CI 0.30 to 0.72) or octreotide alone (RR 0.56, 95% CI 0.33 to 0.96), but each subgroup only included one small trial. None of the remaining subgroup or sensitivity analyses found differences between terlipressin and other vasoactive drugs. We downgraded the evidence to very low quality because of the high risk of bias, imprecision, and the results of the Trial Sequential Analyses. This review found insufficient evidence to support or refute beneficial or harmful effects of terlipressin and albumin versus other vasoactive drugs and albumin. Additional research is needed to evaluate if clinically meaningful differences exist between interventions.

Plain-language summary: We included 10 clinical trials with 474 participants. Seven trials compared terlipressin and albumin versus noradrenaline and albumin. The remaining three trials compared terlipressin and albumin versus midodrine and octreotide, or octreotide alone, or dopamine. In total, 241 participants received terlipressin and 233 participants received other vasoactive drugs (drugs that change blood pressure; noradrenaline, octreotide, midodrine, or dopamine). In five trials, investigators specifically stated that they did not receive funding from organisations that could profit from the trial results. We did not have information about the funding source from the remaining five trials. Our analyses found uncertain evidence to support or refute terlipressin versus other vasoactive drugs in the treatment of hepatorenal syndrome when evaluating mortality or serious side effects. Our analyses suggested that treatment with terlipressin may have a beneficial effect on hepatorenal syndrome by reducing the number of participants with persistent hepatorenal syndrome. Additional analyses showed that the number of participants in the trials was too small for us to be sure about this. Accordingly, we found that important differences between terlipressin and other vasoactive drugs may be overlooked. We found that the evidence was of very low quality due to the high risk of bias and the small number of participants. We need additional large trials of a high quality to evaluate if terlipressin is more beneficial or safer than other vasoactive drugs.