Antonio Facciorusso1, Apoorva K Chandar2, M Hassan Murad3, Larry J Prokop4, Nicola Muscatiello1, Patrick S Kamath5, Siddharth Singh6. 1. Gastroenterology Unit, Department of Medical Sciences, University of Foggia, Foggia, Italy. 2. Division of Gastroenterology and Liver Diseases, Case Western Reserve University, Cleveland, OH, USA. 3. Robert D and Patricia E Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA. 4. Department of Library Services, Mayo Clinic, Rochester, MN, USA. 5. Division of Gastroenterology, Mayo Clinic, Rochester, MN, USA. 6. Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA; Division of Biomedical Informatics, University of California San Diego, La Jolla, CA, USA. Electronic address: sis040@ucsd.edu.
Abstract
BACKGROUND: Several drugs have been studied to improve outcomes for patients with hepatorenal syndrome, but trials have reported variable efficacy. We aimed to compare the efficacy of different management strategies for type 1 hepatorenal syndrome. METHODS: For this systematic review and network meta-analysis, we searched Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Scopus, and Web of Science for papers published up to June 9, 2016. We selected randomised controlled trials of adults (>18 years) with decompensated cirrhosis and type 1 hepatorenal syndrome that compared the efficacy of active vasoactive drugs (terlipressin, midodrine, octreotide, noradrenaline, and dopamine; alone or in combination) with placebo or each other. The primary outcome was reduction in short-term mortality. Secondary outcomes were reversal of hepatorenal syndrome, relapse of hepatorenal syndrome after initial reversal, and adverse events. We did pairwise and network meta-analyses to produce odds ratios (ORs) and 95% CIs. We used the GRADE criteria to appraise quality of evidence. FINDINGS: We identified 13 randomised controlled trials done in 739 adults with type 1 hepatorenal syndrome. All participants received supportive therapy with albumin. Moderate-quality evidence might support the use of terlipressin over placebo for reduction of short-term mortality (OR 0·65, 95% CI 0·41-1·05), whereas only low-quality evidence supported the use of noradrenaline, midodrine plus octreotide, and dopamine plus furosemide over placebo to reduce mortality, and no ORs for any of the comparisons versus placebo were significant. Moderate-quality evidence supported the use of terlipressin over midodrine plus octreotide (OR 26·25, 95% CI 3·07-224·21) to reverse hepatorenal syndrome, with low-quality evidence supporting the use of noradrenaline over placebo (4·17, 1·37-12·50) and over midodrine plus octreotide (10·00, 1·49-50·00) for this outcome. A median of 16% (range 5-20) of terlipressin-treated patients, and 33% (range 6-40) noradrenaline-treated patients with reversal of hepatorenal syndrome had recurrence on discontinuation of therapy. A median of 8% (range 4-22) terlipressin-treated patients required discontinuation of therapy due to serious adverse events. INTERPRETATION: Terlipressin with albumin might reduce short-term mortality compared with placebo in patients with type 1 hepatorenal syndrome. Terlipressin with albumin and noradrenaline with albumin are both superior to midodrine plus octreotide with albumin for reversal of hepatorenal syndrome. Pragmatic clinical trials of terlipressin with albumin are warranted to evaluate real-world effectiveness and safety in patients with type 1 hepatorenal syndrome. FUNDING: None.
BACKGROUND: Several drugs have been studied to improve outcomes for patients with hepatorenal syndrome, but trials have reported variable efficacy. We aimed to compare the efficacy of different management strategies for type 1 hepatorenal syndrome. METHODS: For this systematic review and network meta-analysis, we searched Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Scopus, and Web of Science for papers published up to June 9, 2016. We selected randomised controlled trials of adults (>18 years) with decompensated cirrhosis and type 1 hepatorenal syndrome that compared the efficacy of active vasoactive drugs (terlipressin, midodrine, octreotide, noradrenaline, and dopamine; alone or in combination) with placebo or each other. The primary outcome was reduction in short-term mortality. Secondary outcomes were reversal of hepatorenal syndrome, relapse of hepatorenal syndrome after initial reversal, and adverse events. We did pairwise and network meta-analyses to produce odds ratios (ORs) and 95% CIs. We used the GRADE criteria to appraise quality of evidence. FINDINGS: We identified 13 randomised controlled trials done in 739 adults with type 1 hepatorenal syndrome. All participants received supportive therapy with albumin. Moderate-quality evidence might support the use of terlipressin over placebo for reduction of short-term mortality (OR 0·65, 95% CI 0·41-1·05), whereas only low-quality evidence supported the use of noradrenaline, midodrine plus octreotide, and dopamine plus furosemide over placebo to reduce mortality, and no ORs for any of the comparisons versus placebo were significant. Moderate-quality evidence supported the use of terlipressin over midodrine plus octreotide (OR 26·25, 95% CI 3·07-224·21) to reverse hepatorenal syndrome, with low-quality evidence supporting the use of noradrenaline over placebo (4·17, 1·37-12·50) and over midodrine plus octreotide (10·00, 1·49-50·00) for this outcome. A median of 16% (range 5-20) of terlipressin-treated patients, and 33% (range 6-40) noradrenaline-treated patients with reversal of hepatorenal syndrome had recurrence on discontinuation of therapy. A median of 8% (range 4-22) terlipressin-treated patients required discontinuation of therapy due to serious adverse events. INTERPRETATION: Terlipressin with albumin might reduce short-term mortality compared with placebo in patients with type 1 hepatorenal syndrome. Terlipressin with albumin and noradrenaline with albumin are both superior to midodrine plus octreotide with albumin for reversal of hepatorenal syndrome. Pragmatic clinical trials of terlipressin with albumin are warranted to evaluate real-world effectiveness and safety in patients with type 1 hepatorenal syndrome. FUNDING: None.