Tolvaptan for Refractory Ascites in Cirrhosis: Systematic Review and Meta-Analysis

ABSTRACT Background & Aims: Refractory ascites marks a decisive transition to decompensated cirrhosis, with limited effective therapeutic options and a persistently poor prognosis. Tolvaptan, which is an oral vasopressin V₂-receptor antagonist, offers an aquaretic mechanism distinct from conventional natriuretic diuretics. Despite broadly consistent short-term physiological effects, its clinical adoption has diverged sharply between Japan and Western recommendations. This systematic review and meta-analysis sought to quantify efficacy and safety, interrogate the evidentiary basis for the Japan–West translational gap, and define the pharmacovigilance infrastructure required for safe use. Methods: A PRISMA 2020-compliant systematic review and meta-analysis (PROSPERO: CRD420251276165). PubMed, Embase, CENTRAL, and Japanese databases (Japic-CTI, UMIN) were searched. Risk of bias was assessed using Cochrane RoB 2 and ROBINS-I. Random-effects meta-analyses were performed for physiological outcomes; certainty was graded using GRADE. Safety data were synthesised from randomised trials and large pharmacovigilance cohorts. Results: Sixteen studies (9 RCTs, 7 prospective cohorts; n=2,154) were included. Meta-analysis of RCTs provided moderate-certainty evidence for short-term improvements in urine output (mean difference [MD] +1240 mL/day, 95% CI +1050 to +1430), body weight (MD -1.48 kg, 95% CI -1.92 to -1.04), and serum sodium (MD +2.61 mmol/L, 95% CI +1.87 to +3.35). Evidence for effects on paracentesis frequency or mortality was of low or very low certainty. Hepatic function abnormalities represent a confirmed, frequent adverse drug reaction (9.6% in real-world surveillance), with clinically significant ALT elevations occurring 3–14 months after treatment initiation, mandating protocolised monthly liver function monitoring as a non-negotiable component of therapy. Japanese practice integrates surrogate endpoint evidence for symptom control within structured specialist pathways, whereas Western guidelines, citing drug-induced liver injury (DILI) risk and the absence of high-certainty outcome data, contraindicate or do not recommend its use. Conclusions: The evidence base is best understood as a gradient: moderate certainty for short-term physiological benefit alongside low certainty for patient-centred clinical outcomes. Divergent risk–benefit appraisals and differing healthcare infrastructures plausibly account for the Japan–West divide. The DILI signal is not an absolute barrier but a systems-dependent constraint, tightly linking feasibility to robust monitoring infrastructure. A definitive outcomes trial, coupled with validated, context-adapted monitoring protocols, is a prerequisite for global therapeutic reconsideration.