Real‐World Effectiveness of Tolvaptan for Hyponatremia in Cirrhosis Across Global Regions: A Target Trial Emulation

ABSTRACT Background Tolvaptan promotes electrolyte‐free water excretion and is widely used in Asia for ascites, but in Western countries its use is limited to hyponatremia because of hepatotoxicity concerns. Methods We performed a retrospective cohort study using the TriNetX Research Network, emulating a target trial of cirrhotic patients with hyponatremia in global regions. Patients receiving tolvaptan plus sodium supplementation were compared with those receiving sodium supplementation alone. The primary outcome was 30‐day all‐cause mortality; secondary outcomes included correction of hyponatremia, changes in liver and renal function, and initiation of hemodialysis. Survival was analyzed using Kaplan–Meier curves with the log‐rank test and Cox proportional hazards models. Propensity score matching was applied to balance baseline covariates. Results Among 188 707 eligible patients, 2130 received tolvaptan. After 1:1 matching, 1983 patients were analyzed in each group. Baseline characteristics were balanced, although serum sodium remained slightly lower in the tolvaptan group. Thirty‐day mortality was 14.4% in the tolvaptan group and 16.1% in the control group (HR 0.87, 95% CI 0.74–1.02; log‐rank p = 0.09). By the end of the follow‐up, serum sodium levels were significantly lower in the tolvaptan group. Changes in renal and liver function were comparable between groups, with no signal of excess hepatotoxicity. Rates of hemodialysis initiation did not differ significantly. Conclusions In this large real‐world target trial emulation across global regions with ethnic diversity, in the context of longstanding safety concerns in cirrhosis, tolvaptan was not associated with excess short‐term mortality, with point estimates consistently favoring its use. Further studies are warranted to clarify its safety and effectiveness in diverse clinical settings.