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

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 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.