Letter: The Unresolved Issue of NSBB Confounding in Statin Research for Cirrhosis

We read with interest the systematic review and meta-analysis by Moraes et al., which provides a timely update on the potential benefits of statins in cirrhosis and particularly by offering a key mechanism—reduction in hepatic venous pressure gradient (HVPG)—for improved survival outcomes [1]. While commending this work, we wish to highlight a fundamental methodological concern that may affect the interpretation of the findings: the role of non-selective beta-blockers (NSBBs) not merely as an unaddressed confounder, but as a potential effect modifier in evaluating statin therapy. The authors conducted a post hoc sensitivity analysis of HVPG, restricted to RCTs in which all patients received NSBBs, suggesting an additive effect. However, NSBB use was not systematically accounted for in the pooled analyses of primary clinical outcomes, such as decompensation, HCC and mortality. As presented in table 1, NSBB utilisation varied widely across studies (0%–100%), with inconsistent reporting in observational cohorts. For example, while some RCTs (e.g., Abraldes 2016) maintained 100% NSBB use, observational studies such as Kumar 2014 showed differential baseline rates between statin users and non-users (67% vs. 74%). This heterogeneity may introduce residual confounding and could mask important pharmacodynamic interactions between statins and NSBBs. Notably, statins did not significantly reduce decompensation in RCTs (OR 0.75, 95% CI 0.52–1.09), whereas observational data showed a protective effect. This discrepancy may extend beyond residual confounding and could reflect context-dependent statin efficacy, influenced by background NSBB therapy. The central question thus evolves from whether confounding exists to what constitutes the true therapeutic interplay between statins and NSBBs. While short-term hemodynamic studies support an additive effect on HVPG, long-term RCTs (e.g., Kronborg 2023) did not demonstrate incremental HVPG reduction. This suggests that statin efficacy, both alone and in combination, may be modulated by treatment duration, aetiology and stage of cirrhosis. We therefore propose that future evidence synthesis should formally assess NSBBs as an effect modifier, ideally using individual participant data for stratified or interaction analyses. In clinical trial design and reporting, NSBB regimens should be standardised and included as a pre-specified covariate to distinguish between the independent effects of statins and the benefits of combined therapy. In conclusion, Moraes et al. have strengthened the evidence base for statins in cirrhosis. However, the interactive role of NSBBs remains incompletely defined. Clarifying whether statins act as independent disease-modifying agents or as synergistic adjuncts to NSBBs is essential for refining clinical practice. Future research must address this complexity to better position statins within the broader management strategy for portal hypertension. Deliang Huang: writing – review and editing, writing – original draft, methodology. Zhibin Zhu: writing – original draft, methodology. Jun Chen: writing – original draft, writing – review and editing. The authors have nothing to report. The authors have nothing to report. The authors have nothing to report. The authors declare no conflicts of interest. This article is linked to Moraes et al papers. To view these articles, visit https://doi.org/10.1111/apt.70526 and https://doi.org/10.1111/apt.70563. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.