Magnitude of Portal Pressure Reduction and Clinical Outcomes in Randomized Trials.

Abstract

Background & aims: Portal hypertension is a major driver of complications of cirrhosis. Observational studies suggest that reductions in hepatic venous pressure gradient (HVPG) improve prognosis, but the magnitude of risk reduction per unit HVPG decrease has not been quantified across randomized controlled trials (RCTs). We performed a meta-regression of RCTs to quantify this relationship.

Methods: We systematically searched for RCTs testing pharmacological interventions against placebo or no treatment in portal hypertension that reported both HVPG measurements and clinical outcomes. The predictor was the between-group difference in HVPG change (treatment minus control, in mmHg). Primary endpoints were all-cause mortality and variceal events, defined hierarchically as variceal progression (when reported) or variceal bleeding. We used random-effects meta-regression, weighted by the inverse variance of the log odds ratio. Sensitivity analyses tested alternative weighting schemes accounting for HVPG measurement error.

Results: Twenty-two RCTs (2,871 patients; 1,991 with HVPG measurements) were included. Each 1 mmHg greater HVPG reduction in the treatment versus control group was associated with significantly lower all-cause mortality (OR 0.850, 95% CI 0.771-0.937; p=0.004; I²=0%) and fewer variceal events (OR 0.852, 95% CI 0.744-0.976; p=0.032; I²=18.8%). Results were consistent across outcome-based, joint, and iteratively reweighted meta-regression models. Exploratory non-linear analyses showed no evidence against a linear relationship within the observed range.

Conclusions: Each mmHg of HVPG reduction achieved by pharmacological therapy is associated with, at the trial level, approximately 15% lower odds of mortality and variceal events. These findings provide a quantitative framework for interpreting HVPG changes in Phase II trials and informing the design of Phase III studies.

Impact and implications: Lowering portal pressure is central to preventing complications of cirrhosis, but the clinical benefit associated with a given treatment-related reduction in hepatic venous pressure gradient has not been quantified across randomized trials. In 22 trials, each additional 1 mmHg reduction was associated at the trial level with approximately 15% lower odds of death and variceal events. This quantitative relationship may help researchers and drug developers interpret phase II hemodynamic results and inform go/no-go decisions and phase III trial design. Because the analysis uses aggregate trial-level data, it does not establish causality or predict benefit for individual patients.