The relationship between mean arterial pressure and terlipressin in hepatorenal syndrome-acute kidney injury reversal: A post hoc analysis

Background and Aims: – Terlipressin reverses hepatorenal syndrome-acute kidney injury (HRS-AKI) by increasing mean arterial pressure (MAP). To further characterize the relationship between terlipressin and MAP and their impact on HRS-AKI reversal, we used patient-level data from phase 3 clinical trials REVERSE and CONFIRM. Approach and Results: – In this post hoc analysis we employed a linear mixed-effects model to assess terlipressin’s impact on MAP, exploring the relationship between MAP, treatment group, and time, incorporating a random intercept for individual patients. Time-dependent Cox models analyzed MAP’s role in HRS-AKI reversal. We conducted a mediation analysis to evaluate how time-weighted MAP mediated HRS-AKI reversal. This analysis included 487 patients (60% terlipressin, 40% placebo). At baseline, there were no differences in median MAP between terlipressin and placebo (77 mm Hg vs. 76 mm Hg, p=0.3); the terlipressin group had significantly higher MAPs after randomization (day 1: 85 mm Hg vs. 75 mm Hg; day 3: 81 mm Hg vs. 76 mm Hg; all: p<0.001). In mixed-effects models, terlipressin was associated with a 6.0 mm Hg increase in MAP over placebo occurring on day 1, with no significant interaction between the treatment group and time (p>0.05). In time-dependent Cox models, each 5 mm Hg increase in MAP was associated with 1.17× the hazard of HRS-AKI reversal (95% CI: 1.11–1.22). In mediation analysis, MAP significantly mediated HRS-AKI reversal, regardless of treatment group (average proportion mediated: 33%, 95% CI: 14–76). Conclusions: – These data highlight that terlipressin leads to an early, sustained increase in MAP, which is a key pharmacodynamic target for HRS-AKI reversal.