HRS reversal feasible in select HRS patients despite terlipressin dose interruption

In patients with hepatorenal syndrome (HRS) accompanied by rapidly progressive worsening in kidney function, a dose interruption of terlipressin did not appear to influence the achievement of HRS reversal, according to the results from the phase III CONFIRM study presented at DDW 2024.

Among patients who had a dose interruption, the improvement in renal function was numerically greater in the terlipressin vs the placebo arm, as reflected by the higher rates of verified HRS reversal (39.4 vs 28.6 percent; p=0.318) and HRS reversal with the former vs the latter (47 vs 28.6 percent; p=0.098). [DDW 2024, poster Sa1578]

This treatment effect favouring terlipressin over placebo was similarly seen among those who did not have a dose interruption, but the between-group differences were significant (23.9 vs 11.3 percent; p=0.030 [verified HRS reversal] and 30.6 vs 12.7 percent; p=0.004 [HRS reversal]).

When comparing the subgroups of terlipressin-treated patients who did and did not have a dose interruption, the rates of verified HRS reversal and HRS reversal were higher in the former vs the latter group (p=0.023 for both). The same was true for the placebo arm (p=0.035 and p=0.059, respectively).

Verified HRS reversal – the study’s primary endpoint – was defined as two consecutive serum creatinine (sCr) measurements ≤1.5 mg/dL (133 μmol/L) at least 2 hours apart up to day 14 and survival in the absence of renal replacement therapy for at least an additional 10 days. HRS reversal, a prespecified secondary endpoint, was defined as sCr ≤1.5 mg/dL up to day 14. [N Engl J Med 2021;384:818-828]

To determine whether a dose interruption affected the achievement of HRS reversal, Mumtaz and colleagues conducted a retrospective analysis of the safety population of CONFIRM (n=299). Thirty-three percent of terlipressin recipients had a dose interruption for any reason; the corresponding rate in the placebo arm was 28.3 percent.

The proportions of patients with a dose interruption due to AEs were similar between the terlipressin and placebo arms (7 vs 7.1 percent; p=0.982). As per protocol, following a dose interruption, the study drug may be restarted at a reduced dose of 0.5 or 1 mg every 6–12 hours (vs the original dose of 1 mg every 6 hours).

The rate of permanent withdrawals owing to adverse events (AEs) was nonsignificantly higher in the terlipressin vs the placebo arm (12 vs 5.1 percent; p=0.056). In addition, the rates of permanent withdrawals owing to study drug-related AEs were also similar between arms (6 vs 3 percent; p=0.400).

“With careful adjustments to terlipressin dose, select patients can achieve HRS reversal at rates that are not lower than those among patients who did not require a dose modification,” said lead author Dr Khalid Mumtaz from the Division of Gastroenterology, Hepatology and Nutrition, Ohio State University, Columbus, Ohio, US.

Mumtaz and colleagues also underlined the need for clinical judgment in managing individual patients, including drug dose interruptions or modifications.