Subgroup analysis CONFIRMs telipressin potential for treating HRS, alcoholic hepatitis

In individuals with hepatorenal syndrome (HRS) compounded by alcoholic hepatitis (AH), treatment with the synthetic, long-acting vasopressin analogue terlipressin led to the achievement of verified HRS reversal, a subgroup analysis of the phase III CONFIRM trial has shown.

“In this subgroup analysis, verified HRS reversal was achieved by a substantially greater proportion of subjects on terlipressin compared with those on placebo (31 percent vs 8 percent). The between-group difference was statistically evident (p=0.005),” said Dr Kevin Korenblat from Washington University School of Medicine, St Louis, Missouri, US, during his presentation at DDW 2023.

Quantitately speaking, the 8 percent verified HRS reversal rate in the placebo arm represented only three out of 39 patients, as opposed to 25 out of the 81 terlipressin-treated patients.

The verified HRS reversal rate in the terlipressin arm was similar to that seen in the parent trial (32 percent), whereas the rate in the placebo arm was much lower than the rate reported in the parent CONFIRM cohort (17 percent). [N Engl J Med 2021;348:818-828]

Rates of admission to the intensive care unit (ICU) were similar between arms (17 percent vs 18 percent), but those in the terlipressin arm tended to have a shorter length of stay in the ICU by an average of about 5 days compared with those in the placebo arm (6.9 vs 12.4 days). Korenblat noted that the difference was not statistically inferable (p=0.514). [DDW 2023, abstract 651]

At day 90, median transplant-free survival (TFS) was longer with terlipressin vs placebo (28 vs 15 days), but the survival plots revealed no significant difference between arms (p=0.207). This effect, according to Korenblat, might have been driven by the small sample size.

Renal replacement therapy rate by day 30 was slightly lower with terlipressin vs placebo (21 percent vs 26 percent; p=0.5675). The rate in the terlipressin arm roughly mirrors that seen in the CONFIRM trial while for placebo, it was higher.

Study entry criteria required doubling of serum creatinine to ≥2.25 mg/dL within 14 days prior to randomization despite diuretic withdrawal and 48 hours of albumin administration. Three-hundred subjects were randomized 2:1 to receive either terlipressin 1 mg IV Q6H or placebo. Concomitant albumin was recommended (1 g/kg on day 1 up to 100 g then 20–40 g/day as clinically warranted).

Subjects received 10 doses of the study drug, which was stopped if creatinine remained at or above baseline, or continued if it improved after the starting dose (if the improvement was ≤30 percent from baseline, the dose was doubled). Responders received the medication until serum creatinine reached ≤1.5 mg/dL ≥2 hours apart or until day 14. Subjects were followed for 90 days.

The current analysis focused on participants with known or suspected AH (n=120), which further amplifies the high mortality risk of HRS. AH also harbours a poor prognosis. Mean age was about 50 years in the terlipressin arm and 46 years in the placebo arm. About 70 percent of the population were male. Median serum creatinine was 3.4 mg/dL in both arms.

In summary, the current data suggest that treatment with terlipressin was associated with higher rates of verified HRS reversal in a subgroup of patients with HRS and concurrent AH. This subgroup of terlipressin recipients also had shorter durations of ICU stay, longer TFS, and a numerically lower rate of renal replacement therapy.

“These data strongly support the role for terlipressin for individuals with type 1 HRS and AH,” Korenblat concluded.

Terlipressin has been approved by the US FDA in September 2022 for the treatment of HRS.