The synthetic vasopressin analog terlipressin improves kidney function in patients with type 1 hepatorenal syndrome (HRS- 1)—but with a high rate of serious adverse events, reports a clinical trial in The New England Journal of Medicine.
The CONFIRM Study (A Multi-Center, Randomized, Placebo Controlled, Double-Blind Study to Confirm Efficacy and Safety of Terlipressin in Subjects with Hepatorenal Syndrome Type 1), a randomized, phase 3 trial, included 300 adults with cirrhosis and HRS-1 treated at 60 North American centers. In a 2:1 ratio, patients were assigned to 30 days of treatment with terlipressin or placebo; concomitant albumin therapy was “strongly recommended” for both groups. The main efficacy outcome was reversal of HRS, verified by two consecutive serum creatinine levels of 1.5 mg/dL or less (at least 2 hours apart) and survival free of kidney replacement therapy for at least 10 days after the end of treatment.
Terlipressin was associated with a higher rate of verified reversal of HRS: 32% compared to 17% in the placebo group. Secondary outcome analysis also favored terlipressin, including any serum creatinine level of 1.5 mg/dL or less within 14 days, 39% versus 18%; HRS reversal without kidney replacement therapy within 30 days, 34% versus 17%; HRS reversal among patients with systemic inflammatory response syndrome, 37% versus 6%; and verified reversal of HRS without recurrence by 30 days, 26% versus 17%.
By 90 days, 23% of patients in the terlipressin group and 29% in the placebo group had undergone liver transplantation. Ninety-day mortality rates were 51% and 45%, respectively. Terlipressin was associated with higher rates of adverse events, including abdominal pain, nausea, diarrhea, and respiratory failure. Adverse outcomes included an 11% rate of death due to respiratory disorders in the terlipressin group compared to 2% in the placebo group.
With its vasoconstrictor activity, terlipressin is used as a treatment for HRS-1 in some parts of the world and is included in European clinical practice guidelines. The CONFIRM trial was designed to confirm the efficacy of terlipressin plus albumin for adults with cirrhosis and HRS-1.
The results show significant improvements in verified reversal of HRS-1 and initial survival in patients treated with terlipressin compared to placebo. However, terlipressin is associated with substantial rates of serious adverse events, including respiratory failure. The researchers write, “Terlipressin should be used with caution in patients who have the most advanced liver disease” [Wong F, et al. Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome. N Engl J Med 2021; 384:818–828. doi: 10.1056/NEJMoa2008290].