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Use of the vasoconstrictor was associated with increased risk for death due to respiratory disorders.
Findings from a new study confirmed the efficacy of terlipressin in adults with cirrhosis and type 1 hepatorenal syndrome (HRS-1).
Although the vasoconstrictor led to improved renal function, it was nonetheless associated with serious adverse events, including respiratory failure.
The phase 3 CONFIRM trial, led by Florence Wong, MD, Department of Medicine, University of Toronto, evaluated patients with HRS-1, cirrhosis, ascites, and rapidly progressive kidney failure.
The primary outcome sought by the investigators was verified reversal of HRS, which they defined as “2 consecutive serum creatinine measurements of 1.5 mg per deciliter or less at least 2 hours apart and survival without renal-replacement therapy for at least 10 days after the completion of treatment.”
Terlipressin and HRS-1
Wong and colleagues randomized a total of 300 patients 2:1 to receive terlipressin or placebo, with a recommended addition of albumin.
Treatment was administered for up to 14 days, and included intravenous administration of 1 mg of either agent over 2 minutes every 5.5-6.5 hours.
“On day 4, patients with a serum creatinine level that had decreased by less than 30% from the baseline level after a minimum of 10 doses of terlipressin or placebo could receive 2 mg every 6 hours, except in those with coronary artery disease, circulatory overload, pulmonary edema, or bronchospasm,” noted the investigators.
As such, of the entire population, verified HRS reversal was identified in 32% of patients in the terlipressin group and 17% in the placebo group (P = .006).
“With respect to the prespecified secondary end points," the team wrote, "HRS reversal, defined as any serum creatinine level of 1.5 mg per deciliter or less during the first 14 days, was reported in 78 patients (39%) in the terlipressin group and 18 (18%) in the placebo group (P < .001)."
Further, 34% in the terlipressin group and 17% in the placebo experienced HRS reversal without renal-replacement therapy by day 30 (P = .001).
The investigators also noted that 84 patients in the terlipressin group and 48 patients in the placebo group had systemic inflammatory response syndrome. As such, 37% and 6%, respectively, likewise experienced verified HRS reversal without recurrence by day 30 (P < .001).
Verified reversal of HRS without recurrence by day 30 occurred in 26% of terlipressin patients and 17% in the placebo group (P = .08).
Safety and Adverse Events
Liver transplantation occurred in 23% in the terlipressin group and 29% in the placebo group at day 90; however, death occurred in 51% of terlipressin-users and 45% of placebo-users.
Adverse events, including abdominal pain, nausea, diarrhea, and respiratory failure, were reported more often with terlipressin than placebo.
And finally, death within 90 days due to respiratory disorders occurred in 11% of terlipressin patients and 2% in placebo patients.
“Overall, the results of the CONFIRM Study are in accordance with the data from previous clinical trials that provided evidence that terlipressin improves kidney function in patients with HRS-1,” indicated Wong and team.
Nonetheless, they cautioned use of the drug in patients who are more advanced in liver disease—citing the increased risk for adverse events and death.
The study, “Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome,” was published online at New England Journal of Medicine.