LandmarkRCT

CONFIRM

Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome

New England Journal of Medicine, 2021 · Phase 3, multicenter, randomized (2:1), placebo-controlled trial

Clinical question

Does terlipressin plus albumin reverse type 1 hepatorenal syndrome compared with placebo plus albumin?

Population: 300 adults with cirrhosis and type 1 hepatorenal syndrome (199 randomized to terlipressin, 101 to placebo).
Intervention: Terlipressin for up to 14 days, with concomitant albumin strongly recommended.
Comparator: Placebo for up to 14 days, with concomitant albumin strongly recommended.
Primary outcome: Verified reversal of HRS: two consecutive serum creatinine values of 1.5 mg/dL or less at least 2 hours apart, and survival without renal-replacement therapy for at least 10 days after treatment.
Secondary outcomes: HRS reversal (any creatinine of 1.5 mg/dL or less in the first 14 days).
HRS reversal without renal-replacement therapy by day 30.
HRS reversal among patients with systemic inflammatory response syndrome.
Verified HRS reversal without recurrence by day 30.
Result: Terlipressin improved verified HRS reversal but caused more serious adverse events, including respiratory failure, and 90-day mortality was not lower. (Verified HRS reversal 32% vs 17%; death within 90 days from respiratory disorders 11% vs 2%; death at 90 days 51% vs 45%., p = 0.006 for verified HRS reversal)

What the trial found

Verified reversal of HRS occurred in 63 of 199 patients (32%) on terlipressin and 17 of 101 (17%) on placebo. More adverse events occurred with terlipressin, including abdominal pain, nausea, diarrhea and respiratory failure; death within 90 days from respiratory disorders was 11% vs 2%. At day 90, death had occurred in 51% vs 45% and liver transplantation in 23% vs 29%.

Current guideline position

AASLD 2021 guidance supports vasoconstrictor therapy for HRS-AKI when indicated. After CONFIRM, terlipressin was approved by the US FDA in 2022 with a boxed warning for serious or fatal respiratory failure.

Clinical interpretation

CONFIRM shows terlipressin plus albumin improves renal function in HRS-AKI but does not by itself show a survival benefit, and the respiratory-failure signal means selection and monitoring (volume status, oxygenation) matter. It is a bridge to recovery or transplant, not definitive therapy.

Limitations

The primary end point was renal reversal rather than survival; 90-day mortality was 51% vs 45%.
Albumin use was strongly recommended rather than mandated, and the trial was funded by the manufacturer.
Respiratory failure was more frequent with terlipressin, which limits use in patients with volume overload or poor oxygenation.

Moderate certainty

Clinical Context & Relevant Topics (2)

Disease Reference

Hepatorenal Syndrome–AKI

Diagnosis and ICU management of HRS-AKI with albumin, vasoconstrictors, respiratory-safety monitoring, RRT and transplant planning

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Decompensated Cirrhosis & ACLF

Recognition and organ-support of decompensated cirrhosis and acute-on-chronic liver failure, including bleeding, infection, encephalopathy and transplant triage

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