What Is Terlipressin (Terlivaz)? The Vasopressin Analog Peptide for Hepatorenal Syndrome and What the CONFIRM Trial Found

Terlipressin is a 12 amino acid synthetic peptide built on lysine-vasopressin, and in the United States it is sold as Terlivaz to improve kidney function in adults with hepatorenal syndrome, a kidney failure that develops in people with advanced cirrhosis. The [Terlivaz label](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3a35b86c-f451-4fac-8499-43019e4da354) lists an initial U.S. approval in 2022, and terlipressin is given in the hospital as an intravenous injection of 0.85 mg every 6 hours, alongside albumin, for a maximum of 14 days.

Terlipressin had been used in Europe and other parts of the world for years before it reached the U.S. market, and its path to approval says a lot about how hard hepatorenal syndrome is to treat. One large American trial missed its primary endpoint, a second one hit it, and the drug that finally won approval carries a boxed warning for serious or fatal respiratory failure. This article explains what terlipressin is and how the peptide works, walks through what the CONFIRM, REVERSE and comparison trials found, and then covers who should not receive it and what the evidence still does not answer. It is educational content about published research, not medical advice.

Hepatorenal syndrome is a form of kidney failure that happens in people with advanced cirrhosis and fluid in the abdomen (ascites), even though the kidneys themselves are structurally normal. The kidneys fail because of how severe liver disease reshapes blood flow: blood pools in the dilated vessels of the gut and the portal system, the effective blood volume reaching the rest of the body falls, and the kidneys respond by clamping down their own circulation.

Because the kidney damage in hepatorenal syndrome is functional rather than structural, it can in principle be reversed. The [REVERSE trial investigators](https://doi.org/10.1053/j.gastro.2016.02.026) described type 1 hepatorenal syndrome as "a functional, potentially reversible, form of acute kidney injury" in patients with cirrhosis and ascites, and newer terminology calls the same condition hepatorenal syndrome with acute kidney injury (HRS-AKI).

The definitive treatment for hepatorenal syndrome is a liver transplant, because a new liver removes the circulatory problem that drives the kidney failure. Terlipressin is used to buy time, with the goal of getting kidney function back while the patient is evaluated for, or waiting for, a transplant. If you are interested in how other drugs act on kidney outcomes, the [GLP-1 kidney disease and FLOW trial article](/articles/glp-1-kidney-disease-flow-trial) covers a very different population with chronic kidney disease.

Terlipressin works by squeezing the overly relaxed blood vessels of the gut and portal system, which pushes more blood back into the general circulation and raises the pressure that drives blood through the kidneys. The Terlivaz label states that terlipressin "is thought to increase renal blood flow in patients with hepatorenal syndrome by reducing portal hypertension and blood circulation in portal vessels and increasing effective arterial volume and mean arterial pressure."

Terlipressin acts on vasopressin receptors, and according to the label it has twice the selectivity for vasopressin V1 receptors, which constrict blood vessels, as for V2 receptors, which control water retention in the kidney. That V1 preference is the reason terlipressin is used as a vasoconstrictor rather than as an antidiuretic.

The label's pharmacodynamic data show how fast terlipressin acts. After a single 0.85 mg dose in patients with type 1 hepatorenal syndrome, blood pressure rose and heart rate fell within 5 minutes and stayed changed for at least 6 hours. The largest effect came at 1.2 to 2 hours after the dose, with an estimated maximum increase in mean arterial pressure of 16.2 mmHg and an estimated maximum decrease in heart rate of 10.6 beats per minute.

Terlipressin is lysine-vasopressin with three extra glycine units attached to its front end. The Terlivaz label gives its chemical name as N-[N-(N-glycylglycyl)glycyl]-8-L-lysinevasopressin, describes it as a 12 amino acid peptide, and lists an average molecular weight of 1227.38 as the free base.

Those added glycines turn terlipressin into a prodrug, because peptidases in body tissues clip the glycine units off and release lysine-vasopressin, the active hormone. The label notes that terlipressin "acts as both a prodrug for lysine-vasopressin, as well as having pharmacologic activity on its own." Terlipressin is not broken down in blood or plasma, and less than 1% is excreted in urine.

The prodrug design changes the timing of the drug. In the label's population pharmacokinetic model of 69 patients with type 1 hepatorenal syndrome, the terminal half life was 0.9 hours for terlipressin itself and 3.0 hours for the lysine-vasopressin it releases. For a broader explanation of why half life drives how often a peptide is dosed, see the [peptide half life and dosing frequency guide](/articles/peptide-half-life-dosing-frequency).

The CONFIRM trial found that terlipressin plus albumin roughly doubled the rate of verified hepatorenal syndrome reversal compared with albumin alone, but it did not improve survival and it increased respiratory failure. Wong and colleagues published CONFIRM in the [New England Journal of Medicine in 2021](https://doi.org/10.1056/NEJMoa2008290), and it is the trial the FDA relied on for approval.

CONFIRM randomized 300 adults with cirrhosis and type 1 hepatorenal syndrome in a 2:1 ratio, 199 to terlipressin and 101 to placebo, for up to 14 days, and albumin was strongly recommended in both groups. The label describes a sick population with a median age of 55, 40% with alcoholic hepatitis, 19% with grade 3 ACLF, a mean serum creatinine of 3.5 mg/dL and a mean MELD score of 33. Patients needed a serum creatinine of at least 2.25 mg/dL to enter, and those above 7.0 mg/dL were excluded.

The primary endpoint was verified reversal of hepatorenal syndrome, meaning two consecutive serum creatinine values of 1.5 mg/dL or less at least 2 hours apart, plus survival without dialysis for at least 10 days after treatment ended.

The primary result was statistically significant (P = 0.006). The subgroup with systemic inflammatory response syndrome (SIRS) showed the widest gap, with 37% reversal on terlipressin versus 6% on placebo, while reversal that lasted to day 30 without recurrence, 26% versus 17%, did not reach significance (P = 0.08).

The FDA label presents a slightly different count for the same trial. In the label's efficacy table, verified HRS reversal was 58 of 199 (29.1%) on Terlivaz versus 16 of 101 (15.8%) on placebo (p = 0.012). The direction and size of the effect are the same, and the difference reflects how the label's version of the endpoint was analyzed, so you should expect to see both the 32% and the 29.1% figures when comparing sources.

The REVERSE trial, published by Boyer and colleagues in [Gastroenterology in 2016](https://doi.org/10.1053/j.gastro.2016.02.026), did not show a statistically significant improvement on its primary endpoint. REVERSE randomized 196 patients at 50 U.S. and 2 Canadian sites between 2010 and 2013 to terlipressin 1 mg every 6 hours (97 patients) or placebo (99 patients), both with albumin.

Confirmed hepatorenal syndrome reversal occurred in 19.6% on terlipressin versus 13.1% on placebo (P = .22), and any HRS reversal was 23.7% versus 15.2%. Serum creatinine did fall more on terlipressin, by 1.1 mg/dL versus 0.6 mg/dL, a difference that was significant, but transplant free and overall survival were similar.

CONFIRM was larger and was designed with a 2:1 randomization to gather more data on terlipressin. The mixed REVERSE result is part of why the evidence for terlipressin is usually discussed in terms of how large and how durable the kidney benefit is compared with its safety cost.

Before Terlivaz was approved, U.S. hospitals commonly treated hepatorenal syndrome with midodrine, an oral vasoconstrictor, plus octreotide, a somatostatin analog peptide, together with albumin. In the one randomized comparison of the two approaches, terlipressin worked clearly better.

Cavallin and colleagues, writing in [Hepatology in 2015](https://doi.org/10.1002/hep.27709), randomized 27 patients to terlipressin plus albumin and 22 to midodrine and octreotide plus albumin. Kidney function recovered in 19 of 27 (70.4%) on terlipressin versus 6 of 21 (28.6%) on midodrine and octreotide (P = 0.01).

The trial was small, and terlipressin was given as a continuous infusion that started at 3 mg per 24 hours, so the dosing differs from the U.S. label. For background on octreotide itself, see the [octreotide somatostatin analog article](/articles/octreotide-somatostatin-analog-acromegaly-neuroendocrine-tumors).

The Terlivaz label dose is 0.85 mg (one vial) by slow intravenous bolus over 2 minutes every 6 hours on Days 1 to 3, followed by a Day 4 adjustment based on serum creatinine. Each vial contains 0.85 mg terlipressin, equivalent to 1 mg terlipressin acetate.

Treatment continues until 24 hours after two consecutive serum creatinine values of 1.5 mg/dL or less taken at least 2 hours apart, or for a maximum of 14 days. Before the first dose, the label requires a baseline oxygen saturation reading and an assessment of ACLF grade and volume status, followed by continuous pulse oximetry during treatment.

The vial is a powder that is reconstituted with 5 mL of 0.9% sodium chloride. Unopened vials are stored refrigerated at 2°C to 8°C (36°F to 46°F), and reconstituted solution can be held refrigerated for up to 48 hours.

A continuous infusion of terlipressin was better tolerated than boluses in one Italian trial, although the U.S. label specifies bolus dosing. Cavallin and colleagues ([Hepatology, 2016](https://doi.org/10.1002/hep.28396)) randomized 78 patients with type 1 hepatorenal syndrome, and adverse events occurred in 35.29% of the infusion group versus 62.16% of the bolus group.

Response rates were 76.47% versus 64.85%, which was not a significant difference, and the mean daily effective dose was lower with infusion, 2.23 versus 3.51 mg per day. No large trial in the U.S. has tested infusion dosing.

The most common side effects of terlipressin in CONFIRM were abdominal pain, nausea, respiratory failure, diarrhea and shortness of breath, each affecting at least 10% of treated patients. Most of these follow from terlipressin's main action, which is constricting blood vessels, including those that supply the gut.

Treatment was stopped because of adverse events in 12.0% of Terlivaz patients and 5.1% of placebo patients. Postmarketing reports with terlipressin worldwide include headache, low sodium (hyponatremia), skin necrosis and gangrene.

Slowing of the heart rate is expected from the drug's mechanism. A pooled analysis of the three North American phase 3 trials, OT-0401, REVERSE and CONFIRM ([Bajaj, Alimentary Pharmacology and Therapeutics, 2025](https://doi.org/10.1111/apt.70297)), found bradycardia in 6.3% of terlipressin patients (22 of 349) versus 0.8% on placebo (2 of 249). None of the bradycardia events were serious, and other arrhythmias occurred at similar rates, 7.4% versus 8.8%.

Terlipressin carries a boxed warning because serious or fatal respiratory failure occurred in 14% of Terlivaz patients compared with 5% on placebo in CONFIRM, according to the label. Fluid overload is one likely contributor, since patients also receive albumin, and the label advises managing it by reducing or stopping albumin and other fluids.

The risk was concentrated in the sickest patients. In a post hoc analysis of CONFIRM ([Wong, Alimentary Pharmacology and Therapeutics, 2022](https://doi.org/10.1111/apt.17195)), respiratory failure on terlipressin occurred in 9.4% of patients with grades 1 to 2 ACLF but in 30% of those with grade 3 ACLF, while in the placebo group the rates were 6.2% and 0%.

Ninety day survival in grade 3 ACLF was 27.55% on terlipressin versus 50.0% on placebo, while in grades 1 to 2 it was similar, 55.5% versus 56.6%. That is why the label says to avoid use in patients with ACLF grade 3, not to start treatment when oxygen saturation is below 90%, and to stop treatment if saturation falls below 90% during therapy.

Terlipressin is contraindicated in people with low oxygen levels or worsening breathing symptoms, and in people with ongoing coronary, peripheral or mesenteric ischemia. Beyond the formal contraindications, the label narrows the group most likely to benefit.

The transplant point matters because respiratory failure or ischemia could make a listed patient ineligible for surgery, which is why the label says that for patients with a MELD score of 35 or higher the benefits may not outweigh the risks.

Terlipressin may help transplant candidates arrive at surgery with better kidney function, according to a post hoc analysis of CONFIRM. Weinberg and colleagues ([Liver Transplantation, 2024](https://doi.org/10.1097/LVT.0000000000000277)) followed the 70 CONFIRM patients (23%) who received a liver transplant alone for 12 months.

Among those transplant recipients, hepatorenal syndrome reversal before transplant was 37% on terlipressin versus 15% on placebo. The need for dialysis was lower before transplant in the terlipressin group, and at 12 months fewer surviving terlipressin patients needed dialysis after transplant. Because this is a post hoc analysis of a subgroup, the finding is supportive rather than definitive.

The terlipressin evidence clearly supports one thing, which is that more patients with hepatorenal syndrome get their kidney function back, but several important questions remain open.

Neither CONFIRM nor REVERSE showed that terlipressin helps people live longer, and CONFIRM's day 90 mortality was numerically higher on terlipressin (51% versus 45%). The best way to give the drug is also unsettled, since the U.S. label uses boluses while the 2016 Italian trial suggests a continuous infusion is better tolerated at lower doses.

The respiratory failure signal shows that choosing the right patient, meaning a lower ACLF grade, normal oxygen and controlled fluid status, matters as much as the drug itself. Finally, the comparison with midodrine and octreotide comes from a single trial of 49 patients, so the size of terlipressin's advantage over the older regimen is not precisely known.

Terlipressin (Terlivaz) is a 12 amino acid vasopressin analog peptide that works as a prodrug for lysine-vasopressin, tightening the blood vessels of the gut and portal system so that more blood reaches the kidneys. In the CONFIRM trial it roughly doubled the rate of verified hepatorenal syndrome reversal compared with albumin alone, and in a small head to head trial it outperformed midodrine and octreotide.

That kidney benefit comes with a real cost, because respiratory failure was more common on terlipressin and was concentrated in patients with grade 3 ACLF, and no trial has shown that terlipressin helps people live longer. Terlipressin is a hospital drug for a narrow group of very sick patients, and the decisions about who should get it belong to hepatology and transplant teams.