Dataset Information

Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies.

ABSTRACT:

Background

The goal of hepatorenal syndrome type 1 (HRS-1) treatment is to improve renal function. Terlipressin, a synthetic vasopressin analogue, is a systemic vasoconstrictor used for the treatment of HRS-1, where it is available.

Aim

To compare the efficacy of terlipressin plus albumin vs. placebo plus albumin in patients with HRS-1.

Methods

Pooled patient-level data from two large phase 3, randomised, placebo-controlled studies were analysed for HRS reversal [serum creatinine (SCr) value ≤133 μmol/L], 90-day survival, need for renal replacement therapy and predictors of HRS reversal. Patients received intravenous terlipressin 1-2 mg every 6 hours plus albumin or placebo plus albumin up to 14 days.

Results

The pooled analysis comprised 308 patients (terlipressin: n = 153; placebo: n = 155). HRS reversal was significantly more frequent with terlipressin vs. placebo (27% vs. 14%; P = 0.004). Terlipressin was associated with a more significant improvement in renal function from baseline until end of treatment, with a mean between-group difference in SCr concentration of -53.0 μmol/L (P < 0.0001). Lower SCr, lower mean arterial pressure and lower total bilirubin and absence of known precipitating factors for HRS were independent predictors of HRS reversal and longer survival in terlipressin-treated patients.

Conclusions

Terlipressin plus albumin resulted in a significantly higher rate of HRS reversal vs. albumin alone in patients with HRS-1. Terlipressin treatment is associated with improved renal function. (ClinicalTrials.gov identifier: OT-0401, NCT00089570; REVERSE, NCT01143246).

SUBMITTER: Sanyal AJ

PROVIDER: S-EPMC5434950 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Publications

Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies.

Sanyal A J AJ Boyer T D TD Frederick R T RT Wong F F Rossaro L L Araya V V Vargas H E HE Reddy K R KR Pappas S C SC Teuber P P Escalante S S Jamil K K

Alimentary pharmacology & therapeutics 20170329 11

<h4>Background</h4>The goal of hepatorenal syndrome type 1 (HRS-1) treatment is to improve renal function. Terlipressin, a synthetic vasopressin analogue, is a systemic vasoconstrictor used for the treatment of HRS-1, where it is available.<h4>Aim</h4>To compare the efficacy of terlipressin plus albumin vs. placebo plus albumin in patients with HRS-1.<h4>Methods</h4>Pooled patient-level data from two large phase 3, randomised, placebo-controlled studies were analysed for HRS reversal [serum crea ...[more]

PMID: 28370090

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Project description:IntroductionIn series of cases and animal models suffering hemorrhagic shock, the use of vasopressors has shown potential benefits regarding hemodynamics and tissue perfusion. Terlipressin is an analogue of vasopressin with a longer half-life that can be administered by bolus injection. We have previously observed that hypertonic albumin improves resuscitation following controlled hemorrhage in piglets. The aim of the present study was to analyze whether the treatment with the combination of terlipressin and hypertonic albumin can produce better hemodynamic and tissular perfusion parameters than normal saline or hypertonic albumin alone at early stages of hemorrhagic shock in an infant animal model.MethodsExperimental, randomized animal study including 39 2-to-3-month-old piglets. Thirty minutes after controlled 30 ml/kg bleed, pigs were randomized to receive either normal saline (NS) 30 ml/kg (n = 13), 5% albumin plus 3% hypertonic saline (AHS) 15 ml/kg (n = 13) or single bolus of terlipressin 15 μg/kg i.v. plus 5% albumin plus 3% hypertonic saline 15 ml/kg (TAHS) (n = 13) over 30 minutes. Global hemodynamic and tissular perfusion parameters were compared.ResultsAfter controlled bleed a significant decrease of blood pressure, cardiac index, central venous saturation, carotid and peripheral blood flow, brain saturation and an increase of heart rate, gastric PCO2 and lactate was observed. After treatment no significant differences in most hemodynamic (cardiac index, mean arterial pressure) and perfusion parameters (lactate, gastric PCO2, brain saturation, cutaneous blood flow) were observed between the three therapeutic groups. AHS and TAHS produced higher increase in stroke volume index and carotid blood flow than NS.ConclusionsIn this pediatric animal model of hypovolemic shock, albumin plus hypertonic saline with or without terlipressin achieved similar hemodynamics and perfusion parameters than twice the volume of NS. Addition of terlipressin did not produce better results than AHS.

Project description:IntroductionHepatorenal syndrome (HRS), a special form of acute kidney failure, is a rare, acute, life-threatening complication of cirrhosis and has a very poor prognosis. Terlipressin (TERLIVAZ®) is the first and only pharmacological treatment approved by Food and Drug Administration (September 2022) to improve kidney function for adults with HRS with rapid reduction in kidney function. We constructed a decision analytic economic model to estimate the cost per complete response/HRS reversal of terlipressin + albumin from a United States hospital perspective.MethodsA decision analytic model was developed to estimate the HRS treatment-related cost per response over an HRS hospitalization (assuming 14 days). Patients can experience either HRS reversal (complete response) or no HRS reversal (partial/no response) upon receipt of treatment. The efficacy, safety, and treatment duration data were from published head-to-head randomized international trials. Total treatment cost comprised drug acquisition and treatment-related costs (intensive care unit [ICU], dialysis [intermittent or continuous], pulse oximetry monitoring for terlipressin, and adverse events) sourced from the published literature. Cost per response, defined as the total treatment cost per HRS reversal was estimated for each treatment. The number needed to treat (NNT), defined as the number of patients treated to achieve HRS reversal in 1 additional patient, was estimated.ResultsCost per response of terlipressin + albumin was lower than midodrine and octreotide + albumin (M&O) (US$85,315 vs. $467,794) and norepinephrine + albumin ($81,614 vs. $139,324). NNT for HRS reversal was 2 patients with terlipressin + albumin vs. M&O + albumin and 4 patients with terlipressin + albumin vs. norepinephrine + albumin, respectively.ConclusionsThe analysis shows that terlipressin is a cost-effective treatment due to its higher efficacy and administration in the non-ICU setting. Terlipressin is a value-based treatment option for appropriate adults with HRS with rapid reduction in kidney function.

Project description:The treatment of choice for hepatorenal syndrome-acute kidney injury (HRS-AKI) is vasoconstrictor therapy in combination with albumin, preferably norepinephrine or terlipressin as recommended by recent guidelines. In the absence of larger head-to-head trials comparing the efficacy of terlipressin and norepinephrine, meta-analysis of smaller studies can provide insights needed to understand the comparative effects of these medications. Additionally, recent changes in the HRS diagnosis and treatment guidelines underscore the need for newer analyses comparing terlipressin and norepinephrine. In this systematic review, we aimed to assess reversal of hepatorenal syndrome (HRS) and 1-month mortality in subjects receiving terlipressin or norepinephrine for the management of HRS-AKI. We searched literature databases, including PubMed, Cochrane, Clinicaltrials.gov, International Clinical Trials Registry Platform, Embase, and ResearchGate, for randomized controlled trials (RCTs) published from January 2007 to June 2023 on June 26, 2023. Only trials comparing norepinephrine and albumin with terlipressin and albumin for the treatment of HRS-AKI in adults were included, and trials without HRS reversal as an endpoint or nonresponders were excluded. Pairwise meta-analyses with the random effects model were conducted to estimate odds ratios (ORs) for HRS reversal and 1-month mortality as primary outcomes. Additional outcomes assessed, included HRS recurrence, predictors of response, and incidence of adverse events (AEs). We used the Cochrane risk of bias assessment tool for quality assessment. We included 7 RCTs with a total of 376 subjects with HRS-AKI or HRS type 1. This meta-analysis showed numerically higher rates of HRS reversal (OR 1.33, 95% confidence interval [CI] [0.80-2.22]; P = 0.22) and short-term survival (OR 1.50, 95% CI [0.64-3.53]; P = 0.26) with terlipressin, though these results did not reach statistical significance. Terlipressin was associated with AEs such as abdominal pain and diarrhea, whereas norepinephrine was associated with cardiovascular AEs such as chest pain and ischemia. Most of the AEs were reversible with a reduction in dose or discontinuation of therapy across both arms. Of the terlipressin-treated subjects, 5.3% discontinued therapy due to serious AEs compared to 2.7% of the norepinephrine-treated subjects. Limitations of this analysis included small sample size and study differences in HRS-AKI diagnostic criteria. As more studies using the new HRS-AKI criteria comparing terlipressin and norepinephrine are completed, a clearer understanding of the comparability of these 2 therapies will emerge.

Dataset Information

Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies.

Background

Aim

Methods

Results

Conclusions

Publications

Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies.

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