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Previous studies suggested increased mortality in patients with hepatorenal syndrome type 1 (HRS1) and advanced acute-on-chronic liver failure (ACLF).To assess mortality and respiratory failure (RF) in patients with HRS1 and ACLF treated with terlipressin.In the CONFIRM study, we randomised 299 patients with HRS1 2:1 to terlipressin or placebo, both with albumin. At enrolment, all patients were assessed for organ failure (OF) using a validated ACLF grading system. Post hoc analyses assessed the effects of terlipressin vs. placebo on the incidence of RF and 90-day mortality.The incidence of RF with terlipressin (n = 200) was 9.4% in patients with grades 1-2 ACLF, and 30% with grade 3 ACLF (p = 0.0002); no such difference was observed in placebo-treated patients (n = 99) (6.2% grades 1-2 vs. 0% grade 3 ACLF, p 0.05). RF incidence between terlipressin and placebo in patients with grade 3 ACLF was significant (p = 0.01). Baseline predictors of RF with terlipressin were INR (p = 0.011), mean arterial pressure (p = 0.037), and SpOTerlipressin should be used with caution in patients with HRS1 and grade 3 ACLF. Patients with hypoxaemia are at increased risk of RF and mortality.

Summary Background Hepatorenal syndrome and acute kidney injury are common complications of decompensated cirrhosis, and terlipressin is recommended as first‐line vasoconstrictor therapy. However, data on its use outside of clinical trials are lacking. Aims To assess practice patterns and outcomes around vasoconstrictor use for hepatorenal syndrome in UK hospitals. Methods This was a multicentre chart review study. Data were extracted from medical records of patients diagnosed with hepatorenal syndrome and treated by vasoconstrictor drugs between January 2013 and December 2017 at 26 hospitals in the United Kingdom. The primary outcome was improvement of kidney function, defined as complete response (serum creatinine improved to ≤1.5 mg/dL), partial response (serum creatinine reduction of ≥20% but >1.5 mg/dL) and overall response (complete or partial response). Other outcomes included need for dialysis, mortality, liver transplantation and adverse events. Results Of the 225 patients included in the analysis, 203 (90%) were treated with terlipressin (median duration, 6 days; range: 2‐24 days). Mean (±standard deviation) serum creatinine at vasopressor initiation was 3.25 ± 1.64 mg/dL. Terlipressin overall response rate was 73%. Overall response was higher in patients with mild acute kidney injury (baseline serum creatinine

Background Hepatorenal syndrome type 1 (HRS-1), a form of acute kidney injury (AKI) in cirrhosis, has a median survival of days to weeks if untreated. The impact of reduction in AKI stage on overall survival in cirrhosis, independent of HRS reversal, is unclear. Methods The Randomized, placEbo-controlled, double-blind study to confirm the reVERSal of HRS-1 with terlipressin study assessed terlipressin versus placebo, both with albumin, as treatment for HRS-1 for ≤14 days. Renal dysfunction severity was categorized by AKI stage at enrollment. Baseline patient characteristics were evaluated as predictors of AKI improvement using a multivariate model; the association between AKI stage reduction and 90-day survival was assessed using linear regression. Results A total of 184 patients (terlipressin: n = 91; placebo: n = 93) with similar numbers in AKI Stages 1–3 (terlipressin/placebo, Stage 1: n = 25/26; Stage 2: n = 35/33; Stage 3: n = 31/34) were included. Predictors of AKI improvement were absence of alcoholic hepatitis, baseline serum creatinine and male gender. Overall survival was not significantly different across AKI stages (range 53–65%). In patients with no AKI worsening, 90-day survival was consistently better when AKI improved independent of HRS reversal, regardless of the initial AKI stage, with patients with Stage 1 at initial diagnosis achieving the greatest clinical benefit. A significant association was observed between AKI reduction and overall 90-day survival (P = 0.0022). Conclusions A reduction in AKI stage, independent of HRS reversal, was sufficient to improve overall survival in patients with HRS-1. The goal for HRS-1 treatment should be less stringent than absolute HRS reversal.

This study evaluated the characteristics, healthcare resource utilization (HCRU), and costs, from the payer perspective, of hepatorenal syndrome (HRS) patients covered by commercial and Medicare insurance. Mortality was assessed as a secondary outcome.Patients were identified from claims databases of commercially insured patients (OptumHealth Care Solutions Inc.) in 1998-2014 and Medicare beneficiaries in 2009-2013 (5% Standard Analytic Files). At the time of their first inpatient admission ("index date") with an HRS diagnosis (ICD-9 code 572.4), commercially insured patients must be aged 18-64 and Medicare patients must be aged 65 and older.A total of 784 commercially insured and 1061 Medicare HRS patients met the sample selection criteria. Patients were disproportionately male (commercial: 63.0%; Medicare: 57.9%) with a mean age of 54.1 among commercially insured and 74.1 among Medicare patients. Within the first 30 days, the average hospital length of stay (LOS) was 12.3 days among commercially insured and 10.8 days among Medicare patients. Based on Kaplan-Meier analyses, 36% of commercially insured and 26% of Medicare patients were readmitted within the next 30 days. During follow-up, many patients received dialysis (commercial: 33.0%; Medicare: 22.1%) or liver transplant (commercial: 10.7%; Medicare: 1.6%). Average costs within the 90 day follow-up were $157,665 for commercially insured and $48,322 for Medicare patients, with 68.3% and 78.3% of the costs incurred within the first 30 days. The primary cost driver was inpatient visits (commercial: 90.3% of costs; Medicare: 83.1% of costs), with differences between the populations consistent with lower mortality, higher dialysis rates, and higher transplant rates (both liver and kidney) among the commercially insured. Using US population and prevalence statistics, these results suggest that HRS imposes an annual total direct medical cost burden of approximately $3.0-$3.8 billion to payers over the period.HRS imposes a significant economic burden.

Summary 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

Objectives: Hepatorenal Syndrome (HRS) is characterized by renal failure in patients with advanced chronic liver disease (CLD) and is the leading cause of hospitalizations in CLD. This study examines the clinical and economic burden, outcomes, and unmet need of HRS treatment in US hospitals. Method: A retrospective cohort study was conducted based on a large electronic health records database (Cerner HealthFacts) with records for hospitalized HRS patients from January 2009–June 2015. Demographics, clinical characteristics, treatment patterns, and economic outcomes were analyzed. Prognostic indicators of cirrhosis, kidney injury, end-stage liver disease, and acute-on-chronic liver failure were used to determine mortality risk. Results: A total of 2,542 patients hospitalized with HRS were identified (average age = 57.9 years, 61.8% males, 74.2% Caucasian), with an average total hospital charge of $91,504 per patient and a mean length of stay (LOS) of 30.5 days. The mortality rate was 36.9% with 8.9% of patients discharged to hospice. Of all patients, 1,660 patients had acute kidney injury, 859 with Stage 3 disease, and 26.7% had dialysis. The 30-day readmission rate was 33.1%, 41% of which were unplanned. Nearly one-third of study patients had commercial insurance (30.2%), followed by Medicare (29.9%); hospital charges varied by LOS, receipt of dialysis, and discharge status. Regression analysis demonstrated that HRS costs are associated with LOS, dialysis, and hospital mortality. Conclusion: HRS is associated with poor outcomes and high hospital costs. Analysis of HRS cost drivers demonstrated an unmet need for additional treatment options to improve outcomes in this patient population.

Background & Aims Patients with systemic inflammatory response syndrome (SIRS) along with decompensated cirrhosis and renal dysfunction have a poor prognosis and a lower response to treatment. We evaluated the effect of SIRS on the response of hepatorenal syndrome type 1 (HRS-1) to terlipressin. Methods We performed a retrospective study of data from a trial of the effects of terlipressin (1 mg every 6 hours or placebo with concomitant albumin) in 198 patients with HRS-1, performed at 50 investigational sites in the United States and 2 in Canada from October 2010 through February 2013. We identified patients with 2 or more criteria for SIRS, without untreated infections (28 received terlipressin and 30 received placebo), and patients with less than 2 criteria for SIRS (control subjects). Primary endpoints included HRS reversal (a decrease in serum level of creatinine to ≤1.5 mg/dL), confirmed HRS reversal (defined as 2 serum creatinine levels ≤1.5 mg/dL, ≥ 48 hours apart), and survival for 90 days after treatment. Results Baseline characteristics were similar between groups, apart from slightly higher white blood cell counts and heart rates, and slightly lower serum levels of bicarbonate in patients with SIRS versus without SIRS. HRS was reversed in 42.9% of patients who received terlipressin with SIRS (12/28) versus 6.7% of patients who received placebo (2/30) ( P = .0018); confirmed HRS reversal occurred in 32.1% of patients who received terlipressin with SIRS (9/28) versus 3.3% who received placebo (1/30) ( P = .0048). A larger proportion of patients with SIRS who received terlipressin survived for 90 days without a transplant (13/28; 46.4%) than patients with SIRS who received placebo (7/30; 23.3%) ( P = .076). Conclusions In an analysis of data from a placebo-controlled study, we found that terlipressin improved renal function and reversed HRS in a higher proportion of patients with HRS-1 and SIRS than patients who received albumin plus placebo. ClincialTrials.gov, number NCT 01143246.

Hepatorenal syndrome type 1 (HRS-1) in patients with cirrhosis and ascites is a functional, potentially reversible, form of acute kidney injury characterized by rapid (2 wk) and progressive deterioration of renal function. Terlipressin is a synthetic vasopressin analogue that acts, via vascular vasopressin V1 receptors, as a systemic vasoconstrictor. We performed a phase 3 study to evaluate the efficacy and safety of intravenous terlipressin plus albumin vs placebo plus albumin in patients with HRS-1.Adult patients with cirrhosis, ascites, and HRS-1 (based on the 2007 International Club of Ascites criteria of rapidly deteriorating renal function) were assigned randomly to groups given intravenous terlipressin (1 mg, n = 97) or placebo (n = 99) every 6 hours with concomitant albumin. Treatment continued through day 14 unless the following occurred: confirmed HRS reversal (CHRSR, defined as 2 serum creatinine [SCr] values ≤1.5 mg/dL, at least 40 hours apart, on treatment without renal replacement therapy or liver transplantation) or SCr at or above baseline on day 4. The primary end point was the percentage of patients with confirmed CHRSR. Secondary end points included the incidence of HRS reversal (defined as at least 1 SCr value ≤1.5 mg/dL while on treatment), transplant-free survival, and overall survival. The study was performed at 50 investigational sites in the United States and 2 in Canada, from October 2010 through February 2013.Baseline demographic/clinical characteristics were similar between groups. CHRSR was observed in 19 of 97 patients (19.6%) receiving terlipressin vs 13 of 99 patients (13.1%) receiving placebo (P = .22). HRS reversal was achieved in 23 of 97 (23.7%) patients receiving terlipressin vs 15 of 99 (15.2%) receiving placebo (P = .13). SCr decreased by 1.1 mg/dL in patients receiving terlipressin and by only 0.6 mg/dL in patients receiving placebo (P.001). Decreases in SCr and survival were correlated (r(2) = .882; P.001). Transplant-free and overall survival were similar between groups. A significantly greater proportion of patients with CHRSR who received terlipressin survived until day 90 than patients who did not have CHRSR after receiving terlipressin (P.001); this difference was not observed in patients who did vs did not have CHRSR after receiving placebo (P = .28). There were similar numbers of adverse events in each group, but patients in the terlipressin group had more ischemic events.Terlipressin plus albumin was associated with greater improvement in renal function vs albumin alone in patients with cirrhosis and HRS-1. Patients had similar rates of HRS reversal with terlipressin as they did with albumin. ClinicalTrials.gov no: NCT01143246.