Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome.

BACKGROUND: The vasoconstrictor terlipressin is used for type 1 hepatorenal syndrome (HRS-1) in many parts of the world and is part of the clinical practice guidelines in Europe. METHODS: We conducted a phase 3 trial to confirm the efficacy and safety of terlipressin plus albumin in adults with HRS-1. The patients were randomly assigned in a 2:1 ratio to receive terlipressin or placebo for up to 14 days; in both groups, concomitant use of albumin was strongly recommended. The primary end point was verified reversal of HRS, defined as two 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. Four prespecified secondary end points were analyzed with the Hochberg procedure to account for multiple comparisons. RESULTS: A total of 300 patients underwent randomization - 199 were assigned to the terlipressin group and 101 to the placebo group. Verified reversal of HRS was reported in 63 patients (32%) in the terlipressin group and 17 patients (17%) in the placebo group (P = 0.006). With respect to the prespecified secondary end points, 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<0.001); HRS reversal without renal-replacement therapy by day 30, in 68 (34%) and 17 (17%), respectively (P = 0.001); HRS reversal among patients with systemic inflammatory response syndrome (84 patients in the terlipressin group and 48 patients in the placebo group), in 31 (37%) and 3 (6%), respectively (P<0.001); and verified reversal of HRS without recurrence by day 30, in 52 (26%) and 17 (17%), respectively (P = 0.08). At day 90, liver transplantations had been performed in 46 patients (23%) in the terlipressin group and 29 patients (29%) in the placebo group, and death occurred in 101 (51%) and 45 (45%), respectively. More adverse events, including abdominal pain, nausea, diarrhea, and respiratory failure, occurred with terlipressin than with placebo. Death within 90 days due to respiratory disorders occurred in 22 patients (11%) in the terlipressin group and 2 patients (2%) in the placebo group. CONCLUSIONS: In this trial involving adults with cirrhosis and HRS-1, terlipressin was more effective than placebo in improving renal function but was associated with serious adverse events, including respiratory failure. (Funded by Mallinckrodt Pharmaceuticals; CONFIRM ClinicalTrials.gov number, NCT02770716.).

Reduction in acute kidney injury stage predicts survival in patients with type-1 hepatorenal syndrome.

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.

Terlipressin Improves Renal Function and Reverses Hepatorenal Syndrome in Patients With Systemic Inflammatory Response Syndrome.

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.

An Analysis of Time to Improvement in Oxygenation in Japanese Preterm and Late Preterm or Term Neonates With Hypoxic Respiratory Failure and Pulmonary Hypertension.

PURPOSE: We analyzed data from an ongoing registry to determine time to improvement in oxygenation in preterm and late preterm or term neonates with hypoxic respiratory failure and pulmonary hypertension receiving inhaled nitric oxide (iNO) in Japan. METHODS: Registry neonates received iNO ≤7 days after birth (February 26, 2010, to October 9, 2012). Efficacy and safety profile data were collected up to 96 h after iNO initiation and, if necessary, every 24 h thereafter and before iNO discontinuation. Patients were stratified by gestational age (GA), oxygenation index (OI), and shunt direction at baseline. FINDINGS: Data were evaluated for 1106 neonates (431 with a GA <34 weeks and 675 with a GA of ≥34 weeks). Sixty percent of patients had improved OI; rates were similar for those with GAs of <34 versus ≥34 weeks (61% vs 59%). Overall, mean time to improvement was 11.4 h and tended to be shorter in the groups with a GA <34 weeks versus ≥34 weeks (9.2 vs 12.9 h). Thirty percent of responding neonates required >1 h to achieve improvement in oxygenation. Neonates with higher baseline OI had the greatest decrease in OI during the first hour of treatment. The mortality rate was higher among iNO-treated patients with a baseline OI ≥25 versus those with OI ≥15 to <25 (25% vs 12%; P = 0.0073). IMPLICATIONS: iNO treatment provided acute, sustained improvement in oxygenation in neonates with GAs <34 and ≥34 weeks; 70% of patients had improvement within 1 h, but the remaining 30% took >1 h to respond. Initiation of iNO at lower OIs was associated with reduced mortality compared with higher OI.