Randomized clinical trial on safety of the natriuretic peptide ularitide as treatment of refractory cirrhotic ascites.

BACKGROUND: Sodium and water retention is a mainstay of the pathophysiology leading to ascites formation in patients with advanced cirrhosis. Refractory ascites denotes the most severe ascites status with limited treatment options and a poor prognosis. We investigated the efficacy and safety of the natriuretic peptide ularitide in patients with refractory cirrhotic ascites. METHODS: We conducted a randomized placebo-controlled trial investigating ularitide to manage refractory ascites. Until trial termination after interim analyses, we randomized 17 participants in a 2:1 ratio between ularitide (n=11) and placebo (n=6). While hospitalized, the participants received treatment for up to 48 hours. The primary efficacy endpoint was a change in renal water excretion, and secondary end points included changes in renal sodium excretion rate and body weight. The starting dose was 30 ng/kg/min, though later reduced to 20 for safety reasons. RESULTS: In contrast to the study hypothesis, the mean urine production decreased after 24 hours of ularitide treatment compared with the baseline level (22.8 vs. 47.5 mL/h, p=0.04) and decreased more in participants randomized to ularitide than placebo (24.7 vs. -6.2 mL/h, p=0.05). Ularitide did not increase the renal sodium excretion rate or reduce the weight gain. The incidence rate ratio of adverse reactions in ularitide versus placebo was 8.5 (95% CI: 2-35, p=0.003). Participants treated with ularitide developed serious blood pressure reductions, impacting their renal responsiveness. CONCLUSIONS: Ularitide in doses of 20-30 ng/kg/min did not benefit urine production and renal sodium excretion rate in patients with refractory ascites. The participants randomized to ularitide overall developed more adverse reactions than placebo. EudraCT no. 2019-002268-28.

Novel prognostic biomarkers in decompensated cirrhosis: a systematic review and meta-analysis.

BACKGROUND: Patients with decompensated cirrhosis experience high mortality rates. Current prognostic scores, including the model for end-stage liver disease (MELD), may underperform in settings other than in those they were initially developed. Novel biomarkers have been proposed to improve prognostication accuracy and even to predict development of complications. METHODS: We performed a systematic review and meta-analysis on novel urine and blood biomarkers and their ability to predict 90-day mortality in patients with decompensated cirrhosis. Secondary outcomes included 28-day and 1-year mortality, and development of acute-on-chronic liver failure, acute kidney injury and other complications. To overcome differences in units, temporal changes in assays and reporting heterogeneity, we used the ratio of means (RoM) as measure of association for assessing strength in predicting outcomes. An RoM>1 implies that the mean biomarker level is higher in those that develop the outcome than in those that do not. RESULTS: Of 6629 unique references, 103 were included, reporting on 29 different biomarkers, with a total of 31 362 biomarker patients. Most studies were prospective cohorts of hospitalised patients (median Child-Pugh-Turcotte score of 9 and MELD score of 18). The pooled 90-day mortality rate was 0.27 (95% CI 0.24 to 0.29). The RoM for predicting 90-day mortality was highest for interleukin 6 (IL-6) (2.56, 95% CI 2.39 to 2.74), followed by urinary neutrophil gelatinase-associated lipocalin (uNGAL) (2.42, 95% CI 2.20 to 2.66) and copeptin (2.33, 95% CI 2.17 to 2.50). These RoMs were all higher than for MELD (1.44, 95% CI 1.42 to 1.46). CONCLUSION: Novel biomarkers, including IL-6, uNGAL and copeptin, can probably improve prognostication of patients with decompensated cirrhosis compared with MELD alone.

Non-Selective Beta-Blockers and Risk of Sepsis in Patients with Cirrhosis and Ascites: Results from a Large Observational Study.

Background and Aims: Previous studies have not been able to determine whether non-selective beta-blockers (NSBB) reduce the risk of sepsis in cirrhosis. We aimed to examine this question with data from 1198 patients with cirrhosis and ascites included in clinical studies of satavaptan, a vasopressin receptor antagonist with no effect on infection risk. Methods: Risk of sepsis was estimated for NSBB users vs nonusers. Patients were examined every four weeks, or in relation to hospitalization, for the one-year duration of the trials. We computed the cumulative risk of sepsis for patients who did vs did not use NSBB at baseline. We used Cox regression to compare hazard rates of sepsis between current users and nonusers, accounting for changes in NSBB use over time. We adjusted for patient sex and age, MELD-Na score, albumin, use of antibiotics, use of proton pump inhibitors, cirrhosis etiology, history of variceal bleeding or SBP, severity of ascites and HE, HCC, other cancers, and diabetes, while stratifying on geographical region. Results: Of the 1198 patients, 54% used NSBB at some time. There were 56 sepsis episodes. The 1-year risk of sepsis was reduced to 5.7% (95% confidence interval [CI] 2.8-8.6) in baseline NSBB users vs 11.6% (95% CI 7.0-15.9) in baseline nonusers. The hazard ratio of sepsis for current NSBB users vs current nonusers was reduced to 0.5 (95% CI 0.3-0.8) and after adjustment to 0.7 (95% CI 0.4-1.3). Conclusion: NSBB use may reduce the risk of sepsis in patients with cirrhosis and ascites, but the precision of the estimate was limited by the number of episodes of sepsis.

Household clustering supports a novel chemoprophylaxis trial design for a mosquito-borne viral disease.

Infections because of chikungunya and other mosquito-borne viruses, such as dengue and Zika, represent an area of significant unmet medical need. There are currently no approved medicines for prophylaxis or treatment of these diseases, and the development and implementation of vaccines against these viruses have proved problematic. Although antiviral molecules with treatment and prophylactic potential against the chikungunya virus have been identified, no successful field trials have been reported. Chemoprophylaxis may be attractive for unvaccinated at-risk populations; however, performing a successful chemoprophylaxis trial during a chikungunya outbreak will require a clearly identifiable at-risk population. We propose the application of a household transmission model as used in testing drugs against respiratory viruses. Current evidence on household clustering of chikungunya and other Aedes mosquito-borne viral infections is supportive. We suggest that this model may improve prophylaxis trial feasibility and focus research and future treatment on a population likely to benefit.