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Personalised human albumin in patients with cirrhosis and ascites: design and rationale for the ALB-TRIAL - a randomised clinical biomarker validation trial
Torp, N., Israelsen, M., Coenraad, M., Papp, M., Shawcross, D., Korenjak, M., Angeli, P., Laleman, W., Juanola, A., Gines, P., et al
BMJ open. 2024;14(2):e079309
Abstract
INTRODUCTION Human albumin is used in the treatment of complications of cirrhosis. However, the use of long-term human albumin administration is costly and resource demanding for both patients and healthcare systems. A precision medicine approach with biomarkers to predict human albumin treatment response, so-called predictive biomarkers, could make this a viable treatment option in patients with cirrhosis and ascites. METHODS AND ANALYSIS ALB-TRIAL is a multinational, double-blind, placebo-controlled randomised controlled trial. We aim to validate a predictive biomarker, consisting of a panel of circulating metabolites, to predict the treatment response to human albumin in patients with cirrhosis and ascites. All enrolled patients are stratified into a high-expected or low-expected effect stratum of human albumin based on the biomarker outcome. After stratification, patients in each group are randomised into either active treatment (20% human albumin) or corresponding placebo (0.9% NaCl) every 10th day for 6 months. The primary outcome is the cumulative number of liver-related events (composite of decompensation episodes, transjugular intrahepatic shunt insertion, liver transplantation and death). Key secondary outcomes include time-to-event analysis of primary outcome components, an analysis of the total healthcare burden and a health economic analysis. ETHICS AND DISSEMINATION The trial obtained ethical and regulatory approval in Denmark, Germany, the Netherlands, Belgium, Hungary and Spain through the Clinical Trials Information System (CTIS) from 13 February 2023, while UK approvals from the Health Regulatory Authority, Medicines and Healthcare products Regulatory Agency and Research Ethics Committee are pending. Findings will be published in peer-reviewed journals, presented at conferences, communicated to relevant stakeholders and in the public registry of CTIS, following trial completion. TRIAL REGISTRATION NUMBER NCT05056220 EU CT 2022-501006-34-01.
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A Study of Impact of Fixed-Dose Albumin Infusion on Outcome in Patients With Cirrhosis and Infection: A Randomized Open-label Clinical Trial
Devisetty, J. V., Mallick, B., Praharaj, D., Tiwari, A., Kumar, R., Nath, P., Panigrahi, S. C., Anand, A. C., Acharya, S. K., Chawla, Y. K.
Journal of clinical and experimental hepatology. 2024;14(1):101270
Abstract
BACKGROUND AND AIM Antibiotics and albumin infusion constitute the standard of treatment in patients with decompensated cirrhosis who have spontaneous bacterial peritonitis (SBP). Recent studies have also shown that the use of albumin in patients with advanced liver disease who have infections other than SBP leads to the resolution of acute and chronic liver failure and prevents the development of nosocomial infections. The recommended dose of albumin for these patients is out of reach for many in resource-limited settings like India. The evidence for this recommendation is also scarce. This study aimed to assess the efficacy of a lower dose of albumin infusion in addition to antibiotics on short-term mortality and morbidity in patients with cirrhosis and infections. PATIENTS AND METHODS A prospective, open-label, randomized control study was performed. Consecutive patients with cirrhosis and infections were randomized in a 2:1 ratio into two groups: group A (116) and group B (58) patients. In addition to antibiotics and standard medical therapy, group A was given albumin in a dose of 20 g/day for five days, and group B was given the recommended dose (1.5 g/kg/body weight and 1 g/kg body weight on days one and three, respectively). The primary outcome was in-hospital mortality. Secondary outcomes were improvements in clinical and laboratory parameters. RESULTS Except for etiology, all the baseline clinical and laboratory variables in both groups were comparable. The in-hospital mortality in groups A and B was (11 [10.67%] vs. 6 [10.09%], (P = 0.965). The duration of hospitalization, 30-day mortality, improvement in shock and sensorium, and absolute improvements in serum creatinine, international normalized ratio (INR), and serum bilirubin were also comparable in both groups. CONCLUSION Low-dose albumin infusion in patients with cirrhosis and infections can have the same results as standard-dose albumin and can be used in resource-limited situations. CLINICAL TRIAL REGISTRATION NUMBER CTRI/2020/03/023794.
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Comparative metabolome analysis reveals higher potential of haemoperfusion adsorption in providing favourable outcome in ACLF patients
Yadav, M., Maiwal, R., Kumar Br, V., Tripathi, G., Sharma, N., Sharma, N., Bindal, V., Mathew, B., Pandey, S., Singh, S. P., et al
Liver international : official journal of the International Association for the Study of the Liver. 2024
Abstract
BACKGROUND AND AIMS Acute-on-chronic liver failure (ACLF) is a serious illness associated with altered metabolome, organ failure and high mortality. Need for therapies to improve the metabolic milieu and support liver regeneration are urgently needed. METHODS We investigated the ability of haemoperfusion adsorption (HA) and therapeutic plasma exchange (TPE) in improving the metabolic profile and survival in ACLF patients. Altogether, 45 ACLF patients were randomized into three groups: standard medical therapy (SMT), HA and TPE groups. Plasma metabolomics was performed at baseline, post-HA and TPE sessions on days 7 and 14 using high-resolution mass spectrometry. RESULTS The baseline clinical/metabolic profiles of study groups were comparable. We identified 477 metabolites. Of these, 256 metabolites were significantly altered post 7 days of HA therapy (p < .05, FC > 1.5) and significantly reduced metabolites linked to purine (12 metabolites), tryptophan (7 metabolites), primary bile acid (6 metabolites) and arginine-proline metabolism (6 metabolites) and microbial metabolism respectively (p < .05). Metabolites linked to taurine-hypotaurine and histidine metabolism were reduced and temporal increase in metabolites linked to phenylalanine and tryptophan metabolism was observed post-TPE therapy (p < .05). Finally, weighted metabolite correlation network analysis (WMCNA) along with inter/intragroup analysis confirmed significant reduction in inflammatory (tryptophan, arachidonic acid and bile acid metabolism) and secondary energy metabolic pathways post-HA therapy compared to TPE and SMT (p < .05). Higher baseline plasma level of 11-deoxycorticosterone (C03205; AUROC > 0.90, HR > 3.2) correlated with severity (r(2) > 0.5, p < .05) and mortality (log-rank-p < .05). Notably, 51 of the 64 metabolite signatures (ACLF non-survivor) were reversed post-HA treatment compared to TPE and SMT(p < .05). CONCLUSION HA more potentially (~80%) improves plasma milieu compared to TPE and SMT. High baseline plasma 11-deoxycorticosterone level correlates with early mortality in ACLF patients.
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Terlipressin in combination with albumin as a therapy for hepatorenal syndrome in patients aged 65 years or older
Mujtaba, M. A., Gamilla-Crudo, A. K., Merwat, S. N., Hussain, S. A., Kueht, M., Karim, A., Khattak, M. W., Rooney, P. J., Jamil, K.
Annals of hepatology. 2023;28(5):101126
Abstract
INTRODUCTION AND OBJECTIVES Clinical data for older patients with advanced liver disease are limited. This post hoc analysis evaluated the efficacy and safety of terlipressin in patients aged ≥65 years with hepatorenal syndrome using data from 3 Phase III, randomized, placebo-controlled studies (OT-0401, REVERSE, CONFIRM). PATIENTS AND METHODS The pooled population of patients aged ≥65 years (terlipressin, n = 54; placebo, n = 36) was evaluated for hepatorenal syndrome reversal-defined as a serum creatinine level ≤1.5 mg/dL (≤132.6 μmol/L) while receiving terlipressin or placebo, without renal replacement therapy, liver transplantation, or death-and the incidence of renal replacement therapy (RRT). Safety analyses included an assessment of adverse events. RESULTS Hepatorenal syndrome reversal was almost 2-times higher in terlipressin-treated patients compared with patients who received placebo (31.5% vs 16.7%; P = 0.143). Among surviving patients, the need for RRT was significantly reduced in the terlipressin group, with an almost 3-times lower incidence of RRT versus the placebo group (Day 90: 25.0% vs 70.6%; P = 0.005). Among 23 liver-transplant-listed patients, significantly fewer patients in the terlipressin versus placebo group needed RRT by Days 30 and 60 (P = 0.027 each). Fewer patients in the terlipressin group needed RRT post-transplant (P = 0.011). More terlipressin-treated patients who were listed for and received a liver transplant were alive and RRT-free by Day 90. No new safety signals were revealed in the older subpopulation compared with previously published data. CONCLUSIONS Terlipressin therapy may lead to clinical improvements in highly vulnerable patients aged ≥65 years with hepatorenal syndrome. CLINICAL TRIAL NUMBERS OT-0401, NCT00089570; REVERSE, NCT01143246; CONFIRM, NCT02770716.
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Parenclitic network mapping identifies response to targeted albumin therapy in patients hospitalized with decompensated cirrhosis
Oyelade T, Forrest E, Moore KP, O'Brien A, Mani AR
Clinical and translational gastroenterology. 2023
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Abstract
BACKGROUND The efficacy of targeted albumin therapy in the management of decompensatory events in cirrhosis is unclear with different reports showing conflicting results. It is possible that only certain subgroups of patients may benefit from targeted albumin administration. However, extensive conventional subgroup analyses have not yet identified these subgroups. Albumin is an important regulator of physiological networks and may interact with homeostatic mechanism differently in patients according to the integrity of their physiological network. In the present study we aimed to assess the value of network mapping in predicting response to targeted albumin therapy in patients with cirrhosis. METHOD This is a sub-study of the ATTIRE trial; a multicentre, randomized trial conducted to assess the effect of targeted albumin therapy in cirrhosis. Baseline serum bilirubin, albumin, sodium, creatinine, CRP, and white cell count (WCC), international normalised ratio, heart rate, and blood pressure of 777 patients followed up for 6 months were used for network mapping using parenclitic analysis. Parenclitic network analysis involves measuring the deviation of each individual patient from the existing network of physiological interactions in a reference population. RESULT Overall network connectivity as well as deviations along WCC-CRP axis predicted 6-month survival independent of age and model for end-stage liver disease (MELD) in the standard care arm. Patients with lower deviation along the WCC-CRP axis showed lower survival in response to targeted albumin administration over 6-month follow-up period. Likewise, patients with higher overall physiological connectivity survived significantly less than the standard care group following targeted albumin infusion. CONCLUSION The parenclitic network mapping can predict survival of patients with cirrhosis and identify patient subgroups that don't benefit from targeted albumin therapy.
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Midodrine versus Albumin to Prevent Paracentesis Induced Circulatory Dysfunction in Acute on Chronic Liver Failure Patients in the Outpatient Clinic-a Randomized Controlled Trial
Sujith Reddy, J. S. N., Jagtap, N., Kalpala, R., Kulkarni, A., Gupta, R., Nagaraja Rao, P., Iyengar, S., Alla, M., Nageshwar Reddy, D., Sharma, M.
Journal of clinical and experimental hepatology. 2023;13(4):576-585
Abstract
BACKGROUND Paracentesis-induced circulatory disturbance (PICD) occurs in 12-20% of patients receiving human albumin for large-volume paracentesis, and can occur at lower than five liter paracentesis in acute-on-chronic liver failure (ACLF). Albumin infusions are associated with higher costs and more prolonged daycare admissions. The aim of the study was to determine if oral midodrine-hydrochloride can prevent PICD in these patients by increasing the mean arterial pressure (MAP). METHODS This open-labeled randomized controlled trial included ACLF patients undergoing paracentesis between 3 and 5 L, who were randomized to receive either 20% human albumin or midodrine hydrochloride 7.5 mg thrice daily for three days, 2 h before paracentesis. MAP was recorded daily. The primary outcome was the plasma renin activity (PRA) on day six, and a 50% increase from baseline was considered PICD. RESULTS 183 consecutive patients of ACLF were screened, and 50 patients were randomized to either arms. Alcohol was the most common underlying cause of cirrhosis. On day 6, PRA was non-significantly (P = 0.056) higher in the midodrine group. The absolute change of PRA between the two groups was not significant (P = 0.093). Four (16%) patients in the albumin group and five (20%) in the midodrine group developed PICD. MAP increase was not different between the albumin and midodrine arms (P = 0.851). Midodrine was found to be more cost-effective. CONCLUSIONS Three days of oral midodrine is as effective as a human-albumin infusion in preventing PICD in ACLF patients undergoing paracentesis lesser than that done in large volume paracentesis.
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Safety and efficacy of double plasma molecular adsorption system with sequential low-volume plasma exchange in intermediate-stage hepatitis B virus-related acute-on-chronic liver failure
Xu W, Zhu S, Yang L, Li Z, Wu L, Zhang Y, Chen J, Deng Z, Luo Q, Peng L
Journal of medical virology. 2023
Abstract
BACKGROUND Current evidence suggests that the mortality rate of intermediate-stage hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) remains high. We aimed to investigate the safety and efficacy of double plasma molecular adsorption system (DPMAS) with sequential low-volume plasma exchange (LPE) treatment in intermediate-stage HBV-related ACLF. METHODS This prospective study recruited intermediate-stage HBV-related ACLF patients and was registered on ClinicalTrials.gov (NCT04597164). Eligible patients were randomly divided into a trial group and a control group. Patients in both groups received comprehensive medical treatment. Patients in the trial group further received DPMAS with sequential LPE. Data were recorded from baseline to week 12. RESULTS 50 patients with intermediate-stage HBV-related ACLF were included in this study. The incidence of bleeding events and allergic reactions in the trial group was 12% and 4%, respectively, with no other treatment-related adverse events. The levels of TBIL and PT-INR, and MELD scores after each session of DPMAS with sequential LPE were significantly lower than those before treatment (all p<0.05). The 12-week cumulative liver transplantation-free survival rates in the trial and control groups were 52% and 24%, respectively (p=0.041). The 12-week cumulative overall survival rates in the trial and control groups were 64% and 36%, respectively (p=0.048). The Kaplan-Meier survival analysis revealed significant differences in liver transplantation-free survival (p=0.047) and overall survival (p=0.038) between the trial and control groups. COX regression analysis indicated that BUN (p=0.038), DPMAS with sequential LPE (p=0.048) and COSSH-ACLF II score (p<0.001) were significant risk factors for mortality. CONCLUSION DPMAS with sequential LPE treatment is safe and effective for patients with intermediate-stage HBV-related ACLF. This article is protected by copyright. All rights reserved.
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Tolerance of standard dose albumin infused over 6 hrs for treatment of spontaneous bacterial peritonitis-A randomized controlled trial
Kar, P. S., Venishetty, S., Laroia, S. T., Jindal, A., Maiwall, R., Sood, A. K., Shasthry, S. M., Rajan, V., Arora, V., Bhardwaj, A., et al
Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology. 2023
Abstract
BACKGROUND AND AIMS Twenty per cent albumin (1.5 g/kg at diagnosis and 1 g/kg on day three, infused over six-hour duration) is recommended particularly in high-risk spontaneous bacterial peritonitis (SBP). Whether reduced dose albumin infusion is as effective as the standard dose albumin infusion is not clear. The aim of this study was to compare standard dose albumin infusion with reduced dose albumin infusion in acute kidney injury (AKI) development or progression in patients with cirrhosis and high-risk SBP. METHODS Sixty-three patients were randomized to the standard dose albumin arm (n = 31) and reduced dose albumin arm (n = 32, 0.75 g/kg at diagnosis and 0.5 g/kg 48 h later). The albumin was infused over six-hour duration in both groups. When the patient developed respiratory distress, the albumin infusion was stopped and that dose (i.e. of day one or day three) was not restarted and no attempt was made to finish the whole dose of that day. However, the next dose was started at the pre-calculated infusion rate if there was no evidence of respiratory distress at the start of next infusion. RESULTS All 31 patients in standard dose and two (6.25%) in the reduced dose group developed symptomatic circulatory overload (p < 0.001), with infusions being stopped prematurely. The actual albumin dose received on day one was similar in both groups and only slightly higher in the standard dose group on day three. Resolution of SBP, progression of AKI to higher stage, in-hospital mortality and 28 days' mortality were similar in both groups. CONCLUSIONS For treatment of SBP, standard dose albumin infusion (1.5 g/kg at diagnosis and 1 g/kg 48 hours later) infused over six hours is not tolerated by Indian patients. The effectiveness of standard dose albumin infused over more prolonged periods, as compared to reduced dose albumin, should be evaluated in further studies. TRIAL REGISTRATION Clinical Trials.gov Identifier: NCT04273373 .
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Lusutrombopag for thrombocytopenia in Chinese patients with chronic liver disease undergoing invasive procedures
Ding, Z., Wu, H., Zeng, Y., Kuang, M., Yang, W., Meng, Z., Chen, Y., Hao, C., Zou, S., Sun, H., et al
Hepatology International. 2023;17(1):180-189
Abstract
PURPOSE Probing efficacy and safety of lusutrombopag in Chinese chronic liver disease (CLD) and severe thrombocytopenia (PLT < 50 × 10(9)/L) patients undergoing elective invasive procedures. METHODS In this double-blind, parallel-group phase 3 study, 66 patients with CLD and severe thrombocytopenia were randomized 2:1 to lusutrombopag or placebo arm treatment regimens for seven days at 9 centers in China. Responders (PLT ≥ 50 × 10(9)/L that increased to ≥ 20 × 10(9)/L from the baseline and not received rescue therapy for bleeding) on Day 8 (the day after seven-day treatment) were assessed. PLT ≥ 50 × 10(9)/L on or after Day 8 and within 2 days before invasive procedure (alternative criteria for not requiring platelet transfusion) were also analyzed. Adverse events (AEs) were recorded. RESULTS The proportion of responders on Day 8 was evidently higher (p = 0.0011) in the lusutrombopag group (43.2%, 19/44) versus placebo (4.5%, 1/22). And 72.7% (32/44) patients receiving lusutrombopag met the alternative criteria for not requiring platelet transfusion, while 18.2% (4/22) in the placebo group. The median maximum PLT in lusutrombopag group increased to 80.5 × 10(9)/L, and median time to reach maximum was 14.5 days. Compared with placebo, the lusutrombopag group had a lower incidence of bleeding events (6.8% versus 13.6%), and only one patient had thrombotic-related AE. Overall, the incidence of treatment-emergent AEs was comparable between two groups. CONCLUSIONS Lusutrombopag was effective in raising PLT, diminishing platelet transfusion requirement, and documented a safety profile like the placebo in CLD and severe thrombocytopenia patients in a Chinese cohort undergoing elective invasive procedures. Chinese clinical trial registration number: CTR20192384.
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Comparison of clinical effect of octreotide and pituitrin in treatment of upper gastrointestinal hemorrhage in cirrhosis
Zhu Y, Ren Y, Li C, Si Z, Chi N
Indian journal of pharmacology. 2023;55(1):21-26
Abstract
OBJECTIVE The objective of the study was to compare and observe the therapeutic effect of octreotide and pituitrin in upper gastrointestinal hemorrhage caused by cirrhosis. MATERIALS AND METHODS In this prospective, randomized, open, single-blind, controlled, and single-center study, patients with upper gastrointestinal hemorrhage induced by cirrhosis were divided into control group (treated with pituitrin) and experimental group (treated with octreotide). The effective time, hemostasis time, and average bleeding volume of the two groups were observed and recorded, and the incidence of adverse reactions, rebleeding rate, and total effective rate of the two groups were compared. RESULTS One hundred and thirty-two patients with upper gastrointestinal hemorrhage caused by cirrhosis were included from March 2017 to September 2018. By a single-blind method, the patients were randomly divided into control group (n = 66) and experimental group (n = 66). Compared with the control group, the effective time and hemostasis time of the drug were significantly shorter in the experimental group, whereas the average bleeding volume of patients was lower (average P < 0.05). Compare with the control group, the total effective rate was higher in the experimental group, whereas the incidence of adverse reactions was lower (average P < 0.05). During 1-year follow-up, early and late rebleeding rates and hemorrhage-related mortality between the two groups have no difference (average P > 0.05). CONCLUSION In the treatment of upper gastrointestinal hemorrhage in cirrhosis, octreotide is superior to pituitrin, with advantages of quick onset, short hemostasis time, and less adverse reactions, which is helpful to control the rebleeding rate and bleeding-related mortality.