Abstract

AIM: Avatrombopag, a thrombopoietin receptor agonist, can reduce the need for platelet transfusions or rescue interventions for bleeding in patients with chronic liver disease (CLD) and thrombocytopenia undergoing scheduled procedures. A model analysis indicated that the effect of avatrombopag on platelet production was reduced in East Asian versus non-East Asian patients; however, the difference was deemed not clinically significant. Furthermore, a subgroup analysis of pooled Phase 3 trials showed similar avatrombopag efficacy across racial subgroups. The aim of this Phase 2 study was to corroborate the efficacy and safety of avatrombopag in Japanese patients with thrombocytopenia due to CLD. METHODS Japanese patients with CLD and thrombocytopenia were randomized to receive placebo or avatrombopag 20, 40, or 60 mg daily for 5 days. The primary endpoint was responder rate in platelet counts at Visit 4 (10-13 days after treatment initiation), defined as the proportion of patients with platelet count ≥50×10(9) /L and ≥20×10(9) /L increase from baseline. RESULTS Thirty-nine patients were randomized and completed the study (placebo, n=11; avatrombopag 20 mg, n=7; 40 mg, n=11; 60 mg, n=10). Avatrombopag treatment was associated with significant increases in responder rate at Visit 4 in the 40 mg (63.6%; P=0.004) and 60 mg (40%; P=0.024) groups versus placebo (9.1%). Avatrombopag was well tolerated and no new safety signals were detected. CONCLUSIONS Efficacy and safety results from this study were consistent with previous studies in patients with CLD and thrombocytopenia undergoing elective procedures, supporting treatment with avatrombopag in the Japanese population. ClinicalTrials.gov identifier: NCT02227693. This article is protected by copyright. All rights reserved.

Abstract

BACKGROUND High volume plasma-exchange (HVPE) improves survival in patients with acute liver failure (ALF), but apprehension regarding volume overload and worsening of cerebral edema remain. METHODS In an open-label randomized controlled trial, 40 consecutive patients of ALF were randomized 1:1 to either standard medical treatment (SMT) or SMT with standard-volume plasma-exchange (SVPE). SVPE was performed using centrifugal apheresis [target volume of 1.5 to 2.0 plasma volumes per session] until desired response was achieved. Cerebral edema was assessed by brain imaging. Results were analyzed in an intention-to-treat analysis. Primary outcome was 21-day transplant-free survival. The levels of cytokines, damage-associated molecular patterns (DAMPs) and endotoxins were analyzed at baseline and day 5. RESULTS ALF patients [aged 31.5 ± 12.2 years, 60% male, 78% viral, 83% hyperacute, 70% with SIRS were included. At day 5, SVPE [mean sessions 2.15 ± 1.42, median plasma volume replaced 5.049 L] compared to SMT alone, resulted in higher lactate clearance (p = .02), amelioration of SIRS (84% vs. 26%; P = .02), reduction in ammonia levels [(221.5 ± 96.9) vs.(439 ± 385.6) μg/dl, P = .02) and SOFA scores [9.9(±3.3) vs. 14.6(±4.8); P = .001]. There were no treatment related deaths. SVPE was associated with a higher 21-day transplant free-survival [75% vs. 45%; P = .04, HR 0.30, 95%CI 0.01-0.88]. A significant decrease in levels of pro-inflammatory cytokines and an increase in anti-inflammatory cytokines along with a decrease in endotoxin and DAMPs was seen with SVPE. CONCLUSION In ALF patients with cerebral edema, SVPE is safe and effective and improves survival possibly by a reduction in cytokine storm and ammonia. CLINICALTRIAL gov (identifier: NCT02718079).

Abstract

BACKGROUND The presence of esophageal varices is considered a relative contraindication to transesophageal echocardiography (TEE) by cardiology professional societies, so gastroenterologists are often consulted to perform upper endoscopy prior to TEE in patients with cirrhosis. AIM: To perform a systematic review to quantify the risk of bleeding complications in patients with cirrhosis following TEE. METHODS Two reviewers searched Ovid MEDLINE, MEDLINE In-Process and EMBASE databases from January 1992 to May 2021 for studies reporting bleeding complications from TEE in patients with cirrhosis. We calculated the pooled incidence rate of bleeding events using the metaprop command with a random effect model. RESULTS We identified 21 studies comprising 4050 unique patients with cirrhosis; 9 studies (n = 3015) assessed the risk of intraoperative TEE during liver transplant (LT) and 12 studies (n = 1035) assessed bleeding risk in patients undergoing TEE for other indications. The pooled incidence of bleeding post-TEE was 0.37% (95% CI 0.04-0.94%) across all studies. Bleeding complications were low among patients undergoing TEE during LT as well as those undergoing TEE for other diagnostic reasons (0.97% vs. 0.004%) and among studies with mean MELD >18 compared to those with mean MELD <18 (0.43% vs. 0.08%). Few studies had a comparator arm, and data on patient-level factors impacting bleeding complications (including degree of liver dysfunction and coagulopathy) were limited across studies. CONCLUSIONS The risk of bleeding complications following TEE is low in patients with cirrhosis, suggesting TEE is safe and risk stratification with upper endoscopy may not be necessary.

Abstract

INTRODUCTION Few data have been published on the ethnic sensitivity of effectiveness, pharmacokinetics (PK), and pharmacodynamics (PD) of avatrombopag for the management of thrombocytopenia in patients with chronic liver disease (CLD). METHODS An ethnic sensitivity analysis was performed based on the results from two phase III studies (ADAPT-1 and ADAPT-2), with a primary endpoint of the proportion of patients without the requirement of platelet transfusion or rescue treatment for bleeding after randomization to 7 days following a scheduled procedure, and three phase I studies in healthy subjects. Cochran-Mantel-Haenszel and Fisher's exact tests were used to compare the differences in effectiveness in different ethnicities and overall population. RESULTS In total, 435 patients (placebo, n = 158; avatrombopag, n = 277) were stratified into various ethnic groups: 121 East Asians, including the subgroup of 27 Chinese, and 259 Caucasians. The proportion of patients who did not receive a platelet transfusion and those with a platelet count ⩾50 × 10(9)/L in the avatrombopag 40 and 60 mg groups were higher than that of placebo for all ethnicities and in the overall population. Statistical significance was obtained in the overall population and for all ethnicities other than Chinese patients, a group with a very small sample size. No significant difference was observed in the proportion of responders in each ethnic group compared to overall population (p > 0.05). The incidence of adverse events in East Asians was similar to that in both Caucasians and the overall population. CONCLUSION Avatrombopag was effective and safe in the management of thrombocytopenia in Chinese patients with CLD. Ethnicity does not appear to influence the efficacy, safety, PK, or PD of avatrombopag.

Abstract

BACKGROUND AND AIMS Both insulin and plasma exchange (PE) are used in hypertriglyceridemic acute pancreatitis (HTG-AP). Our aim was to compare the efficacy of both treatments. METHODS A randomized, parallel group study performed in a tertiary hospital in 22 HTG-AP patients with non-severe prognosis and triglycerides between 15 and 40 mmol/L. Patients were randomized to daily PE or insulin infusion until triglycerides were <10 mmol/L. Primary outcome was % reduction in triglycerides within 24 h. Secondary outcomes were days needed to lower triglycerides <10 mmol/L, highest CRP and percentage of patients with a severe course of pancreatitis. RESULTS There was a trend toward a greater decrease in triglycerides within the first 24 h in the PE group (67 ± 17% vs. 53 ± 17%, p = 0.07), but the absolute difference was modest [mean difference of 6 mmol/L (14% of initial value)]. Triglycerides fell below 10 mmol/L in a median (IQR) of 1 (1-2) and 2 (1-2) days, respectively (p = 0.25). Secondary outcomes related to disease severity were also comparable: highest CRP 229 vs. 211 mg/L (p = 0.69) and severe course of pancreatitis in 2/11 cases in both groups (p = 1.0). Regarding treatment complications, there was one mild hypoglycemia and one allergic reaction during PE. Survival was 100% in both groups. CONCLUSION There was no significant difference, but only a trend toward a greater decrease in triglycerides with PE, and the clinical course was also comparable. These results do not support universal use of PE in patients with HTG-AP. CLINICAL TRIAL REGISTRATION [ClinicalTrials.gov], identifier [NCT02622854].

Abstract

OBJECTIVE Liver cirrhosis is a common, often progressive, and usually fatal disorder. Upper gastrointestinal bleeding is a leading cause of death in patients with liver cirrhosis. The purpose of this study was to evaluate the effectiveness of somatostatin combined with restricted fluid resuscitation in the treatment of upper gastrointestinal bleeding in the patients with liver cirrhosis. METHODS From January 2018 to December 2020, 84 patients with liver cirrhosis complicated by upper gastrointestinal bleeding admitted to the Department of Gastroenterology of Ningbo Yinzhou No. 2 Hospital were selected as study participants. They were randomly assigned into the study group (n = 42) and control group (n = 42). All patients were given intravenous drip of somatostatin. The study group was supplemented with restricted fluid resuscitation therapy. The hemoglobin (Hb), platelet, fibrinogen, hematocrit, transfusion volume of red blood cells, hemostatic time, hemostatic rates in 0 h-24 h, 24 h-48 h, and >48 h, rebleeding rates, resuscitation rate, and incidence rates of complications were compared between the two groups 48 h after treatment. RESULTS It was found that the Hb, platelet, fibrinogen, and hematocrit were notably increased in the study group compared to the control group 48 h after treatment (P < 0.01). The proportion of patients with excellent response was notably higher in the study group than in the control group (P < 0.05). The overall response rate of the study group was 90.48%, which was significantly higher than 71.43% in the control group (P < 0.05). The study group had lower transfusion volume of red blood cells, shorter hemostatic time, and lower rebleeding rates than the control group (P < 0.01). The hemostatic rate of 0 h-24 h in the study group was remarkably higher than that in the control group (P < 0.05). The hemostatic rate of >48 h in the study group was lower than that in the control group (P < 0.05). The overall incidence rate of complications in the study group was 9.52%, which was significantly lower than 30.95% in the control group (P < 0.05). CONCLUSION These data suggest that intravenous drip of somatostatin followed by restricted fluid resuscitation leads to a better clinical efficacy in treating upper gastrointestinal bleeding in patients with liver cirrhosis considering higher resuscitation rate and hemostatic rate and reduced incidence of complications, which is conducive to the recovery of patients and worthy of further clinical promotion.

Abstract

The optimal treatment for gastric varices (GVs) has not yet been fully determined. This study compared the efficacy and safety of endoscopic cyanoacrylate injection and balloon-occluded retrograde transvenous obliteration (BRTO) to prevent rebleeding in patients with cirrhosis and GVs after primary hemostasis. Patients with cirrhosis and history of bleeding from gastroesophageal varices type 2 or isolated gastric varices type 1 were randomized to cyanoacrylate injection (n = 32) or BRTO treatment (n = 32). The primary outcomes were gastric variceal rebleeding or all-cause rebleeding. The patient characteristics were well-balanced between two groups. The mean follow-up time was 27.1 ± 12 months in a cyanoacrylate injection group and 27.6 ± 14.3 months in a BRTO group. The probability of gastric variceal rebleeding was higher in the cyanoacrylate injection group than in the BRTO group (p = 0.024). The probability of remaining free of all-cause rebleeding at 1 and 2 years for cyanoacrylate injection vs BRTO was 77% vs 96.3% and 65.2% vs 92.6% (p = 0.004). The survival rates, frequency of complications, and worsening of EVs were similar in both groups. BRTO resulted in fewer hospitalizations, inpatient stays, and lower medical costs. CONCLUSIONS BRTO is more effective than cyanoacrylate injection in preventing rebleeding from GVs, with similar frequencies of complications and mortalities.

Abstract

Introduction and objectives It has been suggested that albumin administration could alter the natural history of cirrhosis, and also, that long-term treatment with albumin might be associated with improvement in survival, control of ascites, reduction in the incidence bacterial infections, renal dysfunction, hepatic encephalopathy (HE) and hyponatremia, as well as reduction in length of hospitalization in patients with cirrhosis and ascites. The objective of the present study is to evaluate the role of albumin in the management of HE. Materiales and methods:: This is a systematic review of randomized controlled trials that evaluated the use of albumin in adult patients with cirrhosis and HE. The search for eligible studies was performed in MEDLINE, EMBASE, and Cochrane CENTRAL databases until June 2020. The outcomes of interest were the complete reversal of HE and mortality. Meta-analysis was performed using the random effects model, through the Mantel-Haenszel method. Results: This systematic review was registered at the PROSPERO platform (CRD42020194181). The search strategy retrieved 1,118 articles. After reviewing titles and abstracts, 24 studies were considered potentially eligible, but 22 were excluded after full-text analysis. Finally, 2 studies were included. In the meta-analysis, albumin was associated to significant lower risks of persistent HE (risk ratio - RR = 0.60; 95% confidence interval - CI = 0.38-0.95, p = 0.03) and mortality (RR = 0.54; 95% CI = 0.33-0.90, p = 0.02). Conclusion: Albumin administration improves HE and reduces mortality in patients with cirrhosis and HE.

Abstract

BACKGROUND Vasoactive drugs can reduce portal venous pressure and control variceal bleeding. However, few studies have explored the hemodynamic effects of terlipressin and high-dose octreotide in such patients. Our purpose was to evaluate the hemodynamic changes and safety of using terlipressin and high-dose octreotide in patients with decompensated liver cirrhosis. METHODS A multi-center randomized controlled trial was conducted. Cirrhotic patients with a history of variceal bleeding were included. Terlipressin or high-dose octreotide was administered during the procedure of measuring hepatic venous pressure gradient (HVPG). Hemodynamic parameters and symptoms were recorded. RESULTS A total of 88 patients were included. HVPG was significantly reduced at 10, 20, and 30 min after drug administration in the terlipressin group (16.3±6.4 vs. 14.7±5.9, 14.0±6.1, and 13.8±6.1, respectively, P<0.001) and the high-dose octreotide group (17.4±6.6 vs. 15.1±5.8, 15.3±6.2, and 16.1±6.0, respectively P<0.01). Decreased heart rate and increased mean arterial pressure were more often observed in the terlipressin group. The overall response rates were not significantly different between the groups (52.8% vs. 44.8%, P=0.524). The terlipressin group had significantly higher response rates at 30 min compared to the high-dose octreotide group in those with alcoholic liver cirrhosis [6/6 (100%) vs. 0/4 (0%), P=0.005]. The incidence of adverse drug events was rare and similar in the two groups. CONCLUSIONS Both terlipressin and high-dose octreotide were effective and safe for reducing HVPG. The pharmacodynamic effect of terlipressin persisted longer. The terlipressin group had higher response rates in those with alcoholic cirrhosis (trial number: NCT02119884).

Abstract

Thrombopoietin receptor agonists (TPO-RAs) can mitigate preprocedural thrombocytopenia in patients with chronic liver disease (CLD) however their effects on procedural outcomes is unclear. In this meta-analysis, we aimed to better define the efficacy, thrombotic risk and bleeding mitigation associated with the use of preoperative TPO-RAs in patients with CLD. We performed a systematic review and meta-analysis of randomized placebo-controlled clinical trials to assess the use of preprocedural TPO-RAs in patients with CLD, searching MEDLINE, EMBASE and the Cochrane library database. Six publications comprising eight randomized trials (1229 patients; 717 received TPO-RAs, 512 received placebo) and three unique TPO-RAs were retrieved. The majority of the included procedures were endoscopic. TPO-RAs were significantly more likely to result in a preoperative platelet count greater than 50 x 10(9)/L (72.1% vs 15.6%, RR 4.8, 95% CI 3.6-6.4 p < .00001. NNT 1.8) and reduced the incidence of platelet transfusions (22.5% vs 67.8%, RR 0.33, 95% CI 0.3-0.4 p < .00001. NNT 2.2). Total periprocedural bleeding was decreased in patients who received TPO-RAs (11.6% vs 15.6%, RR 0.64, 95% CI 0.5-0.9 p = .01. NNT 24.7) and there was no increase in the rate of thrombosis (2.2% vs 1.8% RR 1.25, 95% CI 0.6-2.9 p = .60. NNH 211.1). In patients with CLD the use of preprocedural TPO-RAs resulted in significant increased platelet counts, and decreased the incidence of platelet transfusions as compared to placebo. TPO use likewise decreased the incidence of total periprocedural bleeding without increasing the rate of thrombosis.