Primary Prophylaxis Of Variceal Bleeding Research Articles

Combination of carvedilol with variceal band ligation in prevention of first variceal bleed in Child-Turcotte-Pugh B and C cirrhosis with high-risk oesophageal varices: the ‘CAVARLY TRIAL’

ObjectivesBeta-blockers and endoscopic variceal band ligation (VBL) have been preferred therapies for primary prophylaxis of variceal bleeding. However, the choice of therapy in patients with advanced liver disease with high-risk...

Improving primary prophylaxis of variceal bleeding by adapting therapy to the clinical stage of cirrhosis. A competing-risk meta-analysis of individual participant data.

Non-selective β-blockers (NSBBs) and endoscopic variceal-ligation (EVL) have similar efficacy preventing first variceal bleeding. Compensated and decompensated cirrhosis are markedly different stages, which may impact treatment outcomes. We aimed to assess the efficacy of NSBBs vs EVL on survival in patients with high-risk varices without previous bleeding, stratifying risk according to compensated/decompensated stage of cirrhosis. By systematic review, we identified RCTs comparing NSBBs vs EVL, in monotherapy or combined, for primary bleeding prevention. We performed a competing-risk, time-to-event meta-analysis, using individual patient data (IPD) obtained from principal investigators of RCTs. Analyses were stratified according to previous decompensation of cirrhosis. Of 25 RCTs eligible, 14 failed to provide IPD and 11 were included, comprising 1400 patients (656 compensated, 744 decompensated), treated with NSBBs (N = 625), EVL (N = 546) or NSBB+EVL (N = 229). Baseline characteristics were similar between groups. Overall, mortality risk was similar with EVL vs. NSBBs (subdistribution hazard-ratio (sHR) = 1.05, 95% CI = 0.75-1.49) and with EVL + NSBBs vs either monotherapy, with low heterogeneity (I2 = 28.7%). In compensated patients, mortality risk was higher with EVL vs NSBBs (sHR = 1.76, 95% CI = 1.11-2.77) and not significantly lower with NSBBs+EVL vs NSBBs, without heterogeneity (I2 = 0%). In decompensated patients, mortality risk was similar with EVL vs. NSBBs and with NSBBs+EVL vs. either monotherapy. In patients with compensated cirrhosis and high-risk varices on primary prophylaxis, NSBBs significantly improved survival vs EVL, with no additional benefit noted adding EVL to NSBBs. In decompensated patients, survival was similar with both therapies. The study suggests that NSBBs are preferable when advising preventive therapy in compensated patients.

Carvedilol as the new non-selective beta-blocker of choice in patients with cirrhosis and portal hypertension.

Portal hypertension (PH) is the most common complication ofcirrhosis and represents the main driver of hepatic decompensation. The overarching goal of PH treatments in patients with compensated cirrhosis is to reduce the risk of hepatic decompensation (i.e development of ascites, variceal bleeding and/or hepatic encephalopathy). In decompensated patients, PH-directed therapies aim at avoiding further decompensation (i.e. recurrent/refractory ascites, variceal rebleeding, recurrent encephalopathy, spontaneous bacterial peritonitis or hepatorenal syndrome) and at improving survival. Carvedilol is a non-selective beta-blocker (NSBB) acting on hyperdynamic circulation/splanchnic vasodilation and on intrahepatic resistance. It has shown superior efficacy than traditional NSBBs in lowering PH in patients with cirrhosis and may be, therefore, the NSBB of choice for the treatment of clinically significant portal hypertension. In primary prophylaxis of variceal bleeding, carvedilol has been demonstrated to be more effective than endoscopic variceal ligation (EVL). In patients with compensated cirrhosis carvedilol achieves higher rate of hemodynamic response than propranolol, resulting in a decreased risk of hepatic decompensation. In secondary prophylaxis, the combination of EVL with carvedilol may prevent rebleeding and non-bleeding further decompensation better than that with propranolol. In patients with ascites and gastroesophageal varices, carvedilol is safe and may improve survival, as long as no impairment of the systemic hemodynamic or renal dysfunction occurs, with maintained arterial blood pressure as suitable safety surrogate. The target dose of carvedilol to treat PH should be 12.5mg/day. This review summarizes the evidence behind Baveno-VII recommendations on the use of carvedilol in patients with cirrhosis.

Nonselective beta-blockers in primary prophylaxis of esophageal variceal bleeding in patients with ascites waitlisted for liver transplantation

Objective: to determine the efficacy of non-selective beta-blockers (NSBBs) in the primary prevention of bleeding esophageal varices and to assess their impact on the survival of patients with ascites enrolled in the liver transplant waiting list (LTWL).Materials and methods. We carried out a retrospective comparative study of cirrhotic patients with severe ascites and esophageal varices without bleeding before enrollment in the LTWL. Primary prophylaxis of variceal bleeding included the use of NSBBs (n = 97, group 1). These drugs were not used in the other patients (n = 91, group 2).Results. There were no significant differences between the groups in terms of clinical, laboratory and demographic parameters, MELD scores and Child-Turcotte-Pugh (CTP) classes for cirrhosis. Patient groups included in the study had no significant differences with respect to incidence of medium- and large-sized varices and incidence of severe ascites. Bleeding incidence was significantly lower in the NSBBs group than in the non-NSBBs group (52.6% and 95.6%, respectively, p = 0.0001).Conclusion. NSBBs constitute an efficacious therapy in primary prophylaxis of esophageal variceal bleeding, thereby saving life and preventing delisting of patients with ascites from the LTWL.

Impact and outcome of primary prophylaxis of variceal bleeding among Egyptian hepatocellular carcinoma patients with portal vein thrombosis treated with Sorafenib

Impact and outcome of primary prophylaxis of variceal bleeding among Egyptian hepatocellular carcinoma patients with portal vein thrombosis treated with Sorafenib

Porto-sinusoidal vascular disease: a new definition of an old clinical entity.

Porto-sinusoidal vascular disease (PSVD) is defined as a vascular liver disease characterized by the absence of cirrhosis and the presence of characteristic histological features, with or without the presence of portal hypertension (PH). Half of the patients with PSVD also have associated disease that may contribute to the development of PSVD. Patients usually remain asymptomatic until complications of PH arise. Variceal bleeding and portal vein thrombosis are major complications associated with PSVD. The treatment is focused on managing complications of PH, mainly through primary prophylaxis of variceal bleeding and treatment of portal vein thrombosis. Currently, there is insufficient evidence to support the use of anticoagulants for thrombosis prevention in these patients. Despite the increase of recognition of PSVD, further research is needed to enable early disease diagnosis, establish optimal screening methods, and develop strategies to slow down disease progression.

Carvedilol versus Band Ligation for Primary Prophylaxis of Variceal Bleeding in ‎Cirrhosis with Systemic Hypertension: A Randomized Controlled Trial

Carvedilol versus Band Ligation for Primary Prophylaxis of Variceal Bleeding in ‎Cirrhosis with Systemic Hypertension: A Randomized Controlled Trial

Efficacy and Safety of Endoscopic Primary Prophylaxis of Bleeding in Children With High-Risk Gastroesophageal Varices.

Primary prophylaxis of bleeding is debated in children with gastroesophageal varices; one of the reasons is the limited number of studies concerning its efficacy and safety. We report our experience with endoscopic primary prophylaxis. From 2006 to 2019, 145 children (median age, 3.5 years; cirrhosis, n = 116) with high-risk gastroesophageal varices underwent primary prophylaxis (banding, n = 114; sclerotherapy n = 31, primarily in smaller children). We observed the eradication of varices in 93% of children after a mean of 6 months, at least one recurrence of varices in 45% after eradication, and gastrointestinal bleeding in 17% of children. Irrespective of the cause of portal hypertension, grade 3 esophageal varices, presence of gastric varices along the cardia and a lower composite score of endoscopic severity were associated with a worse probability of eradication, a longer time to eradication and a lower risk of a first recurrence and of bleeding following the procedure, respectively. Ten-year probabilities of overall survival and of bleeding-free survival were 95% and 75%, respectively. Endoscopic primary prophylaxis of variceal bleeding is reasonably effective and safe in children with high-risk gastroesophageal varices. Worse results are observed in children with more advanced endoscopic features. This pleads for endoscopic screening in children with portal hypertension and early detection of varices warranting primary prophylaxis.

Propranolol vs. band ligation for primary prophylaxis of variceal hemorrhage in cirrhotic patients with ascites: a randomized controlled trial.

Recent studies have debated the utility of beta-blockers to prevent variceal hemorrhage (V.H.) in cirrhosis patients with ascites. We aimed to evaluate the safety and efficacy of propranolol (PPL) compared to endoscopic variceal ligation (EVL) for V.H. primary prevention in patients with ascites. Cirrhosis patients with ≥ grade 2 ascites and varices needing primary prophylaxis were randomly assigned to receive either PPL (n = 80) or EVL (n = 80). Patients were followed monthly until 12months or transplant or death. The primary endpoint was 12-month transplant-free-survival (TFS). Secondary endpoints were the incidence of V.H., acute kidney injury (AKI), and control of ascites. Baseline characteristics were similar between the groups. PPL-group had a lower 12-month TFS (76.0% vs. 89.7%; p = 0.02) as compared with EVL-group. Mean arterial pressure ≤ 82mmHg and MELD-sodium were the independent predictors of mortality. Incidence of VH was comparable between PPL and EVL-groups [6 (7.5%) vs. 2 (2.5%), p = 0.13]. In PPL vs. EVL-group, more patients had worsening of ascites (15% vs. 5%; p = 0.03), developed refractory ascites (13.7% vs.3.7%; p = 0.02), relapse of ascites (37.1% vs. 16.4%, p < 0.01), and AKI (26.2% vs. 12.5%; p = 0.02). Side effects were comparable between the two groups. Primary VH-prophylaxis with PPL is associated with lower survival, poor control of ascites, and increased risk of AKI in cirrhosis patients with ≥ grade 2 ascites. PPL and EVL are equally effective in preventing V.H. Serial monitoring of blood pressures and renal functions is needed in cirrhosis patients with ascites on PPL (NCT02649335).

Management of Liver Decompensation in Advanced Chronic Liver Disease: Ascites, Hyponatremia, and Gastroesophageal Variceal Bleeding

Portal hypertension is a major complication of cirrhosis characterized by a pathological hepatic venous pressure gradient (HVPG) ≥ 5 mmHg. The structural changes observed in the liver leading to intrahepatic vascular resistance and, consequently, portal hypertension appear in the early stages of cirrhosis. Clinically significant portal hypertension (HVPG ≥ 10 mmHg) is associated with several clinical consequences, such as ascites, hyponatremia, gastroesophageal variceal bleeding, hepatorenal syndrome, cardiopulmonary complications, adrenal insufficiency, and hepatic encephalopathy. The diagnosis and management of these complications depend on their early identification and treatment. Regarding ascites, diuretics are a useful treatment, although plasma sodium levels must be properly controlled to avoid hyponatremia. The management of hypovolemic hyponatremia usually consists in stopping diuretics and the administration of volume. On the contrary, hypervolemic hyponatremia is managed with fluid and sodium restriction. Transjugular intrahepatic portosystemic shunt (TIPS) should be considered in patients with refractory ascites. Primary prophylaxis of variceal bleeding should be based mainly on non-selective beta-blockers. Management of acute gastroesophageal variceal bleeding includes vasoactive drugs and endoscopic band ligation and, in patients at high risk of failure and rebleeding, preemptive use of TIPS. Secondary prophylaxis with a combination of non-selective beta-blockers and endoscopic band ligation is the treatment of choice. This article focuses on the management of ascites, hyponatremia, and gastroesophageal variceal bleeding.

Risk of variceal hemorrhage and pretransplant mortality in children with biliary atresia.

Background and AimsThe natural history of gastroesophageal variceal hemorrhage (VH) in biliary atresia (BA) is not well characterized. We analyzed risk factors, incidence, and outcomes of VH in a longitudinal multicenter study.Approach and ResultsParticipants enrolled in either an incident (Prospective Database of Infants with Cholestasis [PROBE]) or prevalent (Biliary Atresia Study of Infants and Children [BASIC]) cohort of BA were included. Variceal hemorrhage (VH) was defined based on gastrointestinal bleeding in the presence of varices accompanied by endoscopic or nontransplant surgical intervention. Cumulative incidence of VH and transplant‐free survival was compared based on features of portal hypertension (e.g., splenomegaly, thrombocytopenia) and clinical parameters at baseline in each cohort (PROBE: 1.5 to 4.5 months after hepatoportoenterostomy [HPE]; BASIC: at enrollment > 3 years of age). Analyses were conducted on 869 children with BA enrolled between June 2004 and December 2020 (521 in PROBE [262 (51%) with a functioning HPE] and 348 in BASIC). The overall incidence of first observed VH at 5 years was 9.4% (95% CI: 7.0–12.4) in PROBE and 8.0% (5.2–11.5) in BASIC. Features of portal hypertension, platelet count, total bilirubin, aspartate aminotransferase (AST), albumin, and AST‐to‐platelet ratio index at baseline were associated with an increased risk of subsequent VH in both cohorts. Transplant‐free survival at 5 years was 45.1% (40.5–49.6) in PROBE and 79.2% (74.1–83.4) in BASIC. Two (2.5%) of 80 participants who had VH died, whereas 10 (12.5%) underwent transplant within 6 weeks of VH.ConclusionsThe low risk of VH and associated mortality in children with BA needs to be considered in decisions related to screening for varices and primary prophylaxis of VH.

Combined Pharmacological and Endoscopic Treatment for Worsening Gastroesophageal Varices in Patients with Cirrhosis.

BackgroundAt the present time, in patients with liver cirrhosis and gastroesophageal varices, primary prophylaxis of variceal bleeding made with combination therapy with non-selective β-blockers (NSBBs) and endoscopic band ligation (EBL) is not recommended. The aim of this study was to evaluate if patients with worsening varices while on NSBBs regimen benefit, in terms of bleeding and survival, from adding treatment with EBL.MethodsPatients with cirrhosis and endoscopic finding of gastroesophageal varices with high risk feature (increased variceal size and/or development of red signs) during primary prophylaxis with NSBBs, followed at the Unit of Internal Medicine and Hepatology, University and General Hospital of Padova, Italy, from 2012 to 2019, were retrospectively evaluated. When an increased bleeding risk of the varices was confirmed, patients maintained the pharmacological therapy alone or underwent also EBL. The primary endpoint of the study was the rate of variceal bleeding, the secondary endpoint was mortality at 30 months.ResultsCompared to patients treated only with NSBBs (n=56), in patients treated also with EBL (n=45), the 30‐month probability of variceal bleeding (29.1% vs 5.1%; P =0.036) was significantly reduced, while the probability of survival was similar (59.6% vs 65.7%; P=0.61). On multivariate analysis, treatment with EBL was found to be a weak protective factor for mortality (HR 0.47, P=0.044).ConclusionIn patients with liver cirrhosis, when varices show endoscopic feature of increased haemorrhagic risk, adding EBL to NSBBs is effective in reducing the probability of first bleeding.

Primary prophylaxis of variceal bleeding in patients with cirrhosis: A comparison of different strategies.

Patients with cirrhosis and esophageal varices bleed at a yearly rate of 5%-15%, and, when variceal hemorrhage develops, mortality reaches 20%. Patients are deemed at high risk of bleeding when they present with medium or large-sized varices, when they have red signs on varices of any size and when they are classified as Child-Pugh C and have varices of any size. In order to avoid variceal bleeding and death, individuals with cirrhosis at high risk of bleeding must undergo primary prophylaxis, for which currently recommended strategies are the use of traditional non-selective beta-blockers (NSBBs) (i.e., propranolol or nadolol), carvedilol (a NSBB with additional alpha-adrenergic blocking effect) or endoscopic variceal ligation (EVL). The superiority of one of these alternatives over the others is controversial. While EVL might be superior to pharmacological therapy regarding the prevention of the first bleeding episode, either traditional NSBBs or carvedilol seem to play a more prominent role in mortality reduction, probably due to their capacity of preventing other complications of cirrhosis through the decrease in portal hypertension. A sequential strategy, in which patients unresponsive to pharmacological therapy would be submitted to endoscopic treatment, or the combination of pharmacological and endoscopic strategies might be beneficial and deserve further investigation.

Clinical algorithms for the prevention of variceal bleeding and rebleeding in patients with liver cirrhosis.

Portal hypertension (PH), a common complication of liver cirrhosis, results in development of esophageal varices. When esophageal varices rupture, they cause significant upper gastrointestinal bleeding with mortality rates up to 20% despite state-of-the-art treatment. Thus, prophylactic measures are of utmost importance to improve outcomes of patients with PH. Several high-quality studies have demonstrated that non-selective beta blockers (NSBBs) or endoscopic band ligation (EBL) are effective for primary prophylaxis of variceal bleeding. In secondary prophylaxis, a combination of NSBB + EBL should be routinely used. Once esophageal varices develop and variceal bleeding occurs, standardized treatment algorithms should be followed to minimize bleeding-associated mortality. Special attention should be paid to avoidance of overtransfusion, early initiation of vasoconstrictive therapy, prophylactic antibiotics and early endoscopic therapy. Pre-emptive transjugular intrahepatic portosystemic shunt should be used in all Child C10-C13 patients experiencing variceal bleeding, and potentially in Child B patients with active bleeding at endoscopy. The use of carvedilol, safety of NSBBs in advanced cirrhosis (i.e. with refractory ascites) and assessment of hepatic venous pressure gradient response to NSBB is discussed. In the present review, we give an overview on the rationale behind the latest guidelines and summarize key papers that have led to significant advances in the field.

Primary prevention of bleeding from esophageal varices in patients with liver cirrhosis: An update and review of the literature.

All patients with liver cirrhosis and portal hypertension should be stratified by risk groups to individualize different therapeutic strategies to increase the effectiveness of treatment. In this regard, the development of primary prophylaxis of variceal bleeding and its management according to the severity of portal hypertension may be promising. This paper is to describe the modern principles of primary prophylaxis of esophageal variceal bleeding in patients with liver cirrhosis. The PubMed and EMbase databases, Web of Science, Google Scholar, and the Cochrane Database of Systematic Reviews were used to search for relevant publications from 1999 to 2019. The results suggested that depending on the severity of portal hypertension, patients with cirrhosis should be divided into those who need preprimary prophylaxis, which aims to prevent the formation of esophageal varices, and those who require measures that aim to prevent esophageal variceal bleeding. In subclinical portal hypertension, therapy should be etiological and pathogenetic. Cirrhosis with clinically significant portal hypertension should receive nonselective β-blockers if they have small esophageal varices and risk factors for variceal bleeding. Nonselective β-blockers are the first-line drugs for the primary prevention of bleeding from medium to large-sized esophageal varices. Endoscopic band ligation is indicated for the patients who are intolerant to nonselective β-blockers or in the case of contraindications to pharmacological therapy. In summary, the stratification of cirrhotic patients by the severity of portal hypertension and an individual approach to the choice of treatment may increase the effectiveness of therapy as well as improve survival rate of these patients.

Multiparametric magnetic resonance imaging of liver and spleen is a reliable non-invasive predictor of clinically relevant hepatic venous pressure gradient thresholds and predicts failure of primary prophylaxis for variceal bleeding

Multiparametric magnetic resonance imaging of liver and spleen is a reliable non-invasive predictor of clinically relevant hepatic venous pressure gradient thresholds and predicts failure of primary prophylaxis for variceal bleeding

The Clinical Efficacy and Safety of Simvastatin in the Management of Portal Hypertension in Cirrhotic Patients: A Systematic Review

Background: Variceal bleeding is a serious complication of portal hypertension in liver cirrhosis. Current guidelines recommend non-selective beta blockers (NSBBs) and endoscopic variceal ligation for primary prophylaxis of variceal bleeding. However, NSBBs are associated with low response rates and systemic adverse effects. Simvastatin has been shown to reduce portal hypertension in previous studies. Our aim was to assess its clinical efficacy and safety in reducing portal hypertension in cirrhotic patients. Method: We searched PubMed, The Cochrane Library, ScienceDirect, ProQuest, CINAHL, Scopus, and Clinicaltrials.gov, and manually browsed abstracts of major hepatology conferences for selection of studies. We selected randomized controlled trials with a population of cirrhotic patients, simvastatin as an intervention, HVPG change as an outcome, and English as the primary language. The quality of selected studies was assessed using the Cochrane Risk of Bias tool. We extracted change in HVPG from baseline to post-treatment as the principal summary measure, with safety as the secondary outcome.Results: Two full articles were included for qualitative analysis. Both studies reported reductions in HVPG from baseline to post-treatment in the simvastatin group, with this reduction being significantly higher as compared to the control group. Adverse effects were homogenously distributed in both groups, and good safety was reported by both studies. Simvastatin’s HVPG lowering effects are possibly additive to those of NSBBs. Conclusion: Simvastatin effectively reduces HVPG in cirrhotic patients with portal hypertension, although more clinical trials are needed to validate these results. Simvastatin could potentially be combined with NSBBs to achieve greater results.

Sclerotherapy versus sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis.

Portal hypertension commonly accompanies advanced liver disease and often gives rise to life-threatening complications, including bleeding (haemorrhage) from oesophageal and gastrointestinal varices. Variceal bleeding commonly occurs in children with chronic liver disease or portal vein obstruction. Therefore, prevention is important. Primary prophylaxis of variceal bleeding in adults is the established standard of care because of the results of numerous randomised clinical trials demonstrating the efficacy of non-selective beta-blockers or endoscopic variceal ligation in decreasing the incidence of variceal bleeding. In children, band ligation, beta-blockers, and sclerotherapy have been proposed as alternatives for primary prophylaxis of oesophageal variceal bleeding. However, it is unknown whether those treatments are of benefit or harm when used for primary prophylaxis in children. To assess the benefits and harms of sclerotherapy compared with sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, PubMed, Embase Elsevier, and two other registers in February 2019. We scrutinised the reference lists of the retrieved publications, and performed a manual search of the main paediatric gastroenterology and hepatology conference (NASPGHAN and ESPGHAN) abstracts from January 2008 to December 2018. We searched four registries for ongoing clinical trials. There were no language or document type restrictions. We included randomised clinical trials irrespective of blinding, language, or publication status assessing sclerotherapy versus sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. We used standard Cochrane methodology to perform this systematic review. We used the intention-to-treat principle to analyse outcome data, and GRADE to assess the certainty of evidence per outcome. We found only one randomised clinical trial that fulfilled our inclusion criteria. The trial was at high risk of bias. The trial included 108 Brazilian children with median age of 4.3 years (range 11 months to 13 years). Fifty-six children were randomised to prophylactic sclerotherapy (ethanolamine oleate 2%) and 52 children to no intervention (control). Children were followed up for a median of 4.5 years. Eight children (six from the sclerotherapy group versus two from the control group) dropped out before the end of the trial. The follow-up was from 18 months to eight years. Mortality was 16% (9/56 children) in the sclerotherapy group versus 15% (8/52 children) in the control group (risk ration (RR) 1.04, 95% confidence interval (CI) 0.44 to 2.50; very low-certainty evidence). Upper gastrointestinal bleeding occurred in 21% (12/56) of the children in the sclerotherapy group versus 46% (24/52) in the control group (RR 0.46, 95% CI 0.26 to 0.83; very low-certainty evidence). There were more children with congestive hypertensive gastropathy in the sclerotherapy group than in the control group (14% (8/56) versus 6% (3/52); RR 2.48, 95% CI 0.69 to 8.84; very low-certainty evidence). The incidence of gastric varices was similar between the sclerotherapy group and the control group (11% (6/56) versus 10% (5/52); RR 1.11, 95% CI 0.36 to 3.43; very low-certainty evidence). The incidence of bleeding from gastric varices was higher in the sclerotherapy group than in the control group (4% (3/56) versus 0% (0/52); RR 6.51, 95% CI 0.34 to 123.06; very low-certainty evidence). The study did not assess health-related quality of life. Oesophageal variceal bleeding occurred in 5% (3/56) of the children in the sclerotherapy group versus 40% (21/52) of the children in the control group (RR 0.13, 95% CI 0.04 to 0.42; very low-certainty evidence). The most prevalent complications (defined as non-serious) were pain and fever after the procedure, which promptly resolved with analgesics. However, numerical data on the frequency of these adverse events and their occurrences in the two groups were lacking. No funding information was provided. We found no ongoing trials. The evidence, obtained from one randomised clinical trial at high risk of bias, is very uncertain on whether sclerotherapy has an influence on mortality and if it may decrease first upper gastrointestinal or oesophageal variceal bleeding in children. The evidence is very uncertain on whether sclerotherapy has an influence on congestive hypertensive gastropathy, incidence on gastric varices, and incidence of bleeding from gastric varices. Health-related quality of life was not measured. There were no serious events caused by sclerotherapy, and analysis of non-serious adverse events could not be performed due to lack of numerical data. The GRADE assessment of each outcome showed a very low-certainty evidence. The results of the trial need to be interpreted with caution. Larger randomised clinical trials, following the SPIRIT and CONSORT statements, assessing the benefits and harms of sclerotherapy compared with sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis are needed. The trials should include important clinical outcomes such as death, failure to control bleeding, and adverse events.

Hemodynamic Effects of Adding Simvastatin to Carvedilol for Primary Prophylaxis of Variceal Bleeding: A Randomized Controlled Trial.

Beta-blockers are the mainstay agents for portal pressure reduction and to modestly reduce hepatic venous pressure gradient (HVPG). We studied whether addition of simvastatin to carvedilol in cirrhotic patients for primary prophylaxis improves the hemodynamic response. Cirrhotic patients with esophageal varices and with baseline HVPG > 12 mm Hg were prospectively randomized for primary prophylaxis to receive either carvedilol (group A, n = 110) or carvedilol plus simvastatin (group B, n = 110). Primary objective was to compare hemodynamic response (HVPG reduction of ≥20% or <12 mm Hg) at 3 months, and secondary objectives were to compare first bleed episodes, death, and adverse events. The groups were comparable at baseline. The proportion of patients achieving HVPG response at 3 months was comparable between groups (group A-36/62 [58.1%], group B-36/59 [61%], P = 0.85). The degree of mean HVPG reduction (17.3% and 17.8%, respectively, P = 0.98) and hemodynamic response (odds ratio [OR]: 0.88; 95% confidence interval [CI]: 0.43-1.83, P = 0.74) was also not different between the groups. Patients who achieved target heart rate with no hypotensive episodes in either group showed better hemodynamic response (77.8% vs 59.2%, P = 0.04). Failure to achieve target heart rate (OR: 0.48; 95% CI: 0.22-1.06) and Child C cirrhosis (OR: 4.49; 95% CI: 1.20-16.8) predicted nonresponse. Three (3.7%) patients on simvastatin developed transient transaminitis and elevated creatine phosphokinase and improved with drug withdrawal. Two patients in each group bled (P = 0.99). Three patients and 1 patient, respectively, in group A and B died (P = 0.32), with sepsis being the cause of death. Addition of simvastatin to carvedilol for 3 months for primary prophylaxis of variceal bleeding does not improve hemodynamic response over carvedilol monotherapy. Simvastatin usage should be closely monitored for adverse effects in Child C cirrhotic patients.

Sclerotherapy versus beta-blockers for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis.

Portal hypertension commonly accompanies advanced liver disease and often gives rise to life-threatening complications, including bleeding (haemorrhage) from oesophageal and gastrointestinal varices. Variceal bleeding commonly occurs in children with chronic liver disease or portal vein obstruction. Prevention is therefore important. Primary prophylaxis of variceal bleeding in adults is the established standard of care because of the results of numerous randomised clinical trials demonstrating the efficacy of non-selective beta-blockers or endoscopic variceal ligation in decreasing the incidence of variceal bleeding. However, sclerotherapy is the only endoscopic prophylactic option currently available in infants weighing less than 10 kg of bodyweight due to the size of the endoscopic ligator. To assess the benefits and harms of sclerotherapy versus any type of beta-blocker for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, PubMed, Embase Elsevier, LILACS (Bireme), and Science Citation Index Expanded (Web of Science) in February 2019. We scrutinised the reference lists of the retrieved publications and performed a manual search from the main paediatric gastroenterology and hepatology conferences (NASPGHAN and ESPGHAN) abstract books from January 2008 to December 2018. We searched ClinicalTrials.gov, FDA, EMA, and WHO, for ongoing clinical trials. There were no language or document type restrictions. We planned to include randomised clinical trials irrespective of blinding, language, or publication status, assessing sclerotherapy versus any type of beta-blocker for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis. We planned to include quasi-randomised and other observational studies retrieved with the searches for randomised clinical trials for report of harm. We planned to collect and summarise data from randomised clinical trials as described in our protocol, using standard Cochrane methodologies. We found no randomised clinical trials assessing sclerotherapy versus beta-blockers for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis. Randomised clinical trials assessing the benefits or harms of sclerotherapy versus beta-blockers for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis are lacking. Therefore, trials with adequate power and proper design, assessing the benefits and harms of sclerotherapy versus beta-blockers on patient-relevant clinical outcomes such as mortality, failure to control bleeding, and adverse events are needed. Unless such trials are conducted and the results become published, we cannot make any conclusions regarding the benefits or harms of the two interventions.