Systematic review and meta-analysis: incidence of variceal hemorrhage in patients with cirrhosis undergoing transesophageal echocardiography
Alimentary pharmacology & therapeutics. 2022
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.
Band ligation versus sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis
The Cochrane database of systematic reviews. 2021;1:Cd011561
BACKGROUND 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 and adolescents with chronic liver disease or portal vein thrombosis. Prevention is, therefore, important. Randomised clinical trials have shown that non-selective beta-blockers and endoscopic variceal band ligation decrease the incidence of variceal bleeding in adults. In children and adolescents, band ligation, beta-blockers, and sclerotherapy have been proposed as primary prophylaxis alternatives for oesophageal variceal bleeding. However, it is unknown whether these interventions are of benefit or harm when used for primary prophylaxis in children and adolescents. OBJECTIVES To assess the benefits and harms of band ligation compared with sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, PubMed, Embase, and two other databases (April 2020). We scrutinised the reference lists of the retrieved publications, and we also handsearched abstract books of the two main paediatric gastroenterology and hepatology conferences from January 2008 to December 2019. We also searched clinicaltrials.gov, the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the World Health Organization (WHO) for ongoing clinical trials. We imposed no language or document type restrictions on our search. SELECTION CRITERIA We aimed to include randomised clinical trials irrespective of blinding, language, or publication status, to assess the benefits and harms of band ligation versus sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. If the search for randomised clinical trials retrieved quasi-randomised and other observational studies, then we read them through to extract information on harm. DATA COLLECTION AND ANALYSIS We used standard Cochrane methodology to perform this systematic review. We used GRADE to assess the certainty of evidence for each outcome. Our primary outcomes were all-cause mortality, serious adverse events and liver-related morbidity, and quality of life. Our secondary outcomes were oesophageal variceal bleeding and adverse events not considered serious. We used the intention-to-treat principle. We analysed data using Review Manager 5. MAIN RESULTS One conference abstract, describing a feasibility multi-centre randomised clinical trial, fulfilled our review inclusion criteria. We judged the trial at overall high risk of bias. This trial was conducted in three hospital centres in the United Kingdom. The aim of the trial was to determine the feasibility and safety of further larger randomised clinical trials of prophylactic band ligation versus no active treatment in children with portal hypertension and large oesophageal varices. Twelve children received prophylactic band ligation and 10 children received no active treatment. There was no information on the age of the children included, or about the diagnosis of any child included. All children were followed up for at least six months. Mortality was 8% (1/12) in the band ligation group versus 0% (0/10) in the no active intervention group (risk ratio (RR) 2.54, 95% confidence interval (CI) 0.11 to 56.25; very low certainty of evidence). The abstract did not report when the death occurred, but we assume it happened between the six-month follow-up and one year. No child (0%) in the band ligation group developed adverse events (RR 0.28, 95% CI 0.01 to 6.25; very low certainty of evidence) but one child out of 10 (10%) in the no active intervention group developed idiopathic thrombocytopaenic purpura. One child out of 12 (8%) in the band ligation group underwent liver transplantation versus none in the no active intervention group (0%) (RR 2.54, 95% CI 0.11 to 56.25; very low certainty of evidence). The trial reported no other serious adverse events or liver-related morbidity. Quality of life was not reported. Oesophageal variceal bleeding occurred in 8% (1/12) of the children in the band ligation group versus 30% (3/10) of the children in the no active intervention group (RR 0.28, 95% CI 0.03 to 2.27; very low certainty of evidence). No adverse events considered non-serious were reported. Two children were lost to follow-up by one-year. Ten children in total completed the trial at two-year follow-up. There was no information on funding. We found two observational studies on endoscopic variceal ligation when searching for randomised trials. One found no harm, and the other reported E nterobacter cloacae septicaemia in one child and mild, transient, upper oesophageal sphincter stenosis in another. We did not assess these studies for risk of bias. We did not find any ongoing randomised clinical trials of interest to our review. AUTHORS' CONCLUSIONS The evidence, obtained from only one feasibility randomised clinical trial at high risk of bias, is very scanty. It is very uncertain about whether prophylactic band ligation versus sham or no (active) intervention may affect mortality, serious adverse events and liver-related morbidity, or oesophageal variceal bleeding in children and adolescents with portal hypertension and large oesophageal varices. We have no data on quality of life. No adverse events considered non-serious were reported. The results presented in the trial need to be interpreted with caution. In addition, the highly limited data cover only part of our research question; namely, children with portal hypertension and large oesophageal varices. Data on children with portal vein thrombosis are lacking. Larger randomised clinical trials assessing the benefits and harms of band ligation compared with sham treatment for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis are needed. The trials should include important clinical outcomes such as death, quality of life, failure to control bleeding, and adverse events.
Terlipressin effect on hepatorenal syndrome: Updated meta-analysis of randomized controlled trials
JGH open : an open access journal of gastroenterology and hepatology. 2021;5(8):896-901
BACKGROUND AND AIM Hepatorenal syndrome (HRS) is a fatal complication of liver cirrhosis with a limited pharmacological option. Terlipressin is a vasoconstrictor that is approved in many countries but not yet in the United States. This is a meta-analysis of randomized controlled trials (RCTs) to review terlipressin effect on HRS and the safety profile. METHODS We searched electronic databases for RCTs comparing terlipressin versus placebo in addition to albumin in patients with type 1 or 2 HRS. Primary outcome was HRS reversal. Secondary outcomes were change in serum creatinine (Cr), requirement for renal replacement therapy (RRT) at 30 days of randomization, and 90-day survival. Risk ratios (RRs) and mean differences (MD) were calculated with 95% confidence intervals (CIs) using a random-effects model. RESULTS We identified eight RCTs with a total of 974 patients, and median follow up of 100 days. Mean age was 55 ± 10 years, 61% were males. Alcoholic liver disease represented 56%. Compared with placebo, terlipressin was associated with a significantly higher likelihood of HRS reversal (RR 2.08; 95% CI [1.51, 2.86], P < 0.001), significantly lower serum Cr (MD -0.64; 95% CI (-1.02, -0.27), P < 0.001], and a trend toward less RRT requirements (RR 0.61; 95% CI [0.36, 1.02], P = 0.06). There was no difference in survival at 90 days between groups (RR 1.09; 95% CI (0.84, 1.43), P = 0.52). Major adverse effects (AEs) were gastrointestinal cramps, discomfort, and respiratory distress. CONCLUSION In patients with liver cirrhosis complicated by HRS, terlipressin was associated with significant HRS reversal and decrease in serum Cr. No survival benefit was detected at 90 days.
Treatment for bleeding oesophageal varices in people with decompensated liver cirrhosis: a network meta-analysis
The Cochrane database of systematic reviews. 2021;4:Cd013155
BACKGROUND Approximately 40% to 95% of people with liver cirrhosis have oesophageal varices. About 15% to 20% of oesophageal varices bleed within about one to three years after diagnosis. Several different treatments are available, including, among others, endoscopic sclerotherapy, variceal band ligation, somatostatin analogues, vasopressin analogues, and balloon tamponade. However, there is uncertainty surrounding the individual and relative benefits and harms of these treatments. OBJECTIVES To compare the benefits and harms of different initial treatments for variceal bleeding from oesophageal varices in adults with decompensated liver cirrhosis, through a network meta-analysis; and to generate rankings of the different treatments for acute bleeding oesophageal varices, according to their benefits and harms. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until 17 December 2019, to identify randomised clinical trials (RCTs) in people with cirrhosis and acute bleeding from oesophageal varices. SELECTION CRITERIA We included only RCTs (irrespective of language, blinding, or status) in adults with cirrhosis and acutely bleeding oesophageal varices. We excluded RCTs in which participants had bleeding only from gastric varices, those who failed previous treatment (refractory bleeding), those in whom initial haemostasis was achieved before inclusion into the trial, and those who had previously undergone liver transplantation. DATA COLLECTION AND ANALYSIS We performed a network meta-analysis with OpenBUGS software, using Bayesian methods, and calculated the differences in treatments using odds ratios (OR) and rate ratios with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. We performed also the direct comparisons from RCTs using the same codes and the same technical details. MAIN RESULTS We included a total of 52 RCTs (4580 participants) in the review. Forty-eight trials (4042 participants) were included in one or more comparisons in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies and those with and without a previous history of bleeding. We included outcomes assessed up to six weeks. All trials were at high risk of bias. A total of 19 interventions were compared in the trials (sclerotherapy, somatostatin analogues, vasopressin analogues, sclerotherapy plus somatostatin analogues, variceal band ligation, balloon tamponade, somatostatin analogues plus variceal band ligation, nitrates plus vasopressin analogues, no active intervention, sclerotherapy plus variceal band ligation, balloon tamponade plus sclerotherapy, balloon tamponade plus somatostatin analogues, balloon tamponade plus vasopressin analogues, variceal band ligation plus vasopressin analogues, balloon tamponade plus nitrates plus vasopressin analogues, balloon tamponade plus variceal band ligation, portocaval shunt, sclerotherapy plus transjugular intrahepatic portosystemic shunt (TIPS), and sclerotherapy plus vasopressin analogues). We have reported the effect estimates for the primary and secondary outcomes when there was evidence of differences between the interventions against the reference treatment of sclerotherapy, but reported the other results of the primary and secondary outcomes versus the reference treatment of sclerotherapy without the effect estimates when there was no evidence of differences in order to provide a concise summary of the results. Overall, 15.8% of the trial participants who received the reference treatment of sclerotherapy (chosen because this was the commonest treatment compared in the trials) died during the follow-up periods, which ranged from three days to six weeks. Based on moderate-certainty evidence, somatostatin analogues alone had higher mortality than sclerotherapy (OR 1.57, 95% CrI 1.04 to 2.41; network estimate; direct comparison: 4 trials; 353 participants) and vasopressin analogues alone had higher mortality than sclerotherapy (OR 1.70, 95% CrI 1.13 to 2.62; network estimate; direct comparison: 2 trials; 438 participants). None of the trials reported health-related quality of life. Based on low-certainty evidence, a higher proportion of people receiving balloon tamponade plus sclerotherapy had more serious adverse events than those receiving only sclerotherapy (OR 4.23, 95% CrI 1.22 to 17.80; direct estimate; 1 RCT; 60 participants). Based on moderate-certainty evidence, people receiving vasopressin analogues alone and those receiving variceal band ligation had fewer adverse events than those receiving only sclerotherapy (rate ratio 0.59, 95% CrI 0.35 to 0.96; network estimate; direct comparison: 1 RCT; 219 participants; and rate ratio 0.40, 95% CrI 0.21 to 0.74; network estimate; direct comparison: 1 RCT; 77 participants; respectively). Based on low-certainty evidence, the proportion of people who developed symptomatic rebleed was smaller in people who received sclerotherapy plus somatostatin analogues than those receiving only sclerotherapy (OR 0.21, 95% CrI 0.03 to 0.94; direct estimate; 1 RCT; 105 participants). The evidence suggests considerable uncertainty about the effect of the interventions in the remaining comparisons where sclerotherapy was the control intervention. AUTHORS' CONCLUSIONS Based on moderate-certainty evidence, somatostatin analogues alone and vasopressin analogues alone (with supportive therapy) probably result in increased mortality, compared to endoscopic sclerotherapy. Based on moderate-certainty evidence, vasopressin analogues alone and band ligation alone probably result in fewer adverse events compared to endoscopic sclerotherapy. Based on low-certainty evidence, balloon tamponade plus sclerotherapy may result in large increases in serious adverse events compared to sclerotherapy. Based on low-certainty evidence, sclerotherapy plus somatostatin analogues may result in large decreases in symptomatic rebleed compared to sclerotherapy. In the remaining comparisons, the evidence indicates considerable uncertainty about the effects of the interventions, compared to sclerotherapy.
Primary prevention of variceal bleeding in people with oesophageal varices due to liver cirrhosis: a network meta-analysis
The Cochrane database of systematic reviews. 2021;4:Cd013121
BACKGROUND Approximately 40% to 95% of people with cirrhosis have oesophageal varices. About 15% to 20% of oesophageal varices bleed in about one to three years. There are several different treatments to prevent bleeding, including: beta-blockers, endoscopic sclerotherapy, and variceal band ligation. However, there is uncertainty surrounding their individual and relative benefits and harms. OBJECTIVES To compare the benefits and harms of different treatments for prevention of first variceal bleeding from oesophageal varices in adults with liver cirrhosis through a network meta-analysis and to generate rankings of the different treatments for prevention of first variceal bleeding from oesophageal varices according to their safety and efficacy. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers to December 2019 to identify randomised clinical trials in people with cirrhosis and oesophageal varices with no history of bleeding. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis and oesophageal varices with no history of bleeding. We excluded randomised clinical trials in which participants had previous bleeding from oesophageal varices and those who had previously undergone liver transplantation or previously received prophylactic treatment for oesophageal varices. DATA COLLECTION AND ANALYSIS We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the differences in treatments using hazard ratios (HR), odds ratios (OR), and rate ratios with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute for Health and Care Excellence Decision Support Unit guidance. We performed the direct comparisons from randomised clinical trials using the same codes and the same technical details. MAIN RESULTS We included 66 randomised clinical trials (6653 participants) in the review. Sixty trials (6212 participants) provided data for one or more comparisons in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies and those at high risk of bleeding from oesophageal varices. The follow-up in the trials that reported outcomes ranged from 6 months to 60 months. All but one of the trials were at high risk of bias. The interventions compared included beta-blockers, no active intervention, variceal band ligation, sclerotherapy, beta-blockers plus variceal band ligation, beta-blockers plus nitrates, nitrates, beta-blockers plus sclerotherapy, and portocaval shunt. Overall, 21.2% of participants who received non-selective beta-blockers ('beta-blockers') - the reference treatment (chosen because this was the most common treatment compared in the trials) - died during 8-month to 60-month follow-up. Based on low-certainty evidence, beta-blockers, variceal band ligation, sclerotherapy, and beta-blockers plus nitrates all had lower mortality versus no active intervention (beta-blockers: HR 0.49, 95% CrI 0.36 to 0.67; direct comparison HR: 0.59, 95% CrI 0.42 to 0.83; 10 trials, 1200 participants; variceal band ligation: HR 0.51, 95% CrI 0.35 to 0.74; direct comparison HR 0.49, 95% CrI 0.12 to 2.14; 3 trials, 355 participants; sclerotherapy: HR 0.66, 95% CrI 0.51 to 0.85; direct comparison HR 0.61, 95% CrI 0.41 to 0.90; 18 trials, 1666 participants; beta-blockers plus nitrates: HR 0.41, 95% CrI 0.20 to 0.85; no direct comparison). No trials reported health-related quality of life. Based on low-certainty evidence, variceal band ligation had a higher number of serious adverse events (number of events) than beta-blockers (rate ratio 10.49, 95% CrI 2.83 to 60.64; 1 trial, 168 participants). Based on low-certainty evidence, beta-blockers plus nitrates had a higher number of 'any adverse events (number of participants)' than beta-blockers alone (OR 3.41, 95% CrI 1.11 to 11.28; 1 trial, 57 participants). Based on low-certainty evidence, adverse events (number of events) were higher in sclerotherapy than in beta-blockers (rate ratio 2.49, 95% CrI 1.53 to 4.22; direct comparison rate ratio 2.47, 95% CrI 1.27 to 5.06; 2 trials, 90 participants), and in beta-blockers plus variceal band ligation than in beta-blockers (direct comparison rate ratio 1.72, 95% CrI 1.08 to 2.76; 1 trial, 140 participants). Based on low-certainty evidence, any variceal bleed was lower in beta-blockers plus variceal band ligation than in beta-blockers (direct comparison HR 0.21, 95% CrI 0.04 to 0.71; 1 trial, 173 participants). Based on low-certainty evidence, any variceal bleed was higher in nitrates than beta-blockers (direct comparison HR 6.40, 95% CrI 1.58 to 47.42; 1 trial, 52 participants). The evidence indicates considerable uncertainty about the effect of the interventions in the remaining comparisons. AUTHORS' CONCLUSIONS Based on low-certainty evidence, beta-blockers, variceal band ligation, sclerotherapy, and beta-blockers plus nitrates may decrease mortality compared to no intervention in people with high-risk oesophageal varices in people with cirrhosis and no previous history of bleeding. Based on low-certainty evidence, variceal band ligation may result in a higher number of serious adverse events than beta-blockers. The evidence indicates considerable uncertainty about the effect of beta-blockers versus variceal band ligation on variceal bleeding. The evidence also indicates considerable uncertainty about the effect of the interventions in most of the remaining comparisons.
Efficacy and safety of albumin infusion for overt hepatic encephalopathy: A systematic review and meta-analysis
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2021
BACKGROUND AND AIMS The efficacy and safety of albumin infusion for treatment and prevention of overt hepatic encephalopathy (OHE) among cirrhosis patients remained controversial. We performed a systematic review and meta-analysis to evaluate the benefit of albumin infusion for the treatment and prevention of OHE. METHODS We performed a systematic search of 4 electronic databases up to 31st January 2021. The primary outcome was the resolution of OHE. Secondary outcomes were inpatient mortality and albumin-associated adverse events. We assessed the pooled odds' risk, pooled mean differences, 95% confidence interval and heterogeneity using Review Manager Version 5.3. RESULTS A total of 12 studies (2,087 subjects) were identified. Among cirrhosis patients with OHE, albumin infusion was associated with a lower pooled risk of OHE (OR=0.43, 95%CI: 0.27, 0.68; I(2)=0%). Among patients without baseline OHE, albumin infusion was associated with a lower pooled risk of developing OHE (OR=0.53, 95%CI: 0.32, 0.86; I(2)=62%). Albumin infusion was associated with a lower pooled risk of inpatient mortality (OR=0.36, 95%CI: 0.21, 0.60; I(2)=0%). CONCLUSION Well-powered randomized trials are required to confirm the benefits of albumin infusion for the prevention and treatment of overt hepatic encephalopathy among decompensated cirrhosis patients.
Albumin in the management of hepatic encephalopathy: A systematic review and meta-analysis
Annals of hepatology. 2021;26:100541
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.
Secondary Prophylaxis of Gastric Variceal Bleeding: A Systematic Review and Network Meta-analysis
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2021
BACKGROUND There is no clear consensus regarding the optimal approach for secondary prophylaxis of gastric variceal bleeding (GVB) in patients with cirrhosis. We conducted a systematic review and network metanalysis (NMA) to compare the efficacy of available treatments. METHODS A comprehensive search of several databases from each database's inception to March 23rd, 2021 was conducted to identify relevant randomized controlled trials (RCTs). Outcomes of interest were rebleeding and mortality. Results were expressed as relative risk (RR) and 95% confidence interval (CI). We followed the Grading of Recommendations Assessment, Development, and Evaluation approach to rate the certainty of evidence. RESULTS We included 9 RCTs with 579 patients, who had history of GVB and follow-up > 6 weeks. Nine interventions were included in the NMA. Balloon-occluded retrograde transvenous obliteration (BRTO) was associated with a lower risk of rebleeding when compared to beta-blockers (RR 0.04, 95%CI 0.01-0.26; low certainty), endoscopic injection sclerotherapy (EIS-CYA) (RR 0.18, 95%CI 0.04-0.77; low certainty). Beta-blockers were associated with a higher risk of rebleeding compared to most interventions and with increased mortality compared to EIS-CYA (RR 4.85, 95%CI 1.04-22.67; low certainty) and EIS-CYA+BB (RR 5.47, 95% CI 1.07-28.01; low certainty). CONCLUSION Analysis based on indirect comparisons suggests that BRTO may be the best intervention in preventing rebleeding whereas beta-blocker monotherapy is likely the worst in preventing rebleeding and mortality. Head-to-head RCTs are needed to validate these results.
Novel Therapies for the Treatment of Drug-Induced Liver Injury: A Systematic Review
Frontiers in pharmacology. 2021;12:785790
Many drugs with different mechanisms of action and indications available on the market today are capable of inducing hepatotoxicity. Drug-induced liver injury (DILI) has been a treatment challenge nowadays as it was in the past. We searched Medline (via PubMed), CENTRAL, Science Citation Index Expanded, clinical trials registries and databases of DILI and hepatotoxicity up to 2021 for novel therapies for the management of adult patients with DILI based on the combination of three main search terms: 1) treatment, 2) novel, and 3) drug-induced liver injury. The mechanism of action of novel therapies, the potential of their benefit in clinical settings, and adverse drug reactions related to novel therapies were extracted. Cochrane Risk of bias tool and Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment approach was involved in the assessment of the certainty of the evidence for primary outcomes of included studies. One thousand three hundred seventy-two articles were identified. Twenty-eight articles were included in the final analysis. Eight randomized controlled trials (RCTs) were detected and for six the available data were sufficient for analysis. In abstract form only we found six studies which were also anaylzed. Investigated agents included: bicyclol, calmangafodipir, cytisin amidophospate, fomepizole, livina-polyherbal preparation, magnesium isoglycyrrhizinate (MgIG), picroliv, plasma exchange, radix Paeoniae Rubra, and S-adenosylmethionine. The primary outcomes of included trials mainly included laboratory markers improvement. Based on the moderate-certainty evidence, more patients treated with MgIG experienced alanine aminotransferase (ALT) normalization compared to placebo. Low-certainty evidence suggests that bicyclol treatment leads to a reduction of ALT levels compared to phosphatidylcholine. For the remaining eight interventions, the certainty of the evidence for primary outcomes was assessed as very low and we are very uncertain in any estimate of effect. More effort should be involved to investigate the novel treatment of DILI. Well-designed RCTs with appropriate sample sizes, comparable groups and precise, not only surrogate outcomes are urgently welcome.
Vasoactive Agents for the Management of Acute Variceal Bleeding: A Systematic Review and Meta-analysis
Journal of gastrointestinal and liver diseases : JGLD. 2021;30(1):110-121
BACKGROUND AND AIMS Vasoactive agents with endoscopic therapy are used to treat acute variceal bleeding (AVB). There are two main groups of vasoactive agents: terlipressin and vasopressin (T-V), and octreotide and somatostatin (O-S). However, the benefit/harm balance is unclear. Our aim was to assess the efficacy and safety of T-V versus O-S for the management of AVB. METHODS We performed a systematic search for randomized controlled trials (RCTs) in PubMed, Scopus, and CENTRAL. Our main outcomes were mortality and adverse events. Secondary outcomes were bleeding control, rebleeding, blood transfusion, hospital stay. We evaluated the certainty of evidence using GRADE methodology. RESULTS We included 21 RCTs. The risk of mortality (RR: 1.01; 95%CI: 0.83-1.22), bleeding control (RR: 0.96; 95%CI: 0.91-1.02; I 2 =53%), early rebleeding (RR: 0.91; 95%CI: 0.66-1.24: I 2 =0%), late rebleeding (RR: 0.94; 95 CI: 0.56-1.60; I 2 =0%), blood transfusion (MD: 0.04; 95%CI: -0.31-0.39; I 2 =68%) and hospital stay (MD: -1.06; 95%CI: -2.80-0.69; I 2 =0%) were similar between T-V and O-S groups. Only 15 studies reported adverse events, which were significantly higher in the T-V compared to the O-S group (RR 2.39; 95%CI: 1.58-3.63; I 2 =57%). The certainty of evidence was moderate for the main outcomes, and low or very low for others. CONCLUSIONS In cirrhotic patients with AVB, those treated with T-V had similar mortality risk compared to O-S. However, the use of T-V showed an increased risk of adverse events compared to O-S.