Summary The susceptibility to developing alcohol dependence and significant alcohol-related liver injury is determined by a number of constitutional, environmental and genetic factors, although the ...nature and level of interplay between them remains unclear. The familiality and heritability of alcohol dependence is well-documented but, to date, no strong candidate genes conferring increased risk have emerged, although variants in alcohol dehydrogenase and acetaldehyde dehydrogenase have been shown to confer protection, predominantly in individuals of East Asian ancestry. Population contamination with confounders such as drug co-dependence and psychiatric and physical co-morbidity may explain the essentially negative genome-wide association studies in this disorder. The familiality and hereditability of alcohol-related cirrhosis is not as well-documented but three strong candidate genes PNPLA3 , TM6SF2 and MBOAT7 , have been identified. The mechanisms by which variants in these genes confer risk and the nature of the functional interplay between them remains to be determined but, when elucidated, will undoubtedly increase our understanding of the pathophysiology of this disease. The way in which this genetic information could potentially inform patient management has yet to be determined and tested.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Nonabsorbable disaccharides (NADs) have been used to treat hepatic encephalopathy (HE) since 1966. However, a Cochrane Review, published in 2004, found insufficient evidence to recommend their use in ...this context. This updated systematic review evaluates the effects of the NADs, lactulose and lactitol, for the treatment and prevention of HE in patients with cirrhosis. Thirty‐eight randomized controlled trials, involving 1,828 patients, were identified through electronic and manual searches; 31 randomized controlled trials looked at the treatment of HE, while seven looked at its primary/secondary prevention. Random‐effects meta‐analyses showed that, compared to placebo/no intervention, NADs had a beneficial effect on HE (relative risk RR = 0.63, 95% confidence interval CI 0.53‐0.74, number needed to treat NNT = 4) and serious liver‐related adverse events such as liver failure, variceal bleeding, serious infections, spontaneous bacterial peritonitis, and hepatorenal syndrome (RR = 0.42, 95% CI 0.26‐0.69, NNT = 50). Treatment was also associated with a reduction in mortality in patients with overt HE (RR = 0.36, 95% CI 0.14‐0.94, NNT = 20), although not in patients with minimal HE. Meta‐analyses of the prevention randomized controlled trials showed that NADs prevented the development of HE (RR = 0.47, 95% CI 0.33‐0.68, NNT = 6), the risk of developing serious liver‐related adverse events (RR = 0.48, 95% CI 0.33‐0.70, NNT = 6), and reduced mortality (RR = 0.63, 95% CI 0.40‐0.98, NNT = 20). Use of NADs was associated with nonserious gastrointestinal adverse events. There were no differences in the efficacy or safety of lactulose and lactitol. Conclusions: NADs have beneficial effects in the treatment and prevention of HE; their use, in this context, confers additional benefits including a reduction in serious liver‐related morbidities and all‐cause mortality. (Hepatology 2016;64:908‐922)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Non‐absorbable disaccharides (lactulose and lactitol) are recommended as first‐line treatment for hepatic encephalopathy. The previous (second) version of this review included 10 ...randomised clinical trials (RCTs) evaluating non‐absorbable disaccharides versus placebo/no intervention and eight RCTs evaluating lactulose versus lactitol for people with cirrhosis and hepatic encephalopathy. The review found no evidence to either support or refute the use of the non‐absorbable disaccharides and no differences between lactulose versus lactitol.
Objectives
To assess the beneficial and harmful effects of i) non‐absorbable disaccharides versus placebo/no intervention and ii) lactulose versus lactitol in people with cirrhosis and hepatic encephalopathy.
Search methods
We carried out electronic searches of the Cochrane Hepato‐Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 10), MEDLINE, EMBASE, and Science Citation Index Expanded to 19 October 2015; manual searches of meetings and conference proceedings; checks of bibliographies; and correspondence with investigators and pharmaceutical companies.
Selection criteria
We included RCTs, irrespective of publication status, language, or blinding.
Data collection and analysis
Two review authors, working independently, retrieved data from published reports and correspondence with investigators. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We presented the results of meta‐analyses as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed the quality of the evidence using 'Grading of Recommendations Assessment Development and Evaluation' (GRADE) and bias control using the Cochrane Hepato‐Biliary Group domains. Our analyses included regression analyses of publication bias and other small study effects, Trial Sequential Analyses to detect type 1 and type 2 errors, and subgroup and sensitivity analyses.
Main results
We included 38 RCTs with a total of 1828 participants. Eight RCTs had a low risk of bias in the assessment of mortality. All trials had a high risk of bias in the assessment of the remaining outcomes. Random‐effects meta‐analysis showed a beneficial effect of non‐absorbable disaccharides versus placebo/no intervention on mortality when including all RCTs with extractable data (RR 0.59, 95% CI 0.40 to 0.87; 1487 participants; 24 RCTs; I2 = 0%; moderate quality evidence) and in the eight RCTs with a low risk of bias (RR 0.63, 95% CI 0.41 to 0.97; 705 participants). The Trial Sequential Analysis with the relative risk reduction (RRR) reduced to 30% confirmed the findings when including all RCTs, but not when including only RCTs with a low risk of bias or when we reduced the RRR to 22%. Compared with placebo/no intervention, the non‐absorbable disaccharides were associated with beneficial effects on hepatic encephalopathy (RR 0.58, 95% CI 0.50 to 0.69; 1415 participants; 22 RCTs; I2 = 32%; moderate quality evidence). Additional analyses showed that non‐absorbable disaccharides can help to reduce serious adverse events associated with the underlying liver disease including liver failure, hepatorenal syndrome, and variceal bleeding (RR 0.47, 95% CI 0.36 to 0.60; 1487 participants; 24 RCTs; I2 = 0%; moderate quality evidence). We confirmed the results in Trial Sequential Analysis. Tests for subgroup differences showed no statistical differences between RCTs evaluating prevention, overt, or minimal hepatic encephalopathy. The evaluation of secondary outcomes showed a potential beneficial effect of the non‐absorbable disaccharides on quality of life, but we were not able to include the data in an overall meta‐analysis (very low quality evidence). Non‐absorbable disaccharides were associated with non‐serious (mainly gastrointestinal) adverse events (very low quality evidence). None of the RCTs comparing lactulose versus lactitol evaluated quality of life. The review found no differences between lactulose and lactitol for the remaining outcomes (very low quality evidence).
Authors' conclusions
This review includes a large number of RCTs evaluating the prevention or treatment of hepatic encephalopathy. The analyses found evidence that non‐absorbable disaccharides may be associated with a beneficial effect on clinically relevant outcomes compared with placebo/no intervention.
Nitrogen metabolism plays a major role in the development of hepatic encephalopathy (HE) in patients with cirrhosis. Modulation of this relationship is key to the management of HE, but is not the ...only nutritional issue that needs to be addressed. The assessment of nutritional status in patients with cirrhosis is problematic. In addition, there are significant sex‐related differences in body composition and in the characteristics of tissue loss, which limit the usefulness of techniques based on measures of muscle mass and function in women. Techniques that combine subjective and objective variables provide reasonably accurate information and are recommended. Energy and nitrogen requirements in patients with HE are unlikely to differ substantially from those recommended in patients with cirrhosis per se viz. 35‐45 kcal/g and 1.2‐1.5g/kg protein daily. Small meals evenly distributed throughout the day and a late‐night snack of complex carbohydrates will help minimize protein utilization. Compliance is, however, likely to be a problem. Diets rich in vegetables and dairy protein may be beneficial and are therefore recommended, but tolerance varies considerably in relation to the nature of the staple diet. Branched chain amino acid supplements may be of value in the occasional patient intolerant of dietary protein. Increasing dietary fiber may be of value, but the utility of probiotics is, as yet, unclear. Short‐term multivitamin supplementation should be considered in patients admitted with decompensated cirrhosis. Hyponatremia may worsen HE; it should be prevented as far as possible and should always be corrected slowly. Conclusion: Effective management of these patients requires an integrated multidimensional approach. However, further research is needed to fill the gaps in the current evidence base to optimize the nutritional management of patients with cirrhosis and HE. (Hepatology 2013)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Non-absorbable disaccharides (lactulose and lactitol) are recommended as first-line treatment for hepatic encephalopathy. The previous (second) version of this review included 10 randomised clinical ...trials (RCTs) evaluating non-absorbable disaccharides versus placebo/no intervention and eight RCTs evaluating lactulose versus lactitol for people with cirrhosis and hepatic encephalopathy. The review found no evidence to either support or refute the use of the non-absorbable disaccharides and no differences between lactulose versus lactitol.
To assess the beneficial and harmful effects of i) non-absorbable disaccharides versus placebo/no intervention and ii) lactulose versus lactitol in people with cirrhosis and hepatic encephalopathy.
We carried out electronic searches of the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 10), MEDLINE, EMBASE, and Science Citation Index Expanded to 19 October 2015; manual searches of meetings and conference proceedings; checks of bibliographies; and correspondence with investigators and pharmaceutical companies.
We included RCTs, irrespective of publication status, language, or blinding.
Two review authors, working independently, retrieved data from published reports and correspondence with investigators. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We presented the results of meta-analyses as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed the quality of the evidence using 'Grading of Recommendations Assessment Development and Evaluation' (GRADE) and bias control using the Cochrane Hepato-Biliary Group domains. Our analyses included regression analyses of publication bias and other small study effects, Trial Sequential Analyses to detect type 1 and type 2 errors, and subgroup and sensitivity analyses.
We included 38 RCTs with a total of 1828 participants. Eight RCTs had a low risk of bias in the assessment of mortality. All trials had a high risk of bias in the assessment of the remaining outcomes. Random-effects meta-analysis showed a beneficial effect of non-absorbable disaccharides versus placebo/no intervention on mortality when including all RCTs with extractable data (RR 0.59, 95% CI 0.40 to 0.87; 1487 participants; 24 RCTs; I(2) = 0%; moderate quality evidence) and in the eight RCTs with a low risk of bias (RR 0.63, 95% CI 0.41 to 0.97; 705 participants). The Trial Sequential Analysis with the relative risk reduction (RRR) reduced to 30% confirmed the findings when including all RCTs, but not when including only RCTs with a low risk of bias or when we reduced the RRR to 22%. Compared with placebo/no intervention, the non-absorbable disaccharides were associated with beneficial effects on hepatic encephalopathy (RR 0.58, 95% CI 0.50 to 0.69; 1415 participants; 22 RCTs; I(2) = 32%; moderate quality evidence). Additional analyses showed that non-absorbable disaccharides can help to reduce serious adverse events associated with the underlying liver disease including liver failure, hepatorenal syndrome, and variceal bleeding (RR 0.47, 95% CI 0.36 to 0.60; 1487 participants; 24 RCTs; I(2) = 0%; moderate quality evidence). We confirmed the results in Trial Sequential Analysis. Tests for subgroup differences showed no statistical differences between RCTs evaluating prevention, overt, or minimal hepatic encephalopathy. The evaluation of secondary outcomes showed a potential beneficial effect of the non-absorbable disaccharides on quality of life, but we were not able to include the data in an overall meta-analysis (very low quality evidence). Non-absorbable disaccharides were associated with non-serious (mainly gastrointestinal) adverse events (very low quality evidence). None of the RCTs comparing lactulose versus lactitol evaluated quality of life. The review found no differences between lactulose and lactitol for the remaining outcomes (very low quality evidence).
This review includes a large number of RCTs evaluating the prevention or treatment of hepatic encephalopathy. The analyses found evidence that non-absorbable disaccharides may be associated with a beneficial effect on clinically relevant outcomes compared with placebo/no intervention.
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NUK, OILJ, UL, UM, UPUK, VSZLJ
Summary
Background
The influence of genetic factors on survival following a diagnosis of hepatocellular carcinoma (HCC) remains unclear.
Aim
To assess whether genetic polymorphisms influencing the ...susceptibility to develop HCC are also associated with HCC prognosis.
Methods
We included United Kingdom Biobank (UKB) participants diagnosed with HCC after study enrolment. The primary outcome was all‐cause mortality. Patients were followed from the date of HCC diagnosis to death or the registry completion date. Five HCC susceptibility loci were investigated: rs738409 (PNPLA3), rs58542926 (TM6SF2); rs72613567 (HSD17B13); rs2242652 (TERT) and rs708113 (WNT3A). The associations between these genetic variants and HCC mortality risk were assessed using Cox regression, adjusted for age, sex, ethnicity, aetiology, severity of the underlying liver disease and receipt of curative HCC treatment.
Results
The final sample included 439 patients; 74% had either non‐alcoholic fatty liver disease or alcohol‐related liver disease. There were 321 deaths during a mean follow‐up of 1.9 years per participant. Kaplan–Meier survival estimates at 1, 3 and 5 years were 53.2%, 31.2% and 22.6% respectively.
In multivariate analysis, rs72613567:TA (HSD17B13) was the only genetic susceptibility variant significantly associated with all‐cause mortality risk (aHR: 0.74; 95% CI: 0.61–0.90; p = 0.003). Other associated factors were Baveno stage 3–4 (aHR: 1.65; 95% CI: 1.05–2.59; p = 0.03) and HCC treatment with curative intent (aHR: 0.25; 95% CI: 0.17–0.37; p < 0.001).
Conclusions
The rs72613567:TA polymorphism in HSD17B13 is not only associated with a reduction in the risk of developing HCC but with a survival benefit in HCC once established. Therapeutic inhibition of HSD17B13 may augment survival in individuals with HCC.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Hepatic encephalopathy is a common complication of cirrhosis and has high associated morbidity and mortality. The condition is classified as overt if it is clinically apparent or minimal ...if only evident though psychometric testing. The exact pathogenesis of this syndrome is unknown although ammonia is thought to play a key role. L‐ornithine L‐aspartate has ammonia‐lowering properties and may, therefore, benefit people with cirrhosis and hepatic encephalopathy.
Objectives
To evaluate the beneficial and harmful effects of L‐ornithine L‐aspartate versus placebo, no intervention, or other active interventions in people with cirrhosis and hepatic encephalopathy.
Search methods
We undertook electronic searches of The Cochrane Hepato‐Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS and Science Citation Index Expanded to December 2017 and manual searches of meetings and conference proceedings; checks of bibliographies; and corresponded with investigators and pharmaceutical companies.
Selection criteria
We included randomised clinical trials, irrespective of publication status, language, or blinding. We included participants with cirrhosis who had minimal or overt hepatic encephalopathy or who were at risk for developing hepatic encephalopathy. We compared: L‐ornithine L‐aspartate versus placebo or no intervention; and L‐ornithine L‐aspartate versus other active agents such as non‐absorbable disaccharides, antibiotics, probiotics, or branched‐chain amino acids.
Data collection and analysis
Two review authors, working independently, retrieved data from published reports and correspondence with investigators and pharmaceutical companies. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We undertook meta‐analyses and presented the results as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed bias control using the Cochrane Hepato‐Biliary Group domains; we evaluated the risk of publication bias and other small trial effects in regression analyses; conducted subgroup and sensitivity analyses; and performed Trial Sequential Analyses. We determined the quality of the evidence using GRADE.
Main results
We identified 36 randomised clinical trials, involving at least 2377 registered participants, which fulfilled our inclusion criteria including 10 unpublished randomised clinical trials. However, we were only able to access outcome data from 29 trials involving 1891 participants. Five of the included trials assessed prevention, while 31 trials assessed treatment. Five trials were at low risk of bias in the overall assessment of mortality; one trial was at low risk of bias in the assessment of the remaining outcomes.
L‐ornithine L‐aspartate had a beneficial effect on mortality compared with placebo or no intervention when including all trials (RR 0.42, 95% CI 0.24 to 0.72; I2 = 0%; 19 trials; 1489 participants; very low quality evidence), but not when the analysis was restricted to the trials at low risk of bias (RR 0.47, 95% CI 0.06 to 3.58; 4 trials; 244 participants). It had a beneficial effect on hepatic encephalopathy compared with placebo or no intervention when including all trials (RR 0.70, 95% CI 0.59 to 0.83; 22 trials; 1375 participants; I2 = 62%; very low quality evidence), but not in the one trial at low risk of bias (RR 0.96, 95% CI 0.85 to 1.07; 63 participants). The analysis of serious adverse events showed a potential benefit of L‐ornithine L‐aspartate when including all randomised clinical trials (RR 0.63, 95% CI 0.45 to 0.90; 1 trial; 1489 participants; I2 = 0%; very low quality evidence), but not in the one trial at low risk of bias for this outcome (RR 0.83, 95% CI 0.15 to 4.65; 63 participants). The Trial Sequential Analyses of mortality, hepatic encephalopathy, and serious adverse events found insufficient evidence to support or refute beneficial effects. Subgroup analyses showed no difference in outcomes in the trials evaluating evaluating the prevention or treatment of either overt or minimal hepatic encephalopathy or trials evaluating oral versus intravenous administration We were unable to undertake a meta‐analysis of the three trials involving 288 participants evaluating health‐related quality of life. Overall, we found no difference between L‐ornithine L‐aspartate and placebo or no intervention in non‐serious adverse events (RR 1.15, 95% CI 0.75 to 1.77; 14 trials; 1076 participants; I2 = 40%). In comparison with lactulose, L‐ornithine L‐aspartate had no effect on mortality (RR 0.68, 95% CI 0.11 to 4.17; 4 trials; 175 participants; I2 = 0%); hepatic encephalopathy (RR 1.13, 95% CI 0.81 to 1.57); serious adverse events (RR 0.69, 95% CI 0.22 to 2.11); or non‐serious adverse events (RR 0.05, 95% CI 0.01 to 0.18). In comparison with probiotics, L‐ornithine L‐aspartate had no effect on mortality (RR 1.01, 95% CI 0.11 to 9.51); serious adverse events (RR 1.07, 95% CI 0.23 to 4.88); or changes in blood ammonia concentrations from baseline (RR ‐2.30 95% CI ‐6.08 to 1.48), but it had a possible beneficial effect on hepatic encephalopathy (RR 0.71, 95% CI 0.56 to 0.90). Finally, in comparison with rifaximin, L‐ornithine L‐aspartate had no effect on mortality (RR 0.33, 95% CI 0.04 to 3.03; 2 trials; 105 participants); hepatic encephalopathy (RR 1.06, 95% CI 0.57 to 1.96); serious adverse events (RR 0.32, 95% CI 0.01 to 7.42), or non‐serious adverse events (RR 0.32, 95% CI 0.01 to 7.42).
Authors' conclusions
The results of this review suggest a possible beneficial effect of L‐ornithine L‐aspartate on mortality, hepatic encephalopathy, and serious adverse events in comparisons with placebo or no‐intervention, but, because the quality of the evidence is very low, we are very uncertain about these findings. There was very low quality evidence of a possible beneficial effect of L‐ornithine L‐aspartate on hepatic encephalopathy, when compared with probiotics, but no other benefits were demonstrated in comparison with other active agents. Additional access to data from completed, but unpublished trials, and new randomised placebo‐controlled, double‐blind clinical trials are needed.
Long-chain fatty acyl CoA synthetases (ACSLs) activate fatty acids by CoA addition thus facilitating their intracellular metabolism. Dysregulated ACSL expression features in several cancers and can ...affect processes such as ferroptosis, fatty acid β-oxidation, prostaglandin biosynthesis, steroidogenesis and phospholipid acyl chain remodelling. Here we investigate long chain acyl-CoA synthetase 3 (ACSL3) and long chain acyl-CoA synthetase 4 (ACSL4) expression in liver malignancies. The expression and subcellular localisations of the ACSL3 and ACSL4 isoforms in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA) and hepatic metastases were assessed by immunohistochemical analyses of multiple tumour tissue arrays and by subcellular fractionation of cultured HepG2 cells. The expression of both enzymes was increased in HCC compared with normal liver. Expression of ACSL3 was similar in HCC and hepatic metastases but lower in healthy tissue. Increased ACSL3 expression distinguished HCC from CCA with a sensitivity of 87.2% and a specificity of 75%. ACSL4 expression was significantly greater in HCC than in all other tumours and distinguished HCC from normal liver tissue with a sensitivity of 93.8% and specificity of 93.6%. Combined ACSL3 and ACSL4 staining scores distinguished HCC from hepatic metastases with 80.1% sensitivity and 77.1% specificity. These enzymes had partially overlapping intracellular distributions, ACSL4 localised to the plasma membrane and both isoforms associated with lipid droplets and the endoplasmic reticulum (ER). In conclusion, analysis of ACSL3 and ACSL4 expression can distinguish different classes of hepatic tumours.
Background
Although malnutrition and sarcopenia are prevalent in cirrhosis, their impact on outcomes following liver transplantation is not well documented.
Methods
The associations of nutritional ...status and sarcopenia with post‐transplant infections, requirement for mechanical ventilation, intensive care (ICU) and hospital stay, and 1 year mortality were assessed in 232 consecutive transplant recipients. Nutritional status and sarcopenia were assessed using the Royal Free Hospital‐Global Assessment (RFH‐GA) tool and the L3‐psoas muscle index (L3‐PMI) on CT, respectively.
Results
A wide range of RFH‐SGA and L3‐PMI were observed within similar Model for End‐stage Liver Disease (MELD) sub‐categories. Malnutrition and sarcopenia were independent predictors of all outcomes. Post‐transplant infections were associated with MELD (OR = 1.055, 95%CI = 1.002–1.11) and severe malnutrition (OR = 6.55, 95%CI = 1.99–21.5); ventilation > 24 h with MELD (OR = 1.1, 95%CI = 1.036–1.168), severe malnutrition (OR = 8.5, 95%CI = 1.48–48.87) and suboptimal donor liver (OR = 2.326, 95%CI = 1.056–5.12); ICU stay > 5 days, with age (OR = 1.054, 95%CI = 1.004–1.106), MELD (OR = 1.137, 95%CI = 1.057–1.223) and severe malnutrition (OR = 7.46, 95%CI = 1.57–35.43); hospital stay > 20 days with male sex (OR = 2.107, 95%CI = 1.004–4.419) and L3‐PMI (OR = 0.996, 95%CI = 0.994–0.999); 1 year mortality with L3‐PMI (OR = 0.996, 95%CI = 0.992–0.999). Patients at the lowest L3‐PMI receiving suboptimal grafts had longer ICU/hospital stay and higher incidence of infections.
Conclusions
Malnutrition and sarcopenia are associated with early post‐liver transplant morbidity/mortality. Allocation indices do not include nutritional status and may jeopardize outcomes in nutritionally compromised individuals.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Non‐selective beta‐blockers are recommended for the prevention of bleeding in people with cirrhosis, portal hypertension and gastroesophageal varices. Carvedilol is a non‐selective ...beta‐blocker with additional intrinsic alpha1‐blocking effects, which may be superior to traditional, non‐selective beta‐blockers in reducing portal pressure and, therefore, in reducing the risk of upper gastrointestinal bleeding.
Objectives
To assess the beneficial and harmful effects of carvedilol compared with traditional, non‐selective beta‐blockers for adults with cirrhosis and gastroesophageal varices.
Search methods
We combined searches in the Cochrane Hepato‐Biliary's Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, and Science Citation Index with manual searches. The last search update was 08 May 2018.
Selection criteria
We included randomised clinical trials comparing carvedilol versus traditional, non‐selective beta‐blockers, irrespective of publication status, blinding, or language. We included trials evaluating both primary and secondary prevention of upper gastrointestinal bleeding in adults with cirrhosis and verified gastroesophageal varices.
Data collection and analysis
Three review authors (AZ, RJ and LH), independently extracted data. The primary outcome measures were mortality, upper gastrointestinal bleeding and serious adverse events. We undertook meta‐analyses and presented results using risk ratios (RR) or mean differences (MD), both with 95% confidence intervals (CIs), and I2 values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato‐Biliary domains and the quality of the evidence with GRADE.
Main results
Eleven trials fulfilled our inclusion criteria. One trial did not report clinical outcomes. We included the remaining 10 randomised clinical trials, involving 810 participants with cirrhosis and oesophageal varices, in our analyses. The intervention comparisons were carvedilol versus propranolol (nine trials), or nadolol (one trial). Six trials were of short duration (mean 6 (range 1 to 12) weeks), while four were of longer duration (13.5 (6 to 30) months). Three trials evaluated primary prevention; three evaluated secondary prevention; while four evaluated both primary and secondary prevention. We classified all trials as at 'high risk of bias'. We gathered mortality data from seven trials involving 507 participants; no events occurred in four of these. Sixteen of 254 participants receiving carvedilol and 19 of 253 participants receiving propranolol or nadolol died (RR 0.86, 95% CI 0.48 to 1.53; I2 = 0%, low‐quality evidence). There appeared to be no differences between carvedilol versus traditional, non‐selective beta‐blockers and the risks of upper gastrointestinal bleeding (RR 0.77, 95% CI 0.43 to 1.37; 810 participants; 10 trials; I2 = 45%, very low‐quality evidence) and serious adverse events (RR 0.97, 95% CI 0.67 to 1.42; 810 participants; 10 trials; I2 = 14%, low‐quality evidence). Significantly more deaths, episodes of upper gastrointestinal bleeding and serious adverse events occurred in the long‐term trials but there was not enough information to determine whether there were differences between carvedilol and traditional, non‐selective beta‐blockers, by trial duration. There was also insufficient information to detect differences in the effects of these interventions in trials evaluating primary or secondary prevention. There appeared to be no differences in the risk of non‐serious adverse events between carvedilol versus its comparators (RR 0.55, 95% CI 0.23 to 1.29; 596 participants; 6 trials; I2 = 88%; very low‐quality evidence). Use of carvedilol was associated with a greater reduction in hepatic venous pressure gradient than traditional, non‐selective beta‐blockers both in absolute (MD ‐1.75 mmHg, 95% CI ‐2.60 to ‐0.89; 368 participants; 6 trials; I2 = 0%; low‐quality evidence) and percentage terms (MD ‐8.02%, 95% CI ‐11.49% to ‐4.55%; 368 participants; 6 trials; I2 = 0%; low‐quality evidence). However, we did not observe a concomitant reduction in the number of participants who failed to achieve a sufficient haemodynamic response (RR 0.76, 95% CI 0.57 to 1.02; 368 participants; 6 trials; I2 = 42%; very low‐quality evidence) or in clinical outcomes.
Authors' conclusions
We found no clear beneficial or harmful effects of carvedilol versus traditional, non‐selective beta‐blockers on mortality, upper gastrointestinal bleeding, serious or non‐serious adverse events despite the fact that carvedilol was more effective at reducing the hepatic venous pressure gradient. However, the evidence was of low or very low quality, and hence the findings are uncertain. Additional evidence is required from adequately powered, long‐term, double‐blind, randomised clinical trials, which evaluate both clinical and haemodynamic outcomes.
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