Glucocorticosteroids for people with alcoholic hepatitis

Abstract

Background: Alcoholic hepatitis is a form of alcoholic liver disease, characterised by steatosis, necroinflammation, fibrosis, and potential complications to the liver disease. Typically, alcoholic hepatitis presents in people between 40 and 50 years of age. Alcoholic hepatitis can be resolved if people abstain from drinking, but the risk of death will depend on the severity of the liver damage and abstinence from alcohol. Glucocorticosteroids are used as anti-inflammatory drugs for people with alcoholic hepatitis. Glucocorticosteroids have been studied extensively in randomised clinical trials in order to assess their benefits and harms. However, the results have been contradictory.

Objectives: To assess the benefits and harms of glucocorticosteroids in people with alcoholic hepatitis.

Search methods: We identified trials through electronic searches in Cochrane Hepato-Biliary's (CHB) Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, and Science Citation Index Expanded. We looked for ongoing or unpublished trials in clinical trials registers and pharmaceutical company sources. We also scanned reference lists of the studies retrieved. The last search was 20 October 2016.

Selection criteria: Randomised clinical trials assessing glucocorticosteroids versus placebo or no intervention in people with alcoholic hepatitis, irrespective of year, language of publication, or format. We considered trials with adult participants diagnosed with alcoholic hepatitis, which could have been established through clinical or biochemical diagnostic criteria or both. We defined alcoholic hepatitis as mild (Maddrey's score less than 32) and severe (Maddrey's score 32 or more). We allowed co-interventions in the trial groups, provided they were similar.

Data collection and analysis: We followed Cochrane and CHB methodology, performing the meta-analyses using Review Manager 5 and Trial Sequential Analysis. We presented the results of dichotomous outcomes as risk ratios (RR) and those of the continuous outcomes as mean difference (MD). We applied both the fixed-effect model and the random-effects model meta-analyses. Whenever there were significant discrepancies in the results, we reported the more conservative point estimate of the two. We considered a P value of 0.01 or less, two-tailed, as statistically significant if the required information size was reached due to our three primary outcomes (all-cause mortality, health-related quality of life, and serious adverse events during treatment) and our post hoc decision to include analyses of mortality at more time points. We presented heterogeneity using the I² statistic. If trialists used intention-to-treat analysis to deal with missing data, we used these data in our primary analysis; otherwise, we used the available data. We assessed the bias risk of the trials using bias risk domains and the quality of the evidence using GRADE.

Main results: Sixteen trials fulfilled the inclusion criteria. All trials were at high risk of bias. Fifteen trials provided data for analysis (927 participants received glucocorticosteroids and 934 participants received placebo or no intervention). The glucocorticosteroids were administered orally or parenterally for a median of 28 days (range 3 days to 12 weeks). The participants were between 25 and 70 years old, had different stages of alcoholic liver disease, and 65% were men. The follow-up of trial participants, when it was reported, was up to the moment of discharge from the hospital, until they died (a median of 63 days), or for at least a year. There was no evidence of effect of glucocorticosteroids on all-cause mortality up to three months following randomisation neither with traditional meta-analysis (random-effects RR 0.90, 95% CI 0.70 to 1.15; participants = 1861; trials = 15; I² = 45% (moderate heterogeneity) nor with Trial Sequential Analysis. Meta-analysis showed no evidence of effect on health-related quality of life up to three months (MD -0.04 points; 95% CI -0.11 to 0.03; participants = 377; trial = 1; low-quality evidence), measured with the European Quality of Life - 5 Dimensions-3 Levels (EQ- 5D-3L) scale. There was no evidence of effect on the occurrence of serious adverse events during treatment, neither with traditional meta-analysis (random-effects RR 1.05, 95% CI 0.85 to 1.29; participants = 1861; trials = 15; I² = 36% (moderate heterogeneity), liver-related mortality up to three months following randomisation (random-effects RR 0.89, 95% CI 0.69 to 1.14; participants = 1861; trials = 15; I² = 46% (moderate heterogeneity), frequency of any complications up to three months following randomisation (random-effects RR 1.04, 95% CI 0.86 to 1.27; participants = 1861; I² = 42% (moderate heterogeneity), and frequency of non-serious adverse events up to three months' follow-up after end of treatment (random-effects RR 1.99, 95% CI 0.72 to 5.48; participants = 160; trials = 4; I² = 0% (no heterogeneity) nor with Trial Sequential Analysis. Nine of the trials were industry-funded.

Authors' conclusions: We found no evidence of a difference between glucocorticosteroids and placebo or no intervention on all-cause mortality, health-related quality of life, and serious adverse events during treatment. The risk of bias was high and the quality of evidence was very low or low. Therefore, we are very uncertain about this effect estimate. Due to inadequate reporting, we cannot exclude increases in adverse events. As the confidence intervals were wide, we cannot rule out significant benefits and harms of glucocorticosteroids. Therefore, we need placebo-controlled, randomised clinical trials, designed according to the SPIRIT guidelines and reported according to the CONSORT guidelines. Future trials ought to report depersonalised individual participant data, so that proper individual participant data meta-analyses of the effects of glucocorticosteroids in subgroups can be conducted.

Figure 1

Study flow diagram

Figure 2

Risk of bias graph: review authors' judgements about each risk of bias domain presented as percentages across all included studies

Figure 3

Risk of bias summary: review authors' judgements about each risk of bias domain for each included study

Figure 4

All‐cause mortality up to three months after randomisation. Fifteen trials provided data. The diversity‐adjusted required information size (DARIS) was calculated based on all‐cause mortality of 30% in the control group; risk ratio reduction in the glucocorticosteroid group of 20%; type I error of 1%; and type II error of 20% (80% power). Trial diversity was 62%. The required information size was 6734 participants. The cumulative Z‐curve (blue line) did not cross the trial sequential monitoring boundaries for benefit or harm (red inward sloping lines) and did not enter the trial sequential monitoring area for futility (inner‐wedge with red outward sloping lines). The green dotted lines show the conventional boundaries of the naive alpha of 5% equal to Z‐scores of +1.96 and ‐1.96.

Figure 5

Funnel plot of comparison 1. Glucocorticosteroids versus no intervention/placebo, outcome 1.1 all‐cause mortality

Figure 6

All‐cause mortality at the end of treatment (median 28 days (range 3 days to 12 weeks) (post hoc analysis). Fourteen trials provided data. The diversity‐adjusted required information size (DARIS) was calculated based on all‐cause mortality of 22% in the control group; risk ratio reduction in the glucocorticosteroid group of 20%; type I error of 1%; and type II error of 20% (80% power). Trial diversity was 59%. The required information size was 9242 participants. The cumulative Z‐curve (blue line) did not cross the trial sequential monitoring boundaries for benefit or harm (red inward sloping lines) and did not enter the trial sequential monitoring area for futility (inner‐wedge with red outward sloping lines). The green dotted lines show the conventional boundaries of the naive alpha of 5% equal to Z‐scores of +1.96 and ‐1.96.

Figure 7

All‐cause mortality up to 1 year (post hoc analysis). Three trials provided data. The diversity‐adjusted required information size (DARIS) was calculated based on mortality in the control group of 40%; risk ratio reduction of 20% in the glucocorticosteroid group; type I error of 1%; and type II error of 20% (80% power). Trial diversity was 0%. The required information size was 1695 participants. The cumulative Z‐curve (blue line) did not cross the trial sequential monitoring boundaries for benefit or harm (red inward sloping lines). The cumulative Z‐curve crossed the inner‐wedge futility line (red outward sloping lines). The green dotted lines show the conventional boundaries of the naive alpha of 5% equal to Z‐scores of +1.96 and ‐1.96.

Figure 8

Serious adverse events during treatment. There are 15 trials providing data. The diversity‐adjusted required information size (DARIS) was calculated based on an incidence rate of serious adverse events in the control group of 36%; risk ratio reduction of 20% in the glucocorticosteroid group; type I error of 1%; and type II error of 20% (80% power). Trial diversity was 70%. The required information size was 6566 participants. The cumulative Z‐curve (blue line) did not cross the trial sequential monitoring boundaries for benefit or harm (red inward sloping lines), but it entered the trial sequential monitoring area for futility (inner‐wedge futility line red outward sloping lines) indicating that sufficient information was provided. The green dotted lines show the conventional boundaries of the naive alpha of 5% equal to Z‐scores of +1.96 and ‐1.96.

Figure 9

Liver‐related mortality up to three months after randomisation. Fifteen trials provided data. The diversity‐adjusted required information size (DARIS) was calculated based on liver‐ related mortality of 30% in the control group; risk ratio reduction in the glucocorticosteroid group of 20%; type I error of 1%; and type II error of 20% (80% power). Trial diversity was 68%. The required information size was 8059 participants. The cumulative Z‐curve (blue line) did not cross the trial sequential monitoring boundaries for benefit or harm (red inward sloping lines) and did not enter the trial sequential monitoring area for futility (inner‐wedge with red outward sloping lines). The green dotted lines show the conventional boundaries of the naive alpha of 5% equal to Z‐scores of +1.96 and ‐1.96.

Figure 10

Any complications up to three months after randomisation. Fifteen trials provided data. The diversity‐adjusted required information size (DARIS) was calculated based on any complications of 44% in the control group; risk ratio reduction in the glucocorticosteroid group of 20%; type I error of 1%; and type II error of 20% (80% power). Trial diversity was 75%. The required information size was 5887 participants. The cumulative Z‐curve (blue line) did not cross the trial sequential monitoring boundaries for benefit or harm (red inward sloping lines). The cumulative Z‐curve crossed the inner‐wedge futility line (red outward sloping lines). The green dotted lines show the conventional boundaries of the naive alpha of 5% equal to Z‐scores of +1.96 and ‐1.96.

Figure 11

Non‐serious adverse events up to three months after randomisation. Four trials provided data. The diversity‐adjusted required information size (DARIS) was calculated based on non‐serious adverse events of 5% in the control group; risk ratio reduction in the glucocorticosteroid group of 50%; type I error of 1%; and type II error of 20% (80% power). Trial diversity was 0%. The required information size was 2698 participants. The cumulative Z‐curve (blue line) did not cross the trial sequential monitoring boundaries for benefit or harm (red inward sloping lines) and did not enter the trial sequential monitoring area for futility (inner‐wedge with red outward sloping lines). The green dotted lines show the conventional boundaries of the naive alpha of 5% equal to Z‐scores of +1.96 and ‐1.96.

Analysis 1.1

Comparison 1 Glucocorticosteroids versus no intervention/placebo, Outcome 1 All‐cause mortality.

Analysis 1.2

Comparison 1 Glucocorticosteroids versus no intervention/placebo, Outcome 2 Health‐related quality of life.

Analysis 1.3

Comparison 1 Glucocorticosteroids versus no intervention/placebo, Outcome 3 Number of participants with serious adverse events during treatment.

Analysis 1.4

Comparison 1 Glucocorticosteroids versus no intervention/placebo, Outcome 4 Liver‐related mortality.

Analysis 1.5

Comparison 1 Glucocorticosteroids versus no intervention/placebo, Outcome 5 Any complication.

Analysis 1.6

Comparison 1 Glucocorticosteroids versus no intervention/placebo, Outcome 6 Number of participants with non‐serious adverse events up to 3 months' follow‐up after randomisation.

Analysis 2.1

Comparison 2 Subgroup analysis: all‐cause mortality up to 3 months after randomisation, Outcome 1 Severity of alcoholic hepatitis.

Analysis 2.2

Comparison 2 Subgroup analysis: all‐cause mortality up to 3 months after randomisation, Outcome 2 Glucocorticosteroid (prednisolone) dose.

Analysis 2.3

Comparison 2 Subgroup analysis: all‐cause mortality up to 3 months after randomisation, Outcome 3 Alcoholic hepatitis without cirrhosis and with cirrhosis.

Analysis 2.4

Comparison 2 Subgroup analysis: all‐cause mortality up to 3 months after randomisation, Outcome 4 Hepatorenal syndrome.

Analysis 2.5

Comparison 2 Subgroup analysis: all‐cause mortality up to 3 months after randomisation, Outcome 5 Ascites.

Analysis 3.1

Comparison 3 Sensitivity analysis: all‐cause mortality, Outcome 1 Best‐worst scenario all‐cause mortality to 3 months follow‐up.

Analysis 3.2

Comparison 3 Sensitivity analysis: all‐cause mortality, Outcome 2 Worst‐best scenario all‐cause mortality to 3 months follow‐up.

Analysis 4.1

Comparison 4 Sensitivity analysis: serious adverse events, Outcome 1 Best‐worse scenario of serious adverse events during treatment.

Analysis 4.2

Comparison 4 Sensitivity analysis: serious adverse events, Outcome 2 Worst‐best scenario of serious adverse events during treatment.