Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH
Introduction
Thirteen randomized controlled trials that evaluated corticosteroids in patients with alcoholic hepatitis (AH) yielded inconsistent results [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13].
Three meta-analyses concluded that corticosteroids improved short-term survival of patients with a severe form of AH [14], [15], [16]. However, the latest meta-analysis which attempted to adjust for prognostic factors, questioned the efficacy of corticosteroids in AH [17]. This meta-analysis used a different weighting method than previous meta-analyses that may overweight Mendenhall's RCT.
No accurate criteria for assessing disease severity in AH were available until Maddrey et al. described a discriminant function (DF) [6] and later modified it [12] to its more widely used form. This modified DF is calculated as follows: 4.6 (prothrombin time-control time [in seconds])+serum bilirubin (in micromoles per liter)/17.
Recently, representatives of the American College of Gastroenterology recommended glucocorticosteroids for patients with severe AH as defined by the Maddrey DF [18]. However, Christensen et al. suggested that the proposed guidelines were not sufficiently evidence-based [19]. They encouraged the authors of the largest trial (Mendenhall et al.) to make their data available for more elaborate analysis as this study preceded the Maddrey DF for assessment of disease severity and based severity only on the serum bilirubin level (i.e.=5 mg/dl) [10].
To determine whether corticosteroids are effective in severe AH, the most accurate approach would be to combine the individual data of patients with DF≥32 from previous randomized placebo controlled trials. In the present study, individual data from the three most recent randomized controlled trials were combined [10], [12], [13]. Thus, using the individual data on patients with DF≥32, we aimed to assess the efficacy of corticosteroid treatment and to identify the independent prognostic factors associated with short-term survival.
Section snippets
Patients
The three studies were conducted in a randomized, double-blind fashion. Randomized treatments consisted of prednisolone or placebo.
Inclusion and exclusion criteria in each study
Carithers' and Ramond studies included only patients with severe AH defined by DF≥32 or spontaneous hepatic encephalopathy. The three studies excluded patients with active peptic ulcer, neoplasms, non-alcoholic liver disease, active infection or positive test for hepatitis B surface antigen. Gastrointestinal bleeding was an exclusion criterion in Carithers' and
Survival data of each trial regardless of DF function
In Mendenhall's study the 28-day-survival of placebo (n=88) and corticosteroids (n=91) were not significantly different: 80.5±4% vs. 83±4%. In Carithers' and Ramond' studies that included only patients with severe form of AH (DF≥32 or presence of encephalopathy), corticosteroids patients had higher survival than placebo patients: 94±4% vs. 63±8.9% (P<0.01) and 87.5±5.8% vs. 62±9% (P=0.03).
Identification of patients with a DF≥32 in the three trials
We retrospectively identified the randomized patients with a DF≥32 at admission or at the first day of
Discussion
Meta-analyses evaluating corticosteroids in AH yielded controversial results and included trials too heterogeneous [14], [15], [16], [17]. The authors of the last meta-analysis used multivariate statistics to adjust for confounding variables between corticosteroid and control groups [17]. In a recent correspondence, Imperiale et al. found this method to be problematic [20]. They pointed out that the ability of this method to detect a treatment effect of corticosteroids is low because of the
Acknowledgments
The authors thank Sylvain Lavergne for his contribution in the data capture for the statistical analysis. This work is supported by a grant from the Association pour la Recherche contre le Cancer, France.
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