Elsevier

Journal of Hepatology

Volume 68, Issue 3, March 2018, Pages 511-518
Journal of Hepatology

Research Article
Application of prognostic scores in the STOPAH trial: Discriminant function is no longer the optimal scoring system in alcoholic hepatitis

https://doi.org/10.1016/j.jhep.2017.11.017Get rights and content

Highlights

  • Newer ‘static’ scores (MELD, ABIC, GAHS) are superior to DF in Alcoholic Hepatitis.

  • Consistently low ‘static’ scores have a favourable outcome not improved with prednisolone.

  • Scores incorporating evolution of bilirubin or change of ‘static’ scores predict 90-day outcome.

  • Limiting treatment to high ‘static’ scores reduces exposure to prednisolone and improves outcome.

Background & Aims

‘Static’ prognostic models in alcoholic hepatitis, using data from a single time point, include the discriminant function (DF), Glasgow alcoholic hepatitis score (GAHS), the age, serum bilirubin, international normalized ratio and serum creatinine (ABIC) score and the model of end-stage liver disease (MELD). 'Dynamic' scores, incorporating evolution of bilirubin at seven days, include the Lille score. The aim of this study was to assess these scores’ performance in patients from the STOPAH trial.

Methods

Predictive performance of scores was assessed by area under the receiver operating curve (AUC). The effect of different therapeutic strategies upon survival was assessed by Kaplan-Meier analysis and tested using the log-rank test.

Results

A total of 1,068 patients were studied. The AUCs for the DF were significantly lower than for MELD, ABIC and GAHS for both 28- and 90-day outcomes: 90-day values were 0.670, 0.704, 0.726 and 0.713, respectively. ‘Dynamic’ scores and change in ‘static’ scores by Day 7 had similar AUCs. Patients with consistently low ‘static’ scores had low 28-day mortalities that were not improved with prednisolone (MELD <25: 8.6%; ABIC <6.71: 6.6%; GAHS <9: 5.9%). In patients with high ‘static’ scores without gastrointestinal bleeding or sepsis, prednisolone reduced 28-day mortality (MELD: 22.2% vs. 28.9%, p = 0.13; ABIC 14.6% vs. 21%, p = 0.02; GAHS 21% vs. 29.3%, p = 0.04). Overall mortality from treating all patients with a DF ≥32 and Lille assessment (90-day mortality 26.8%) was greater than combining newer ‘static’ and ‘dynamic’ scores (90-day mortality: MELD/Lille 21.8%; ABIC/Lille 23.7%; GAHS/Lille 20.6%).

Conclusion

MELD, ABIC and GAHS are superior to the DF in alcoholic hepatitis. Consistently low scores have a favourable outcome not improved with prednisolone. Combined baseline ‘static’ and Day 7 scores reduce the number of patients exposed to corticosteroids and improve 90-day outcome.

Lay summary

Alcoholic hepatitis is a life-threatening condition. Several scores exist to determine the outcome of these patients as well as to identify those who may benefit from treatment. This study looked at the performance of existing scores in patients who had been recruited to the largest alcoholic hepatitis clinical trial: STOPAH. ‘Static’ scores are calculable at the start of assessment. The three newer static scores (ABIC, GAHS and MELD) were shown to be superior to the oldest score (DF). ABIC and GAHS could also identify patients who had a survival benefit 28 days after starting prednisolone treatment. ‘Dynamic’ scores relate to the change in disease over the first week of treatment. Combination of the ‘static’ scores ‘with the ‘dynamic’ scores or change in ‘static’ scores allowed identification of patients who could benefit from prednisolone up to 90 days.

Introduction

Alcoholic hepatitis is an acute manifestation of alcoholic liver disease with high short and medium-term mortality.1 Recognition of those at risk of a poor outcome is fundamental to structuring patient management. Several prognostic scores have been developed to predict the course of alcoholic hepatitis. However, to be useful in a clinical context, scores should not only identify patients with a poor prognosis but also direct patient care.2

The discriminant function (DF) has become established in clinical practice with a threshold greater than or equal to 32 identifying those with severe disease.[3], [4] However concerns have been raised regarding the reliability of the DF as it uses the absolute value of prothrombin time rather than a ratiometric value, such as the international normalized ratio (INR).5 Combined analysis of five alcoholic hepatitis trials which used the DF to determine severity showed 28-day mortality of 20% for corticosteroid treated patients and 35% for untreated patients.6 However, several of these studies were more than twenty years old.[3], [7], [8] More recent studies including the Steroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial have shown improvements in 28-day outcome.[9], [10], [11] These improved outcomes with the modern management of alcoholic hepatitis will likely reduce further the specificity of the DF to identify those at greatest risk of death compared with historical trials.

Three alternative scores have been proposed to determine prognosis based upon variables obtained from a single time point described as ‘static’ scores. These are the Glasgow alcoholic hepatitis score (GAHS),1 the age, serum bilirubin, INR and creatinine (ABIC) score,12 and the model of end-stage liver disease (MELD) score. These scores seek to stratify patients into two (GAHS, MELD) or three (ABIC) groups characterised by significantly different prognoses. Well established cut-offs exist for the GAHS (severe disease: >8) and ABIC (low: <6.71; intermediate: 6.71–8.99; high: >8.99) scores. There is no widely accepted optimal cut-off for MELD; proposed values range from 18 to 30.5.[13], [14], [15], [16] The ABIC score seeks to stratify patients into those at low, intermediate or high risk of death with those in the intermediate group perhaps most likely to benefit from corticosteroids. In a retrospective study the GAHS has been suggested to identify those who are likely to benefit from corticosteroid treatment.17

‘Dynamic’ scores which include the change in bilirubin levels over the first week of treatment have been used to assess likely benefit from corticosteroid therapy. These are the early change in bilirubin levels (ECBL),18 percentage change in serum bilirubin (%ΔBili)19 and the Lille score.20 These scores were originally described to be used in a dichotomous fashion with any fall in bilirubin (ECBL), a greater than or equal to 25%ΔBili or a Lille score less than 0.45 being associated with a favourable outcome, or corticosteroid 'response'. Patients admitted with alcoholic hepatitis present at different stages of their illness. Whilst some will present at a point where their disease severity is at its worst and then improve; others will present at a point where their disease is on a continuing trajectory of deterioration. Given this variation it is not unexpected that baseline severity scores, although they can give an index of severity and mortality risk, may have relatively low predictive value. By the same logic, it would be anticipated that a means of assessment of the severity that incorporates the evolution of disease over time, with or without treatment, would be more accurate in predicting outcome. The combination of a ‘static’ score with a ‘dynamic’ score would seem to be a reasonable strategy to identify those with an initial poor prognosis whose condition does not show improvement after starting corticosteroid treatment.21

The aim of this study was to assess the performance of these existing scores for alcoholic hepatitis to predict outcome and to assess their application to different treatment strategies in patients recruited to the STOPAH trial.

Section snippets

Patients and methods

Patients recruited to the STOPAH trial were studied. The characteristics of these patients have been described in detail previously.22 Inclusion was based upon a clinical diagnosis of alcoholic hepatitis with recent onset of jaundice and heavy alcohol misuse and no other forms of liver disease. All patients had a baseline DF greater than or equal to 32. Patients were randomised by a factorial design to receive prednisolone and placebo, pentoxifylline and placebo, prednisolone and pentoxifylline

Results

Data on 1,068 patients recruited to the STOPAH trial were available for analysis: of whom 534 received prednisolone. Patient characteristics are shown (Table 1). GIB and/or sepsis were features of initial presentation in 199 patients leaving 869 patients who presented without either of these complications. At Day 7 data was available on 720 patients to calculate the dynamic scores indicating corticosteroid effect: GIB or sepsis were presenting features of 143 patients who had Day 7 data

Discussion

Prognostic scores should be clinically useful as well as statistically sound. The DF has provided a consistency to clinical treatment and research in alcoholic hepatitis. However, it is a sensitive score with less impressive specificity and alternative scores have been proposed: ‘static’ scores based on variables at a single timepoint such as MELD, ABIC and GAHS[1], [12], [13] and ‘dynamic’ scores based upon evolution of serum bilirubin over the first week of corticosteroid treatment, such as

Financial support

STOPAH trial funded by the National Institute for Health Research Health Technology Assessment program.

Conflicts of interest

The authors declare no conflicts of interest that pertain to this work.

Please refer to the accompanying ICMJE disclosure forms for further details.

Authors’ contributions

Study Concept and Design: EHF, SRA, MA; Analysis and Interpretation of Data: EHF, SRA, MA; Drafting of Manuscript: EHF; SRA, MA; Critical Revision of Manuscript for Important Intellectual Content: EHF, SRA, PR, SM, MRT, MA, SR.

Acknowledgments

Dr Alan H Forrest, Fellow of Royal Statistical Society, and Dr Caroline E. Haig, Robertson Centre for Biostatistics, University of Glasgow for statistical advice. MRT and SA were supported by the NIHR Imperial Biomedical Research Centre.

References (25)

  • J.R.L. Carithers et al.

    Methylprednisolone therapy in patients with severe alcoholic hepatitis: a randomized multicenter trial

    Ann Intern Med

    (1989)
  • P. Mathurin et al.

    Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data

    Gut

    (2011)
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