STOPAH
STOPAH: Prednisolone or Pentoxifylline for Alcoholic Hepatitis
Thursz. NEJM 2015; 372:1619-28. doi:10.1056/NEJMoa1412278
Clinical Question
- In adult patients with alcoholic hepatitis, does prednisolone and / or pentoxifylline compared to placebo reduce mortality?
Design
- Multi-centre, randomised, controlled trial
- 2-by-2 factorial design with 4 treatment groups
- Web-based electronic randomisation and assignment, with block sizes of 4 and stratification by geographical area and risk category (high vs intermediate)
- Double-blinded (patients and clinicians / investigators)
- Intention-to-treat analysis method
- Power calculation:
- 28-day mortality without drug 30%
- 28-day mortality with drug 21%
- Powered at 90%
- Statistical significance level of 0.05
- Patients required 1,026
- Target recruitment 1,200 allowing 10% loss
Setting
- 65 hospitals from across the UK
- January 2011 to February 2014
Population
- Inclusion: clinical diagnosis of alcoholic hepatitis
- History of recent excess alcohol consumption
- Men > 80g/day (10 units/day)
- Women > 60 g/day (7.5 units/day)
- Bilirubin > 80 µmol/l (4.7 mg/dl)
- Maddrey Discriminant Function > 32
- Age over 18 years
- History of recent excess alcohol consumption
- Exclusion:
- Patients with severe kidney injury, uncontrolled sepsis, active gastrointestinal bleeding or requiring inopressor support were excluded unless stabilised within 7 days after admission
- Jaundice > 3 months
- Cessation of alcohol consumption > 2 months
- Other cause of liver disease
- Serum aspartate aminotransferase (AST) > 500 IU/l or serum alanine transaminase (ALT) > 300 IU/l
- 5,234 screened –> 1,103 randomised
- Baseline characters were similar between groups (data are mean ±SD of all patients):
- Age: 48.7±10.2 years
- Alcohol consumption:
- women 149.5±104.3 g/day (18.7±13.0 units/day)
- men 200.1±125.2 g/day (25.0±15.6 units/day)
- Discriminant Function: 62.6±27.2
Intervention
- Pentoxifylline 400mg + placebo
- Prednisolone 40mg + placebo
- Pentoxifylline 400mg + Prednisolone 40mg
- All drugs prescribed for 28 days
Control
- Placebo
- Identical and prescribed for 28 days
Outcome
- Primary outcome: mortality at 28 days was not statistically different between any individual group – p-value for drug interaction was 0.41
- Prednisolone + placebo: 14.3%
- Pentoxifylline + placebo: 19.4%
- Prednisolone + pentoxifylline: 13.5%
- Placebo: 16.7%
- Logistic regression: adjusting for risk category and factorial design, demonstrated no statistically significant difference with either prednisolone or pentoxifylline individually
- Prednisolone
- Odds ratio: 0.72 (95% CI 0.52 – 1.01)
- p-value: 0.06
- Pentoxifylline
- Odds ratio: 1.07 (95% CI 0.77 – 1.49)
- P value: 0.69
- Prednisolone
- Secondary outcomes:
- 90-day mortality or transplant: no difference between groups
- Prednisolone: OR 1.02 (95% CI 0.77–1.35); p-value 0.87
- Pentoxifylline: OR 0.97 (95% CI 0.73–1.28); p-value 0.81
- 1-year mortality or transplant: no difference between groups
- Prednisolone: OR 1.01 (95% CI 0.76–1.35); p-value 0.94
- Pentoxifylline: OR 0.99 (95% CI 0.74–1.33); p-value 0.97
- Multivariate analysis of primary outcome: demonstrated benefit with prednisolone with statistically significant benefit
- Prednisolone: OR 0.61 (95% CI 0.41–0.91); p-value 0.02; NNT 16
- Pentoxifylline: OR 1.10 (95% CI 0.74–1.64); p-value 0.62
- 90-day mortality or transplant: no difference between groups
- Adverse events:
- Serious adverse events of infection: statistically significant difference demonstrating increased infections with prednisolone
- Prednisolone 13% vs no-prednisolone 7%
- Absolute risk increase: 6.01% (95% CI 2.47% to 9.54%)
- Number-needed-to-harm: 17 (95% CI 10.5 to 40.5)
- Serious adverse events leading to death: no statistically significant difference between individual groups or drug / no-drug comparisons
- Serious adverse events of infection: statistically significant difference demonstrating increased infections with prednisolone
Authors’ Conclusions
- Pentoxifylline, at 400mg for 28 days, did not improve mortality in this trial
- Prednisolone, at 40mg for 28 days, may have a beneficial effect at 1 month but this was not demonstrated to persist to 90 days or 1 year
Strengths
- Highly relevant research question
- Pragmatic and efficient 2-by-2 factorial design
- Good methodology with low risk of bias
- Good follow-up in a population that can be difficult to research
Weaknesses
- Diagnosis of alcoholic hepatitis was clinical rather than histological, which may be criticised by some — this is, however, a more pragmatic, ‘real-world’ approach
- Power calculation over-estimated mortality — 16% actual compared with 35% expected — so effective power of this study was reduced and a false-negative conclusion is possible
- Power calculation based on anticipated effect of a 30% reduction in mortality for each drug — is this a very optimistic aim?
- Exclusion incidence and reasons not provided – did they need to exclude those with severe kidney injury, sepsis, GI bleeding or inopressor requirement? How frequently did this happen? This possibly limits generalisability.
- ‘Statistical significance’ only demonstrated after extensive multivariate post-hoc analysis — this should not be considered a certain conclusion
- Funding limitations meant that not all patients were followed-up for 90-day and 1-year outcomes — study terminated after last recruited patient followed-up to 28-day outcome
The Bottom Line
- This study was under-powered to demonstrate clinically relevant effects
- However, it suggests strongly with a low risk of bias that pentoxifylline 400mg daily for 28 days has no beneficial effect whilst prednisolone 40mg daily for 28 days may be beneficial for short-term outcomes but not for medium or long-term outcomes
- From these data (with wide confidence intervals that cross the null hypothesis line)
- Prednisolone NNT (28-day mortality) is 23
- Prednisolone NNH (serious adverse infection) is 16
External Links
- [article] STOPAH: Prednisolone or Pentoxifylline for Alcoholic Hepatitis
- [study protocol] STOPAH study protocol
- [videocast] STOPAH
Metadata
Summary author: @DuncanChambler
Summary date: 5 May 2015
Peer-review editor: @DavidSlessor