Torres: Effect of Corticosteroids on Treatment Failure Among Hospitalized Patients with Severe Community-Acquired Pneumonia and High Inflammatory Response

Torres. JAMA 2015; 313(7):677-687. doi:10.1001/jama.2015.88

Clinical Question

• In patients with severe community-acquired pneumonia and high inflammatory response, does the use of corticosteroids compared to placebo improve outcome?

Design

• Multi-centre
• Double-blind, randomised-controlled trial
• Sample size calculation
  • 80% power to detect absolute risk reduction of 20% in treatment failure (assuming placebo group failure rate of 35%)
  • Sample size n = 60
  • Pre-specified interim analysis resulted in no change in sample size target

Setting

• 3 Spanish teaching hospitals
• June 2004 – February 2012

Population

• Inclusion
  • Age > 18
  • Clinical symptoms suggestive of community-acquired pneumonia (CAP)
  • New chest radiographic infiltrates
  • Severe CAP as defined by either/or
    • Modified American Thoracic Society criteria for severe CAP
    • Pneumonia Severity Index risk class 4
  • C-reactive Protein (CRP) > 150mg/L
• Exclusion
  • Prior treatment with systemic corticosteroids
  • Nosocomial pneumonia
  • Reported severe immunosuppression
  • Pre-existing medical condition with a life expectancy of less than 3 months
  • Uncontrolled diabetes mellitus
  • Major gastrointestinal bleed within 3 months
  • Condition requiring acute treatment with > 1mg/kg/day of methylprednisolone equivalent
  • H1N1 influenza A pneumonia
• 519 screened, 120 patients randomised (61 to intervention, 59 to control)

Intervention

• Methylprednisolone
  • 0.5mg/kg per 12 hours of methylprednisolone for 5 days
  • Commenced within 36 hours of hospital admission

Control

• Identical placebo
  • Placebo injection every 12 hours for 5 days
  • Commenced within 36 hours of hospital admission

Antibiotic therapy according to international guidelines

Outcome

Table defining primary outcome

• Primary outcome: less overall (early + late) treatment failure occurred in the methylprednisolone group
  • This was predominantly due to a difference in late treatment failures, and specifically the occurrence of increased pulmonary infiltrates on radiographs
• Secondary outcomes: there were no significant differences in the duration until stability, length of stay or mortality

Table of results

Authors’ Conclusions

• Among patients with severe CAP and high initial inflammatory response, the acute use of methylprednisolone compared to placebo decreased treatment failure.

Strengths

• Randomised, blinded, multi-centre
• Patients, investigators and data assessors were blinded
  • It’s likely bedside clinicians were blinded too, although not explicitly stated
• Targeted severe CAP as defined by recognised definitions
• Adequate power calculation and observed baseline rate in control group approximated that assumed for the power calculation

Weaknesses

• Long trial duration
  • Other practices may have changed during the trial
  • Authors compared first 3 years against last 4 years and found no differences
  • Unlikely to affect internal validity but generalisability may be reduced
• Treatment discontinued in 10% of patients in intervention group
• Choice and duration of antibiotics not specified
• Unusual composite primary outcome makes it difficult to clinically apply
  • Authors argue that ‘treatment failure’ is a surrogate for resource use and patient mortality
• Fragility index = 2 (see further reading link below)
  • If 2 additional patients of the 61 in the intervention group had been ‘treatment failures’ then the result would have been non-significant (p > 0.05) and the conclusion may have been drawn differently