CRASH-1

Effect of intravenous corticosteroids on death within 14 days in 10 008 adults with clinically significant head injury: randomised placebo-controlled trial

Roberts et al for the CRASH trial collaborators. Lancet 2004; 364:1321-28. doi:10.1016/S0140-6736(04)17188-2

Clinical Question

  • In adults with a head injury, do early corticosteroids compared to placebo reduce death and disability?

Design

  • Randomised, controlled trial
  • Centralised (21%) and non-centralised (79%) randomised concealed allocation method
  • Blinding of clinicians, patients, and data analysts
  • Annual interim analyses, with unmasking only if:
    • “proof beyond reasonable doubt of a difference” was found or,
    • new published data removed equipoise and uncertainty regarding corticosteroid use
  • Intention-to-treat analysis
  • Powered at 90% to detect 2% difference in mortality from baseline of 15%, with accepted type I error of 0.01 (chance of false positive), if 20,000 patients were recruited

Setting

  • 239 hospitals from 49 countries
    • Europe 38%, Asia 27%, South America 16%, Africa 14%, North America 4%, Oceania 1%
  • April 1999 to May 2004

Population

  • Inclusion: adults over 16 years with head injuries, who presented within 8 hours of injury with GCS ≤ 14
  • Exclusion: clear indication or contraindication for steroids
  • 10,008 patients randomised

Intervention

  • Administration of methylprednisolone for 48 hours
    • Loading dose of 2 g over 1 hour in 100 ml 0.9% NaCl
    • Maintenance of 0.4 g per hour for 48 hours in 20 ml per hour 0.9% NaCl

Control

  • Identical regime of placebo

Outcome

  • Primary outcome: unmasking of randomisation took place after 10,008 patients due to a clear difference favouring placebo for mortality at 2-weeks
    • Corticosteroid group 21% mortality vs placebo group 18% mortality
    • Relative risk 1.18 (95% CI 1.09–1.27; p=0.0001)
    • Absolute risk increase 3.15% (95% CI 1.60%–4.70%; NNH 32)
  • Secondary outcome: 6-month follow-up favoured placebo for mortality and severe disability

 

Primary Outcome
Measure Corticosteroids Placebo RR ARR NNH
2-week mortality 1052 (21.1%) 893 (17.9%) 1.18
(95% CI 1.09–1.27; p=0.0001)
-3.15%
(95% CI 1.60%–4.70%)
31
CI = confidence interval; p = p-value; RR = relative risk; ARR = absolute risk reduction; NNH = number-needed-to-harm.
Secondary Outcomes
Measure Corticosteroids Placebo RR ARR NNH
6-month mortality 1248 (25.7%) 1075 (22.3%) 1.15
(95% CI 1.07–1.24; p=0.0001)
-3.40%
(95% CI 1.70%–5.10%)
29
6-month mortality or severe disability 1828 (38.1%) 1728 (36.3%) 1.05
(95% CI 0.99–1.10; p=0.079)
-1.80%
(95% CI -0.12%–3.72%)
55

Authors’ Conclusions

  • “Corticosteroids should not be used routinely to treat head injury, whatever the severity.”

Strengths

  • Excellent external validity due to worldwide recruitment and minimal exclusion criteria
  • Robust statistical thresholds in planning phase (⍺<0.01, β=90%)
  • Primary outcome data available for over 99% of patients
  • Rapid publication of important outcome with secondary outcomes published later

Weaknesses

  • Halting at interim stage may produce results that are due to an extreme play of chance
  • Hyperglycaemia from corticosteroid administration may have unblinded clinicians and / or led to unbalanced management of the two groups (see Lancet comments)
  • Cause of death not investigated, so further theories and an explanation for the results are limited

The Bottom Line

  • Corticosteroids should not be given to patients with head injuries, unless other specific indications exist that outweigh the increased risk of death demonstrated by this trial

Metadata

Summary author: @DuncanChambler
Summary date: 15 August 2014
Peer-review editor: @davidslessor

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