CRASH trial

CRASH-1 Trial Summary

Objective

The CRASH-1 (Corticosteroid Randomisation After Significant Head Injury) trial aimed to determine whether early administration of corticosteroids reduces death and disability in adults with TBI compared to placebo.

Methods

• Design: Randomised, placebo-controlled trial with centralised and non-centralised randomised concealed allocation.
• Blinding: Clinicians, patients, and data analysts were blinded.
• Analysis: Intention-to-treat analysis with annual interim analyses.
• Power: 90% to detect a 2% difference in mortality with a type I error of 0.01.
• Setting: 239 hospitals across 49 countries (Europe 38%, Asia 27%, South America 16%, Africa 14%, North America 4%, Oceania 1%).
• Duration: April 1999 to May 2004.

Population

• Inclusion Criteria: Adults over 16 years with head injuries, presenting within 8 hours of injury with a Glasgow Coma Scale (GCS) score of ≤14.
• Exclusion Criteria: Clear indication or contraindication for steroids.
• Participants: 10,008 patients.

Interventions

• Corticosteroid Group: Administration of methylprednisolone for 48 hours (2 g loading dose over 1 hour, then 0.4 g per hour for 48 hours).
• Control Group: Identical regime of placebo.

Outcomes

Primary Outcome

Mortality within 2 weeks.

• Corticosteroid group: 21.1% mortality.
• Placebo group: 17.9% mortality.
• Relative risk (RR): 1.18 (95% CI 1.09–1.27; p=0.0001).
• Absolute risk increase (ARI): 3.15% (95% CI 1.60%–4.70%).
• Number needed to harm (NNH): 32.

Secondary Outcome

Mortality and severe disability at 6 months.

• 6-month mortality: 25.7% (corticosteroids) vs. 22.3% (placebo); RR 1.15 (95% CI 1.07–1.24; p=0.0001); ARI 3.40% (95% CI 1.70%–5.10%); NNH 29.
• 6-month mortality or severe disability: 38.1% (corticosteroids) vs. 36.3% (placebo); RR 1.05 (95% CI 0.99–1.10; p=0.079); ARI 1.80% (95% CI -0.12%–3.72%); NNH 55.

Conclusion

The CRASH-1 trial concluded that corticosteroids should not be used routinely to treat head injury due to an increased risk of death.

Strengths

• Excellent external validity due to worldwide recruitment and minimal exclusion criteria.
• Robust statistical thresholds in the planning phase.
• Primary outcome data available for over 99% of patients.
• Rapid publication of important outcomes.

Weaknesses

• Interim halting may produce results due to an extreme play of chance.
• Hyperglycaemia from corticosteroid administration may have unblinded clinicians.
• Cause of death was not investigated, limiting further theories and explanations.

Reference

Roberts I, Yates D, Sandercock P, et al. Effect of intravenous corticosteroids on death within 14 days in 10,008 adults with clinically significant head injury: randomised placebo-controlled trial. Lancet. 2004; 364:1321-28. doi:10.1016/S0140-6736(04)17188-2. File:CRASH-trial.pdf