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

File:CRASH-trial.pdf 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.