Therapy
Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial
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Summary
Posted By: Gordon S. Doig
E-Mail: gdoig@med.usyd.edu.au
Posted Date: 4 Apr 2005
Title: Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial
Authors: CRASH trial collaborators
Reference: The Lancet, Volume 364, Issue 9442 , 9 October 2004, Pages 1321-1328
Link: Click here for a direct link to the paper. A password may be required for access to fulltext.
Abstract: BACKGROUND: Corticosteroids have been used to treat head injuries for more than 30 years. In 1997, findings of a systematic review suggested that these drugs reduce risk of death by 1-2%. The CRASH trial--a multicentre international collaboration--aimed to confirm or refute such an effect by recruiting 20000 patients. In May, 2004, the data monitoring committee disclosed the unmasked results to the steering committee, which stopped recruitment.
METHODS: 10008 adults with head injury and a Glasgow coma score (GCS) of 14 or less within 8 h of injury were randomly allocated 48 h infusion of corticosteroids (methylprednisolone) or placebo. Primary outcomes were death within 2 weeks of injury and death or disability at 6 months. Prespecified subgroup analyses were based on injury severity (GCS) at randomisation and on time from injury to randomisation. Analysis was by intention to treat. Effects on outcomes within 2 weeks of randomisation are presented in this report. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN74459797.
FINDINGS: Compared with placebo, the risk of death from all causes within 2 weeks was higher in the group allocated corticosteroids (1052 [21.1%] vs 893 [17.9%] deaths; relative risk 1.18 [95% CI 1.09-1.27]; p=0.0001). The relative increase in deaths due to corticosteroids did not differ by injury severity (p=0.22) or time since injury (p=0.05).
INTERPRETATION: Our results show there is no reduction in mortality with methylprednisolone in the 2 weeks after head injury. The cause of the rise in risk of death within 2 weeks is unclear.
 
Are the Results Valid?
1. Was the assignment of patients to treatments randomized? (Was allocation concealment maintained?)
Yes. Concealment of the allocation sequence was maintained by the use of a central call in randomization office or the use of on-site 'allocation packs'.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
2a. Was followup complete?
Yes. 10,008 patients were randomised. Two week outcomes were available on 99.6% of all patients in each group.
2b. Were patients analyzed in the groups to which they were randomized?
Yes. Patients were analyzed in the groups to which they were initially randomized, regardless of whether they actually received the assigned treatment.
3. Were patients, health workers, and study personnel blind to treatment?
Yes. This was a placebo controlled trial.
4. Were the groups similar at the start of the trial?
Table 1 suggests that both groups were similar with respect to important prognostic variables.
5. Aside from the experimental intervention, were the groups treated equally?
Crude antibiotic treatment rates, admission to the ICU, frequency of neurosurgery and composite complication rates were reported and not found to be different.
Duration of ICU stay, duration of mechanical ventilation, need for dialysis and other specific treatments that may have been received were not reported.
What are the Results?
1. How large was the treatment effect?
At two weeks post-randomization, 21% (1052/4985) of patients who received steroids died as compared to 18% (893/4979) of placebo patients (p=0.0001).
2. How precise was the estimate of the treatment effect?
The 95% confidence interval for the relative risk of death associated with steroid use was:
1.09 to 1.27.
The 95% confidence interval for the absolute risk of mortality increase associated with steroid use was:
2% to 5% ARI
Will the Results Help Me In Caring For My Patients?
1. Can the results be applied to my patient care?
Yes, this trial enrolled a large, representative sample of patients.
2. Were all clinically important outcomes considered?
No. This first paper only reports mortality at 2 weeks. This is not a widely accepted primary outcome for head trauma trials.
Definitive results can be expected when 6 month mortality and functional (QoL) outcomes are reported.
3. Are the likely treatment benefits worth the potential harms and costs?
Not at this point in time however caution is recommended in the use of steroids pending the definitive outcomes.

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Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial

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