CRASH-3: Tranexamic acid in traumatic brain injury

Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial.

The CRASH-3 trial collaborators. Lancet 2019; 394: 1713–23 

Aim of Study

Assess the effects of tranexamic acid in patients with traumatic brain injury (TBI).

Design and Location

Randomised, double-blinded, placebo-controlled trial was done in 175 hospitals in 29 countries.

Methodology

Adults with TBI who were within 3 h of injury, had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding were eligible.

The time-window for eligibility was originally 8 h but in 2016, the protocol was changed to limit recruitment to patients within 3 h of injury. They randomly assigned (1:1) patients to receive tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo.

Primary Outcome

Head injury-related death in hospital within 28 days of injury in patients randomly assigned within 3 h of injury.

Secondary Outcomes

Early head injury-related death (within 24 h after injury), all-cause and cause-specific mortality, disability, vascular occlusive events (myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism), seizures, complications, neurosurgery, days in intensive care unit, and adverse events within 28 days of randomisation.

Statistics

  • All analyses were on an intention-to-treat basis. For each binary outcome, they  calculated RRs and 95% CIs.
  • The effects of tranexamic acid on the primary outcome were stratified by three baseline characteristics: severity of head injury, time to treatment, and age. Severity of head injury was assessed using the baseline GCS score.
  • Effect of severity was assessed in a regression analysis that included continuous terms for GCS and its square.
  • Effect of treatment on time was assessed in a subgroup analysis of the effect of tranexamic acid according to the estimated time interval between injury and treatment (≤1, >1 to ≤3, >3 h). Variables were controlled in a multivariable model.
  • Lastly they examined the effect of tranexamic acid on head injury-related death stratified by age. For subgroup analyses, they reported p-values for the test for heterogeneity.

Results

  • Reduction in the risk of head injury-related death with tranexamic acid in patients with mild-to-moderate head injury (RR 0·78 [95% CI 0·64–0·95]).
  • Early treatment was more effective than later treatment in patients with mild and moderate head injury (p=0·005).
  • The RR of head injury-related death was 0·81 (95% CI 0·69–0·95) within 24 h.
  • The prevalence of disability among survivors was similar between groups.
  • The risk of vascular occlusive events and other complications was similar in the tranexamic acid and placebo groups.

Conclusions/Discussions

This trial provides evidence that the administration of tranexamic acid to patients with TBI within 3 h of injury reduces head injury-related death, with no evidence of adverse effects or complications.

Strengths

  • Large, multi-centre trial, range of countries
  • Small numbers of loss to follow up with intention-to-treat analysis, balanced baseline characteristics
  • Pre-specified subgroups: GCS and pupil reactions easy to assess clinically
  • Patient-focused secondary outcomes

Weaknesses

  • No statistical difference in primary outcome
  • Assessment of GCS and pupil response subject to errors made by clinicians
  • Time-to-treatment bias

Does it change our practice?

  • Good external validity of study.
  • No increase in adverse events with intervention
  • We should consider TXA in mild-to-moderate TBI patients presenting within 3hours of injury. 

Summary by Dr Maggie Zou

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