EBQ:CRASH-3 Trial

Complete Journal Club Article

The CRASH-3 Trial Collaborators. "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 Lancet. 2019. 394(10210):1713-1723.
PubMed Full text

Clinical Question

Does tranexamic acid reduce head injury-related death in patients with traumatic brain injury (TBI)?

Conclusion

Tranexamic acid is safe in patients with TBI and, when administered within 3 hours of injury, reduces head injury-related death. The benefit is most apparent in patients with mild-to-moderate TBI (GCS 9-15) rather than those with severe TBI (GCS 3). Patients should be treated as soon as possible after injury.

Major Points

• CRASH-3 was designed as a follow-up to the landmark CRASH-2 trial which demonstrated survival benefit of TXA in trauma patients with hemorrhage
• The primary analysis showed a non-significant trend toward reduced head injury-related death with TXA (18.5% vs 19.8%; RR 0.94, 95% CI 0.86-1.02)
• A prespecified sensitivity analysis excluding patients with GCS 3 or bilateral unreactive pupils (who had minimal potential to benefit) showed a more notable reduction (12.5% vs 14.0%; RR 0.89, 95% CI 0.80-1.00)
• The effect was greatest in patients with mild-to-moderate TBI (GCS 9-15)
• No increase in vascular occlusive events (MI, stroke, DVT, PE) was observed with TXA
• The trial enrolled 12,737 patients across 175 hospitals in 29 countries, making it the largest TXA trial in TBI

Study Design

• Multicenter, randomized, double-blind, placebo-controlled trial
• 175 hospitals in 29 countries
• 12,737 patients randomized
  • TXA group: n=6,406
  • Placebo group: n=6,331
• Intention-to-treat analysis
• 28-day follow-up

Population

Inclusion Criteria

• Adults with TBI
• Within 3 hours of injury
• GCS 12 or lower OR any intracranial bleeding on CT scan
• No significant extracranial bleeding

Exclusion Criteria

• Clear indication or contraindication to tranexamic acid
• Significant extracranial hemorrhage

Baseline Characteristics

• Male: ~80%
• Mean age: 41.7 years
• GCS 3-8: ~30%
• GCS 9-12: ~20%
• GCS 13-15 with intracranial bleeding: ~50%
• Bilateral nonreactive pupils: ~9%
• Intracranial bleeding on CT: ~75%

Interventions

• TXA group: Loading dose of 1g IV over 10 minutes, followed by 1g IV infusion over 8 hours
• Placebo group: Matching placebo (0.9% saline)

Outcomes

Primary Outcome

• Head injury-related death in hospital within 28 days of injury:
  • TXA: 855/4613 (18.5%)
  • Placebo: 892/4514 (19.8%)
  • RR 0.94 (95% CI 0.86-1.02), p=0.14
• Prespecified sensitivity analysis (excluding GCS 3 and bilateral unreactive pupils):
  • TXA: 485/3880 (12.5%)
  • Placebo: 525/3757 (14.0%)
  • RR 0.89 (95% CI 0.80-1.00), p=0.047

Secondary Outcomes

• All-cause mortality: No significant difference
• Early head injury-related death (within 24 hours): Reduced with TXA (risk reduction most evident in this early period)
• Disability (Disability Rating Scale): No significant difference
• Vascular occlusive events (MI, CVA, DVT, PE): Similar in TXA vs placebo groups
• Seizures: Similar between groups
• Neurosurgical intervention: Similar between groups

Subgroup Analysis

• Greatest benefit in patients with mild-to-moderate TBI (GCS 9-15)
• Patients with severe TBI (GCS 3) and bilateral unreactive pupils showed minimal benefit
• Benefit diminished with increasing time to treatment

Criticisms

• Primary outcome did not reach statistical significance in the full intention-to-treat analysis (p=0.14)
• The prespecified sensitivity analysis (excluding GCS 3 and bilateral unreactive pupils) is what demonstrated significance, which weakens the overall conclusion
• Potential for undersensing adverse events (thrombotic events) since a diagnostic test was required to confirm the event
• The trial was designed for a larger treatment effect than was observed, suggesting it may have been underpowered for the primary outcome
• Majority of patients had mild-to-moderate TBI; applicability to severe TBI remains uncertain
• Different from CRASH-2 in that TBI patients have different pathophysiology of coagulopathy compared to hemorrhagic shock

Funding

• National Institute for Health Research Health Technology Assessment
• JP Moulton Charitable Trust
• Department of Health and Social Care
• Department for International Development
• Global Challenges Research Fund
• Medical Research Council
• Wellcome Trust (Joint Global Health Trials Scheme)

See Also

• EBQ:CRASH-2 Trial
• Traumatic brain injury
• Intracranial hemorrhage

References

• CRASH-3 trial collaborators. 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. Lancet. 2019;394(10210):1713-1723. PMID 31623894