EBQ:CRASH-3 Trial

Incomplete 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. {{{volume}}}:{{{pages}}}.
PubMed Full text

Clinical Question

Is tranexamic acid beneficial in patients with TBI?

Conclusion

"Our results show that tranexamic acid is safe in patients with TBI and that treatment within 3 hours of injury reduces head injury-related death. Patients should be treated as soon as possible after injury"

Intracranial Hemorrhage

Design

• Randomized, placebo controlled trial of 12,737 patients done in 175 hospitals in 29 countries on patients with TBI.

Population Studied

Inclusion Criteria

• Adults with TBI were within 3 hours of injury, GCS 12 or lower or any intracranial bleeding on CT scan.

Baseline Characteristics

• 80% men, 19% female
• Mean age 41.7 years
• Bilateral nonreactive pupils 9%

Interventions

Loading dose 1 g over 10 min followed by infusion of 1g over 8 hours

Outcomes/Results

Primary Outcomes

Head injury-related death in hospital within 28 days of injury

• Among patients treated within 3 hours of injury, risk of head injury-related death was 18.5% in TXA group versus 19.8% in placebo group (CI 0.86-1.02).

Prespecified sensitivity analysis that excluded patients with a GCS of 3 and those with bilateral unreactive pupils at baseline

• There was a 12.5% risk of head injury related death compared to 14% in placebo (CI 0.80-1.00)

Secondary Outcomes

• Early head injury-related death (within 24 h after injury)
• All-cause and cause-specific mortality
• Disability
• Vascular occlusive events (MI, CVA, DVT, PE) - Similar in TXA vs. placebo
• Seizures
• complications
• Neurosurgery days in ICU
• Adverse events within 28 days

Discussion

This trial provides evidence that 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. Effect more prominent in mild and moderate head injuries compared to those with severe head injury. Anticipated that GCS 3 patients with bilateral unreactive pupils would have little potential to benefit and that inclusion may bias treatment effect towards null, which is why there was a prespecified subgroup.

Criticism

There remains a possibility of undersensing adverse events such as thrombotic event due to requirement of a diagnostic test confirming presence of the thrombotic event.

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, and Welcome Trust (Joint Global Health Trials Scheme)