Conclusion: TXA appears safe and showed a trend to improve mortality in patients with acute traumatic brain injury, with the largest benefit seen in those treated early with mild-to-moderate TBI
- CRASH-3 was an international, multi-centre, randomised, placebo-controlled trial of the effects of tranexamic acid on death and disability in patients with TBI
- Eligible patients were adults with TBI who were within 3 h of injury, had a GCS of <13 or any intracranial bleeding on CT scan, and no major extracranial bleeding
- The study enrolled 12,737 patients, 9,202 of whom were randomized within 3 hours; this number was slightly below the authors’ goal of approximately 10,000 patients to have 90% power to detect a difference
- Participants were randomly allocated to receive a loading dose of 1 g of TXA infused over 10 min followed by an intravenous infusion of 1 g over 8 h, or saline placebo
- The primary outcome was head injury-related death in hospital within 28 days of injury
- Secondary outcomes included:
- Early head injury-related death (within 24 h after injury)
- All-cause and cause-specific mortality
- Disability
- Vascular occlusive events (AMI, stroke, DVT, PE)
- Seizures
- Complications
- Neurosurgery
- Days in intensive care unit
- Adverse events within 28 days of randomisation
- Results: the risk of head injury-related death was 18·5% in the tranexamic acid group versus 19·8% in the placebo group (855 vs 892 events, RR 0·94 [95% CI 0·86–1·02])
- A prespecified sensitivity analysis that excluded patients with a GCS score of 3 or bilateral unreactive pupils at baseline reported the results were 12·5% in the tranexamic acid group versus 14·0% in the placebo group (485 vs 525 events, 0·89 [0·80–1·00])
- Linear regression analysis reported that TXA was more effective in less severely injured patients (those GCS 9-12) (p=0·007)
- Importantly, the difference seen with TXA was in disease-specific mortality (head-injury-related death), but there was no difference in all-cause mortality
- There was no difference seen in risk of vascular occlusive events or other complications
- Strengths:
- Very large multinational trial increases external validity
- The method of randomisation ensured that participating clinicians had no knowledge of the treatment allocation and the use of placebo control ensured that outcome assessments were blind to the intervention
- Limitations:
- Although the CRASH-3 trial is one of the largest trials in patients with TBI, the CIs were wide and compatible with both a substantial reduction in head injury-related death but also little or no benefit
- Mortality at 28 days may feasibly miss some patients die of sequelae related to their TBI
- Technically speaking the author’s conclusion that “treatment within 3 h of injury reduces head-injury associated death” is not statistically correct as the primary outcome has a 95% CI that crosses zero
Full article: https://www.thelancet.com/action/showPdf?pii=S0140-6736%2819%2932233-0
Reference: 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 Nov 9;394(10210):1713-1723.
