CRASH-3

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. The Lancet, 2019; doi.org/10.1016/S1040-6736(19)32233-0

Clinical Question

• In patients with traumatic brain injury (TBI), does the administration of tranexamic acid (TXA) under 3 hours from injury, compared with placebo, reduce head injury associated in-hospital mortality within 28 days?

N = 12737, 175 hospitals in 29 countries

Outcome

Primary Outcome:

• 28 day in-hospital head injury associated mortality in patients assigned within 3 hours of injury - no significant difference
  • TXA group 855/4613 (18.5%) vs. 892/4514 (19.8%) in placebo
    - RR 0.94 (95% CI 0.86 – 1.02)
  • ARR 1.23% (95% CI -0.39 – 2.84%)

Pre-specified Subgroup Analysis of Primary Outcome

• Excluding those with GCS 3 or bilateral unreactive pupils-no significant difference
  • 28 day in hospital TBI associated mortality in TXA group 485/3880 (12.5%) vs. 525/3757 (14.0%) in placebo
    • RR 0.89 (95% CI 0.80 – 1.00)
    • ARR 1.47% (95% CI -0.05 – 2.99%)
• Patients with Mild to Moderate TBI (GCS 9-15) -significantly reduced in TXA group
  • 28 day in hospital TBI associated mortality in TXA group 166/2846 (5.8%) vs. 207/2769 (7.5%) in placebo
    • RR 0.78 (95% CI 0.64 – 0.95)
    • ARR 1.64% (95% CI 0.34 – 2.95%)

Other secondary outcomes

Timing of TXA:

• < 1 hr RR 0.96 (95% CI 0.79 – 1.17)
• 1-3 hr RR 0.93 (0.85 – 1.02)
• Early treatment was more effective than later treatment in mild – moderate injury (p=0.005), but timing had no effect in severe injury
• No statistical difference noted in high income vs low and middle income countries

Disability Measures:

• Disability Rating Scale similar, 4.99 in TXA vs 5.03 in placebo (if TXA used within 3 hours)
• 4 – 6 is classed as a moderate disability
• No difference between groups for patient derived disability measures

Complications:

• No increased risk of vaso-occlusive events (1.6% in both groups) or seizures (3.2% in TXA group vs 3.0% in placebo)

Authors’ Conclusions

-  TXA safe in TBI and that treatment within three hours reduces head injury associated deaths

The Bottom Line

• This is an enormous and well-designed, pragmatic trial designed to answer a question with limited evidence base
• TBI still has a 28 day in hospital mortality of nearly 20% in the placebo group – this is similar to the MRC CRASH trial which started recruitment in 1999
• TXA administration in TBI appears safe, however by conventional statistics it does not appear to reduce in hospital TBI associated death at 28 days when administered < 3 hours
• Hopefully longer term data will be published in due course
• Interesting debate will continue to occur as to whether subgroup analyses can be used to drive changes in clinical practice
• If it was my loved one with a mild-moderate TBI, I would be advocating for them to receive TXA given its low risk of harm