CRASH-3: Tranexamic Acid in Traumatic Brain Injury

TXA reduces head-injury death — but only if given early + GCS isn't already 3.

Population

12,737 adults with TBI (GCS ≤12 or any intracranial bleeding on CT) within 3 hours of injury at 175 hospitals across 29 countries.

Intervention

TXA 1 g IV bolus over 10 min, then 1 g over 8 h.

Comparison

Placebo.

Outcome

Head-injury-related death within 28 days.

Randomized, placebo-controlled, multicenter pragmatic trial. Pre-hospital + early-ED randomization. Primary analysis stratified by time to treatment + GCS severity.

• Primary outcome: 18.5% (TXA) vs 19.8% (placebo). RR 0.94, 95% CI 0.86-1.02 (p=0.11). Negative on the overall primary endpoint.
• BUT: in the pre-specified subgroup of MILD-MODERATE TBI (GCS 9-15), TXA reduced head-injury death (RR 0.78, 95% CI 0.64-0.95).
• TIMING: benefit confined to early treatment (<3 h after injury).
• Severe TBI (GCS 3-8): no benefit. Patients with GCS 3 + bilateral fixed pupils derived no benefit.
• Vascular occlusive events: no significant increase.

TXA has narrow but real value in TBI: give it within 3 h to patients with mild-to-moderate TBI (GCS 9-15) when intracranial bleed is suspected or confirmed. Don't expect benefit in already-devastated patients (bilateral fixed pupils, GCS 3). Combine with TXA for any concurrent extracranial hemorrhage (CRASH-2 indication). Modern trauma protocols now include TXA in the prehospital + early-ED window.

• Negative primary outcome — subgroup effect, even if pre-specified, is hypothesis-generating.
• Heterogeneous TBI population.
• Some hospitals contributed many patients — possible cluster effects.

1. What is your prehospital + ED TXA protocol for TBI? Is the time-to-administration auditable?
2. Should we treat any patient with suspected TBI within 3 hours, or restrict to those with confirmed intracranial bleed?
3. Is it ethical to withhold TXA in GCS 3 patients given a 'no benefit' subgroup analysis when it's such a low-risk drug?