CRASH-3 Trial: Tranexamic Acid in Traumatic Brain Injury
Direct Answer
Tranexamic acid (TXA) administered within 3 hours of traumatic brain injury reduces head injury-related death by 22% in patients with mild-to-moderate TBI (RR 0.78,95% CI 0.64-0.95), but provides no benefit in severe TBI and should not be given to patients with GCS of 3 or bilateral unreactive pupils. 1
Patient Selection Algorithm
Who Benefits:
- Patients with mild-to-moderate TBI (GCS >3) 1
- Patients with at least one reactive pupil 2
- Treatment initiated within 3 hours of injury, ideally within 1 hour 1
Who Does NOT Benefit:
- Patients with GCS score of 3 2
- Patients with bilateral unreactive pupils 2
- Patients with severe TBI (these showed no mortality reduction: RR 0.99,95% CI 0.91-1.07) 1
- Treatment delayed beyond 3 hours (may actually increase mortality risk) 3
Critical Timing Considerations
The earlier, the better—with dramatic differences:
- Treatment within 1 hour: 65% lower 30-day mortality (HR 0.35,95% CI 0.19-0.65) 3
- Treatment between 1-3 hours: still effective but benefit decreases approximately 10% for every 15-minute delay 3
- Treatment after 3 hours: contraindicated as it may increase risk of death due to bleeding (RR 1.44,95% CI 1.12-1.84) 4
The CRASH-3 trial demonstrated that early treatment (within 1 hour) was particularly effective in mild-to-moderate head injury (p=0.005 for time-to-treatment effect), but time to treatment had no obvious effect in severe head injury (p=0.73) 1
Dosing Protocol
Standard regimen endorsed by multiple guidelines:
- Loading dose: 1 g IV over 10 minutes 4, 1
- Maintenance infusion: 1 g IV over 8 hours 4, 1
- Must be initiated within 3 hours of injury 4, 1
Mechanism and Rationale
The CRASH-3 trial enrolled 12,737 patients with TBI, of whom 9,202 were treated within 3 hours of injury. 1 An exploratory analysis revealed that TXA reduces early deaths (within 24 hours) by 26% (RR 0.74,95% CI 0.58-0.94), but has no effect on deaths occurring beyond 24 hours (RR 0.98,95% CI 0.69-1.12). 5 This suggests TXA works by preventing early intracranial bleeding progression rather than through other neuroprotective mechanisms.
Patients with reactive pupils had median intracranial bleeding volumes of 26 ml compared to 60 ml in those with unreactive pupils, explaining why the former group benefits from TXA while the latter does not—smaller bleeds are more amenable to hemostatic intervention. 6
Safety Profile
TXA demonstrated excellent safety in the CRASH-3 trial:
- No increase in vascular occlusive events (RR 0.98,95% CI 0.74-1.28) 1
- No increase in seizures (RR 1.09,95% CI 0.90-1.33) 1
- No significant adverse events reported 1
This favorable safety profile extends across both isolated TBI and polytrauma patients. 5
Common Pitfalls to Avoid
Delaying for diagnostic workup: Do not wait for CT confirmation if clinical suspicion exists—give TXA empirically before advanced imaging, as every 15-minute delay reduces effectiveness by 10%. 3
Treating moribund patients: Avoid administering TXA to patients with GCS of 3 or bilateral unreactive pupils, as they derive no benefit and resources are better allocated elsewhere. 3, 2
Late administration: Never give TXA beyond 3 hours post-injury, as this may paradoxically increase mortality. 4, 3
Ignoring severity stratification: The CRASH-3 trial showed significant heterogeneity by injury severity (p=0.030 for interaction), with benefit limited to mild-to-moderate TBI. 1 Treating severe TBI patients (GCS 3-8 with unreactive pupils) provides no mortality reduction. 1
Cost-Effectiveness
TXA is highly cost-effective for mild and moderate TBI at £4,288 per quality-adjusted life-year gained from a UK NHS perspective. 2 The cost per life-year gained ranges from $48 in low-income countries to $64 in high-income countries. 4
Implementation Strategy
Pre-hospital administration should be considered: Guidelines suggest protocols for bleeding patients should consider administering the first dose of TXA at the site of injury to ensure treatment within the critical 1-hour window. 4