CRASH-2 Trial: Tranexamic Acid for Traumatic Bleeding
Direct Recommendation
Administer tranexamic acid 1 gram IV over 10 minutes followed by 1 gram IV over 8 hours to all trauma patients with significant bleeding or at risk of significant hemorrhage, starting as early as possible and within 3 hours of injury. 1
Critical Timing Window
The effectiveness of TXA is profoundly time-dependent, with mortality benefit diminishing rapidly after injury:
- Within 1 hour of injury: Maximum benefit with 32% reduction in bleeding deaths (RR 0.68,95% CI 0.57-0.82) 1, 2
- Between 1-3 hours: Moderate benefit with 21% reduction in bleeding deaths (RR 0.79,95% CI 0.64-0.97) 1, 2
- After 3 hours: Potential harm with 44% increased risk of bleeding death (RR 1.44,95% CI 1.12-1.84) 1, 2
- Effectiveness decreases by 10% for every 15-minute delay in administration 3, 4
Do not administer TXA more than 3 hours after injury 1
Pre-Hospital Administration
Consider administering the first dose of TXA en route to the hospital to ensure treatment within the critical 1-hour window 1. Pre-hospital administration has shown particular benefit in patients with shock index <0.9 when given within 1 hour (65% lower 30-day mortality, HR 0.35,95% CI 0.19-0.65) 1.
Patient Selection Algorithm
Administer TXA to all trauma patients with significant bleeding, not just those with massive hemorrhage 1. The CRASH-2 trial demonstrated benefit regardless of:
- Systolic blood pressure level 1, 5
- Glasgow Coma Score (mild, moderate, or severe) 1, 5
- Type of injury (blunt vs penetrating) 1, 5
- Presence or absence of head injury 5
Do not wait for viscoelastic assessment results before administering TXA 1, 3. The time-dependent benefit makes immediate administration critical, and restricting use to only those with documented hyperfibrinolysis would result in thousands of avoidable deaths 6.
Mortality Benefit
The CRASH-2 trial (n=20,211 patients) demonstrated:
- 9% reduction in all-cause mortality (14.5% vs 16.0%, RR 0.91,95% CI 0.85-0.97) 1
- 15% reduction in bleeding deaths (4.9% vs 5.7%, RR 0.85,95% CI 0.76-0.96) 1
- Absolute mortality reduction of 1.5%, translating to one life saved for every 67 patients treated 6
Safety Profile
No increased risk of thrombotic events was demonstrated in CRASH-2, with actually lower rates of myocardial infarction in the TXA group 1. However, post-CRASH-2 observational data suggests in-hospital thrombotic event rates may be higher (5.9%) than in the original trial (2.0%) 7.
Seizure risk increases with higher doses, particularly in cardiac surgery, but was not observed with the standard trauma dosing regimen 1, 3.
Special Considerations for Traumatic Brain Injury
For patients with traumatic brain injury, TXA reduces head injury-related death when administered within 3 hours, particularly in mild to moderate TBI (RR 0.78,95% CI 0.64-0.95), but not in severe TBI (RR 0.99,95% CI 0.91-1.7) 1, 3.
Renal Impairment
Adjust dosing in renal failure as TXA is renally excreted and accumulates in renal impairment 3.
Common Pitfalls to Avoid
- Delaying administration while waiting for laboratory confirmation of coagulopathy or hyperfibrinolysis 1, 3
- Restricting use to only massive transfusion protocols rather than all bleeding trauma patients 1
- Administering after 3 hours post-injury, which may cause harm 1, 2
- Using topical TXA as substitute for IV administration when systemic hemostatic support is needed 3
Cost-Effectiveness
TXA is highly cost-effective across all income settings, with estimated cost per life-year gained of $48-66 in low- to high-income countries 1.