What is the recommended dosage and administration of tranexamic acid (TXA) in patients with traumatic bleeding based on the CRASH 2 trial results?

CRASH-2 Trial Results: Tranexamic Acid Dosing and Administration in Traumatic Bleeding

The CRASH-2 trial established that tranexamic acid (TXA) administered as a 1g loading dose over 10 minutes followed by 1g infusion over 8 hours significantly reduces all-cause mortality (14.5% vs 16.0%, RR 0.91) and bleeding deaths (4.9% vs 5.7%, RR 0.85) in trauma patients with significant hemorrhage, with maximum benefit when given within 3 hours of injury. 1, 2

Core Trial Findings

The CRASH-2 trial randomized 20,211 adult trauma patients across 274 hospitals in 40 countries to receive either TXA or placebo within 8 hours of injury 2. The primary outcome was death in hospital within 4 weeks of injury 1.

Mortality Reduction

• All-cause mortality decreased from 16.0% to 14.5% with TXA treatment (relative risk 0.91,95% CI 0.85-0.97, P=0.0035) 1, 2
• Death due to bleeding specifically decreased from 5.7% to 4.9% (relative risk 0.85,95% CI 0.76-0.96, P=0.0077) 1, 2
• The mortality benefit occurred regardless of systolic blood pressure, Glasgow Coma Scale score, or type of injury (blunt vs penetrating) 1, 3

Critical Time-Dependent Effects

The timing of TXA administration is the single most important determinant of treatment benefit:

Early Treatment (≤1 hour)

• Treatment within 1 hour produced the greatest mortality reduction (5.3% vs 7.7% bleeding deaths; RR 0.68,95% CI 0.57-0.82, P<0.0001) 1
• Effectiveness decreases by 10% for every 15-minute delay in administration 4, 5

Intermediate Treatment (1-3 hours)

• Treatment between 1-3 hours still reduced bleeding deaths (4.8% vs 6.1%; RR 0.79,95% CI 0.64-0.97, P=0.03) 1
• Recent machine learning analysis of CRASH-2 and CRASH-3 data suggests optimal benefit occurs within 2 hours, with rapid decline thereafter 6

Late Treatment (>3 hours)

• Treatment after 3 hours INCREASED the risk of death due to bleeding (4.4% vs 3.1%; RR 1.44,95% CI 1.12-1.84, P=0.004) 1, 3
• TXA should not be administered more than 3 hours following injury 1, 5

Standard Dosing Protocol

The evidence-based dosing regimen from CRASH-2 is:

• Loading dose: 1g IV over 10 minutes 1, 4, 5, 2
• Maintenance infusion: 1g IV over 8 hours 1, 4, 5, 2
• This achieves therapeutic plasma levels of 10 μg/ml necessary to inhibit systemic fibrinolysis, with a plasma half-life of 120 minutes 1, 4

Safety Profile

CRASH-2 demonstrated an excellent safety profile that contradicted theoretical concerns:

• No increase in thrombotic events - in fact, myocardial infarction rates were lower with TXA 1
• No increase in stroke or pulmonary embolism 2
• Post-CRASH-2 systematic review showed pooled thrombotic event rate of 5.9% (vs 2.0% in CRASH-2), though mortality remained lower at 10.1% (vs 14.5% in CRASH-2) 7
• Higher doses (beyond CRASH-2 protocol) are associated with increased seizure risk, particularly in cardiac surgery 1, 4

Implementation Strategy

To maximize the time-dependent benefit, protocols should prioritize early administration:

Pre-Hospital Administration

• Consider administering the first 1g loading dose en route to the hospital to ensure treatment within the critical 3-hour window 1, 4
• Pre-hospital administration should be incorporated into bleeding management protocols 1, 5

Patient Selection

• Administer to ALL trauma patients with significant bleeding or at risk of significant hemorrhage 1, 8
• Do not restrict to only "massive hemorrhage" protocols - only 40% of preventable deaths occur in the highest-risk group 1
• Do not wait for viscoelastic testing or other laboratory confirmation 4

Special Populations

• The benefit persists across all injury types (blunt and penetrating), blood pressures, and Glasgow Coma Scale scores when given early 1, 3
• In patients with severe traumatic brain injury (GCS <9), treatment benefits may extend beyond 2 hours 6

Clinical Pitfalls to Avoid

• Never delay TXA administration beyond 3 hours - this converts benefit to harm 1, 5, 3
• Do not restrict use to only massive transfusion protocols - broader application prevents more deaths 1
• Do not use alternative routes without IV access - current guidelines only support IV administration based on CRASH-2 evidence 9
• Do not use higher doses than the CRASH-2 protocol - this increases seizure risk without proven additional benefit 1, 4

Cost-Effectiveness

The CRASH-2 trial demonstrated exceptional cost-effectiveness across all economic settings, with incremental cost per life-year gained of $48 in Tanzania, $66 in India, and $64 in the UK 1.