What is the benefit of tranexamic acid (TXA) in the CRASH 3 trial for which group of Traumatic Brain Injury (TBI) patients?

CRASH-3 Trial Benefit in Traumatic Brain Injury

Tranexamic acid (TXA) in the CRASH-3 trial demonstrated benefit specifically in patients with mild-to-moderate traumatic brain injury (TBI) when administered within 3 hours of injury, reducing head injury-related death by 22% (RR 0.78,95% CI 0.64-0.95), but showed no benefit in severe TBI. 1, 2

Patient Selection Criteria for TXA Benefit

The CRASH-3 trial enrolled 12,737 TBI patients and identified clear subgroups who benefit from TXA treatment:

Patients Who Benefit:

• Mild-to-moderate TBI patients (GCS >3 with at least one reactive pupil) treated within 3 hours showed reduced head injury death: 12.5% (TXA) vs 14.0% (placebo), RR 0.89 (95% CI 0.80-1.00) 1, 2
• Patients with both pupils reactive at baseline demonstrated cost-effective mortality reduction 1, 3
• Earlier treatment is more effective: patients treated within 1 hour had 65% lower 30-day mortality (HR 0.35,95% CI 0.19-0.65) 1

Patients Who Do NOT Benefit:

• Severe TBI patients (GCS 3 or bilateral unreactive pupils) showed no mortality reduction: RR 0.99 (95% CI 0.91-1.07) 1, 2
• The lack of benefit in severe TBI likely reflects larger baseline intracranial bleeding volumes (median 60 mL vs 26 mL in reactive pupils), where reducing further bleeding has minimal impact 4

Critical Timing Considerations

Time to treatment is the most important determinant of TXA effectiveness in mild-to-moderate TBI:

• Treatment benefit decreases by approximately 10% for every 15-minute delay 5
• The optimal treatment window is within 2 hours of injury based on machine learning analysis of CRASH-2 and CRASH-3 data 6
• Early treatment (within 1 hour) showed the greatest relative risk reduction in mild-to-moderate TBI (p=0.005 for time-to-treatment effect) 1, 2
• Treatment after 3 hours may increase mortality risk and is not recommended 1, 5

Mechanistic Explanation

The differential benefit by injury severity relates to baseline bleeding volume and timing:

• Patients with reactive pupils had median intracranial bleeding of 26 mL (IQR 1-55 mL) versus 60 mL (IQR 18-101 mL) in those with unreactive pupils 4
• For every hour from injury to baseline CT scan, the risk of new bleeding decreased by 12% (adjusted RR 0.88,95% CI 0.80-0.96), explaining why early treatment is critical 4
• Patients with smaller baseline hemorrhages benefit more because TXA can prevent expansion that would otherwise be clinically significant 1, 4

Dosing Protocol

Standard CRASH-3 regimen endorsed by multiple guidelines:

• Loading dose: 1 g IV over 10 minutes
• Maintenance: 1 g IV infusion over 8 hours
• Initiate as soon as possible, within 3 hours of injury 1, 7

Safety Profile

TXA demonstrated an excellent safety profile in the CRASH-3 trial:

• No increase in vascular occlusive events: RR 0.98 (95% CI 0.74-1.28) 2, 7
• No increase in seizures: RR 1.09 (95% CI 0.90-1.33) 1, 2
• No increase in stroke, MI, or venous thromboembolism 7

Implementation Pitfalls to Avoid

Common errors that reduce TXA effectiveness:

1. Delaying administration for diagnostic workup - Give TXA empirically before viscoelastic testing or advanced imaging if clinical suspicion exists 1, 7
2. Treating severe TBI patients (GCS 3, bilateral unreactive pupils) - These patients do not benefit and resources may be better allocated elsewhere 1, 2
3. Administering beyond 3 hours - This may actually increase mortality and should be avoided 1, 5
4. Waiting for CT confirmation - In polytrauma with suspected TBI, early empiric administration is reasonable given the safety profile 7

Cost-Effectiveness

TXA is highly cost-effective in appropriate patients:

• Base case analysis: £4,288 per quality-adjusted life-year gained in mild-to-moderate TBI 8
• Cost-effective specifically in patients with both pupils reactive 1, 8