Does tranexamic acid, when given within 8 hours to patients with or at risk of significant bleeding reduce death within 4 weeks of injury?
Tranexamic acid improves survival when administered early in trauma with known or suspected significant hemorrhage.
Hemorrhage is a leading cause of death among patients with major trauma. Trauma leads to hemorrhage both from primary injury to organs and blood vessels, but also to transient hyperfibrinolysis that is incompletely understood. Tranexamic acid, a synthetic derivative of the amino acid lysine, appears to interfere with this hyperfibrinolysis, prompting investigators to study whether the agent may reduce the morbidity and mortality of traumatic hemorrhage. It has previously been used in controlling bleeding complications in those with hemophilia, those undergoing cardiopulmonary bypass, and those with menorrhagia.
The 2010 Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage 2 (CRASH-2) was an international study of 20,207 trauma patients with or at risk of significant hemorrhage, defined based on hemodynamic instability. Patients were randomized to double-blind treatment with either tranexamic acid or matching placebo, given within 8 hours of presentation. At 4 weeks of follow-up, tranexamic acid was associated with a 1.5% absolute reduction in mortality (14.5% vs. 16%) compared to placebo. A separately published but prespecified subgroup analysis demonstrated that early administration of tranexamic acid (within one hour of injury) was associated with greater reductions in death due to bleeding, while delayed administration (>3 hours from injury) was associated with increased bleeding deaths. All-cause mortality was reduced in the <1 hour and 1-3 hour strata, but not in the >3 hour stratum.
An important consideration is whether the reduction in hemorrhage comes at the expense of an increased risk of vascular occlusion such as MI, stroke, DVT, or PE. Prior studies have demonstrated that tranexamic acid may elevate the risk of VTE, particularly among those with factor IX deficiency. However, in CRASH-2, there were no differences in the rate of vascular occlusive events (1.7% vs. 2.0%).
Tactical Combat Casualty Care (US Military) 2011
- Early administration of 1 gram of tranexamic acid to casualties expected to receive blood transfusions as soon as possible (class I, level B).
- Administration should be no more than 3 hours after initial trauma.
- Multicenter, randomized, placebo-controlled trial
- N=20,207 trauma patients with or at risk of significant hemorrhage
- Tranexamic acid (n=10,093)
- Placebo (n=10,114)
- Setting: 274 hospitals in 40 countries
- Enrollment: Began in 2005
- Follow-up: 4 weeks
- Analysis: Intention-to-treat
- Primary outcome: In-hospital death at 4 weeks
- Adult trauma patients
- Hemorrhagic shock or at risk of significant hemorrhage (systolic BP <90 or HR >110, or both)
- Within 8 hours of injury
- Clear indication for tranexamic acid
- Clear contraindication to tranexamic acid
- Male: 84%
- Mean age: 35 years
- Mean time since injury: 3h
- Blunt trauma: 68%
- Systolic BP <90: 32%
- HR >91: 74%
- GCS: 3-8 (18%), 9-12 (13%), 13-15 (68%)
- Randomized to tranexamic acid or placebo
- Tranexamic acid loading dose 1g over 10 minutes, followed by 1g/8h infusion
Comparisons are tranexamic acid vs. placebo.
- Death in hospital within 4 weeks of injury
- 14.5% vs. 16.0% (RR 0.91, 95% CI 0.85–0.97; P=0.0035)
- Vascular occlusive events (MI, CVA, PE, DVT)
- 1.7% vs. 2.0% (P=0.084)
- Surgical intervention
- 47.9% vs. 48.0% (P=0.79)
- Blood transfusion
- 50.4% vs. 51.3% (P=0.21)
- Death by cause
- Bleeding: 4.9% vs. 5.7%
- Vascular occlusive event: 0.3% vs. 0.5%
- Multiorgan failure: 2.1% vs. 2.3%
- Head injury: 6.0% vs. 6.2%
- Other: 1.3% vs. 1.4%
- Death due to bleeding
- ≤1h from injury: 5.3% vs. 7.7% (RR 0.68, 95% CI 0.57-0.82; P<0.0001)
- 1-3h: 4.8% vs. 6.1% (RR 0.79, 95% CI 0.64-0.97; P<0.00001)
- >3h: 4.4% vs. 3.1% (RR 1.44, 95% CI 1.12-1.84; P<0.0001)
- All-cause mortality
- ≤1h from injury: RR 0.87, 95% CI 0.76-0.97
- 1-3h: RR 0.87, 95% CI 0.77-0.97
- >3h: RR 1.00, 95% CI 0.90-1.13
- Did not measure fibrinolytic activity of participants
- Did not provide full data in subroup analysis of all-cause mortality
Both public (eg, UK NIHR) and private (eg, Pfizer) sources.
- Roberts I, et al. "The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial." Lancet. 2011; 377(9771):1096-10.
- Morrison JJ, et al. "Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study." Arch Surg. 2012;147(2):113-9.
- PDF file - Defense Health Board. "Executive summary: Recommendations regarding the addition of tranexamic acid to the tactical combat casualty care guidelines 2011-06." Letter to Jonathan Woodson MD: 2011-09-23. Accessed 2013-07-03.