Evidence review: efficacy

CRASH-2 trial

The efficacy of tranexamic acid has been assessed by an international randomised controlled trial (CRASH-2)[9]. In this study more than 20,000 patients with trauma who had significant haemorrhage (systolic blood pressure <90 mmHg or heart rate >110 beats per minute, or both) or who were considered to be at risk of significant haemorrhage were assigned to treatment with tranexamic acid or placebo. The primary outcome was death in hospital due to any cause within 4 weeks of injury. Secondary outcomes were vascular occlusive events, receipt of blood transfusion and surgical intervention.

Initiating tranexamic acid in adult trauma patients with or at risk of significant haemorrhage within 8 hours of injury resulted in statistically significant and clinically important reductions in death from any cause. All-cause mortality within 4 weeks of injury was 14.5% with tranexamic acid compared with 16.0% with placebo: an absolute risk reduction of 1.5% and a relative risk reduction of 9% (relative risk [RR] 0.91, 95% confidence interval [CI] 0.85 to 0.97). This risk difference indicates that for every 1000 people in the study overall, there were 160 deaths among people who received placebo, compared with 145 deaths among people who were treated with tranexamic acid. However, in clinical practice, the effectiveness of tranexamic acid in preventing death in absolute terms will depend on the patients' characteristics and risk of death at baseline.

The risk of death due to bleeding was reduced with tranexamic acid (4.9% versus 5.7%, RR 0.85, 95% CI 0.76 to 0.96). No significant differences for other (non-bleeding) causes of death were seen between tranexamic acid and placebo (RR 0.94, 95% CI 0.86 to 1.02).

CRASH-2: exploratory analyses

Effect of time of treatment

The investigators performed an exploratory analysis on pre-specified subgroups from the CRASH-2 study population to examine the effects of time to treatment on outcomes. This analysis suggested that treatment within 3 hours of injury was more effective than later treatment[10]. If administered within 3 hours of injury, tranexamic acid reduced the relative risk of death by 13% compared with placebo (RR 0.87, 95% CI 0.81 to 0.95)[11]. When administered more than 3 hours after injury, tranexamic acid did not reduce the risk of all-cause death (RR 1.00, 95% CI 0.90–1.13). The relative risk of death from bleeding was increased in the group given tranexamic acid 3 hours after injury (RR 1.44, 95% CI 1.12 - 1.84)[10].

Effect of severity of injury

A further exploratory analysis was conducted on a pre-specified subgroup of participants in CRASH-2 who were treated within 3 hours of injury[12]. These were stratified according to risk of death at baseline (<6%, 6–20%, 21–50%, >50%), estimated from a model derived from the CRASH-2 data and validated in a large sample of trauma patients from the UK Trauma and Audit Research Network registry database[13]. These data suggest a similar effect from tranexamic acid on all-cause mortality and deaths from bleeding in all groups in relative terms, and that use should not be restricted to the most severely injured. However, in the lowest risk group the precision of the estimated effect is low, and therefore there remains some uncertainty about the benefits of tranexamic acid in this group[12].

Cochrane review

A Cochrane systematic review of antifibrinolytic drugs following acute traumatic injury found 4 trials that met the inclusion criteria, including the CRASH-2 trial.[14] One small additional trial (n=240) of tranexamic acid added data to the CRASH-2 results on mortality.

The Cochrane review's conclusions were similar to those of CRASH-2. It found that tranexamic acid reduced the relative risk of death by 10% (RR 0.90, 95% CI 0.85 to 0.97). There was no evidence that tranexamic acid increased the risk of vascular occlusive events or need for surgical intervention. There was no substantial difference in the receipt of blood transfusion between tranexamic acid and placebo.

[9] CRASH-2 trial collaborators. (2010) Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 376: 23–32.

[10] CRASH-2 trial collaborators. (2011) The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 377: 1096–101.

[11] Guerriero C, Cairns J, Perel P et al. (2011) Cost-effectiveness analysis of administering tranexamic acid to bleeding trauma patients using evidence from the CRASH-2 trial. PLoS one; 6(5).

[12] Roberts I, Perel P, Prieto-Merino D et al. (2012) Effects of tranexamic acid on mortality in patients with traumatic bleeding: prespecified analysis of data from randomised controlled trial. BMJ 345: e5839.

[13] Perel P, Prieto-Merino D, Shakur H et al. (2012) Predicting early death in patients with traumatic bleeding: development and validation of prognostic model. BMJ 345: e5166.

[14] Roberts I, Shakur H, Ker K et al. (2011) Antifibrinolytic drugs for acute traumatic injury (Review). The Cochrane Collaboration 1.