Tranexamic acid for trauma: optimal timing of administration based on the CRASH-2 and CRASH-3 trials

Tranexamic acid reduces bleeding deaths in trauma patients, but the treatment benefit depends on the time from injury. It is recommended that tranexamic acid be administered immediately and only within 3 h of injury; however, the optimal criteria have not been adequately studied.

We applied machine learning-based causal forest models to investigate heterogeneity in the effects of tranexamic acid on 24-hour mortality rate conditional on covariates (for example age, sex, time from injury, systolic blood pressure, and Glasgow Coma Scale, GCS). We analysed data on 28 448 trauma patients in the CRASH-2 and CRASH-3 randomized trials. We used the policytree algorithm to determine the optimal criteria for tranexamic acid treatment.

The causal forest models showed heterogeneity in the effects of tranexamic acid on 24-hour mortality rate. The relative risk reduction was greatest in patients treated within 2 h of injury but thereafter decreased rapidly. The pattern was similar regardless of age or systolic blood pressure, although with decreasing GCS, the time to treatment effects were weaker, with benefits beyond 3 h. The largest absolute risk reductions were in patients with a low blood pressure and a low GCS when treated soon after injury. The optimal criterion was statistically determined as patients within 2 h of the injury or with GCS < 9.

Tranexamic acid administration was found to be beneficial when given within 2 h of injury. In patients with severe traumatic brain injury, the treatment benefits may persist beyond the 2-hour window.