The CRASH 2 trial showed improved outcomes in trauma from the administration of the antifibrinolytic drug tranexamic acid. A further analysis of the data has shown that benefit was only seen in CRASH-2 when tranexamic acid was administered within 3 hours of injury1.
An accompanying editorial2 makes the following interesting points:
- Acute traumatic coagulopathy is a hyperacute process in which systemic fibrinolysis releases D-dimers that are detectable within 30 min of injury.
- Those severely injured patients who develop acute coagulopathy are much more likely to die and to die early.
- Once fully activated, fibrinolysis has been shown to continue unabated until endogenous antifibrinolytic elements are restored.
- The earlier that tranexamic acid is administered, the more likely it might be to prevent full activation of fibrinolysis.
- Hospital massive transfusion protocols incorporate fresh frozen plasma that contains all the endogenous antifibrinolytic elements in plasma and so the place for tranexamic acid in high income countries with such protocols is unclear.
- The best place for tranexamic acid in developed trauma systems might actually be in the prehospital environment, where trauma bypass policies have extended prehospital times and the administration of plasma is uncommon and often impractical.
BACKGROUND: The aim of the CRASH-2 trial was to assess the effects of early administration of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage. Tranexamic acid significantly reduced all-cause mortality. Because tranexamic acid is thought to exert its effect through inhibition of fibrinolysis, we undertook exploratory analyses of its effect on death due to bleeding.
METHODS: The CRASH-2 trial was undertaken in 274 hospitals in 40 countries. 20,211 adult trauma patients with, or at risk of, significant bleeding were randomly assigned within 8 h of injury to either tranexamic acid (loading dose 1 g over 10 min followed by infusion of 1 g over 8 h) or placebo. Patients were randomly assigned by selection of the lowest numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Both participants and study staff (site investigators and trial coordinating centre staff ) were masked to treatment allocation. We examined the effect of tranexamic acid on death due to bleeding according to time to treatment, severity of haemorrhage as assessed by systolic blood pressure, Glasgow coma score (GCS), and type of injury. All analyses were by intention to treat. The trial is registered as ISRCTN86750102, ClinicalTrials.gov NCT00375258, and South African Clinical Trial Register/Department of Health DOH-27-0607-1919.
FINDINGS: 10,096 patients were allocated to tranexamic acid and 10,115 to placebo, of whom 10,060 and 10,067, respectively, were analysed. 1063 deaths (35%) were due to bleeding. We recorded strong evidence that the effect of tranexamic acid on death due to bleeding varied according to the time from injury to treatment (test for interaction p<0.0001). Early treatment (≤1 h from injury) significantly reduced the risk of death due to bleeding (198/3747 [5.3%] events in tranexamic acid group vs 286/3704 [7.7%] in placebo group; relative risk [RR] 0.68, 95% CI 0.57-0.82; p<0.0001). Treatment given between 1 and 3 h also reduced the risk of death due to bleeding (147/3037 [4.8%] vs 184/2996 [6.1%]; RR 0.79, 0.64-0.97; p=0.03). Treatment given after 3 h seemed to increase the risk of death due to bleeding (144/3272 [4.4%] vs 103/3362 [3.1%]; RR 1.44, 1.12-1.84; p=0.004). We recorded no evidence that the effect of tranexamic acid on death due to bleeding varied by systolic blood pressure, Glasgow coma score, or type of injury.
INTERPRETATION: Tranexamic acid should be given as early as possible to bleeding trauma patients. For trauma patients admitted late after injury, tranexamic acid is less effective and could be harmful.
1. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial
Lancet. 2011 Mar 26;377(9771):1096-101
2. Tranexamic acid for trauma
Lancet. 2011 Mar 26;377(9771):1052-4