title: The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation.
authors: Clinical Trials Unit, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK. crash@lshtm.ac.uk
authors: Ian
authors: I
authors: Roberts
authors: Haleema
authors: H
authors: Shakur
authors: Adefemi
authors: A
authors: Afolabi
authors: Karim
authors: K
authors: Brohi
authors: Tim
authors: T
authors: Coats
authors: Yashbir
authors: Y
authors: Dewan
authors: Satoshi
authors: S
authors: Gando
authors: Gordon
authors: G
authors: Guyatt
authors: B J
authors: BJ
authors: Hunt
authors: Carlos
authors: C
authors: Morales
authors: Pablo
authors: P
authors: Perel
authors: David
authors: D
authors: Prieto-Merino
authors: Tom
authors: T
authors: Woolley
mesh_terms: D000328:Adult; D000933:Antifibrinolytic Agents / Q000627:therapeutic use*; D006470:Hemorrhage / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D016015:Logistic Models; D013997:Time Factors; D014148:Tranexamic Acid / Q000627:therapeutic use*; D014947:Wounds and Injuries / Q000150:complications*
chemical_list: D000933:Antifibrinolytic Agents; D014148:Tranexamic Acid