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^[*]

Abstract

Background

Tranexamic acid can reduce bleeding in patients undergoing elective surgery. We assessed the effects of early administration of a short course of tranexamic acid on death, vascular occlusive events, and the receipt of blood transfusion in trauma patients.

Methods

This randomised controlled 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 then infusion of 1 g over 8 h) or matching placebo. Randomisation was balanced by centre, with an allocation sequence based on a block size of eight, generated with a computer random number generator. Both participants and study staff (site investigators and trial coordinating centre staff) were masked to treatment allocation. The primary outcome was death in hospital within 4 weeks of injury, and was described with the following categories: bleeding, vascular occlusion (myocardial infarction, stroke and pulmonary embolism), multiorgan failure, head injury, and other. All analyses were by intention to treat. This study is registered as ISRCTN86750102, Clinicaltrials.gov NCT00375258, and South African Clinical Trial Register 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. All-cause mortality was significantly reduced with tranexamic acid (1463 [14.5%] tranexamic acid group vs 1613 [16.0%] placebo group; relative risk 0.91, 95% CI 0.85–0.97; p = 0.0035). The risk of death due to bleeding was significantly reduced (489 [4.9%] vs 574 [5.7%]; relative risk 0.85, 95% CI 0.76–0.96; p = 0.0077).

Interpretation

Tranexamic acid safely reduced the risk of death in bleeding trauma patients in this study. On the basis of these results, tranexamic acid should be considered for use in bleeding trauma patients.

Funding

UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation.

^* Republished with permission from Lancet. CRASH-2 Collaborators. 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. 2010 Jul 3;376(9734):23e32. Epub 2010 Jun 14.

• References

• 1 Peden M., McGee K., Sharma G.. The Injury Chart Book: A Graphical Overview of the Global Burden of Injuries. World Health Organization; Geneva: 2002
• 2 Gosselin R.A., Spiegel D.A., Coughlin R., Zirkled L.G.. Injuries: the neglected burden in developing countries. Bull World Health Organ 2009; 87: 246
• 3 Sauaia A., Moore F.A., Moore E.E.. et al Epidemiology of trauma deaths: a reassessment. J Trauma 1995; 38: 185-193
• 4 Lawson J.H., Murphy M.P.. Challenges for providing effective hemostasis in surgery and trauma. Sem Hematol 2004; 41: 55-64
• 5 Henry D.A., Carless P.A., Moxey A.J.. et al Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2007; 04: CD001886
• 6 Okamoto S., Hijikata-Okunomiya A., Wanaka K., Okada Y., Okamoto U.. Enzyme controlling medicines: introduction. Semin Thromb Hemost 1997; 23: 493-501
• 7 Coats T., Roberts I., Shakur H.. Antifibrinolytic drugs for acute traumatic injury. Cochrane Database Syst Rev 2004; 04: CD004896
• 8 Baigent C., Peto R., Gray R., Parish S., Collins R.. Large-scale randomized eviden trials and meta-analyses of trials. In: Warrell D.A., Cox T.M., Firth J.D.. eds Oxford Textbook of Medicine. 5th edn Oxford University Press; Oxford: 2010: 31-45
• 9 Perel P., Edwards P., Shakur H., Roberts I.. Use of the Oxford Handicap Scale at hospital discharge to predict Glasgow Outcome Scale at 6 months in patients with traumatic brain injury. BMC Med Res Methodol 2008; 08: 72
• 10 Duley L., Antman K., Arena J.. et al Specific barriers to the conduct of randomized trials. Clin Trials 2008; 05: 40-48
• 11 Sterne J., White I., Carlin J.. et al Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls. BMJ 2009; 338: b2393
• 12 Rogers A., MacMahon S.. Systematic underestimation of treatment effects as a result of diagnostic test inaccuracy: implications for the interpretation and design of thromboprophylaxis trials. Thromb Haemost 1995; 73: 167-171
• 13 Brohi K., Cohen M.J., Ganter M.T.. et al Acute coagulopathy of trauma: hypo-perfusion induces systemic anticoagulation and hyper-fibrinolysis. J Trauma 2008; 64: 1211-1217
• 14 Ekbäck G., Axelsson K., Ryttberg L.. et al Tranexamic acid reduces blood loss in total hip replacement surgery. Anesth Analg 2000; 91: 1124-1130
• 15 Kauvar D.S., Lefering R., Wade C.E.. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma 2006; 60: S3-S11
• 16 Mock C.N., Jurkovich G.J., nii-Amon-Kotei D., Arreola-Risa C., Maier R.V.. Trauma mortality patterns in three nations at different economic levels: implications for global trauma system development. J Trauma 1998; 44: 804-812
• 17 Wyatt J., Beard D., Gray A., Busuttil A., Robertson C.. The time of death after trauma. BMJ 1995; 310: 1502
• 18 Fiechtner B.K., Nuttall G.A., Johnson M.E.. et al Plasma tranexamic acid concentrations during cardiopulmonary bypass. Anesth Analg 2001; 92: 1131-1136
• 19 Horrow J.C., Van Riper D.F., Strong M.D., Grunewald K.E., Parmet J.L.. The dose-response relationship of tranexamic acid. Anesthesiology 1995; 82: 383-392
• 20 MRC CRASH Trial Collaborators. Predicting outcome after traumatic brain injury: practical prognostic models based on large cohort of international patients. BMJ 2008; 12: 12
• 21 Maas A.I., Steyerberg E.W., Butcher I.. et al Prognostic value of computerized tomography scan characteristics in traumatic brain injury: results from the IMPACT study. J Neurotrauma 2007; 24: 303-314
• 22 Perel P., Roberts I., Bouamra O., Woodford M., Mooney J., Lecky F.. Intracranial bleeding in patients with traumatic brain injury: a prognostic study. BMC Emerg Med 2009; 09: 15
• 23 Hogan M.C., Foreman K.J., Naghavi M.. et al Maternal mortality for 181 countries, 1980–2008: a systematic analysis of progress towards Millennium Development Goal 5. Lancet 2010; 375: 1609-1623
• 24 Ferrer P., Roberts I., Sydenham E., Blackhall K., Shakur H.. Anti-fibrinolytic agents in postpartum haemorrhage: a systematic review. BMC Pregnancy Childbirth 2009; 09: 29
• 25 Shakur H., Elbourne D., Gülmezoglu M.. et al The WOMAN Trial (World Maternal Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind placebo controlled trial. Trials 2010; 11: 40