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The Lancet

Volume 376, Issue 9734, 3–9 July 2010, Pages 23-32
The Lancet

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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

https://doi.org/10.1016/S0140-6736(10)60835-5Get rights and content

Summary

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.

Introduction

Injuries are major causes of death worldwide.1, 2 Every year, more than a million people die as a result of road traffic injuries around the world. Road traffic injuries are the ninth leading cause of death globally, and such injuries are predicted to become the third leading cause of death and disability by 2020. About 1·6 million people die as a result of intentional acts of interpersonal, collective, or self-directed violence every year. More than 90% of trauma deaths occur in low-income and middle-income countries.2 Haemorrhage is responsible for about a third of in-hospital trauma deaths and can also contribute to deaths from multiorgan failure.3

The haemostatic system helps to maintain circulation after severe vascular injury, whether traumatic or surgical in origin.4 Major surgery and trauma trigger similar haemostatic responses, and in both situations severe blood loss presents an extreme challenge to the coagulation system. Part of the response to surgery and trauma is stimulation of clot breakdown (fibrinolysis), which might become pathological (hyper-fibrinolysis) in some cases.4 Antifibrinolytic agents reduce blood loss in patients with both normal and exaggerated fibrinolytic responses to surgery, and do so without apparently increasing the risk of postoperative complications.5

Tranexamic acid is a synthetic derivative of the aminoacid lysine that inhibits fibrinolysis by blocking the lysine binding sites on plasminogen.6 A systematic review of the randomised trials of tranexamic acid in patients undergoing elective surgery identified 53 studies including 3836 participants.5 Tranexamic acid reduced the need for blood transfusion by a third (relative risk [RR] 0·61, 95% CI 0·54–0·70), with no significant reduction in mortality (0·61, 0·32–1·12).5 Because the haemostatic responses to surgery and trauma are similar,4 tranexamic acid might reduce mortality due to bleeding in trauma patients. However, up until now there have been no randomised trials of this drug in such patients.7 We assessed the effects of the early administration of a short course of tranexamic acid on death, vascular occlusive events, and the receipt of blood transfusion in trauma patients with or at risk of significant haemorrhage.

Section snippets

Study design and patients

CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage 2) is a large placebo-controlled trial of the effects of early administration of a short course of tranexamic acid on death, vascular occlusive events, and the receipt of blood transfusion. The trial was undertaken in 274 hospitals in 40 countries. The first patient was enrolled in May, 2005. The study aims, methods, and protocol have been reported previously. The trial protocol was peer-reviewed and published on

Results

Figure 1 shows the trial profile. 20 211 patients were randomly assigned to tranexamic acid or placebo (figure 1), of whom 20 116 were randomly assigned through the local pack system and 95 through telephone randomisation. The data from four patients were removed from the trial because their consent was withdrawn after randomisation. Five patients enrolled in the study were later found to be younger than 16 years. Age was unknown for four patients. 23 patients were enrolled more than 8 h after

Discussion

The results show that the early administration of tranexamic acid to trauma patients with, or at risk of, significant bleeding reduces the risk of death from haemorrhage with no apparent increase in fatal or non-fatal vascular occlusive events. All-cause mortality was significantly reduced with tranexamic acid.

The trial inclusion criteria were clinical and did not depend on the results of laboratory tests. Patients were enrolled if they were judged to have on-going significant haemorrhage, as

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