Fast track — ArticlesEffects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial
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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