Elsevier

The Lancet

Volume 377, Issue 9771, 26 March–1 April 2011, Pages 1096-1101, 1101.e1-1101.e2
The Lancet

Articles
The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial

https://doi.org/10.1016/S0140-6736(11)60278-XGet rights and content

Summary

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.

Funding

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

Introduction

The CRASH-2 trial showed that administration of tranexamic acid to adult trauma patients with, or at risk of, significant haemorrhage, within 8 h of injury, significantly reduces all-cause mortality (relative risk [RR] 0·91, 95% CI 0·85–0·97; p=0·0035) with no apparent increase in vascular occlusive events.1 As a consequence of this trial, tranexamic acid has been incorporated into trauma treatment protocols worldwide.

Results from the CRASH-2 trial raise some important questions. The trial was motivated by the evidence that tranexamic acid reduces bleeding in patients undergoing elective surgery, and the hypothesised mechanism was inhibition of fibrinolysis leading to improved effectiveness of haemostasis.2 However, no significant difference was recorded in transfusion requirements between the tranexamic acid and placebo groups, and the CRASH-2 trial did not measure the effect of this drug on fibrinolytic assays. Thus an alternative hypothesis is that tranexamic acid might act by reducing the pro-inflammatory effects of plasmin, rather than by improving haemostasis.3

There has also been discussion about which trauma patients should be treated with tranexamic acid. The CRASH-2 trial1 reported the few subgroup analyses that were prespecified in the statistical analysis plan. These analyses assessed the effect of tranexamic acid on the primary endpoint of all-cause mortality, according to time since injury, systolic blood pressure, Glasgow coma score, and type of injury. No strong evidence of heterogeneity was recorded for any of these analyses, suggesting that tranexamic acid is likely to be equally effective in all the subgroups examined.

The focus on all-cause mortality was appropriate because it is an outcome that matters to patients and one that is not affected by the methodological problem of competing risks.4 However, the effect of the trial treatment on the biologically relevant outcome could have been diluted by outcomes on which tranexamic acid might have little or no effect. In response to these concerns, we undertook exploratory analyses of the effect of tranexamic acid on mortality due to bleeding. We report the same prespecified subgroup analyses but for the outcome that we hypothesise would be most affected by this drug, specifically mortality due to bleeding.

Section snippets

Study design and patients

The background to the trial, methods, and baseline characteristics of the randomised patients have been previously reported.1 Briefly, we randomly allocated 20 211 adult trauma patients with, or at risk of, significant bleeding who were 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 matching placebo, with 99·6% follow-up. In most hospitals we used a local pack system for randomisation. After eligibility had been confirmed

Results

Of the 3076 deaths from all causes, death due to bleeding accounted for 1063 (35%). The risk of death due to bleeding was significantly reduced with tranexamic acid. 489 of 10 060 (4·9%) patients died because of bleeding in the tranexamic acid group versus 574 of 10 067 (5·7%) in the placebo group (RR 0·85, 95% CI 0·76–0·96; p=0·0077). We noted no significant effect on the risk of death for all other (non-bleeding) causes combined (table 1).

Table 2 shows the baseline characteristics of patients

Discussion

The effect of tranexamic acid on death due to bleeding depends on the time between injury and onset of treatment. Early treatment with this drug seems to be much more effective than does late treatment. These results also raise the possibility that late treatment with tranexamic acid might increase the risk of death due to bleeding, although there was no evidence of any increase in all-cause mortality in patients treated after 3 h (table 1). This finding might indicate that patients treated

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