The importance of early treatment with Tranexamic acid in bleeding trauma patients

Trauma is the leading cause of death and disability worldwide. In both military and civilian settings, hemorrhage remains the most common cause of preventable death after traumatic injury. In recent years, there has been considerable interest in antifibrinolytic agents for the prevention of hemorrhagic death in severe trauma patients.

Tranexamic acid (TXA) is a synthetic lysine derivative that exerts its action by competitively occupying the lysine binding site of plasminogen, thereby blocking interaction with fibrin and subsequent clot breakdown.

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Key Points

The CRASH-2 and MATTERs studies were pivotal, landmark studies that brought the antifibrinolytic agent tranexamic acid (TXA) to the forefront of discussion after evidence suggested improved mortality in civilian and military trauma respectively.

Based on results from the CRASH-2 trial, in March of 2011, TXA was added to the World Health Organization’s list of essential medications.

The The Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage (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.

TXA has shown a mortality benefit in bleeding trauma patients when administered within three hours of injury, however not a decrease in blood product transfusions.

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.

In this study authors examine how patient characteristics vary by time to treatment and explore whether any such variations explain the time-dependent treatment effect.

The time-dependent effect of TXA in bleeding trauma patients is not explained by the type of injury, the presence or absence of head injury or systolic blood pressure. When given within 3 h of injury, TXA reduces death due to bleeding regardless of type of injury, GCS or blood pressure.

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Abstract

Abstract

Background

The CRASH-2 trial showed that tranexamic acid (TXA) administration reduces mortality in bleeding trauma patients. However, the effect appeared to depend on how soon after injury TXA treatment was started. Treatment within 3 h reduced bleeding deaths whereas treatment after 3 h increased the risk. Authors examine how patient characteristics vary by time to treatment and explore whether any such variations explain the time-dependent treatment effect.

Methods

Exploratory analysis were carried out, including per-protocol analyses, of data from the CRASH-2 trial, a randomised placebo-controlled trial of the effect of TXA on mortality in 20,211 trauma patients with, or at risk of, significant bleeding. Authors examine how patient characteristics (age, type of injury, presence or absence of head injury, Glasgow coma scale (GCS), systolic blood pressure and capillary refill time) vary with time to treatment and use univariable (restriction) and multivariable methods to examine whether any such variations explain the time-dependent effect of TXA. If not explained by differences in patient characteristics, authors planned to conduct separate prespecified subgroup analyses for the early benefit and late harm.

Results

There was no substantial variation in age or capillary refill by time to treatment. However, the proportion of patients with blunt trauma, the proportion with head injury and mean systolic blood pressure increased as time to treatment increased. Mean GCS decreased as time to treatment increased. Analyses restricted to patients with blunt trauma, those without head injury and those with a systolic blood pressure <100 mmHg showed that these characteristics did not explain the time-dependent treatment effect. In a multivariable analysis the interaction with time to treatment remained highly significant.

Separate subgroup analyses that examine how the benefits of early TXA treatment and the harms of late TXA treatment vary by systolic blood pressure (≤75, 76–89, >89 mmHg); GCS (severe 3–8, moderate 9–12, mild 13–15); and type of injury (penetrating versus blunt) showed no significant heterogeneity.

Conclusions