Each year, worldwide, there are over 60 million new cases of traumatic brain injury (TBI).1 Low- and middle-income countries (LMIC) bear a disproportionate burden of morbidity and mortality due to TBI compared with high-income countries. In LMIC, TBI is most commonly the result of road traffic accidents, whereas in high-income countries the mechanism of injury for TBI appears to be shifting from road traffic accidents to falls by the elderly.1 With rapid urbanisation in LMIC and the resulting increase in motorisation, cases of TBI are expected to rise.2
The impact of TBI can be devastating for individuals and their families. Survivors of TBI may experience long-term physical, emotional and cognitive dysfunction. This, in turn, has considerable financial consequences through health and social costs and wider economic impacts due to reduced productivity.
Traumatic brain injury mechanism
Traumatic brain injury is an acute injury to the brain from an external mechanical force that temporarily or permanently impairs brain function. TBI is often classified as mild, moderate or severe according to the patient’s level of consciousness. This is assessed clinically using the Glasgow Coma Scale (GCS).3
Bleeding within the skull (known as intracranial haemorrhage) is common after TBI and is associated with increased mortality and morbidity.4 Although bleeding can start from the moment of impact, it often continues for several hours after injury.5,6 In the CRASH-1 (Corticosteroid Randomisation After Significant Head Injury) trial,7 which included 10,008 TBI patients, 73% of patients with moderate or severe TBI had intracranial haemorrhage on computerised tomography (CT) scan. Bleeding progressed in 84% of these patients with confirmed intracranial haemorrhage and moderate or severe TBI.
Management of traumatic brain injury
The skull is a rigid compartment containing three components: brain, blood and cerebrospinal fluid. An increase in one of these components, such as blood, from an intracranial haemorrhage, will need to be compensated by a decrease in one or more of the other components.8 Initially, this increase in volume can be accommodated; however, once these compensatory mechanisms become exhausted, intracranial pressure will rise.8 This may result in the brain tissue shifting and becoming displaced (known as brain herniation), which if left untreated can lead to respiratory depression and ultimately death.
Management of TBI is concerned with reducing intracranial pressures and can be broadly classified as either surgical or medical. Surgical interventions include draining cerebrospinal fluid and decompressive craniectomy.9 This involves removing a portion of the skull to relieve intracranial pressure. Medical options include therapeutic hypothermia, sedation and analgesia, hyperosmolar therapy and hyperventilation.9 Many of the current TBI management options require skilled medical professionals and specialist health-care facilities.
An inexpensive, simple and widely practicable treatment that improves outcomes in patients with TBI could save many thousands of lives and reduce the burden of disability.
Tranexamic acid and traumatic brain injury
Tranexamic acid (TXA) is an antifibrinolytic drug that inhibits the enzymatic breakdown of fibrin blood clots. It is possible that early administration of TXA in patients with TBI might prevent or reduce intracranial haemorrhage expansion and thus avert brain herniation and death.
Approximately one-third of patients with TBI have laboratory evidence of abnormal coagulation at hospital admission.10 These patients have an increased risk of intracranial haemorrhage and higher mortality. Increased clot breakdown (fibrinolysis), as indicated by elevated levels of fibrinogen degradation products, is often seen in patients with TBI and predicts intracranial haemorrhage expansion.11
In addition, it has been shown that progressive tissue damage and oedema develop in regions surrounding intracranial bleeding lesions, and are associated with worse outcomes.12 Tissue plasminogen activator (tPA) has been shown to be an important factor in this process of perilesional oedema.13–15 By blocking the conversion from plasminogen to plasmin, TXA counteracts the effect of tPA and, therefore, it is possible that TXA might also be beneficial in traumatic intracerebral haemorrhage by decreasing perilesional oedema through a specific neuroprotective effect.
Existing research on tranexamic acid
Tranexamic acid is commonly given to surgical patients to reduce bleeding and the need for blood transfusion. A systematic review of randomised trials of TXA in elective surgical patients shows that TXA reduces the number of patients receiving a blood transfusion by about one-third, reduces the volume of blood transfused by about 1 unit and halves the need for further surgery to control bleeding.16 These differences are all highly statistically significant. Furthermore, there is no evidence of any increased risk of vascular occlusive events with TXA.16
More recently, the CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage-2) trial17,18 showed that, in trauma patients with significant extracranial bleeding, early administration (within 3 hours of injury) of TXA reduces bleeding deaths by one-third. Subsequent analyses showed that even a short delay in treatment reduces the benefit of TXA administration.19 Based on these results, TXA was included in guidelines for the pre-hospital care of trauma patients, although patients with isolated TBI were specifically excluded.
Two studies have evaluated the effect of TXA in TBI. The CRASH-2 Intracranial Bleeding Study20 was a nested randomised trial conducted in 270 trauma patients who had evidence of TBI on a pre-randomisation CT scan. A second scan was conducted 24–48 hours after randomisation. There was a reduction in intracranial haemorrhage growth [risk ratio (RR) 0.80, 95% confidence interval (CI) 0.59 to 1.09], fewer ischaemic lesions and lower all-cause mortality (RR 0.60, 95% CI 0.32 to 1.11) in TXA-allocated patients, but these results were not statistically significant.20 A second randomised trial conducted in 240 patients with isolated TBI also found reductions in haemorrhage growth (RR 0.56, 95% CI 0.32 to 0.97) and mortality (RR 0.67, 95% CI 0.34 to 1.32) with TXA, but this trial did not collect data on ischaemic lesions.21
Rationale for trial
Meta-analysis of the two trials shows a significant reduction in haemorrhage growth (RR 0.72, 95% CI 0.55 to 0.94) and mortality (RR 0.63, 95% CI 0.40 to 0.99) with TXA. However, the studies provided no evidence about the effect of TXA on disability or adverse events. The CRASH-3 (Clinical Randomisation of an Antifibrinolytic in Significant Head Injury-3) trial aimed to quantify the effects of TXA on head injury death, disability and adverse events in patients with TBI.19 We also wanted to assess the cost-effectiveness of treating TBI patients with TXA.