Administer tranexamic acid early to injured patients at risk of substantial bleeding

The evidence for change

Tranexamic acid was discovered in the 1950s and has been used during surgery to minimise blood loss. A systematic review evaluated 126 randomised controlled trials in elective surgery and three in emergency surgery (total of 10 488 patients) that had been conducted between 1972 and 2011. This showed that tranexamic acid reduced blood transfusions by a third (risk ratio 0.62, 95% confidence interval 0.58 to 0.65),4 an effect that persisted when only trials with adequate allocation concealment were considered (0.68, 0.62 to 0.74). In these higher quality trials the effect on mortality was uncertain (0.67, 0.33 to 1.34), as was the effect on myocardial infarction, stroke, and venous thromboembolism.

Tranexamic acid seems to work by inhibiting lysine binding sites on plasminogen, preventing its conversion to plasmin. Plasmin has potential fibrinolytic, inflammatory, and neurotoxic effects. The observed reduction in bleeding probably results from reduced fibrinolysis and therefore reduced clot breakdown. Like surgery, severe trauma and haemorrhage can accelerate fibrinolysis,3 which contributes to acute traumatic coagulopathy.2

In a systematic review of antifibrinolytic drugs in trauma5 the only trial to assess haemorrhage was the randomised placebo controlled CRASH-2 trial, which evaluated the effects of tranexamic acid in 20 211 adult trauma patients with or at risk of bleeding in 274 hospitals in 40 countries.6 Tranexamic acid given within eight hours of injury reduced all cause mortality from 16.0% to 14.5% (relative risk 0.91, 95% confidence 0.85 to 0.97), and the risk of death resulting from bleeding from 5.7% to 4.9% (0.85, 0.76 to 0.96).6 There did not seem to be more vascular occlusive events, nor did the effect of tranexamic acid seem to vary by baseline risk of death.7 Subsequent re-examination of the 1063/3076 (35%) deaths that resulted from bleeding found that the benefit of tranexamic acid was greatest when given early (<1h: 0.68, 0.57 to 0.82; 1-3 h: 0.79, 0.64 to 0.97) and that, when given more than three hours after injury, an unexpected increase in deaths from bleeding was observed (1.44, 1.12 to 1.84).8 Extrapolation of the CRASH-2 data led to estimates that more than 100 000 in-hospital deaths globally could be averted annually9 and 315 to 755 life years saved per 1000 trauma patients, at a cost of $45-$64 (£28-£40; €35-€49) per life year saved.10

Military doctors were concerned that many of the patients in the CRASH-2 trial did not resemble their severely injured patients from the battlefield because only half the patients in the CRASH-2 trial needed a blood transfusion or needed surgery yet a comparatively high proportion (compared with battlefield patients) of them died. This concern led to an observational study of 896 patients wounded in Afghanistan, which found tranexamic acid was associated with higher survival and less coagulopathy.11

Barriers to change

The largest barrier to change in trauma management is its incorporation into prominent guidelines on trauma management. Since the introduction of courses on advanced trauma life support in 1976, clinicians have realised the benefit of protocols for trauma management. Tranexamic acid has recently been included in the British armed forces guidelines (Clinical Guidelines for Operations) and the US military guidelines (Joint Theater Trauma System), and its use is reported to have greatly increased, although no data have been published. Adding tranexamic acid to civilian guidelines on advanced trauma life support and to other civilian guidelines would be expected to have a similar effect.

Some clinicians may wonder whether a single trial can provide definitive evidence for practice change in trauma, bearing in mind that the results of single trials are not always upheld in subsequent studies.12 For example, the conclusions of a recent large trial favouring the use of activated protein C in sepsis13 were reversed in subsequent studies. The consistent findings of the effects of tranexamic acid in 126 trials in elective surgery are somewhat reassuring in this regard.4

Another potential barrier to change is uncertainty about the generalisability of the CRASH-2 trial results to all trauma systems. Major trauma is different from elective surgery in that patients usually have multiple problems and survival depends on complex systems of care that coordinate access to necessary prehospital and hospital treatments. Pivotal to survival in haemorrhagic shock is a range of techniques for rapid control of bleeding, correction of coagulopathy, and critical care support. Countries that have invested heavily in trauma systems to coordinate and expedite access to time-critical care have reduced mortality substantially. Less than 2% of the patients in the CRASH-2 trial were treated in countries that are likely to have made such investments (such as Australia, New Zealand, North America, and western Europe).

Adding concern to the uncertainty about the balance of treatment benefits and harms in different settings is the unexplained increase in risk of death caused by bleeding when tranexamic acid was given more than three hours after injury. Plausible explanatory hypotheses, yet to be tested, include an adverse effect in established disseminated intravascular coagulation, development of a prothrombotic state, or a lack of effectiveness in patients in whom time had allowed hypothermia or acidosis to develop. Furthermore it is well established that major trauma elicits within minutes a widespread genomic response; affects the innate and adaptive immune systems; and causes systemic inflammation that can lead to multiple organ failure, sepsis, and death.14 The effects of tranexamic acid on these processes and on coagulation and fibrinolytic pathways, when administered at different times in the course of trauma resuscitation, have not been elucidated. If tranexamic acid has different effects at different administration times, other influences on coagulopathy (such as administration of clotting factor and platelets, temperature management, and timing of surgery) might also alter the balance of risk and benefit. The true incidence and associated harms of deep venous thrombosis and pulmonary embolus among CRASH-2 patients is unknown because most patients were not investigated with Doppler ultrasound scanning or computed tomography. Furthermore, many advanced trauma systems are used to treat patients who are older than most of those in the CRASH-2 trial. The interaction of tranexamic acid with age related comorbidities, pharmacotherapy, and risk of thrombotic complications in trauma is not fully understood.

Lack of certainty around these interactions and how they play out in different systems provides an opportunity to further investigate the effects of tranexamic acid on the biology of injury. However, concerns about external validity and limited understanding of mechanism in trauma should not prevent administration of tranexamic acid to patients similar to those in the CRASH-2 trial. The intervention is cheap, easily administered, and one of very few to be shown to reduce mortality in trauma patients.

How should we change our practice?

Administer tranexamic acid 1g intravenously in 100 mL normal saline over 10 minutes then 1 g over eight hours, starting as early as possible and no later than three hours after injury, to trauma patients who have or are at risk of major haemorrhage. Prehospital services with capacity for drug administration should consider incorporating its administration into protocols for trauma care. Do all other usual assessment and management.

Given some concerns about the generalisability of the CRASH-2 results to highly developed trauma systems, and possible unexplained harm when tranexamic acid is given more than three hours after injury, results in different contexts should be monitored. This should include appropriate screening for vascular occlusive events and vigilance for unanticipated adverse effects. Where there is capacity and sufficient clinical equipoise, confirmatory clinical trials are warranted.