Studies examining the use of tranexamic acid (TXA) inescapably seem to pit our methodological rigorous demons against our practical clinical angels.
The CRASH-2 trial published in the Lancet in 2010 by Shakur et al, randomized 20,211 adult trauma patients presenting to 274 hospitals in 40 different countries to receive 1g of TXA over 10 min and an infusion of an additional 1g over 8 hours, or matching placebo. In this massive trial the authors found a 1.5% absolute difference in their primary outcome, in-hospital mortality at 28-days. But questions regarding the trial’s external validity arose, as many of the sites enrolling patients in this trial, did not have modern trauma systems. Do the benefits of TXA remain if hemorrhage control is achieved rapidly? Nine years following the publication of CRASH-2 this question remains unanswered. CRASH-2 was a massive undertaking, one which we are unlikely to see validated in a modern trauma system. We are tasked with deciding whether to accept the benefits observed in CRASH-2, or if the methodological shortcomings invalidate its findings.
The WOMAN trial, published in the Lancet in 2017 by Shakur et al, was the next mega trial examining the use of TXA in postpartum hemorrhage. The authors included 20,060 women diagnosed clinically with postpartum hemorrhage, randomized to TXA or placebo. In this case, the authors reported no difference in their primary outcome, death within 42 days or hysterectomy (TXA 5.3% vs. placebo 5.5%). Nor did they find a difference in all-cause mortality. However, they did note a statistically significant difference in death due to postpartum hemorrhage, 1.5% in the TXA group vs 1.9% in the placebo group (p = 0.045).
TXA may be efficacious in postpartum hemorrhage, but the signal of benefit was diluted in this cohort due to the low severity of illness. On the other hand, a trial of 20,000 patients with a negative primary outcome and no change in all-cause mortality is about as negative study as you can get.
Similar to CRASH-2, the WOMAN trial is a massive study. Despite its size and quality we are left without a convincing answer. We would like to know the efficacy of TXA in the subset of patients with serious bleeding. Unfortunately, the authors do not present a subgroup analysis examining the patients with major bleeding. When faced with a patient dying from postpartum hemorrhage many will still give TXA despite these negative results.
This brings us to the publication of CRASH-3 in the Lancet in 2019 (3). The authors enrolled adult patients with TBI, within 3 hours of injury, with a GCS ≤ 12 or any intracranial bleeding on CT scan, without signs of major extracranial hemorrhage. The patients were randomized to receive 1g of TXA over 10 min, followed by an infusion of an additional 1g over the next 8 hours or matching placebo.
From July 2012 to January 2019 in 175 hospitals in 29 countries, the authors enrolled a total of 12,737 patients, 6406 (50.3%) to the TXA arm and 6331 (49.7%) to the placebo arm. 9202 (72.2%) patients were treated within 3 hours of injury.
Similar to The WOMAN trial the authors reported no difference in their primary outcome, the rate of head injury related death in hospital within 28 days of injury, 18.5% in the TXA group vs 19.8% in the placebo group (RR 0.94 [95% CI 0.86–1.02]). But once again, the authors present us with a caveat. In the subset of patient which excluded those with devastating neurological injury (patients with a GCS score of 3, or bilateral unreactive pupils at baseline), the authors noted a statistically significant 1.5% absolute reduction in head injury-related death (12.5% in the TXA group vs 14.0% in the placebo group). This reduction did not translate into a difference in all-cause mortality at 28 days or functional status at follow-up, both of which were similar in the TXA and placebo groups.
Despite a massive well done RCT, we are left with a sense of dissatisfaction. There may be a signal of benefit for TXA in the subset of patients with survivable head injury, but at best it is small and does not translate into true patient important outcomes of all-cause mortality or disability. Like CRASH-2 and the WOMAN trial, it is unlikely that efforts to replicate these findings will be conducted in the near future. We are tasked with how to apply this evidence to our clinical practice. The next time a patient presents to the ED with a TBI, should we administer TXA? That of course is a choice each of us has to make individually. Given nominal benefit observed in CRASH-3, we should not make the mistake of prioritizing its administration above other more important, more efficacious interventions.
For additional insight check out:
Josh's take over at PulmCrit
SGEM's Skeptical take
The Rebel's critique
And St Emlyns thoughts
- Shakur H, Roberts I, Bautista R, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376(9734):23-32.
- Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389(10084):2105-2116.
- The CRASH-3 trial collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial.Lancet. 2019