Effect of out-of-hospital tranexamic acid vs placebo on 6-month functional neurologic outcomes in patients with moderate or severe traumatic brain injury
Rowell SE, Meier EN, McKnight B, et al. JAMA. 2020;324(10):961-974.
Tranexamic acid (TXA) decreases bleeding by inhibiting the breakdown of fibrin blood clots; therefore, it could theoretically help prevent or decrease hemorrhage expansion in patients with intracerebral hemorrhage.
With TXA, earlier administration is generally believed to be better. In this trial, the authors examine the value of TXA administered within 2 hours of injury on 6-month neurologic outcomes in patients with moderate or severe traumatic brain injury (TBI).
This was a 3-arm trial with patients randomized to receive an out-of-hospital TXA 1-g IV bolus and an in-hospital TXA 1-g 8-hour infusion (bolus + maintenance); an out-of-hospital tranexamic acid 2-g IV bolus and in-hospital placebo 8-hour infusion (bolus only); or an out-of-hospital placebo bolus and an in-hospital placebo 8-hour infusion (placebo).
The target population for the trial was patients 15 years or older with moderate or severe blunt or penetrating TBI, a Glasgow Coma Scale (GCS) score of 3-12, at least 1 reactive pupil, and a systolic blood pressure of at least 90 mm Hg before randomization.
The primary outcome was the functional neurologic outcome at 6 months after injury, on the basis of the Glasgow Outcome Scale-Extended (GOSE), dichotomized into favorable (GOSE score >4, indicating moderate disability or good recovery) or poor (GOSE score ≤4, indicating severe disability, vegetative state, or death) outcomes.
The study examined many secondary outcomes, including 28-day mortality, progression of intracranial hemorrhage and ICU course.
The authors planned to examine the 2 TXA groups separately but, because of power concerns, ultimately combined the groups and compared them with the placebo group.
Over 2 years, 966 patients were randomized and analyzed. The characteristics were similar across groups: most patients were male and approximately 40 years old, almost 100% had blunt injury, the median Injury Severity Score was 17, and the mean GCS score was 8.
A 6-month follow-up was completed on 84.8% of the sample.
Good neurologic outcomes were seen in 65% of patients in the TXA groups vs 62% in the placebo group; no statistically significant differences were observed in the 28-day mortality (14% TXA vs 17% placebo, 6-month Disability Rating Scale score (6.8 vs 7.6), or progression of intracranial hemorrhage (16% vs 20%).
In terms of safety, thrombotic events were more frequently observed in the bolus-only (9%) and placebo (10%) groups than in the bolus + maintenance group (4%).
The use of a large single bolus is a unique aspect of this trial. Although there was no clear indication that this treatment improved outcomes, a signal of increased harm in the form of seizures (5% vs 2%) was found.
This article has multiple limitations, including that 20% of the enrolled patients had a GCS score ≥13 in the ED and therefore would not have been considered TXA candidates by most providers, and that this trial enrolled patients with TBI in the prehospital setting before a CT and consequently administered TXA to many patients who had no potential for benefit with either no/minimal brain injury or nonsurvivable injury (43%).
EDITOR’S COMMENTARY: In this RCT, the authors try to maximize the benefit of early TXA administration in patients with TBI by randomizing patients in the prehospital setting and administering TXA around the 40-minute mark after injury. Similarly to the CRASH-3 study, this study did not find a statistically significant benefit for all comers, but some methodological issues make me wonder if the small effect they saw would be more robust in a larger trial. I think TXA is safe and may have benefits in some patients with intracranial hemorrhage. We just need to figure out which exactly which subgroups will actually see this benefit.
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