But further study in subgroups may be warranted

Administering the anti-fibrinolytic agent tranexamic acid before traumatic brain injury patients reach the hospital did not improve 6-month outcomes in patients with moderate-to-severe TBI compared with placebo, the phase II Prehospital TXA for TBI trial found.

The primary outcome of achieving a 6-month moderate or less disability on the Glasgow Outcome Scale-Extended was seen in 65% of treatment groups versus 62% for placebo, reported Susan Rowell, MD, MBA, of the Duke University in Durham, North Carolina, and coauthors in JAMA. The difference was not significant.

A nonsignificant absolute difference also was seen in 28-day mortality (14% for the treatment groups vs 17% for placebo; adjusted difference, −2.9%, 95% CI −7.9% to 2.1%).

The study defined three groups based on out-of-hospital treatment (begun within 2 hours of injury) and in-hospital treatment:

  • Out-of-hospital tranexamic acid (1 g) bolus and in-hospital tranexamic acid (1 g) 8-hour infusion (maintenance group; n = 312).
  • Out-of-hospital tranexamic acid (2 g) bolus and in-hospital placebo 8-hour infusion (bolus-only group; n = 345).
  • Placebo infusions out of and in the hospital (n=309).

Although patients in the bolus-only group were more likely to have seizures (5% in the bolus-only group, vs 2% in the maintenance group, vs 2% for placebo), other adverse events including thrombotic events were not significantly different.

“These findings, combined with those of previous studies, provide no definitive evidence to support the routine use of out-of-hospital tranexamic acid for patients with moderate or severe TBI,” wrote David Cone, MD, of Yale University, and coauthors, in an accompanying editorial.

“However, given the clear need to find treatments that improve TBI outcomes, these results provide support for a large effectiveness trial with optimized dosing protocols, a mortality end point, and specific focus on the TBI severity cohorts that are most likely to benefit,” they added.

Many patients unlikely to benefit from the treatment were treated — those who had no or minimal brain injury and those with non-survivable injury, together accounting for 43% of the overall population, they suggested. “These factors might easily have limited the ability to identify cohorts that may have benefited from tranexamic acid but were included in an overall group that included many who could not benefit,” they wrote.

Tranexamic acid is a hemostatic agent used in a range of obstetric, surgical, and other medical settings. The synthetic lysine analog prevents plasminogen from binding to fibrin, and at higher doses inhibits plasmin directly, thus inhibiting plasmin-mediated fibrin cleavage and reducing hemorrhage risk. Adverse effects include thrombotic events, gastrointestinal disturbance, infusion-related hypotension, and seizure.

CRASH2, a 2013 trial in elective surgery patients, suggested the reduced all cause death at 28 days noted with tranexamic acid might be limited to treatment within 3 hours of injury.

CRASH3, published in 2019, focused on tranexamic acid in traumatic brain injury, including adults within 3 hours of injury, a Glasgow Coma Scale score of 12 or lower indicating moderate to severe injury, or any intracranial bleeding on CT scan. Head injury-related death was not different for 12,737 in the active treatment group (18.5%) versus 6,406 receiving placebo (19.8%). CRASH3 subgroup analyses, though, suggested benefit when excluding participants with a GCS score of 3 or bilateral unreactive pupils (risk of head injury-related death 12.5% in the tranexamic acid group vs 14.0% in the placebo group; RR 0.89), as well as benefit for mild-to-moderate but not severe head injury.

“Subgroup findings from the CRASH-3 study have led to implementation of tranexamic acid for patients who have intracranial hemorrhage on initial computed tomographic scan, with ongoing debate about out-of hospital use,” the editorialists noted.

In the Prehospital TXA for TBI study, Rowell and colleagues included participants with out-of-hospital moderate or severe TBI age 15 or older, between May 2015 and November 2017. Participants had a GCS score of 12 or lower and systolic blood pressure of 90 mm Hg or higher. Mean age was 42, 74% were male, and mean initial GCS score was about 8.

Median time from injury to out-of-hospital study drug administration ranged from 40 to 43 minutes, and initial CT imaging showed intracranial hemorrhage in 57-59% across groups. Thrombotic events were seen in 9% of the bolus group, 4% of the maintenance group, and 10% for placebo.

“When the condition being managed is common and the intervention is relatively inexpensive and safe, the minimal clinically important difference is small,” the editorialists observed. “For head injury, a 1% difference could possibly decrease mortality by approximately 560 deaths per year in the U.S., based on an estimated 56,000 TBI-related deaths each year in the U.S. If, on the other hand, the absolute [2.9%] reduction detected in this study is real, use of tranexamic acid could possibly reduce all-cause mortality by more than 1,600 annually.” they wrote.

“A public and professional consensus on the minimal clinically important difference, informed by health economic modeling, is required to balance the benefit of saving these lives against both the cost of delivering the intervention and the cost of the very large trials required to prove effectiveness,” they added.

Limitations of the trial include a dichotomized use of the ordinal Glasgow Outcome Scale-Extended, which may discard relevant information. In addition, survival bias may have affected results, and 15% of patients were lost to 6-month follow-up.

  1. Administering the anti-fibrinolytic agent tranexamic acid out of the hospital did not change 6-month outcomes in patients with moderate-to-severe traumatic brain injury (TBI) compared with placebo, a phase II study found.

  2. Despite this, the results support a large effectiveness trial with optimized dosing protocols, a mortality end point, and specific focus on TBI severity cohorts most likely to benefit, the editorialists maintained.

Paul Smyth, MD, Contributing Writer, BreakingMED™

The Resuscitation Outcomes Consortium institutions participating in the trial were supported by a series of cooperative agreements from the National Heart, Lung and Blood Institute administered by the U.S. Army Medical Research & Material Command.

Rowell reported receiving grants from the US Department of Defense and the National Institutes of Health during the conduct of the study and personal fees from Portola Pharmaceuticals outside the submitted work.

Cone reported no disclosures.

Cat ID: 474

Topic ID: 82,474,730,474,192,925