Effect of Out-of-Hospital Tranexamic Acid vs. Placebo on 6-Month Functional Neurologic Outcomes in Patients With Moderate or Severe Traumatic Brain Injury.
Authors: Rowell SE, Meier EN, McKnight B, et al.
Published in: JAMA, 2020 Sep 8; 324(10): 961–74. Erratum in: JAMA, 2020 Oct 27; 324(16): 1,683.
Over the last decade, the use of tranexamic acid (TXA) for traumatic hemorrhage control has increased. This was due to the results of a clinical trial, published in 2010, that found early administration of TXA was a cost-effective way to reduce the risk of death in bleeding trauma patients.
Further research has shown that TXA is safe for patients with traumatic brain injury (TBI). In this month’s Journal Watch, we review a randomized, double-blind multicenter trial designed to examine the efficacy and safety of out-of-hospital administration of tranexamic acid compared to placebo in participants with moderate or severe TBI who were not in shock.
The objective of this trial was to determine whether TXA administered by EMS within two hours of injury improved neurologic outcome. Read that objective carefully—it will be important when putting the results of this trial into context.
Neurologic outcome was measured using the Glasgow Outcome Score-Extended (GOSE). The authors chose to dichotomize this scale into “favorable” (which included moderate disability or good recovery) and “poor” (which included severe disability, vegetative state, or death) outcomes.
The authors also examined many secondary outcomes, including 28-day mortality, six-month disability, progression of intracranial hemorrhage, incidence of neurosurgical interventions, hospital-free days, ICU-free days, incidence of seizures, and incidence of thrombotic events, to name a few.
The study was conducted in 12 regions across the U.S. and Canada. It included 39 EMS agencies and 20 trauma centers. To be eligible for enrollment in this trial, patients had to be at least 15 years of age, with moderate or severe blunt or penetrating TBI, a GCS score of 3 to 12, at least one reactive pupil, a systolic blood pressure of at least 90 mm Hg, and an IV in place prior to randomization.
Participants were randomized into one of three treatment groups. The first received a 1-gram IV bolus of TXA by EMS followed by a gram of in-hospital TXA infused over eight hours. The next group received a 2-gram TXA bolus by EMS followed by a placebo infusion. The final group received an IV bolus placebo by EMS and a placebo infusion in the hospital. Study kits that appeared identical were shipped to participating EMS agencies for placement on EMS vehicles in random order. Each vehicle only carried one study kit at a time.
The study was conducted between May 2015 and March 2017 under U.S. regulations for exception from informed consent and the Canadian tricouncil policy statement on ethical conduct in research involving humans.
There were 966 patients included in the analysis. Their average age was 42, and almost three-quarters (74%) were male. The average GCS score was 8. The three study groups were similar when comparing demographics and baseline anatomic and physiologic characteristics as well as injury severity. However, the authors note there were fewer penetrating injuries in the bolus-only group.
The median estimated time from injury to EMS administration of the study drug ranged from 40 to 43 minutes. The median time from EMS administration to the start of the in-hospital infusion ranged from 86 to 96 minutes.
The evaluation of the primary study outcome, favorable or poor neurologic function, revealed no statistically significant difference when comparing TXA to placebo (65% vs. 62%, p=0.16). Therefore, the conclusion of this study was that “among patients with moderate or severe TBI, out-of-hospital tranexamic acid administration within two hours of injury did not improve six-month neurologic outcome as measured by the GOSE.”
However, as we discuss often in this column, we should not let statistical significance alone guide our judgment of importance. There was a 3% difference in favorable neurologic outcome. While that difference may not be statistically significant, could it be clinically meaningful?
Now, rather than simply read the objective and conclusion of this paper, let’s dive a little deeper. As mentioned earlier, the authors also examined several secondary outcomes. When evaluating 28-day mortality, the TXA groups showed a 3% improvement (14% vs. 17%). This result was also not statistically significant, with a p-value of 0.26.
There was also an 8% difference in 28-day mortality when comparing the bolus-only group to the placebo group for those patients with intracranial hemorrhage. This difference was statistically significant (p=0.03). The total number of adverse events was also similar between groups.
Why would the authors report such a cut-and-dried conclusion when there seems to be a trend favoring the use of TXA? Well, the authors indicate in their methods section that the study was specifically designed to evaluate neurologic outcomes at six months. This was specified in the original trial registry on ClinicalTrials.gov. The authors had to stick to the primary outcome that was specified prior to the beginning of trial enrollment for the resulting manuscript.
However, the authors are clear that we should carefully interpret their findings. They state in their discussion that “despite no statistically significant difference in the primary outcome in either trial, there were important differences and findings from both trials that warrant consideration and future investigation.”
In other words, the results seem to be trending in a favorable direction when EMS administers TXA early. So, rather than to simply conclude from these findings that TXA is not effective in the treatment of TBI, an important next step would be to design studies that specifically evaluate outcomes other than the dichotomous GOSE score at six months.
As with all studies there are limitations here. There were some difficulties in obtaining follow-up data six months after the injury. This is not surprising, given that patients were enrolled prior to giving consent. There was also a low percentage of patients with intracranial hemorrhage enrolled in the study. This may have diluted the treatment differences.
This was a very well done study that will lead to further analysis of TXA administration. It is also a great example of how we should avoid letting a p-value alone guide our judgment of importance.
I hope you have an opportunity to read the manuscript yourself. There are many other interesting results that could not fit into this month’s Journal Watch. And, as always, I hope to review your study in an upcoming edition soon.
Antonio R. Fernandez, PhD, NRP, FAHA, is a research scientist at ESO and an assistant professor in the department of emergency medicine at the University of North Carolina–Chapel Hill. He is on the board of advisors of the Prehospital Care Research Forum at UCLA.