By Alexander E. Merkler, MD
Assistant Professor of Neurology and Neuroscience, Weill Cornell Medical College, and Assistant Attending Neurologist, New York-Presbyterian Hospital
Dr. Merkler reports he receives grant/research support from the American Heart Association and is a consultant for Medicolegal.
SYNOPSIS: In this randomized, placebo-controlled trial using tranexamic acid to treat patients with moderate or severe traumatic brain injury within two hours of injury, there was no significant difference between treatment groups in either mortality or functional recovery at six months.
SOURCE: Rowell SE, Meier EN, McKnight B, et al. Effect of out-of-hospital tranexamic acid vs placebo on 6-month functional neurologic outcomes in patients with moderate or severe traumatic brain injury. JAMA 2020;324:961-974.
Traumatic brain injury (TBI) is common. Worldwide, 27 million people sustained a TBI in 2016 and there were 288,000 TBI-related hospitalizations in the United States alone.1,2 In addition, more than 3 million Americans live with disability related to TBI.3 Current treatment of acute TBI includes supportive medical management and surgery, yet there are no available medications proven to treat TBI.
Tranexamic acid prevents clot breakdown by inhibiting plasminogen and plasmin. In the randomized clinical trial CRASH-2, tranexamic acid improved survival in patients with severe hemorrhagic shock. Garnering interest from this positive trial, CRASH-3 evaluated the effect of tranexamic acid in more than 12,000 patients with TBI.4 CRASH-3 found that tranexamic acid did not improve mortality from head injury.4 Rowell et al, in this current randomized clinical trial, examined whether tranexamic acid administered within two hours of TBI would result in improved neurological outcomes in patients with moderate or severe TBI. Eligible patients were 15 years of age or older with a Glasgow Coma Scale (GCS) of 3 to 12, at least one reactive pupil, and a systolic blood pressure of at least 90 mmHg. Participants were randomly assigned to one of three treatment groups: 1) out-of-hospital tranexamic bolus with in-hospital tranexamic infusion; 2) out-of-hospital tranexamic bolus with placebo infusion; or 3) out-of-hospital placebo bolus with placebo infusion. Because of concerns with study power, the two tranexamic treatment groups were combined in the analyses. The primary outcome was a favorable functional neurological outcome at six months after injury, defined as a Glasgow Outcome Scale-Extended (GOSE) of > 4.
Nine hundred sixty-six participants were enrolled and included in the analysis. The median age ranged from 36 to 40 years in the treatment groups; 73% to 85% of the participants were men; the median GCS was 7.6 to 7.8; and 48% to 54% needed an out-of-hospital advanced airway. Intracranial hemorrhage was present on the initial brain imaging in 57% to 59% of participants. There was no difference in the primary outcome; a good functional outcome was present in 65% of participants who received tranexamic acid vs. 62% of those who received placebo. Similarly, there was no statistical difference in mortality (14% in the tranexamic group vs. 17% in the placebo group). In addition, among participants with multiple brain imaging, there was no significant difference in progression of intracranial hemorrhage in participants who received tranexamic vs. placebo.
There now are two randomized clinical trials showing no benefit of early tranexamic acid for moderate to severe TBI. Both trials found that tranexamic did not improve survival at 28 days in patients with moderate to severe TBI. Although this trial did not examine patients with less severe injuries, in the subgroup of participants with mild and moderate TBI in CRASH-3, there was an improvement in mortality (risk ratio 0.78). This trial underscores the importance of patient selection — 20% of patients had a GCS of 13 or higher on admission, less than 60% had evidence of hemorrhage on initial brain imaging, and 15% of participants were lost to follow-up. These factors may have led to inaccurate findings. Future studies should evaluate alternative therapies aimed at improving neurological outcomes in patients with TBI, and improved patient selection will be critical. In conclusion, two randomized clinical trials have failed to show a benefit of early tranexamic acid in patients with moderate or severe TBI.
- GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019;18;459-480.
- Peterson AB, Xu L, Daugherty J, Breiding MJ. Surveillance Report of Traumatic Brain Injury-related Emergency Department Visits, Hospitalizations, and Deaths, United States, 2014. Centers for Disease Control and Prevention. https://www.cdc.gov/traumaticbraininjury/pdf/TBI-Surveillance-Report-508.pdf
- Zaloshnja E, Miller T, Langloi JA, Selassie AW. Prevalence of long-term disability from traumatic brain injury in the civilian population of the United States, 2005. J Head Trauma Rehabil 2008;23:394-400.
- 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 randomized, placebo-controlled trial. Lancet 2019;394:1713-1723.