Article In Brief
Tranexamic acid, which inhibits the breakdown of blood clots, did not improve survival in patients with severe TBI and worked best in mild and moderate cases when administered within three hours of injury.
Patients with mild to moderate traumatic brain injury (TBI) had a lower risk of head injury-related death when given the anti-bleeding drug, tranexamic acid, according to a large global randomized placebo-controlled trial.
The study found that the drug, which inhibits the breakdown of blood clots, did not improve survival in patients with severe TBI and worked best in mild and moderate cases if administered within three hours of injury. In that subset of TBI patients, the risk of head injury-related death was 22 percent lower in patients who received tranexamic acid compared with those who received placebo, although in the overall cohort there was little survival difference between the two groups.
The study, known as CRASH-3, was published in the October 14 online edition of the Lancet along with an editorial predicting that the findings “will change practice, and tranexamic acid will benefit future patients with TBI who might reasonably have a chance of recovery from their injuries.”
Ian Roberts, MD, PhD, professor of clinical trials at the London School of Hygiene & Tropical Medicine, who co-led the study, told Neurology Today that he thought the new study results, coupled with results from previous studies involving tranexamic acid, warrant its use in TBI treatment.
“This is a matter for judgment, but since there was no evidence of harm, I would give it to all trauma patients and as soon as possible,” Dr. Roberts said in an email interview.
Tranexamic acid “reduces bleeding by inhibiting the enzymatic breakdown of fibrin blood clots (fibrinolysis),” the paper said. It noted that a prior study known as CRASH-2 “showed that in patients with trauma with major extracranial bleeding, early administration (within three hours of injury) of tranexamic acid reduces bleeding deaths by a third.” The paper said those results has led to the use of the drug in pre-hospital trauma care, but not for TBI.
Several outside experts who were interviewed by Neurology Today, however, were much less enthused about the findings and said the results weren't convincing enough at this point to start routinely giving tranexamic acid to TBI patients.
“I don't think this trial alone will be able to change practice guidelines or cause any kind of practice changes,” said Sachin Agarwal, MD, MPH, assistant professor of neurology at Columbia University, though he believes the study raises some hypotheses that merit further exploration.
Worldwide each year there are more than 60 million cases of TBI, which can result in life-long disability and death, the study authors pointed out. And intracranial bleeding is a major concern in TBI.
An Ambitious Global Study
To test the drug's worth in treating intracranial bleeding related to TBI, a team of international investigators set up a large study involving 175 hospitals in 29 countries. Between July 2012 and January 2019, 12,737 patients with TBI were assigned to either tranexamic acid—a loading dose of 1 gm over 10 minutes followed by an infusion of 1 gm over eight hours—or a matching placebo. When the study began, the window of eligibility was eight hours from time of injury, but the protocol was changed to three hours based on evidence that emerged from research outside the trial.
The primary outcome was head injury-related death in the hospital within 28 days of injury. Patients, caregivers and those assessing outcomes did not know whether the patient received the drug or placebo.
The analysis that appears in Lancet was based on 9,202 patients treated within three hours of injury. The participants had to have a Glasgow Coma Scale (GCS) of 12 or lower or any intracranial bleeding on CT scan, and no evidence of major extracranial bleeding.
The study results require careful reading because the data were parsed in multiple ways.
Among patients treated within three hours of injury, the risk of head injury-related death was 18.5 percent for the tranexamic acid group compared with 19.8 percent for the placebo group.
In a prespecified analysis that excluded patients with a GCS score of 3 or bilateral unreactive pupils at baseline, the risk of head injury-related death was 12.5 percent in the tranexamic group compared with 14 percent for the placebo group.
The drug showed no apparent advantage over placebo in reducing the risk of death when it was given to patients with severe TBI. In cases of mild to moderate TMI, the most common type of TBI, the risk for head-injury related death was 5.8 percent for patients who got the drug compared with 7.5 percent for the placebo group, a relative risk reduction of 22 percent, the researchers reported.
The drug appeared to be safe, according to the paper, which reported no differences in vascular occlusion rates or seizures between the two arms of the study, and there was also no difference in measures of disability among the survivors.
“Our results show that tranexamic acid is safe in patients with TBI and that treatment within three hours of injury reduces head injury-related deaths. Patients should be treated as soon as possible after injury,” the researchers reported.
Dr. Roberts noted that tranexamic acid “is cheap, heat stable, and we found no evidence of adverse events.” While the drug is currently given by IV, “If we could give it by intramuscular injection this may be more practical.”
The accompanying editorial noted that “a clot-stabilizing drug such as tranexamic acid might cause an increase in the risk of venous thromboembolism that was not captured in the study.
The study also did include brain scans to determine whether bleeding was contained or prevented in patients who received the drug, which could have shed some light on the drug's action.
The editorial, written by Andrew Cap, MD, PhD, of the U.S. Army Institute of Surgical Research, said “the hard truths of TBI care learned from war and everyday TBI are quite simple and obvious: Control bleeding, and avoid hypotension and hypoxia, or the patient will die,” he wrote. But finding effective interventions has been frustrating, he wrote.
Dr. Cap said in an interview with Neurology Today that tranexamic acid “is the only drug that has shown a mortality benefit in a large randomized, controlled trial.”
Dr. Agarwal, of Columbia, said that as he read the Lancet paper and the way the analysis unfolded (with various groups and subgroups being considered), he felt “there was a big search for some kind of positive results.”
“I see this as a negative trial with some hypothesis-generating results,” he said. For instance, the findings related to mild to moderate TBI warrant additional research, he said.
“It seems like most of the deaths saved by tranexamic acid are within 24 hours. If you are dying from bleeding you are saved, but otherwise this medicine seems to have no effects on the overall physiology of TBI,” Dr. Agarwal said. He also cautioned that it can be hard differentiating the cause of death information in something as complex as TBI and said that using all-cause mortality (not just head injury-related mortality) may have been revealing.
Emily J. Gilmore, MD, associate professor of neurology at Yale Medical School, said, “It was commendable that the researchers conducted such a large randomized controlled study, but the conclusions of the study are strongly worded and not totally reflective of the primary effort.”
Dr. Gilmore said that while some of the subgroup analyses that were done looked promising, she does not anticipate that tranexamic acid will ultimately be a game-changer for TBI care in the US.
“The challenge is we don't have any successful interventions to improve outcomes for TBI,” Dr. Gilmore said. “People want to grasp at anything that seems potentially effective.”
She said the questions that need to be addressed in assessing any TBI intervention are not just “whether it actually improves survival, but does that translate into meaningful functional neurologic recovery?”
Danielle Sandsmark, MD, assistant professor of neurology and neurocritical care at University of Pennsylvania, said: “I do not believe the new findings are persuasive enough at this point to make tranexamic acid treatment a standard part of neurocritical care for TBI patients. A practical issue is that many TBI patients get to the ICU well after the three-hour timeframe in which the drug seemed most beneficial,” she said.
“I think this is probably more helpful to trauma teams. They don't have to be fearful about giving this (the drug) to someone who had head injury,” she said.
Dr. Sandsmark said more needs to be learned about bleeding risk in TBI so that promising interventions can be targeted at the right patients.
“We don't understand enough about who is at highest risk for bleeding, and we need to develop biomarkers to help predict that,” she said.
Dr. Roberts, Gilmore, Agarwal, and Sandsmark disclosed no competing interests.