Tranexamic Acid Linked to Increased Mortality Risk in Severe TBI

Erik Greb

December 16, 2020

Patients with isolated severe traumatic brain injury (TBI) often receive prophylactic tranexamic acid before hospitalization to mitigate bleeding risk, but new results suggest the agent is linked to an increased mortality risk in these patients.

Dr Patrick Schober

"Our study is the first to show that prehospital use of tranexamic acid is associated with increased mortality in patients with isolated severe TBI, suggesting that tranexamic acid should be used judiciously when no evidence for extracranial hemorrhage is present," study investigator Patrick Schober, MD, PhD, an anesthesiologist at Amsterdam University Medical Center, Amsterdam, the Netherlands, told Medscape Medical News.

The study was published online December 7 in JAMA Neurology.

BRAIN-PROTECT Study

Severe TBI is associated with incident intracranial hemorrhage. Bleeding, in turn, is associated with mortality and worse outcomes for patients with severe TBI. Research has shown that tranexamic acid, an antifibrinolytic agent, stops bleeding and decreases mortality for patients with severe hemorrhage.

However, the agent's effect on outcomes of patients with TBI is uncertain. In the recent CRASH-3 trial, in-hospital administration of the drug did not affect mortality.

Similarly, another recent study found that for a heterogeneous patient cohort, prehospital treatment with tranexamic acid had no effect on mortality or neurologic outcome. Neither trial definitively revealed the effect of treatment of patients with severe isolated TBI.

To learn more, Schober's team analyzed prospective data from the Brain Injury: Prehospital Registry of Outcome, Treatments, and Epidemiology of Cerebral Trauma (BRAIN-PROTECT) study. This study included patients suspected of having severe TBI who underwent treatment at one of four Dutch helicopter emergency medical services between February 2012 and December 2017. Patients were followed up in nine participating trauma centers, and in-hospital data were gathered up to 1 year after study inclusion.

The data gathered in BRAIN-PROTECT included patient characteristics, trauma characteristics, injuries, vital signs, prehospital treatments, and interventions.

The study's primary endpoint was mortality at 30 days. Mortality at 1 year, length of hospital stay, and functional neurologic outcome at discharge, as measured by the Glasgow Outcome Scale, were secondary outcome measures.

The investigators conducted unadjusted and adjusted logistic regression analyses to examine the association between tranexamic acid and mortality at 30 days. The adjusted analysis included variables such as demographics, preinjury medical condition, and injury characteristics and severity.

For planned subgroup analyses, the investigators stratified patients into groups with confirmed severe TBI and isolated severe TBI. Confirmed TBI was defined as a head Abbreviated Injury Score (AIS) of 3 or higher. Isolated TBI was defined as a head AIS of 3 or higher with neck, spine, thorax, abdomen, extremities, and external AIS of 2 or lower.

Because these scores are assigned post hoc after all relevant information is available, they are "more reliable than clinical examination at the injury site to describe patients as actually having a major TBI or having major extracranial injuries," said Schober.

"The fact that AIS scores are not available at the accident site is of course a limitation, and clinicians instead need to apply best clinical judgment to determine whether a patient likely has relevant extracranial injuries or not," he said.

Avoid Use if Possible

Of 2589 patients, 1827 were included in the analysis. Approximately 70% of patients were male, and the median age was 45 years. The investigators categorized 1375 patients as having confirmed TBI and 719 patients as having isolated TBI.

In all, 693 patients (38%) received prehospital tranexamic acid. Most of them (90%) received a dose of 1 g. Four patients (1%) received more than 2 g. Of the 27 patients who received a dose of less than 1 g, 18 (67%) were children.

Those who received prehospital tranexamic acid were older and their injuries were more severe than the injuries of the patients who did not receive the treatment. In addition, in the patients who received prehospital tranexamic acid, heart rates on presentation were higher.

In the unadjusted analysis, the 30-day mortality rate was significantly higher among patients who received tranexamic acid than among those who did not receive it (odds ratio [OR], 1.34). Receiving tranexamic acid also was associated with increased 30-day mortality among patients with confirmed TBI (OR, 1.34) and patients with isolated TBI (OR, 1.74).

After adjusting the data for potential confounders, the investigators found no evidence of increased mortality in the full population and in patients with confirmed TBI. However, for patients with isolated TBI, the odds of 30-day mortality were higher (OR, 4.49). In an analysis using multiple imputations, the researchers again found increased mortality after tranexamic acid administration among patients with isolated TBI (OR, 2.05).

In the unadjusted analysis, among patients in the full population who received tranexamic acid, 1-year mortality was higher (OR, 1.29), Glasgow Outcome Scale scores at discharge were lower (OR, 0.70), and hospital stays were longer (incidence rate ratio, 1.17).

In the adjusted analysis, the significant increase in 1-year mortality persisted in those with isolated TBI who received tranexamic acid (OR, 3.31).

"In the absence of any other data that would support the use of tranexamic acid in [patients with isolated severe TBI], we recommend that tranexamic acid should be avoided when best clinical judgment suggests that a patient has severe TBI without any relevant extracranial injuries," said Schober.

He noted that his team is currently investigating the relationship between other prehospital treatments and outcomes for patients with severe TBI.

Biomarkers Needed

Commenting on the findings for Medscape Medical News, Ramon Diaz-Arrastia, MD, PhD, professor of neurology and director of the Clinical TBI Research Center at the University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, said the study's findings are largely consistent with the recent literature.

Dr Ramon Diaz-Arrastia

"Despite the first-blush impression, the findings are actually comparable to the CRASH-3 study," he said.

The most notable finding of CRASH-3 was the reduction in head injury–related death among patients with mild to moderate TBI who were treated with tranexamic acid but not among patients with severe TBI.

The finding resulted from a post hoc analysis, and head injury–related death was assessed by the responsible clinician, which is problematic, said Diaz-Arrastia. Moreover, "the CRASH investigators did not report all-cause mortality, which would have been more rigorous," he added.

In a reanalysis of CRASH-3 data, investigators found a statistically significant increase in combined fatal stroke, myocardial infarction, and pulmonary embolism among patients treated with tranexamic acid. These outcomes are expected adverse effects of this therapy, said Diaz-Arrastia.

"By inhibiting plasminogen activation, tranexamic acid can promote inappropriate thomboembolism, as well as localized thrombosis," he added. TBI results in a coagulopathy that includes excessive bleeding and excessive thrombosis. The latter condition may influence the clinical outcome in cases in which hemorrhagic shock and exsanguination are not dominant.

"Large trials published over the past 2 years provide an excellent evidence base for the use of tranexamic acid in TBI," said Diaz-Arrastia. When the treatment is used in accordance with guidelines, it does not appear that the neurologic risk offsets the clear benefits of managing extracranial hemorrhage, he added. "But there is no indication of any benefit of tranexamic acid in isolated TBI, and certainly there is the suggestion from the Bossers et al registry study that it could have a negative effect, particularly in severe TBI."

In future investigations, researchers should seek imaging or molecular biomarkers that would identify patients at particular risk for progression of intracranial hemorrhage or for cerebrovascular thrombosis, said Diaz-Arrastia. Such biomarkers "would allow targeted therapy aimed at the primary disturbance in particular patients."

The study was funded by a grant from the Dutch Brain Foundation and a grant from the Achmea Healthcare Foundation. Schober received grants from the Dutch Brain Foundation and Achmea Healthcare Foundation while conducting the study. Diaz-Arrastia has disclosed no relevant financial relationships.

JAMA Neurol. Published online December 7, 2020. Abstract

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