Prehospital Tranexamic Acid Won’t Stave Off Disability After Severe Trauma

Initiated before hospital admission in advanced trauma systems, tranexamic acid provided an early survival benefit that ultimately failed to translate into favorable 6-month outcomes in the PATCH-Trauma trial.

Among people with severe trauma at risk for trauma-induced coagulopathy, the odds of survival with a favorable functional outcome at 6 months after injury were 53.7% with early tranexamic acid administration and a near-identical 53.5% with placebo (RR 1.00, 95% CI 0.90-1.12), reported Russell Gruen, MBBS, PhD, of the Australian National University in Canberra, and colleagues.

Yet there was a brief window in which a between-group mortality difference favoring the tranexamic acid group was evident before narrowing to insignificance by 6 months:

• Mortality at 28 days: 17.3% vs 21.8% (RR 0.79, 95% CI 0.63-0.99)
• Mortality at 6 months: 19% vs 22.9% (RR 0.83, 95% CI 0.67-1.03)

“Our data do not preclude the possibility that tranexamic acid can prevent early death from bleeding in some patients who will go on to make a good recovery,” the investigators wrote in the New England Journal of Medicine.

“However, because we did not find evidence of a between-group difference in subgroups according to age, mechanism of injury, systolic blood pressure, score on the Glasgow Coma Scale, or time to first dose of tranexamic acid or placebo, our findings do not provide a basis for identifying such patients in the prehospital setting,” they said.

Tranexamic acid is an antifibrinolytic FDA approved for heavy menstrual bleeding and short-term prevention in patients with hemophilia. However, it is often used off-label to improve clotting in trauma and surgery.

In the trauma setting, tranexamic acid is supported by the CRASH-2 trial showing reduce 28-day mortality among recipients with suspected bleeding when the drug had been administered within 3 hours after injury. Years later, CRASH-3 found that tranexamic acid initiated in the hospital reduced mortality in mild-to-moderate traumatic brain injury, but not severe traumatic brain injury.

Both trials had been conducted mostly in countries lacking organized region-wide systems of trauma care, however. Subsequent trials in settings with advanced trauma systems did not find clinical benefits to prehospital tranexamic acid therapy.

Even now, PATCH-Trauma should not close the door on such a benefit, suggested CRASH-3 investigators Haleema Shakur‑Still, MSc, and Ian Roberts, MD, PhD, both of the London School of Hygiene and Tropical Medicine’s Clinical Trials Unit.

In an accompanying editorial, the pair highlighted the observation that more patients in the tranexamic acid group survived but were more likely to have severe disability compared with controls in the present trial.

“A patient with an exsanguinating pelvic injury who survives because of tranexamic acid treatment still has a potentially disabling pelvic injury,” the editorialists wrote. Shakur-Still shared her personal experience recovering fully 2 years after a severe traumatic brain injury and hemorrhage.

“The PATCH-Trauma trial helps to move trauma investigation beyond the consideration of survival alone. We want patients to survive and recover fully. But is less than full recovery at 6 months or even longer without value? It is hard to imagine that doctors or paramedics would withhold a treatment that saves lives in the short-term because survivors may be severely disabled at 6 months,” according to Shakur-Still and Roberts.

The PATCH-Trauma trial enlisted 15 participating emergency medical services and 21 hospitals in Australia, New Zealand, and Germany. Trauma patients, enrolled from 2014 to 2021, were eligible if the first dose of tranexamic acid or placebo could be administered within 3 hours after injury and before hospital admission.

Included were 1,310 trauma patients at risk for trauma-induced coagulopathy (mean age 44 years, 70% men). The cohort was randomly split into groups receiving tranexamic acid (administered prehospital as one IV bolus of 1 g, followed by a 1-g infusion over 8 hours at the hospital) or matched placebo.

For the primary analysis, assessment of functional outcome was conducted using a standardized questionnaire by trained telephone interviewers. Scores 5 (lower moderate disability) and higher counted as favorable outcomes on the Glasgow Outcome Scale-Extended, ranging from 1 (death) to 8 (no injury-related problems).

Unlike a previous trial showing a dose-dependent increase in thromboembolism with tranexamic acid therapy, PATCH-Trauma showed no increase in deep venous thrombosis in patients’ legs.

The incidence of vascular occlusive events trended toward a disadvantage for the tranexamic acid group (23.6% vs 19.7%; RR 1.20, 95% CI 0.97-1.48). Other serious adverse events were comparable between groups.

Importantly, the trial logged protocol violations in 35% of the group and lacked primary outcome data for 13%, mostly due to loss to follow-up.

“Although such problems are a reality of the challenges posed by research ‘in the field,’ they can bias the observed treatment effects toward the null,” Shakur-Still and Roberts wrote in defense of tranexamic acid.

One’s level of disability after surviving a traumatic incident can also change over time, perhaps improving with effective rehabilitation, they added.

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