Drug Delivers 'Remarkable' Reduction in Head Injury Deaths

Early Treatment May Save 'Hundreds of Thousands of Lives Worldwide'

Pauline Anderson

October 16, 2019

Tranexamic acid (TXA) (multiple brands), an antifibrinolytic used to treat or prevent excessive blood loss, significantly reduces mortality from traumatic brain injury (TBI), results of a large, multicenter, randomized control trial show.

Investigators found that administering TXA within 3 hours of head trauma was associated with a 20% reduction in deaths among those with mild to moderate TBI, with no evidence of adverse effects or complications.

However, there was no apparent reduction in mortality among those with severe head injury.

"This is a landmark study. After decades of research and many unsuccessful attempts, this is the first-ever trial to show that a drug can reduce mortality after traumatic brain injury. Not only do we think this could save hundreds of thousands of lives worldwide, but it will no doubt renew the enthusiasm for drug discovery research for this devastating condition," study coinvestigator Antonio Belli, MD, neurosurgeon and professor of trauma neurosurgery, University of Birmingham, United Kingdom, said in a statement.

Results of the CRASH-3 study suggest that "all trauma patients should get tranexamic acid at the scene of the injury or as soon as possible thereafter," study coinvestigator Ian Roberts, MB, professor of epidemiology and public health, London School of Hygiene and Tropical Medicine, told Medscape Medical News.

The study was published online October 14 in the Lancet.

TBI Rising

It is estimated that more than 60 million new cases of TBI occur worldwide every year, and the number is rising. Motor vehicle accidents and falls are the main causes.

Intracranial bleeding is a common complication of TBI. Ongoing intracranial bleeding can lead to an increase in intracranial pressure, as well as brain herniation and death.

TXA reduces bleeding by inhibiting the enzymatic breakdown of fibrin blood clots.

Several studies in surgical patients "show that if you give them tranexamic acid just before the surgeon cuts them, they bleed less than if you give them a placebo," said Roberts.

Research has also shown that TXA reduces risk of bleeding in women with postpartum hemorrhage.

An earlier study ― the CRASH­2 trial ― showed that in patients with trauma and major extracranial bleeding, administration of TXA within 3 hours of injury reduced bleeding deaths by one third. However, even a short delay in treatment led to a reduction in benefit.

On the basis of these results, TXA was included in guidelines for the prehospital care of patients with trauma. However, those with isolated TBI were excluded.

"People wondered whether tranexamic acid would be effective in isolated TBI," said Roberts. "There was no evidence that it's effective in patients with just head injuries."

Injury Severity a Factor

For the study, 12,737 patients from 29 countries were randomly assigned to receive either TXA or matching placebo within 3 hours of TBI.

The primary endpoint was head injury death in hospital within 28 days of injury. There were 2560 deaths; the median time to death was 59 hours after injury.

Researchers had outcome data on 9127 patients. Among these, the risk for head injury–related death was 18.5% among the patients who received TXA and 19.8% among those who received placebo (risk ratio [RR], 0.94; 95% confidence interval [CI], 0.86 – 1.02).

A sensitivity analysis excluded patients whose Glasgow Coma Scale (GCS) score was 3 and those with bilateral unreactive pupils.

"For all intents and purposes, these patients are considered unrecoverable at baseline, so before they even received trial treatment," said Roberts. "They were obviously going to be equally distributed between groups and dilute any treatment effect."

In this sensitivity analysis, the rate of head injury–related death was 12.5% in the TXA group, compared to 14.0% in the placebo group (RR, 0.89; 95% CI, 0.80 – 1.00).

"When we excluded these patients who were unsurvivable before treatment, there was a bigger treatment effect; the benefit was larger," said Roberts.

Although the sensitivity analysis excluded patients with bilateral unreactive pupils, patients with unilateral unreactive pupils were not excluded. "If we had excluded those individuals, the treatment effect would get even bigger," said Roberts.

"The treatment looks very good at preventing head injury deaths where there's a potential for benefit, so in people who are salvageable, it's very effective. But the closer you get to unsalvageable, the less and less effective it gets," he said.

No Adverse Events

With regard to time to treatment, for patients who received the intervention within an hour of injury, the RR of head injury–related death was 0.96 (95% CI, 0.79 – 1.17); for those who received the intervention more than 1 to 3 hours after injury, the RR was 0.93 (95% CI 0.85 to 1.02); and for those who received the intervention more than 3 hours after injury, the RR was 0.94 (95% CI 0.81 to 1.09).

The investigators note that patients who are treated soon after TBI often have more severe trauma, and so the effect of time to treatment may be confounded by injury severity.

After adjusting for GCS, systolic blood pressure, and age, early treatment was more effective than later treatment in patients with mild or moderate head injury (P = .005), but there was no obvious effect of time to treatment among patients with severe head injury (P = .73).

The drug is more effective in less severely injured patients because "you can only prevent something that hasn't already happened," said Roberts.

"It's probably less effective in severely comatose patients because they have already bled into their brain. The most potential for benefit is in patients with mild or moderate head injury who are bleeding more slowly into the brain," he said.

The analysis also showed a substantial reduction in head injury–related deaths within 24 hours of the injury in treated patients.

The findings should make guidelines simpler ― perhaps with the recommendation that all trauma patients receive a 1-g injection of TXA as soon as possible after a head injury, said Roberts. Ideally, treatment should occur at the scene of the accident or in the ambulance on the way to the hospital, he added.

The researchers assessed the effect of TXA on disability in survivors by comparing the mean Disability Rating Scale score between the TXA and placebo groups. The mean scores were similar between groups and for patients treated within 3 hours and after 3 hours of treatment.

The risk for vascular occlusive events and other complications was similar for both groups. There was no evidence that TXA increased fatal or nonfatal stroke. The risk for seizures was similar between groups, as was the number of other adverse events.

"We know this intervention is safe; there are absolutely no side effects whatsoever," said Roberts.

Remarkable, Practice Changing

In an accompanying editorial, Andrew P. Cap, MD, PhD, US Army Institute of Surgical Research, Fort Sam Houston, Texas, described the findings as "remarkable" and said they "will change practice."

It represents "an enormous effort in studying a difficult clinical problem," said Cap.

Together, CRASH-3, CRASH-2, and the trial of women with peripartum hemorrhage involved more than 53,000 patients in the study of the effects of TXA on bleeding.

"The results of each study independently and together are clear: tranexamic acid reduces risk of death due to bleeding, regardless of the cause," he writes.

Future studies might explore the effects of increased TXA doses in bleeding patients, or possibly alternative routes of administration, such as intramuscular administration, which might facilitate earlier intervention, he added.

It may also be worth considering combining the antifibrinolytic effects of TXA on bleeding with blockade of bradykinin receptors, which could reduce brain edema and potentially yield greater reductions in mortality.

Commenting on the study for Medscape Medical News, TBI specialist Frank Conidi, MD, immediate past president, Florida Society of Neurology, and director, Florida Center for Headache and Sports Neurology, said he was "quite impressed" with the number of enrolled patients, which provided "significant power" to the results.

Although it's "wonderful" that the study showed a positive reduction in patient mortality, "the real outcome that you want to look at is disability and quality of life," said Conidi. "From a clinical perspective, I think there is potential for patients with higher GCS scores, especially given the low adverse event profile."

Conidi said he would like to know whether the medication's efficacy differed among patients with different subtypes of bleeding, for example, intracranial hemorrhage, subarachnoid hemorrhage, epidural hematoma, and subdural hematoma.

The study was funded by the JP Moulton Charitable Trust, the National Institute for Health Research Health Technology Assessment, Joint Global Health Trials, the Medical Research Council, the UK Department for International Development, the Global Challenges Research Fund, and the Wellcome Trust. Roberts, Belli, Cap, and Conidi report no relevant financial relationships.

Lancet. Published online October 14, 2019. Full text, Editorial

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