Tranexamic acid scores a hit in TBI

The administration of tranexamic acid within 3 hours of sustaining a traumatic brain injury (TBI) led to a reduction in mortality risk, highlighting the importance of early treatment in this setting, the CRASH*-3 trial has shown.

“Ongoing intracranial bleeding can lead to raised intracranial pressure, brain herniation, and death … [Our findings suggest that] early administration of tranexamic acid in patients with TBI … [reduced] intracranial haemorrhage expansion … thus averting brain herniation and death,” said the researchers.

The effect of tranexamic acid (loading dose of 1 g over 10 minutes followed by an intravenous infusion of 1 g over 8 hours) was compared against placebo in 12,737 adults with TBI. Of these, 72.2 percent received treatment within 3 hours of injury. [Lancet 2019;394:1713-1723]

Among those treated within the 3-hour timeframe, the incidence of head injury-related death within 28 days of injury dropped with tranexamic acid vs placebo (18.5 percent vs 19.8 percent, risk ratio [RR], 0.94, 95 percent confidence interval [CI], 0.86–1.02).

A sensitivity analysis was conducted to exclude patients with a Glasgow Coma Scale score of 3 or bilateral unreactive pupils at baseline. “We anticipated that [this subgroup] would have little potential to benefit from tranexamic acid … [As] most patients with bilateral unreactive pupils already have extensive intracranial haemorrhage and brain herniation … tranexamic acid is unlikely to improve [their] outcome,” explained the researchers.

However, the sensitivity analysis proved otherwise, as it favoured tranexamic acid over placebo in reducing the incidence of head injury-related death (12.5 percent vs 14.0 percent, RR, 0.89, 95 percent CI, 0.80–1.00). Nonetheless, the inclusion of patients with unilateral unreactive pupils might have diluted the treatment effect, as these patients may already have brain herniation, they pointed out.

The elements of severity, time

The reduction in the risk of head injury-related death with tranexamic acid was more pronounced among patients with mild-to-moderate injury (RR, 0.78, 95 percent CI, 0.64–0.95) but not in those with severe injury (RR, 0.99, 95 percent CI, 0.91–1.07; p for heterogeneity=0.030).

Patients with severe injury had less to gain from tranexamic acid than those with mild-to-moderate cases, noted the researchers. “[S]uch patients already have extensive intracranial haemorrhage before treatment or other potentially life-threatening intracranial pathologies that are not affected by tranexamic acid.”

Early initiation of tranexamic acid also seemed to confer the greatest mortality benefit in mild-to-moderate cases (p=0.005) but not in severe cases (p=0.73). The time factor appears consistent with literature noting the reduced potential of tranexamic acid to prevent intracranial bleeding with even a short treatment delay, as haemorrhage expansion typically occurs immediately following the injury. [J Neurotrauma 2008;25:629-639; Lancet 2018;391:125-132]

On the heels of CRASH-2

Safety-wise, both arms had similar risks of vascular occlusive events (RR, 0.98, 95 percent CI, 0.74–1.28) and seizures (RR, 1.09, 95 percent CI, 0.90–1.33), which mirrors those found in the CRASH-2 trial, underlining the safety of tranexamic acid in this setting. “[G]iven the absence of adverse effects … the implications of wrongly concluding that tranexamic acid is ineffective are likely to be far more consequential than are those of wrongly concluding that tranexamic acid is effective,” underscored the researchers.

CRASH-2 paved the way for the inclusion of tranexamic acid in guidelines for prehospital care of patients with trauma, with the exclusion of patients with isolated TBI. The current findings provide further evidence corroborating the efficacy and safety of early tranexamic acid administration in this setting, said the researchers.