Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial

Abstract

SummaryBackgroundTranexamic acid reduces surgical bleeding and decreases mortality in patients with traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury (TBI) and can cause brain herniation and death. We aimed to assess the effects of tranexamic acid in patients with TBI.MethodsThis randomised, placebo-controlled trial was done in 175 hospitals in 29 countries. Adults with TBI who were within 3 h of injury, had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding were eligible. The time window for eligibility was originally 8 h but in 2016 the protocol was changed to limit recruitment to patients within 3 h of injury. This change was made blind to the trial data, in response to external evidence suggesting that delayed treatment is unlikely to be effective. We randomly assigned (1:1) patients to receive tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was head injury-related death in hospital within 28 days of injury in patients treated within 3 h of injury. We prespecified a sensitivity analysis that excluded patients with a GCS score of 3 and those with bilateral unreactive pupils at baseline. All analyses were done by intention to treat. This trial was registered with ISRCTN (ISRCTN15088122), ClinicalTrials.gov (NCT01402882), EudraCT (2011-003669-14), and the Pan African Clinical Trial Registry (PACTR20121000441277).ResultsBetween July 20, 2012, and Jan 31, 2019, we randomly allocated 12 737 patients with TBI to receive tranexamic acid (6406 [50·3%] or placebo [6331 [49·7%], of whom 9202 (72·2%) patients were treated within 3 h of injury. Among patients treated within 3 h of injury, the risk of head injury-related death was 18·5% in the tranexamic acid group versus 19·8% in the placebo group (855 vs 892 events; risk ratio [RR] 0·94 [95% CI 0·86–1·02]). In the prespecified sensitivity 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% in the tranexamic acid group versus 14·0% in the placebo group (485 vs 525 events; RR 0·89 [95% CI 0·80–1·00]). The risk of head injury-related death reduced with tranexamic acid in patients with mild-to-moderate head injury (RR 0·78 [95% CI 0·64–0·95]) but not in patients with severe head injury (0·99 [95% CI 0·91–1·07]; p value for heterogeneity 0·030). Early treatment was more effective than was later treatment in patients with mild and moderate head injury (p=0·005) but time to treatment had no obvious effect in patients with severe head injury (p=0·73). The risk of vascular occlusive events was similar in the tranexamic acid and placebo groups (RR 0·98 (0·74–1·28). The risk of seizures wa...

Tranexamic acid is associated with reduced mortality, hemorrhagic expansion, and vascular occlusive events in traumatic brain injury – meta-analysis of randomized controlled trials

“…The timing of administration was less certain, the mean time to injury was assessed in only three studies. CRASH-3 trial showed that the mortality benefits after adjustment were most pronounced when TXA was given < 3 h in mild-moderate Glasgow Coma Scale (GCS) score, however, mortality seemed to be the same in severe GCS score [13]. Which is in accordance with the abovementioned study that the early administration is better [18].…”

“…(Fig. 1) There were a total of 30.522patients from 7 studies [9][10][11][12][13][14][15]. The TXA protocol was mostly 1 g TXA infused over 10 min, followed by IV infusion of 1 g over 8 h. There was 1 study that gave bolus initially and another study that gave initial dose over 30 min.…”

Does Complement-Mediated Hemostatic Disturbance Occur in Traumatic Brain Injury? A Literature Review and Observational Study Protocol

“…However, this remains to be answered. Another driving force behind TBI-induced bleeding is also hyperfibrinolysis [47,103], exemplified in the recently published CRASH-3 trial on the effect of tranexamic acid on death, disability, vascular occlusive events, and in patients with acute TBI [104], where one would expect clinically significant complement overactivation to lead to hypofibrinolysis instead. However, hypofibrinolysis following TBI is usually not seen until a few hours after initial injury [82,84], as opposed to hyperfibrinolysis which is hypothesized to occur almost immediately after injury [84].…”

Is tranexamic acid going to CRASH the management of traumatic brain injury?

“…The rate of follow-up was also incredibly high, with information on the primary outcome being available for 99.2% of patients. The authors concluded that "TXA treatment within 3 h of injury reduced TBI-related death" but correctly underlined in the discussion that the confidence intervals were wide, i.e., compatible both with a substantial reduction in TBI-related death or little or no benefit [1]. In contrast to this prudent comments, the accompanying editorial [3] as well as the infographic distributed by the Lancet within social media presented TXA as "a win for patients with TBI" and as a therapy that "could save 1 in 5 people who would have died following a mild or moderate traumatic brain injury".…”

“…In the recent CRASH-3 randomized trial [1], early (< 3 h) administration of tranexamic acid (TXA) was associated with a non-significant reduction [i.e., from 19.8 to 18.5%; relative risk, RR 0.94 (95% CI 0.86-1.02)] of head injuryrelated 28-day mortality in patients with isolated traumatic brain injury (TBI). However, there was a significant reduction in head injury-related mortality when TXA was administered within 3 h to patients with mild-tomoderate [from 7.5 to 5.8%, RR 0.78 (95% CI 0.64-0.95)] but not severe [from 40.1 to 39.6%, RR 0.99 (95% CI 0.91-1.07)] TBI.…”