ARTICLE: The PATCH-Trauma Investigators and the ANZICS Clinical Trials Group. Prehospital tranexamic acid for severe trauma. N Engl J Med. 2023;389:127-136.
OBJECTIVE
To determine whether prehospital administration of tranexamic acid (TXA) increases the likelihood of survival with a favorable functional outcome at 6 months after injury
BACKGROUND
Trauma is the leading cause of death in young people, and many of the preventable deaths are due to bleeding, which can be worsened by trauma-induced coagulopathy and hemorrhagic shock.1,2 Tranexamic acid, an antifibrinolytic drug, has been shown to decrease the need for blood transfusion and reduce mortality in elective surgical cases. The CRASH-2 Trial, conducted in 2010, demonstrated that TXA reduces mortality among trauma patients with suspected bleeding when administered within 3 hours of injury,3 while CRASH-3 showed reduced mortality specifically among patients with mild-to-moderate traumatic brain injury.4 In these two major trails, however, patients were not followed beyond 28 days and functional outcomes were not reported. In addition, most trial participants were recruited in countries who had not yet implemented regionwide systems of trauma care. It is possible that these findings may not be generalizable to countries with more advanced trauma systems that provide early access to lifesaving critical care, blood products, surgery, and interventional radiology.5
TXA administration also comes with its own risks. Additional studies have found that TXA administered in the prehospital setting for patients at increased risk of hemorrhage6 or with traumatic brain injury7 did not lower 30-day mortality and was associated with a higher incidence of thromboembolic events.8 Taken together, TXA has risks and benefits in trauma that need to be carefully considered, and its role in advanced trauma systems is still uncertain and requires further investigation.
DESIGN
- Double-blind, randomized, placebo-controlled trial
- Patients were recruited by 15 EMS agencies and 21 hospitals in Australia, New Zealand, and Germany and were randomly assigned in 1:1 ratio to receive TXA or placebo utilizing computer-generated random numbers stratified according to national or state jurisdiction and initial GCS (<9 or ≥9)
- Prehospital assessment of coagulopathy risk was performed utilizing Coagulopathy of Severe Trauma (COAST) score, which assigns 1 point for each of the following (total of 7): entrapment in a vehicle, SBP <100mmHg, body temp <35°C, suspected PTX, suspected intra abdominal or pelvic injury. Additional points are assigned if the SBP <90mmHg or if the body temp <32°C
- One dose of 1g TXA or placebo was administered as an IV bolus as soon as possible by EMS on scene or en route to the hospital. After hospital arrival, a second dose was added to 1L NS and infused over 8 hours. In addition to this, patients received usual prehospital, in-hospital, and posthospital care
INCLUSION CRITERIA
- Patients ≥18 years of age with suspected severe traumatic injuries by prehospital providers (paramedics or physicians)
- High risk for trauma-induced coagulopathy as determined by COAST score ≥3
- First dose of TXA or placebo could be administered within 3 hours after injury and before hospital admission
EXCLUSION CRITERIA
- Known or suspected to be pregnant
- Resided in a facility for older persons (eg, nursing homes)
PRIMARY OUTCOME
Survival with a favorable functional outcome at 6 months assessed by Glasgow Outcome Scale Extended (GOS-E), defined as a score ≥5 on an 8 point scale (corresponding to “lower moderate disability” or better).
SECONDARY OUTCOMES
Death within 24 hours, 28 days, and 6 months after injury. Other secondary outcomes include vascular occlusive events (eg, deep venous thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke, or other arterial events) and sepsis that occurred up to the time of death, hospital discharge, or 28 days after injury (whichever occurred first).
KEY RESULTS
- In total, 1310 patients were enrolled and treated. Trial packs for 3 patients were lost in the field and consent was withdrawn for 7 patients, so 1300 patients were included: 657 in the TXA group and 643 in the placebo group.
- The demographic and clinical characteristics of the patients at baseline were similar between the two trial groups
- A total of 24.1% of patients had laboratory evidence of early coagulopathy and 39.3% subsequently received diagnosis of a head or neck injury of more than moderate severity
- Protocol deviations occurred in 215 (32.7%) of patients in the TXA group and 238 (37.0%) of patients in the placebo group
Primary outcome
There was no statistically significant difference in favorable functional outcome (GOS-E level ≥5) at 6 months between the TXA (53.7%) and placebo (53.5%) groups (risk ratio [RR], 1.00; 95% CI, 0.90 to 1.12; P=0.95).
Secondary outcomes
- 24 hours post-injury: 9.7% (64/657) of patients in the TXA group and 14.1% (90/640) in the placebo group had died (RR, 0.69; 95% CI, 0.51 to 0.94)
- 28 days post-injury: 17.3% (113/653) of patients in the TXA group and 21.8% (139/637) in the placebo group had died (RR, 0.79; 95% CI, 0.63 to 0.99)
- 6 months post-injury: 19.0% (123/648) in the TXA group and 22.9% (144/629) in the placebo group had died (RR, 0.83; 95% CI, 0.67 to 1.03)
- Death was attributed to bleeding in 29.3% (36/648) in the TXA group and 36.1% (52/629) in the placebo group (RR, 0.66; 95% CI, 0.43 to 1.01)
- One or more vascular occlusive events occurred in 155 of 657 patients (23.6%) in the TXA group vs 126 of 641 (19.7%) in the placebo group (RR, 1.20; 95% CI, 0.97 to 1.48). The incidences of other adverse events were similar in the two trial groups
LIMITATIONS
- Primary outcome data was missing for 13% of patients largely due to loss to follow-up
- Dosing differences: some patients did not receive all intended doses of TXA and some received open-label TXA in contrast to study protocol
- Lack of generalizability of findings given focus on severely injured patients at risk for trauma-induced coagulopathy in advanced trauma systems as well as insufficient power to detect clinically important heterogeneity of treatment response in penetrating trauma and other subgroups with small numbers
- Treatment regimen of TXA administered intravenously as 1g bolus before hospital admission, followed by 1g infusion over 8 hours in-hospital, does not eliminate possibility of harm or benefit with other dosing regimens
EM TAKE-AWAYS
This multi-center, double-blind RCT went beyond the short-term benefit of TXA on mortality in the trauma patient and concluded that there was no benefit of TXA with respect to functional outcomes at 6 months. However, they found TXA to be beneficial at reducing mortality at 24 hours and 28 days, consistent with findings in the CRASH-2 trial. Additionally, there was no increased incidence of vascular occlusive events in the TXA group compared to placebo. Despite there being no clear long-term benefit in functional outcomes, prehospital and emergency personnel may still consider administering TXA in the bleeding trauma patient given its proven benefit in reducing short-term mortality.
REFERENCES
- GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396:1204-1222.
- Ker K, Roberts I, Shakur H, Coats TJ. Antifibrinolytic drugs for acute traumatic injury. Cochrane Database Syst Rev. 2015;5:CD004896-CD004896.
- CRASH-2 trial collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376(9734):23–32.
- CRASH-3 trial collaborators. 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. Lancet. 2019;394(10210):1713–1723.
- State of Victoria Department of Health. Victorian State Trauma Registry: 1 July 2011 to 30 June 2012 summary report. July.
- Guyette FX, Brown JB, Zenati MS, et al. Tranexamic acid during prehospital transport in patients at risk for hemorrhage after injury: a double-blind, placebo-controlled, randomized clinical trial. JAMA Surg. 2020;156:11-20.
- Rowell SE, Meier EN, McKnight B, et al. Effect of out-of-hospital tranexamic acid vs placebo on 6-month functional neurologic outcomes in patients with moderate or severe traumatic brain injury. JAMA. 2020;324:961-974.
- Spinella PC, Bochicchio K, Thomas KA, et al. The risk of thromboembolic events with early intravenous 2- and 4-g bolus dosing of tranexamic acid compared to placebo in patients with severe traumatic bleeding: a secondary analysis of a randomized, double-blind, placebo-controlled, single-center trial. Transfusion. 2022;62:Suppl 1:S139-S150.