Tranexamic acid (TXA) is an antifibrinolytic agent that competitively inhibits the activation of plasminogen to plasmin, stabilizing previously formed clots (J Thromb Haemost 2015;13:S195-9; Eur J Haematol 2020;104:79-87; Crit Care Clin 2017;33:85-99). TXA has been well studied in non-trauma patients and has been shown to decrease bleeding and improve outcomes (J Thromb Haemost 2015;13:S195-9; Health Technol Assess 2013;17:1-79). Worldwide, trauma continues to be a leading cause of mortality, often due to uncontrolled bleeding. Recent studies have shown that TXA may also be beneficial in trauma patients. However, concerns remain about its administration, dosing, and potential side effects such as thromboembolic events.
CRASH-2 is the largest study conducted on TXA administration in trauma patients. It was a randomized controlled trial conducted across 274 hospitals in 40 countries that enrolled 20,211 adult trauma patients deemed to be at risk for significant bleeding. The investigators found that administration of TXA was associated with a reduction in all-cause mortality and a reduced risk of death due to bleeding without an increased risk of venous thromboembolism (VTE). Treatment with TXA within three hours of injury was beneficial, whereas patients treated with TXA more than three hours after injury had an apparent increase in the risk of death due to bleeding (Health Technol Assess 2013;17:1-79). The conundrum of the increase in mortality with delayed TXA administration (>3 hours from time of injury) has led some to question the utility of widespread administration of TXA in injured patients (Lancet 2011;377:1096-101). This suggests that giving TXA to injured patients is not a straightforward therapy and requires careful consideration.
There are multiple limitations of the CRASH-2 trial. Many of the enrollment centers were in areas without mature trauma networks, calling into question the applicability of the results to countries with more advanced trauma systems. Most injuries were penetrating, and the study did not stratify injury severity. Furthermore, patient enrollment into the trial was based on the “uncertainty principle” of randomization, meaning that patients were only enrolled if the physician was uncertain if there would be a benefit of TXA administration (Crit Care Clin 2017;33:85-99). Due to this method of enrollment, most of the patients in shock were thought to benefit from TXA administration and therefore were not enrolled in the study. This is likely the reason that about half of the patients enrolled in the trial did not receive a transfusion. It is conceivable they would have seen better results in a sicker patient cohort. Also, there was no protocolized approach in the CRASH-2 trial for the detection or diagnosis of the incidence of VTE (Eur J Haematol 2020;104:79-87; Crit Care Clin 2017;33:85-99). This has led some to question the outcome that TXA administration did not increase the incidence of VTE. Lastly, the overall reduction of all-cause mortality and deaths due to bleeding in the TXA group was small (1.5% and 0.8%, respectively). While these results are statistically significant due to the large enrollment, the number needed to treat (NNT) to save one life was rather high (NNT=67).
The Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study was a large, retrospective observational study assessing the use of TXA in the combat setting (Arch Surg 2012;147:113-9). It found that the cohort receiving TXA had a lower mortality, and the greatest survival benefit was seen in patients requiring massive transfusion. The MATTERs II study was a retrospective observational study evaluating the impact of fibrinogen-containing cryoprecipitate in addition to TXA on survival in combat injuries. A total of 1,334 patients were subdivided into the following groups: TXA alone, cryoprecipitate alone, TXA + cryoprecipitate, and no TXA or cryoprecipitate. Of note, the ISS was higher in the cryoprecipitate and TXA + cryoprecipitate groups, but despite this, TXA and cryoprecipitate were independently associated with a reduced mortality.
The CRASH-3 trial was a randomized, placebo-controlled trial performed in 175 hospitals in 29 countries that focused on the effects of early TXA administration in patients with acute traumatic brain injury (TBI) and the effects of TXA on several adverse events, including pneumonia, cardiac arrest, and seizures. The final analysis included 4,613 patients who received TXA within three hours and 4,514 who received placebo. The primary outcome of 28-day in-hospital head injury associated mortality showed no significant difference between the two groups (TXA: 12.5% vs. placebo: 14.0%; RR 0.94 [95% CI, 0.86-1.02]). However, in patients with mild to moderate TBI, mortality was significantly reduced (TXA: 5.8% vs. placebo: 7.5%; RR: 0.78 [95% CI, 0.64-0.95]). The investigators postulated that patients with severe TBI had sustained such extensive intracerebral hemorrhage and brain herniation that TXA would unlikely improve the outcomes. The results of the CRASH-3 trial indicate that administration of TXA to patients with mild to moderate TBI within three hours of injury reduces head injury-related mortality without evidence of adverse effects or complications (Lancet 2019;394:1713-23).
Despite the potential benefits of TXA use, there are also some possible risks. As noted in the CRASH-2 trial, the therapeutic window seems to be limited to administration within three hours of injury. The CRASH-2 collaborators speculated that the adverse effect of TXA administration past three hours may be attributed to the development of disseminated intravascular coagulation in the later phases of trauma, wherein antifibrinolytics may be contraindicated (Health Technol Assess 2013;17:1-79). The CRASH-3 trial also noted that a delay in treatment, possibly due to the hemorrhage expansion that occurs immediately after head injury, could reduce the ability of TXA to decrease intracranial bleeding (Lancet 2019;394:1713-23). Although studies have shown conflicting results regarding TXA-associated seizures, it is important to consider this risk with larger doses of TXA (Crit Care Clin 2017;33:85-99; Lancet 2019;394:1713-23; Lancet 2019;394:1713-23). The mechanism of action is not fully understood, but it is believed to be attributable to cerebral blood flow disturbances and inhibition of both glycine and GABAA receptors (Crit Care Clin 2017;33:85-99; Br J Anaesth 2021;126:12-17).
Several smaller cohort studies evaluated the use of TXA in advanced trauma systems within the United States but did not produce the same results as the CRASH-2 trial, finding instead that TXA did not reduce mortality (Crit Care Clin 2017;33:85-99; J Trauma Acute Care Surg 2015;78:905-9; J Trauma Acute Care Surg 2014;76:1373-8). Furthermore, a study of patients at U.S. military combat support hospitals found that TXA administration was an independent risk factor for VTE (JAMA Surg 2018;153:169-75). The frequency of thrombotic events among trauma patients receiving TXA is unclear and deserves more investigation (Eur J Haematol 2020;104:79-87).
Many questions regarding the benefit of early TXA administration remain. As a result, trauma systems have been slow to adopt its widespread use within their treatment algorithms for hemorrhagic shock. Following the publication of the CRASH-2 trial results, Coats et al. reported low proportions of patients treated with TXA in a longitudinal and cross-sectional study. These results persisted in groups with early physiological abnormalities, indicating a serious risk of hemorrhage (Emerg Med J 2019;36:78-81). Pre-hospital administration of TXA might prove to be an effective strategy since the effects of TXA are time-dependent, but more studies are needed to conclude whether pre-hospital TXA administration improves overall trauma outcomes (ANZ J Surg 2020;90:426-28). A recent analysis of previously collected data from injured patients at a major U.K. trauma center reported that empiric TXA administration was associated with reduced early mortality and appeared to alter the fibrinolytic patterns, but did not increase late mortality, regardless of the fibrinolysis pattern in the first 24 hours after injury (Anesthesiology 2022;136:148-61).
The implementation of TXA in trauma care remains a prominent topic of interest. Its use has the potential to improve survival in patients at risk of hemorrhage or TBI-associated mortality. However, the exact mechanism of action of TXA and potential for thrombotic and fibrinolytic shutdown-related complications remain unclear. Furthermore, outcomes have been shown to be worse when TXA is administered more than three hours after injury. Although further research must be conducted to fully understand the clinical utility and guidelines for administering TXA in trauma patients, recent studies show a clear benefit in hemorrhage control when given within three hours of injury.
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