Association between tranexamic acid administration and mortality based on the trauma phenotype: a retrospective analysis of a nationwide trauma registry in Japan

Despite global efforts to standardise trauma care and improve treatment outcomes, approximately 4.5 million trauma-related deaths occur annually worldwide [1]. Most preventable early trauma deaths are due to haemorrhage [2]. Early trauma-induced coagulopathy (TIC) exacerbates this by contributing to acute bleeding, associated shock, ischaemia–reperfusion injuries, thrombotic complications, and, in severe cases, hyperfibrinolysis, further promoting haemorrhage [3]. Tranexamic acid (TXA), a synthetic derivative of the amino acid—lysine—is an antifibrinolytic that inhibits lysine-binding sites on plasminogen [4]. In the international randomised controlled trials (RCTs)—CRASH-2 [5, 6] and CRASH-3 [7]—TXA demonstrated the potential to improve outcomes in patients with traumatic bleeding and mild-to-moderate traumatic brain injuries. Therefore, early management of bleeding and coagulation abnormalities in trauma care is recommended [8]. The recent PATCH-Trauma trial conducted on adult patients with severe trauma revealed that early prehospital TXA administration in suspected cases of TIC was not beneficial for survival with functional outcomes at 6 months post-injury. However, secondary analyses suggested potential benefits for survival at 24 h and 1-month post-injury [9]. A meta-analysis including RCTs and observational studies that evaluated TXA efficacy in patients with traumatic injuries and brain injuries aged ≥ 15 years suggested that TXA significantly reduced 1-month mortality rates compared to controls, indicating potential benefits across various patient groups [10]. However, some studies lacked data on age, sex, trauma severity, and comorbidities, resulting in heterogeneity among the study groups; thus, patients most suited for TXA administration remained unclear to clinicians. Given the high heterogeneity among patients with trauma, heterogeneity of the treatment effect might exist at a more granular level, even among severely injured patients targeted in previous RCTs [11]. Additionally, less severely injured patients may benefit from TXA administration.

The precision medicine approach, which involves identifying latent subgroups (phenotypes) of diseases with high heterogeneity, such as sepsis and acute respiratory distress syndrome (ARDS), has recently been shown to enhance the identification of more homogenous groups. This approach deepens the understanding of the pathophysiological mechanisms and contributes to the identification of more effective targets for specific treatments through appropriate stratification [12‐14]. This strategy, which identifies subgroups that are more likely to respond to treatment, is called predictive enrichment; it aims to identify specific sub-phenotypes within diseases, reducing heterogeneity and pinpointing subgroups that may respond more favourably to targeted therapeutic interventions [15]. For instance, although an RCT of simvastatin in ARDS did not demonstrate a significant difference in the primary outcome [16], a secondary analysis revealed a beneficial effect in certain phenotypes [17]. This finding underscores the potential of such approaches in enhancing treatment efficacy through refined patient stratification.

Our previous study identified different clinical phenotypes based on the information gathered early in trauma care [18]. The study identified 8 distinct trauma phenotypes (sub-classified into 11 phenotypes) with 14 variables using statistical machine learning techniques. We hypothesised that these subgroup differences would result in heterogenous treatment effects of TXA among trauma phenotypes. Determining whether TXA administration is preferred, based on the trauma phenotype in all patients with blunt trauma, could aid in clinical decision-making and potentially fill the knowledge gap regarding optimal TXA administration. Therefore, this study was conducted using nationwide cohort data to evaluate the association between TXA administration and the survival outcome based on the trauma phenotype in patients with blunt trauma with survival as the outcome measure.

This study used JTDB data to investigate the association between TXA administration and the survival outcome based on trauma phenotypes. Consequently, subgroups were identified within specific trauma phenotypes that may be associated with TXA administration and survival outcomes. These results were supported by sensitivity analyses and contribute to our current understanding of TXA efficacy.

This study has two significant clinical implications. First, it identified subgroups of all patients with blunt trauma for whom TXA administration was likely beneficial and those for whom it was not advisable. Evidence exists for TXA administration in patients at risk of significant haemorrhagic and those with mild-to-moderate head injuries; nonetheless, the truly effective target population for TXA has not been sufficiently clarified. A strength of this study is that it encompassed all patients with blunt trauma, including those with minor injuries, and comprehensively examined the association between TXA administration and the survival outcome based on the trauma phenotype. Additionally, the use of an integrated model that incorporates factors, such as comorbidities, vital signs upon admission, and the type and extent of organ damage, allows for an analysis that considers the heterogeneity of patients with trauma and adds novelty to the study. Meanwhile, studies examining the treatment effect of TXA by baseline risk based on RCTs showed no heterogeneity [31, 32]. This result is at variance with the hypothesis of this study. We aimed to identify subgroups—defined by trauma phenotypes developed in our previous study—that might particularly benefit from TXA, thereby reducing intragroup heterogeneity. Although our study is not a secondary analysis of RCT data and may not be as robust, it serves as an important step in hypothesis generation for future studies. Clinically, the clusters in which TXA administration resulted in reduced mortality rates (trauma phenotypes 1, 2, 6, and 8) exhibited higher median ISSs and a tendency towards greater trauma severity. The PATCH trauma trial included patients with severe multisite injuries and reported reduced mortality rates at 24 h and 1 month after injury in a secondary analysis, consistent with the results for severe trauma phenotypes in this study [9]. In our previous study, proteomic analyses of the molecular pathology of high-mortality phenotypes (trauma phenotype 8 in this study) demonstrated the involvement of coagulation disorders (hyperfibrinolysis) [18]. These findings explain the effectiveness of TXA in this study from a molecular pathology perspective. However, for trauma phenotypes 3 and 4, TXA administration was associated with increased in-hospital mortality rates. Trauma phenotype 3 is characterised by orthopaedic injuries in elderly population, trauma phenotype 4 is primarily seen in younger patients with chest or orthopedic injury, and both are associated with lower trauma severity levels. Additionally, the lower proportion of patients who were administered TXA in these clusters, owing to the minor nature of the injuries, may have amplified the effect of the few mortality cases. Nevertheless, this study represents the first step toward the practice of personalized medicine in trauma care, predicting the efficacy of therapeutic interventions in a highly heterogeneous population. Although accumulating many cases in prospective studies is challenging, assessing the association between TXA administration and the survival outcome using statistical methods is a strength. Validating these results in future prospective studies could lead to more robust and optimised TXA administration.

Second, trauma phenotypes can be identified based on the information available at the early stages of clinical assessment. Early administration of TXA within 3 h post-injury is recommended; therefore, identifying ideal candidates for early administration is crucial. Early intervention is the key to trauma treatment strategies [33]; therefore, efficiently identifying suitable candidates for treatment at a treatable stage is essential. Identifying trauma phenotypes requires the AIS, which necessitates various imaging tests for determination. Spending time on identifying trauma phenotypes risks missing the golden hour for administering TXA, especially in patients whose benefits from TXA have already been established in previous large-scale studies [5, 7], only to base administration on these identifications. For rapidly identifying trauma phenotypes, applications to detect the trauma phenotype and the revision of clinical workflows, such as integrating computed tomography (CT) scans into trauma resuscitation [34, 35], which allow for early CT imaging and, thus, swift identification of trauma phenotypes following imaging, have been developed. While there are many challenges to implementing TXA administration based on trauma phenotypes, this study serves as a hypothesis-generating investigation. Through future validation, it may enable more appropriate targeting of the patient population for whom TXA administration is desirable.

By evaluating the association between TXA administration and the survival outcome based on trauma phenotypes obtained using clinical information in heterogeneous diseases can reduce the variability in treatment effects, potentially leading to more efficient clinical research implementation (predictive enrichment) [15, 36]. Moreover, in several research fields, treatment efficacy has been validated through pre-subgrouping (phenotyping) based on machine learning, thus facilitating more efficient clinical trials [37‐39]. Similar to other studies, future research should elucidate and clinically interpret the molecular pathological features of each trauma phenotype, using trauma phenotypes as an enrichment approach.

This study has some limitations. First, as this study was retrospective in nature, it inherently possessed specific limitations such as the inability to establish causation, potential selection bias in the choice of participants, regression dilution bias, and unmeasured confounding variables that may influence the outcomes. Notably, the database used in this study did not include the timing of TXA administration. Additionally, the time of injury was unknown in 26.0% of the analysed data; thus, the duration from injury to hospital admission was unclear. Early administration of TXA within 3 h after injury is recommended, and delays in administration are potentially harmful [6]. In trauma phenotypes 3, 4, and 5, administration of TXA was associated with an increase in in-hospital mortality, suggesting a possible delay in TXA administration. In the subgroup analysis of cases with known injury times, 92.8% of the patients in the TXA administration group arrived at the hospital within 120 min post-injury, and the sensitivity analysis for these cases yielded results consistent with those of the primary analysis.

Second, the TXA administration protocol was unclear. The Japan Advanced Trauma Evaluation and Care guidelines [40] describe the use of TXA within 3 h post-injury for traumas with a high bleeding risk or mild to moderate traumatic brain injury, as an adjunctive haemostatic therapy, based on the results of two large RCTs [5, 7]. Medical institutions generally follow these guidelines; nonetheless, the degree of adherence varies. Consequently, the study conducted sensitivity analyses considering the facility as having a mixed effect, revealing that TXA administration was favourable in the most severe trauma clusters even after accounting for facility-related influences. Third, only point-of-admission data were considered. This limitation implies that temporal changes in the patient’s condition were not accounted for. This is a significant limitation in assessing the effects of TXA on evolving clinical conditions, suggesting that future research should analyse longitudinal data. Fourth, the exclusion criteria were slightly different from those in the previous study [18]. As the JTDB was modified in the period between the previous and present studies, obtaining information related to pregnancy was no longer possible. However, pregnant women represented only approximately 0.1% of the excluded patients in the previous study; assuming that the frequency was similar in the present study, the impact on the results was likely to be limited. Fifth, our study’s data, sourced solely from Japanese patients, have a limitation in external validity. Our cohort’s mean age was higher and the trauma severity lower than those of other cohorts [41], with physiological parameters not reflecting severe conditions. This discrepancy might stem from the specific criteria for registry enrolment and Japan’s demographic profile, which is characterized by a high aging population among developed nations [42]. Such demographic and clinical features raise concerns about the applicability of our findings to other populations. Consequently, external validation with other trauma cohorts is essential to confirm the robustness of our results. Sixth, despite weighting by IPTW, the ASMD for head injury and ISS exceeded 0.1, which usually indicates an imbalance, and this could be considered a limitation of this study. Meanwhile, based on a study that the ASMD must be smaller than 0.25 for the regression adjustment to be reliable [25], we judge this imbalance to be within acceptable limits.

In summary, this retrospective analysis of a national cohort of patients with blunt trauma evaluated the association between TXA administration and the survival outcome based on the trauma phenotype identified using available clinical information at the early stages of trauma care. This study indicates that TXA administration has the potential to significantly reduce or increase in-hospital mortality rates in patients with certain trauma phenotypes. Our findings suggest variability in the effectiveness of TXA among patients with trauma; further research with an independent dataset with higher external validity and prospective data is needed to confirm our findings. This study could be an offshoot towards the implementation of enrichment strategies in trauma care.