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Efficacy and Safety of Tranexamic Acid in Emergency Trauma: A Systematic Review and Meta-Analysis Journal of Clinical Medicine Article Efficacy and Safety of Tranexamic Acid in Emergency Trauma: A Systematic Review and Meta-Analysis Mahdi Al-Jeabory 1, Lukasz Szarpak 2,* , Kecskes Attila 3, Michael Simpson 4, Adam Smereka 5, Aleksandra Gasecka 6,7 , Wojciech Wieczorek 8, Michal Pruc 1, Maciej Koselak 9, Wladyslaw Gawel 10, Igor Checinski 11, Milosz J. Jaguszewski 12 and Krzysztof J. Filipiak 6 ���������� ������� Citation: Al-Jeabory, M.; Szarpak, L.; Attila, K.; Simpson, M.; Smereka, A.; Gasecka, A.; Wieczorek, W.; Pruc, M.; Koselak, M.; Gawel, W.; et al. Efficacy and Safety of Tranexamic Acid in Emergency Trauma: A Systematic Review and Meta-Analysis. J. Clin. Med. 2021, 10, 1030. https:// doi.org/10.3390/jcm10051030 Academic Editor: Toshiaki Iba Received: 13 February 2021 Accepted: 26 February 2021 Published: 3 March 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Outcomes Research Unit, Polish Society of Disaster Medicine, P.O. Box 78, 05-090 Raszyn, Poland; mmahdi@interia.pl (M.A.-J.); m.pruc@ptmk.org (M.P.) 2 Maria Sklodowska-Curie Bialystok Oncology Center, 15-027 Bialystok, Poland 3 NATO Centre of Excellence for Military Medicine, 1555 Budapest, Hungary; train.nco@coemed.org 4 Central Texas Regional SWAT, Leander, TX 78646, USA; mike@ps-med.com 5 Department of Gastroenterology and Hepatology, Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland; adam.smereka@umed.wroc.pl 6 1st Chair and Department of Cardiology, Medical University of Warsaw, 02-091 Warsaw, Poland; aleksandra.gasecka@wum.edu.pl (A.G.); krzysztof.filipiak@wum.edu.pl (K.J.F.) 7 Department of Cardiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands 8 Department of Emergency Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland; w.wieczorek@easyrescue.pl 9 Maria Sklodowska-Curie Medical Academy in Warsaw, 03-411 Warsaw, Poland; src.emergency@gmail.com 10 Department of Surgery, The Silesian Hospital in Opava, 746 01 Opava, Czech Republic; w.b.gawel@gmail.com 11 Department of Emergency Medical Service, Wroclaw Medical University, 50-367 Wroclaw, Poland; igor.checinski@umed.wroc.pl 12 First Department of Cardiology, Medical University of Gdansk, 80-210 Gdansk, Poland; jamilosz@gmail.com * Correspondence: l.szarpak@fmcgroup.org; Tel.: +48-500186225 Abstract: In trauma patients, bleeding can lead to coagulopathy, hemorrhagic shock, and multiorgan failure, and therefore is of fundamental significance in regard to early morbidity. We conducted a meta-analysis to evaluate the efficacy and safety of tranexamic acid (TXA) in civil and military settings and its impact on in-hospital mortality (survival to hospital discharge or 30-day survival), intensive care unit and hospital length of stay, incidence of adverse events (myocardial infarct and neurological complications), and volume of blood product transfusion. The systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic review of the literature using PubMed, Scopus, EMBASE, Web of Science, and the Cochrane Central Register and Controlled Trials (CENTRAL) database was conducted from inception to 10 January 2021. In-hospital mortality was reported in 14 studies and was 15.5% for the TXA group as compared with 16.4% for the non-TXA group (OR = 0.81, 95% CI 0.62–1.06, I2 = 83%, p = 0.12). In a civilian TXA application, in-hospital mortal- ity in the TXA and non-TXA groups amounted to 15.0% and 17.1%, respectively (OR = 0.69, 95% CI 0.51–0.93, p = 0.02, I2 = 78%). A subgroup analysis of the randomized control trial (RCT) studies showed a statistically significant reduction in in-hospital mortality in the TXA group (14.3%) as com- pared with the non-TXA group (15.7%, OR = 0.89, 95% CI 0.83–0.96, p = 0.003, I2 = 0%). To summarize, TXA used in civilian application reduces in-hospital mortality. Application of TXA is beneficial for severely injured patients who undergoing shock and require massive blood transfusions. Patients who undergo treatment with TXA should be monitored for clinical signs of thromboembolism, since TXA is a standalone risk factor of a thromboembolic event and the D-dimers in traumatic patients are almost always elevated. Keywords: tranexamic acid; trauma; bleeding; mortality; emergency medicine; systematic review; meta-analysis J. Clin. Med. 2021, 10, 1030. https://doi.org/10.3390/jcm10051030 https://www.mdpi.com/journal/jcm https://www.mdpi.com/journal/jcm https://www.mdpi.com https://orcid.org/0000-0002-0973-5455 https://orcid.org/0000-0001-5083-7587 https://doi.org/10.3390/jcm10051030 https://doi.org/10.3390/jcm10051030 https://creativecommons.org/ https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ https://doi.org/10.3390/jcm10051030 https://www.mdpi.com/journal/jcm https://www.mdpi.com/2077-0383/10/5/1030?type=check_update&version=3 J. Clin. Med. 2021, 10, 1030 2 of 12 1. Introduction Trauma is the leading cause of death in the population from 1 to 44 years old [1]. The main cause of early mortality in trauma patients is hemorrhage [2]. Bleeding initiates the cascade of reactions leading to coagulopathy and hemorrhagic shock [3,4], resulting in a higher occurrence of multiorgan failure as compared with patients without coagulopa- thy [5]. Although several mechanisms correlate with the risk of coagulopathy occurrence, for example, dilution and use of anticoagulative agents, due to the plethora of mechanism involved there are still no tangible factors that can be precisely responsible for the induc- tion of coagulopathy [6]. While bleeding in a local wound presents little to no problem because it can usually be stopped by using compression [7], polytrauma patients with severe injury, for example, a broken pelvis, require far more attention and more sophisti- cated methods due to the lack of compression spots [8]. Therefore, we have focused on the use of tranexamic acid (TXA), a drug introduced as early as 1968 for menorrhagia treatment [9], which works by slowing down the conversion of plasminogen to plasmin, subsequently, reducing fibrinolysis and stabilizing the blood clot. The use of TXA, since 1968, has spread across the fields of medicine, including surgery [10], hematology [11] and most interestingly, trauma [12], due to its effectiveness in reducing both bleeding and mortality. The promising results and the lack of synthesis in the emergency setting of TXA administration have inspired us to conduct this meta-analysis on the safety and efficacy of TXA use in this environment. Therefore, we conducted a meta-analysis on the use of TXA in civil and military settings and its impact on in-hospital mortality (survival to hospital discharge or 30-day survival), ICU, hospital length of stay, and incidence of adverse events (myocardial infarct or central nervous system failure), as well as the effect of TXA on the volume of blood product transfusion. 2. Materials and Methods This systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [13]. For this meta-analysis, neither ethics committee approval nor patient consent were required. 2.1. Literature Search A systematic review of the literature using PubMed, Scopus, EMBASE, Web of Science, and the Cochrane Central Register and Controlled Trials (CENTRAL) database was con- ducted from inception to 10 January 2021 with the following search strategy: “tranexamic acid” OR “tranexamic” OR “TXA” OR “hemorrhage control” AND “injuries*” OR “trauma” OR “wounds” AND “prehospital” OR “military” OR “combat” OR “civil*” OR “emergency medicine” OR “ER” OR “ED”. We also searched gray literature repositories such as Google Scholar. Finally, we manually retrieved and further reviewed references to TXA in eligible articles and systematic reviews. 2.2. Eligibility Criteria Studies included in this meta-analysis fulfilled the following criteria (PICOS): (1) par- ticipants, patients with injury 18 years old or older; (2) intervention, tranexamic acid treatment; (3) comparison, non-TXA treatment; (4) outcomes, detailed information for sur- vival; (5) study design, randomized controlled trials, quasi-randomized or observational studies comparing TXA and non-TXA care for their effects in patients with cardiac arrest. Studies were excluded if they were reviews, animal studies, case reports, letters, conference or poster abstracts, or articles not containing original data or focusing on brain injury. 2.3. Data Extraction Raw data were extracted by using a standardized, premade form. We were careful to avoid inclusion of data from duplicate publications. In any case of suspected data discrepancies, we contacted the relevant author directly. Data extracted from eligible studies included the following characteristics: study and year, country, type of participants, J. Clin. Med. 2021, 10, 1030 3 of 12 number of participants, types of therapy, mortality rate, and adverse event occurrence. Two authors (M.A.-J. and W.W.) independently performed the literature search, study selec- tion, and extraction of the baseline characteristics and outcome measures. Disagreements between the authors regarding values or analysis assignments were resolved through discussion with a third researcher (L.S.), and the decision was taken by the majority of the researchers. 2.4. Assessment of Risk of Bias Two investigators (A.G. and L.S.) independently extracted individual study data and evaluated studies for risk of bias. Any disagreements were discussed and resolved in a consensus meeting with the third reviewer (M.J.J.). The ROBINS-I tool (tool to assess risk of bias in non-randomized studies of interventions) was used to assess the quality of non- randomized trials [14] and the RoB 2 tool (revised tool for risk of bias in randomized trials) was used to assess the quality of randomized studies [15]. The Robvis application was used to visualize risk of bias assessments [16]. The scale has seven main domains (confounding, participant selection, classification of interventions, deviation from interventions, missing data, outcome measurement, and selection of reported results) and assigns one point for each of the following four judgements: critical, serious, moderate, and low. The review authors’ judgments about each risk of bias item are provided in Figures S1–S4. 2.5. Outcomes and Subgroups The primary outcome of the current meta-analysis was survival to hospital discharge or 30-day survival. The secondary outcomes were adverse events and other survival period rates. In addition, a subgroup analysis was performed with groups based on the civilian and combat applications of TXA. 2.6. Statistical Analysis All statistical analyses were performed with Review Manager Software 5.4 (The Cochrane Collaboration, Oxford, Copenhagen, Denmark) [17]. The outcomes were summa- rized using the Mantel–Haenszel odds ratios (ODs) or mean differences (MDs). All results are presented with their 95% confidence interval (CI). When the continuous outcome was reported in a study as median, range, and interquartile range, we estimated means and standard deviations using the formula described by Hozo et al. [18].