Efficacy and safety of the second in-hospital dose of tranexamic acid after receiving the prehospital dose: double-blind randomized controlled clinical trial in a level 1 trauma center

Ayman El-Menyar, Khalid Ahmed, Suhail Hakim, Ahad Kanbar, Saji Mathradikkal, Tariq Siddiqui, Hisham Jogol, Basil Younis, Ibrahim Taha, Ismail Mahmood, Ahmed Ajaj, Sajid Atique, Abubaker Alaieb, Ahmed Abdel-Aziz Bahey, Mohammad Asim, Guillaume Alinier, Nicholas R Castle, Ahammed Mekkodathil, Sandro Rizoli, Hassan Al-Thani, Ayman El-Menyar, Khalid Ahmed, Suhail Hakim, Ahad Kanbar, Saji Mathradikkal, Tariq Siddiqui, Hisham Jogol, Basil Younis, Ibrahim Taha, Ismail Mahmood, Ahmed Ajaj, Sajid Atique, Abubaker Alaieb, Ahmed Abdel-Aziz Bahey, Mohammad Asim, Guillaume Alinier, Nicholas R Castle, Ahammed Mekkodathil, Sandro Rizoli, Hassan Al-Thani

Abstract

Background: Prehospital administration of tranexamic acid (TXA) to injured patients is increasing worldwide. However, optimal TXA dose and need of a second infusion on hospital arrival remain undetermined. We investigated the efficacy and safety of the second in-hospital dose of TXA in injured patients receiving 1 g of TXA in the prehospital setting. We hypothesized that a second in-hospital dose of TXA improves survival of trauma patients.

Methods: A prospective, double-blind, placebo-controlled randomized, clinical trial included adult trauma patients receiving 1 g of TXA in the prehospital settings. Patients were then blindly randomized to Group I (second 1-g TXA) and Group II (placebo) on hospital arrival. The primary outcome was 24-h (early) and 28-day (late) mortality. Secondary outcomes were thromboembolic events, blood transfusions, hospital length of stay (HLOS) and organs failure (MOF).

Results: A total of 220 patients were enrolled, 110 in each group. The TXA and placebo groups had a similar early [OR 1.000 (0.062-16.192); p = 0.47] and late mortality [OR 0.476 (95% CI 0.157-1.442), p = 0.18].The cause of death (n = 15) was traumatic brain injury (TBI) in 12 patients and MOF in 3 patients. The need for blood transfusions in the first 24 h, number of transfused blood units, HLOS, thromboembolic events and multiorgan failure were comparable in the TXA and placebo groups. In seriously injured patients (injury severity score > 24), the MTP activation was higher in the placebo group (31.3% vs 11.10%, p = 0.13), whereas pulmonary embolism (6.9% vs 2.9%, p = 0.44) and late mortality (27.6% vs 14.3%, p = 0.17) were higher in the TXA group but did not reach statistical significance.

Conclusion: The second TXA dose did not change the mortality rate, need for blood transfusion, thromboembolic complications, organ failure and HLOS compared to a single prehospital dose and thus its routine administration should be revisited in larger and multicenter studies.

Trial registration: ClinicalTrials.gov Identifier: NCT03846973.

Keywords: Bleeding; Prehospital; Randomized controlled trial; Tranexamic acid; Trauma.

Conflict of interest statement

The authors declare that they have no conflict of interest.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Study flow diagram for the hospital tranexamic acid (TXA) and control group. TXA tranexamic acid; ISS injury severity score; AIS abbreviated injury score; SBP: systolic blood pressure
Fig. 2
Fig. 2
Comparison of outcomes by treatment groups (second dose of TXA vs placebo)
Fig. 3
Fig. 3
Survival rate 28 days post-injury (Group I TXA vs Group II placebo): log rank (Mantel–Cox) (p = 0.18), Breslow (generalized Wilcoxon) (p = 0.19), and Tarone–Ware (p = 0.19)
Fig. 4
Fig. 4
comparison of the outcomes among severely injured patients with injury severity score > 24

References

    1. Almuwallad A, Cole E, Ross J, et al. The impact of prehospital TXA on mortality among bleeding trauma patients: a systematic review and meta-analysis. J Trauma Acute Care Surg. 2021;90(5):901–907. doi: 10.1097/TA.0000000000003120.
    1. Perel P, Prieto-Merino D, Shakur H, et al. Predicting early death in patients with traumatic bleeding: development and validation of prognostic model. BMJ. 2012;15(345):e5166. doi: 10.1136/bmj.e5166.
    1. Sobrino J, Shafi S. Timing and causes of death after injuries. Proc Baylor Univ Med Cent. 2013;26(2):120–123. doi: 10.1080/08998280.2013.11928934.
    1. Niles SE, McLaughlin DF, Perkins JG, et al. Increased mortality associated with the early coagulopathy of trauma in combat casualties. J Trauma. 2008;64(6):1459–1463.
    1. Kauvar D, Lefering R, Wade C. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma. 2006;60(6 Suppl):S3–11.
    1. Sauaia A, Moore FA, Moore EE, et al. Epidemiology of trauma deaths: a reassessment. J Trauma. 1995;38(2):185–193. doi: 10.1097/00005373-199502000-00006.
    1. Paudyal P, Smith J, Robinson M, et al. Tranexamic acid in major trauma: implementation and evaluation across South West England. Eur J Emerg Med. 2017;24(1):44–48. doi: 10.1097/MEJ.0000000000000323.
    1. MacLeod JB, Lynn M, McKenney MG, et al. Early coagulopathy predicts mortality in trauma. J Trauma. 2003;55(1):39–44. doi: 10.1097/01.TA.0000075338.21177.EF.
    1. Brown JB, Neal MD, Guyette FX, et al. Design of the Study of Tranexamic Acid during AirMedical Prehospital Transport (STAAMP) Trial: addressing the knowledge gaps. Prehosp Emerg Care. 2015;19(1):79–86. doi: 10.3109/10903127.2014.936635.
    1. Roberts I. Tranexamic acid in trauma: How should we use it? J Thromb Haemost. 2015;13:S195–S199. doi: 10.1111/jth.12878.
    1. Jawa RS, Singer A, McCormack JE, et al. Tranexamic acid use in united states trauma centers: a national survey. Am Surg. 2016;82(5):439–447. doi: 10.1177/000313481608200520.
    1. Napolitano LM. Prehospital tranexamic acid: what is the current evidence? Trauma Surg Acute Care Open. 2017;2(1):e000056. doi: 10.1136/tsaco-2016-000056.
    1. Boudreau RM, Deshpande KK, Day GM, et al. Prehospital tranexamic acid administration during aeromedical transport after injury. J Surg Res. 2019;233:132–138. doi: 10.1016/j.jss.2018.07.074.
    1. Fisher AD, Carius BM, April MD, et al. An analysis of adherence to tactical combat casualty care guidelines for the administration of tranexamic acid. J Emerg Med. 2019;57(5):646–652. doi: 10.1016/j.jemermed.2019.08.027.
    1. Shakur H, Roberts I, Bautista R, et al. 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. doi: 10.1016/S0140-6736(10)60835-5.
    1. Vu EN, Schlamp RS, Wand RT, et al. Prehospital use of tranexamic acid for hemorrhagic shock in primary and secondary air medical evacuation. Air Med J. 2013;32(5):289–292. doi: 10.1016/j.amj.2013.05.001.
    1. Lipsky AM, Abramovich A, Nadler R, et al. Tranexamic acid in the prehospital setting: Israel Defense Forces' initial experience. Injury. 2014;45(1):66–70. doi: 10.1016/j.injury.2013.08.025.
    1. Wafaisade A, Lefering R, Bouillon B, Trauma Register DGU et al. Prehospital administration of tranexamic acid in trauma patients. Crit Care. 2016;20(1):143. doi: 10.1186/s13054-016-1322-5.
    1. Nishijima DK, Kuppermann N, Roberts I, et al. The effect of tranexamic acid on functional outcomes: an exploratory analysis of the CRASH-2 randomized controlled trial. Ann Emerg Med. 2019;74(1):79–87. doi: 10.1016/j.annemergmed.2018.11.018.
    1. El-Menyar A, Sathian B, Asim M, et al. Efficacy of prehospital administration of tranexamic acid in trauma patients: a meta-analysis of the randomized controlled trials. Am J Emerg Med. 2018;36(6):1079–1087. doi: 10.1016/j.ajem.2018.03.033.
    1. Al-Jeabory M, Szarpak L, Attila K, et al. Efficacy and safety of tranexamic acid in emergency trauma: a systematic review and meta-analysis. J Clin Med. 2021;10(5):1030. doi: 10.3390/jcm10051030.
    1. Lawati KA, Sharif S, Maqbali SA, et al. Efficacy and safety of tranexamic acid in acute traumatic brain injury: a systematic review and meta-analysis of randomized-controlled trials. Intensive Care Med. 2021;47(1):14–27. doi: 10.1007/s00134-020-06279-w.
    1. Yokobori S, Yatabe T, Kondo Y, Kinoshita K, Japan Resuscitation Council (JRC) Neuroresuscitation Task Force and the Guidelines Editorial Committee Efficacy and safety of tranexamic acid administration in traumatic brain injury patients: a systematic review and meta-analysis. J Intensive Care. 2020;8:46. doi: 10.1186/s40560-020-00460-5.
    1. Roberts I, Shakur H, Afolabi A, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011;377:1096–1101. doi: 10.1016/S0140-6736(11)60317-6.
    1. 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. doi: 10.1016/S0140-6736(19)32233-0.
    1. July J, Pranata R. Tranexamic acid is associated with reduced mortality, hemorrhagic expansion, and vascular occlusive events in traumatic brain injury - meta-analysis of randomized controlled trials. BMC Neurol. 2020;20(1):119. doi: 10.1186/s12883-020-01694-4.
    1. Grassin-Delyle S, Theusinger OM, Albrecht R, et al. Optimisation of the dosage of tranexamic acid in trauma patients with population pharmacokinetic analysis. Anaesthesia. 2018;73(6):719–729. doi: 10.1111/anae.14184.
    1. Guo J, Gao X, Ma Y, et al. Different dose regimes and administration methods of tranexamic acid in cardiac surgery: a meta-analysis of randomized trials. BMC Anesthesiol. 2019;19:129. doi: 10.1186/s12871-019-0772-0.
    1. Pabinger I, Fries D, Schöchl H, et al. Tranexamic acid for treatment and prophylaxis of bleeding and hyperfibrinolysis. Wien Klin Wochenschr. 2017;129(9–10):303–316. doi: 10.1007/s00508-017-1194-y.
    1. Morrison JJ, Dubose JJ, Rasmussen TE, et al. Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) study. Arch Surg. 2012;147(2):113–119. doi: 10.1001/archsurg.2011.287.
    1. Roberts I, Shakur-Still H, Afolabi A, et al. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet. 2020;395(10241):1927–1936. doi: 10.1016/S0140-6736(20)30848-5.
    1. Mitra B, Bernard S, Gantner D, PATCH-Trauma study investigators; PATCH-Trauma Study investigators et al. Protocol for a multicentre prehospital randomised controlled trial investigating tranexamic acid in severe trauma: the PATCH-Trauma trial. BMJ Open. 2021;11(3):46522. doi: 10.1136/bmjopen-2020-046522.
    1. Walsh K, O'Keeffe F, Mitra B. Geographical variance in the use of tranexamic acid for major trauma patients. Medicina (Kaunas) 2019;55(9):561. doi: 10.3390/medicina55090561.
    1. 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(1):11–20.
    1. El-Menyar A, Sathian B, Wahlen BM, et al. Prehospital administration of tranexamic acid in trauma patients: A 1:1 matched comparative study from a level 1 trauma center. Am J Emerg Med. 2020;38(2):266–271. doi: 10.1016/j.ajem.2019.04.051.
    1. Stansfield R, Morris D, Jesulola E. The use of tranexamic acid (TXA) for the management of hemorrhage in trauma patients in the prehospital environment: literature review and descriptive analysis of principal themes. Shock. 2020;53(3):277–283. doi: 10.1097/SHK.0000000000001389.
    1. Association of Ambulance Chief Executives . JRCALC clinical guidelines 2019. Bridgwater: Class Professional Publishing; 2019.
    1. Al-Thani H, Mekkodathil A, Hertelendy AJ, et al. Emergency medical services (EMS) transportation of trauma patients by geographic locations and in-hospital outcomes: experience from Qatar. Int J Environ Res Public Health. 2021;18:4016. doi: 10.3390/ijerph18084016.
    1. Wilson P, Alinier G, Reimann T, Morris B. Influential factors on urban and rural response times for emergency ambulances in Qatar. Mediterr J Emerg Med. 2018;26:8–13.
    1. Hutton D, Alinier G. Ambulance service operational improvement. Int Paramed Pract. 2013;3(3):61–63. doi: 10.12968/ippr.2013.3.3.61.
    1. Gangaram P, Alinier G, Menacho AM. Crisis resource management in emergency medical settings in Qatar. Int Paramed Pract. 2017;7(2):18–23. doi: 10.12968/ippr.2017.7.2.18.
    1. El-Menyar A, Abdelrahman H, Alhammoud A, Ghouri SI, Babikir E, Asim M, Mekkodathil A, Al-Thani H. Prognostic role of shock index in traumatic pelvic fracture: a retrospective analysis. J Surg Res. 2019;243:410–418. doi: 10.1016/j.jss.2019.05.062.
    1. Palmer C. Major trauma and the injury severity score–where should we set the bar? Annu Proc Assoc Adv Automot Med. 2007;51:13–29.
    1. Neeki MM, Dong F, Toy J, et al. Efficacy and safety of tranexamic acid in prehospital traumatic hemorrhagic shock: outcomes of the Cal-PAT Study. West J Emerg Med. 2017;18(4):673–683. doi: 10.5811/westjem.2017.2.32044.
    1. van Wessem KJP, Leenen LPH. Does liberal prehospital and in-hospital tranexamic acid influence outcome in severely injured patients? a prospective cohort study. World J Surg. 2021;45(8):2398–2407. doi: 10.1007/s00268-021-06143-y.
    1. Huebner BR, Dorlac WC, Cribari C. Tranexamic acid use in prehospital uncontrolled hemorrhage. Wilderness Environ Med. 2017;28(2S):S50–S60. doi: 10.1016/j.wem.2016.12.006.
    1. Zickenrott V, Greb I, Henkelmann A, et al. Tranexamic acid in the German emergency medical service: a national survey. Anaesthesist. 2017;66(4):249–255. doi: 10.1007/s00101-017-0277-5.
    1. Neeki MM, Dong F, Toy J, et al. Tranexamic acid in civilian trauma care in the California prehospital antifibrinolytic therapy study. West J Emerg Med. 2018;19(6):977–986. doi: 10.5811/westjem.2018.8.39336.
    1. Nadler R, Gendler S, Benov A, et al. Tranexamic acid at the point of injury: the Israeli combined civilian and military experience. J Trauma Acute Care Surg. 2014;77(Suppl. 2):S146–S150. doi: 10.1097/TA.0000000000000325.
    1. Mrochuk M, Ódochartaigh D, Chang E. Rural trauma patients cannot wait: tranexamic acid administration by helicopter emergency medical services. Air Med J. 2015;34(1):37–39. doi: 10.1016/j.amj.2014.09.004.
    1. Schauer SG, April MD, Naylor JF, et al. Prehospital administration of tranexamic acid by ground forces in Afghanistan: the Prehospital Trauma Registry experience. J Spec Oper Med. 2017;17(3):55–58. doi: 10.55460/7U98-J4HL.
    1. Kunze-Szikszay N, Krack LA, Wildenauer P, et al. The pre-hospital administration of tranexamic acid to patients with multiple injuries and its effects on rotational thrombelastometry: a prospective observational study in pre-hospital emergency medicine. Scand J Trauma Resusc Emerg Med. 2016;24(1):122. doi: 10.1186/s13049-016-0314-4.
    1. Imach S, Wafaisade A, Lefering R, et al. The impact of prehospital tranexamic acid on mortality and transfusion requirements: match-pair analysis from the nationwide German TraumaRegister DGU®. Crit Care. 2021;25(1):277. doi: 10.1186/s13054-021-03701-7.
    1. Edelman DA, White MT, Tyburski JG, Wilson RF. Post-traumatic hypotension: should systolic blood pressure of 90–109 mmHg be included? Shock. 2007;27(2):134–138. doi: 10.1097/01.shk.0000239772.18151.18.
    1. Moore HB, Moore EE, Huebner BR, et al. Tranexamic acid is associated with increased mortality in patients with physiological fbrinolysis. J Surg Res. 2017;220:438–443. doi: 10.1016/j.jss.2017.04.028.
    1. Meizoso JP, Dudaryk R, Mulder MB, et al. Increased risk of fbrinolysis shutdown among severely injured trauma patients receiving tranexamic acid. J Trauma Acute Care Surg. 2018;84(3):426–432. doi: 10.1097/TA.0000000000001792.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner