Place of tranexamic acid in traumatic brain injury: a systematic review and meta-analysis of randomized controlled trials
Abstract
BACKGROUND: Traumatic brain injury (TBI) is a leading cause of death and disability. In many cases of TBI-related intracranial hemorrhage (ICH) is associated with a high risk of coagulopathy and may lead to an increased risk of hemorrhage growth. Therefore, tranexamic acid (TXA), which is known as an antifibrinolytic agent that reduces bleeding by inhibiting the breakdown of blood clots, might limit ICH expansion.
MATERIAL AND METHODS: We aimed to quantify the effects of TXA in brain injury and thus performed a literaturę search using PubMed, Web of Science, Scopus, EMBASE, and Cochrane Center Register of Controlled Trials (CENTRAL) for studies that were published between the respective database inception, and April 10, 2021.
RESULTS: A total of nine studies were identified; these included 5845 patients treated with, and 5380 treated without TXA. The 28-day or in-hospital mortality was 17.8% for the TXA group, compared with 19.3% for the no-TXA group (OR = 0.92; 95% CI: 0.83, 1.01; p = 0.08). At 6-months follow-up, mortality was 18.3% vs 19.9% (OR = 0.91; 95% CI: 0.63–1.31; p = 0.60), with and without TXA, respectively. A Glasgow Outcome Scale less than 4 points at 28-days follow-up was reported in 3 studies and was 29.8% vs 34.8% (OR = 0.91; 95% CI: 0.45, 1.82; p = 0.78), with and without TXA, respectively. No differences were found in adverse events between TXA and non-TXA groups.
CONCLUSION: Our analysis found showed no statistical significance between TXA and non-TXA treatment of TBI patients, however, in the TXA group a trend to decrease 28-day mortality compared to non-TXA treatment was observed. More high-quality studies are needed to show the significant benefit of using TXA, especially in moderate and severe TBI patient groups.
Keywords: blood conservationantifibrinolytictranexamic acidhemostasishead traumameta-analysis
References
- Evaluation of the Disability Determination Process for Traumatic Brain Injury in Veterans. 2019.
- Maas AIR, Menon DK, Adelson PD, et al. InTBIR Participants and Investigators. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 2017; 16(12): 987–1048.
- de la Tremblaye PB, O'Neil DA, LaPorte MJ, et al. Elucidating opportunities and pitfalls in the treatment of experimental traumatic brain injury to optimize and facilitate clinical translation. Neurosci Biobehav Rev. 2018; 85: 160–175.
- Saatman KE, Duhaime AC, Bullock R, et al. Workshop Scientific Team and Advisory Panel Members. Classification of traumatic brain injury for targeted therapies. J Neurotrauma. 2008; 25(7): 719–738.
- Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet. 1974; 2(7872): 81–84.
- Thal SC, Neuhaus W. The blood-brain barrier as a target in traumatic brain injury treatment. Arch Med Res. 2014; 45(8): 698–710.
- Report to Congress on Mild Traumatic Brain Injury in the United States: Steps to Prevent a Serious Public Health Problem. PsycEXTRA Dataset. 2003.
- Alexander MP. Mild traumatic brain injury: pathophysiology, natural history, and clinical management. Neurology. 1995; 45(7): 1253–1260.
- Johnson WD, Griswold DP. Traumatic brain injury: a global challenge. Lancet Neurol. 2017; 16(12): 949–950.
- Chang R, Cardenas JC, Wade CE, et al. Advances in the understanding of trauma-induced coagulopathy. Blood. 2016; 128(8): 1043–1049.
- Narayan RK, Maas AIR, Servadei F, et al. Traumatic Intracerebral Hemorrhage Study Group. Progression of traumatic intracerebral hemorrhage: a prospective observational study. J Neurotrauma. 2008; 25(6): 629–639.
- Roberts I, Sydenham E. Barbiturates for acute traumatic brain injury. Cochrane Database Syst Rev. 2012; 12: CD000033.
- 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.
- Moher D, Shamseer L, Clarke M, et al. PRISMA-P Group. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015; 4: 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).
- Al-Jeabory M, Gasecka A, Wieczorek W, et al. Efficacy and safety of tranexamic acid in pediatric trauma patients: Evidence from meta-analysis. Am J Emerg Med. 2021 [Epub ahead of print].
- 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(10): 961–974.
- Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019; 366: l4898.
- Sterne JAc, Hernán MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016; 355: i4919.
- McGuinness LA, Higgins JPT. Risk-of-bias VISualization (robvis): An R package and Shiny web app for visualizing risk-of-bias assessments. Res Synth Methods. 2021; 12(1): 55–61.
- Guyatt GH, Oxman AD, Vist GE, et al. GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008; 336(7650): 924–926.
- Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005; 5: 13.
- Higgins JPT, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003; 327(7414): 557–560.
- IntHout J, Ioannidis JPA, Borm GF. The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method. BMC Med Res Methodol. 2014; 14: 25.
- Schober P, Vetter TR. Meta-Analysis in Clinical Research. Anesth Analg. 2020; 131(4): 1090–1091.
- Safiejko K, Smereka J, Filipiak KJ, et al. Effectiveness and safety of hypotension fluid resuscitation in traumatic hemorrhagic shock: a systematic review and meta-analysis of randomized controlled trials. Cardiol J. 2020 [Epub ahead of print].
- Higgins JPT, Altman DG, Gøtzsche PC, et al. Cochrane Bias Methods Group, Cochrane Statistical Methods Group. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011; 343: d5928.
- Chakroun-Walha O, Samet A, Jerbi M, et al. Benefits of the tranexamic acid in head trauma with no extracranial bleeding: a prospective follow-up of 180 patients. Eur J Trauma Emerg Surg. 2019; 45(4): 719–726.
- 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.
- Fakharian E, Abedzadeh-Kalahroudi M, Atoof F. Effect of Tranexamic Acid on Prevention of Hemorrhagic Mass Growth in Patients with Traumatic Brain Injury. World Neurosurg. 2018; 109: e748–e753.
- Jokar A, Ahmadi K, Salehi T, et al. The effect of tranexamic acid in traumatic brain injury: A randomized controlled trial. Chin J Traumatol. 2017; 20(1): 49–51.
- Mojallal F, Nikooieh M, Hajimaghsoudi M, et al. The effect of intravenous tranexamic acid on preventing the progress of cerebral hemorrhage in patients with brain traumatic injuries compared to placebo: A randomized clinical trial. Med J Islam Repub Iran. 2020; 34: 107.
- Mousavinejad M, Mozafari J, Ilkhchi RB, et al. Intravenous Tranexamic Acid for Brain Contusion with Intraparenchymal Hemorrhage: Randomized, Double-Blind, Placebo-Controlled Trial. Rev Recent Clin Trials. 2020; 15(1): 70–75.
- Perel P, Al-Shahi Salman R, Kawahara T, et al. CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage) intracranial bleeding study: the effect of tranexamic acid in traumatic brain injury--a nested randomised, placebo-controlled trial. Health Technol Assess. 2012; 16(13): iii–xii, 1.
- Yutthakasemsunt S, Kittiwatanagul W, Piyavechvirat P, et al. Tranexamic acid for patients with traumatic brain injury: a randomized, double-blinded, placebo-controlled trial. BMC Emerg Med. 2013; 13: 20.
- Sprigg N, Flaherty K, Appleton JP, et al. Tranexamic acid to improve functional status in adults with spontaneous intracerebral haemorrhage: the TICH-2 RCT. Health Technol Assess. 2019; 23(35): 1–48.
- Roberts I, Edwards P, Prieto D, et al. Tranexamic acid in bleeding trauma patients: an exploration of benefits and harms. Trials. 2017; 18(1): 48.
- Murkin JM, Falter F, Granton J, et al. High-dose tranexamic Acid is associated with nonischemic clinical seizures in cardiac surgical patients. Anesth Analg. 2010; 110(2): 350–353.
- Myers SP, Kutcher ME, Rosengart MR, et al. Tranexamic acid administration is associated with an increased risk of posttraumatic venous thromboembolism. J Trauma Acute Care Surg. 2019; 86(1): 20–27.
- Cole E, Davenport R, Willett K, et al. Tranexamic acid use in severely injured civilian patients and the effects on outcomes: a prospective cohort study. Ann Surg. 2015; 261(2): 390–394.
- Yoshizaki S, Kijima K, Hara M, et al. Tranexamic acid reduces heme cytotoxicity via the TLR4/TNF axis and ameliorates functional recovery after spinal cord injury. J Neuroinflammation. 2019; 16(1): 160.
- Spinella PC, Thomas KA, Turnbull IR, et al. TAMPITI Investigators. The Immunologic Effect of Early Intravenous Two and Four Gram Bolus Dosing of Tranexamic Acid Compared to Placebo in Patients With Severe Traumatic Bleeding (TAMPITI): A Randomized, Double-Blind, Placebo-Controlled, Single-Center Trial. Front Immunol. 2020; 11: 2085.
- Hu W, Xin Y, Chen X, et al. Tranexamic Acid in Cerebral Hemorrhage: A Meta-Analysis and Systematic Review. CNS Drugs. 2019; 33(4): 327–336.