TXA in Trauma Update PDF

Tra n e x a m i c A c i d U p d a t e i n Trau m a a b a, Ricardo J. Ramirez, MD , Philip C. Spinella, MD , Grant V. Bochicchio, MD, MPH * KEYWORDS  Trane...

Tra n e x a m i c A c i d U p d a t e i n Trau m a a b a, Ricardo J. Ramirez, MD , Philip C. Spinella, MD , Grant V. Bochicchio, MD, MPH * KEYWORDS  Tranexamic acid  Trauma  Coagulopathy  Hemorrhage  Antifibrinolytics  Surgery KEY POINTS  Tranexamic acid (TXA), a synthetic lysine derivative, has previously shown efficacy for reducing blood loss in several surgical procedures.  TXA has shown a mortality benefit in bleeding trauma patients when administered within 3 hours of injury; however, there is no decrease in blood product transfusions.  Pharmacokinetics and optimal dosing in trauma patients remain unknown.  Ongoing and future trials are needed to refine current understanding of TXA’s mecha- nisms of action in trauma patients and to optimize drug administration. INTRODUCTION Trauma is the leading cause of death and disability worldwide, with an estimated 5.8 million people dying every year as a result of traumatic injury.1,2 In both military and civilian settings, hemorrhage remains the most common cause of preventable death after traumatic injury.3–6 In recent years, there has been considerable interest in anti- fibrinolytic agents for the prevention of hemorrhagic death in severe trauma patients. The Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage (CRASH)-2 and Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) studies were pivotal, landmark studies that brought the antifibrinolytic agent tranexamic acid (TXA) to the forefront of discussion after evidence suggested improved mortality in civilian and military trauma, respectively.7,8 Based on results Conflicts of Interest: Drs G.V. Bochicchio and P.C. Spinella are principal investigators of the TAMPITI trial being funded by the United States Department of Defense. Dr R.J. Ramirez has declared no conflicts of interest. a Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA; b Department of Pediatrics, Washington University School of Medi- cine, St Louis, MO, USA * Corresponding author. Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, CB 8109, St Louis, MO 63110. E-mail address: [email protected] Crit Care Clin 33 (2017) 85–99 http://dx.doi.org/10.1016/j.ccc.2016.08.004 criticalcare.theclinics.com 0749-0704/17/ª 2016 Published by Elsevier Inc. Downloaded from ClinicalKey.com at University of Kentucky December 19, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved. 86 Ramirez et al from the CRASH-2 trial, in March of 2011, TXA was added to the World Health Orga- nization’s list of essential medications. However, widespread adoption by mature trauma systems in the United States has been slow due to concerns about unknown exact mechanism of action, uncertainty surrounding use in patients with concomitant traumatic brain injury (TBI), unknown precise pharmacokinetics in the trauma patient, and safety.9–11 The results of these landmark studies sparked worldwide debate and prompted funding for several trials to address these and other concerns.12–18 This article provides a brief overview of the history of TXA, reviews the known and proposed mechanisms of action, and examines areas of ongoing and future research aimed at addressing unanswered questions. BACKGROUND TXA is a synthetic lysine derivative that exerts its action by competitively occupying the lysine binding site of plasminogen, thereby blocking interaction with fibrin and sub- sequent clot breakdown.19 TXA has a molecular weight of 157.2 g/mol and its inject- able formulation is marketed under the name Cyklokapron. The pharmacokinetics of TXA in healthy individuals after administration of a 10 mg/kg dose demonstrate peak concentrations at 60 minutes postadministration, with a half-life of approximately 2 hours for the terminal elimination phase, and 90% excretion at 24 hours. An antifibri- nolytic dose remains in tissues for up to 17 hours and in serum for up to 8 hours. It has also been shown to cross the placental barrier, is excreted in breast milk, and rapidly appears in synovial fluids.20 The pharmacokinetics in trauma patients may differ, how- ever, and appropriate dosing in this population may not be reflective of clinically effec- tive concentrations previously described in healthy individuals. Pharmacokinetics and effects of TXA on hemostasis and immune systems are currently subjects of large ongoing trials with US government funding.12,13,15 In 1986, the Food and Drug Administration (FDA) approved intravenous administra- tion of TXA for the indication of prevention or reduction of bleeding in patients with he- mophilia undergoing dental procedures. The oral form of TXA, marketed under the brand name Lysteda, was approved by the FDA in 2009 to control heavy menstrual bleeding.21 The drug has also been widely studied for the reduction of bleeding in car- diopulmonary bypass (CPB) surgery22–29 and orthopedic procedures,30 including its applicability in spine,31 knee,32 and shoulder surgery.33 In the 1990s and early 2000s, the antiinflammatory properties of antifibrinolytics were recognized in patients undergoing CPB surgery. In 2007, Jimenez and colleagues26 published a paper con- firming this observation. The same year, Brohi and colleagues34 described the protein C pathway and its important role in the development of coagulopathy and hyperfibri- nolysis following trauma. This important work gave rise to new interest in antifibrino- lytics and their effects on the intimate relationship that exists between inflammatory and coagulation pathways. A 2012 meta-analysis of surgical studies evaluating TXA included 129 trials (1972 through 2011) with 10,488 subjects mostly in elective surgical procedures, the majority for cardiac surgery. Pooled results from 95 trials evaluating risk of blood product trans- fusion demonstrated that TXA had a 38% risk reduction of perioperative blood product administration (pooled relative risk [RR] 0.62, 95% confidence interval [CI] 0.58–0.65, P 5.001). With adequate allocation concealment, 32 trials showed similar results (pooled RR 0.68, 95% CI 0.62–0.74, P 5.001) and the same was true of 69 trials with adequate blinding (pooled RR 0.63, 95% CI 0.59–0.68, P 5.001). When analyzing the effect of TXA on death, they found that fewer deaths occurred in the TXA group (RR 0.61, 95% CI 0.38–0.98, P 5.04). However, when evaluating only those studies with Downloaded from ClinicalKey.com at University of Kentucky December 19, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.  Tranexamic Acid Update in Trauma 87 adequate concealment, there was uncertainty (RR 0.67, CI 0.33–1.34, P 5.25). Their analysis of TXA’s effect on thromboembolic events also yielded inconclusive results.35 Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage-2 Trial The CRASH-2 trial was a randomized placebo controlled trial carried out in 274 hos- pitals in 40 countries that evaluated the effects of TXA in 20,211 adult trauma subjects who had significant bleeding or were at risk for significant bleeding.8 The design of the study was pragmatic and enrollment in the study depended on whether a responsible doctor was “substantially uncertain about whether or not to treat with TXA.” In other words, those subjects that had either a clear indication or contraindication for admin- istration of antifibrinolytics were excluded. Subjects arriving within 8 hours of injury were randomly assigned to receive a 1 g bolus over 10 minutes followed by a 1 g infu- sion over 8 hours, or matching placebo. Primary outcome was death in hospital within 4 weeks of injury. The study reported a reduction in all-cause mortality of 14.5% in the treatment group versus 16.0% in the placebo group (RR 0.91, 95% CI 0.85–0.97, P 5.0035). A reduction in the risk of death due to bleeding of 4.9% vs 5.7% was also reported (RR 0.85, 95% CI 0.76–0.96, P 5.0077). Vascular occlusive events, including myocardial infarction (MI), stroke, deep vein thrombosis, and pulmonary em- bolism were similar in both groups. There was no significant difference in number of transfusions, need for surgery, or amount of blood products transfused, and baseline demographics for each group were similar.8 In post hoc analysis, it was confirmed that early treatment with TXA was most effective. Subjects for whom the drug was started within 1 hour of injury had the greatest benefit, with nearly a one-third reduction in risk of death due to bleeding (RR 0.68, 95% CI 0.57–0.82, P