The primary outcome measures of the analysis are demonstrated in Table 3. Patients who received TXA had a lower 6-hour mortality rate (16% vs. 34%, p = 0.04) and a higher 24 hour transfusion of plasma (15 vs. 10 units, p = 0.03) within the first 24 hours compared with the No-TXA group. However, there were no differences in 12- (p = 0.24), 18- (p = 0.16), and 24-hour (p = 0.25) and 30-day mortality rates (p = 0.82). Similarly, there were no differences in the transfusion of RBC (p = 0.11) or platelets (p = 0.13) within the first 24 hours, time to achieve hemostasis (p = 0.65), or rebleeding requiring intervention (p = 0.13). The most common cause of death was exsanguination/hemorrhagic shock (30%), followed by traumatic brain injury (TBI; 12%). Additionally, there was no difference in cause of death between the two groups.
The secondary outcome measures of the analysis are demonstrated in Table 4. Patients who received TXA were more likely to develop SIRS (p = 0.007), AKI (p = 0.01), sepsis (p = 0.04), and multiple organ failure (p = 0.01) compared with the No-TXA group. However, there was no difference in the rate of DVT (p = 0.59), PE symptomatic (p = 1.00) or asymptomatic (p = 0.55), infections (p = 0.46), ARDS (p = 0.77), and stroke (p = 1.00). Moreover, hospital LOS (p = 0.30), ICU-free days (p = 0.22), and ventilator-free days (p = 0.52) were similar in both groups.
On subanalysis based on blood product resuscitation ratio, patients who received TXA in the 1:1:1 group had similar 6- (p = 0.31), 12- (p = 0.76), 18- (p = 0.76), and 24-hour (p = 0.82) and 30-day (p = 0.93) mortality rates as well as time to achieve hemostasis (p = 0.65). Patients who received TXA in the 1:1:2 group had lower 18- (7% vs. 39%, p = 0.03) and 24-hour (7% vs. 42%, p = 0.02) mortality rates compared with the No-TXA group. However, there was no difference between the two groups in the 6- (p = 0.07) and 12-hour (p = 0.07) and 30-day (p = 0.55) mortality rates or the time to achieve hemostasis (p = 0.48). The subanalysis based on blood product resuscitation ratio is summarized in Table 5.
In our multicenter propensity-matched analysis of severely injured trauma patients with admission hyperfibrinolysis, TXA administration within 3 hours of injury was not associated with improved 24-hour or 30-day survival. Moreover, patients who received TXA were more likely to receive plasma transfusions within 24 hours of admission and had higher rates of 30-day nonthrombotic complications.
The use of TXA has been established in elective surgery. Its use in trauma was revolutionized by the well-known CRASH-2 trial, which was the largest randomized clinical trial in trauma.17 Subsequent observational study of combat casualties demonstrated the survival benefit of TXA in the Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) study, with a 6.5% reduction in mortality.18 However, because of several methodological flaws in the CRASH-2 trials and different injury mechanisms in the MATTERs study, some have questioned the use of TXA in the advanced trauma care system in the United States. In fact, Swendsen et al.,19 van Haren et al.,20 and Valle et al.21 did not report any survival benefit of TXA in trauma patients. Similarly, Howard et al.,22 in a larger military database analysis, did not demonstrate any survival benefit of TXA after combat casualty. Although Valle et al.21 reported a nonstatistical higher mortality rate for patients who received TXA, after excluding patients who were dead on admission, the mortality rate was significantly higher in patients who received TXA. Similarly, Cole et al.23 reported survival benefit of TXA in a subset of trauma patients who had shock on admission; however, TXA failed to show any difference in mortality in all trauma patients. These studies were not focused on the patients who had hyperfibrinolysis, the population proposed to benefit from TXA administration.
In our multicenter analysis, TXA was associated with a lower 6-hour mortality rate, whereas there was no difference in 12-hour, 24-hour, or 30-day mortality rates in severely injured trauma patients who had hyperfibrinolysis on admission. With recent advances, the conventional measure of blood testing has shifted from measuring INR toward TEG. Using TEG, fibrinolysis has been identified as an integral component of coagulopathy of trauma and is associated with a higher mortality rate. Patients who have hyperfibrinolysis on admission have higher rates of mortality with higher hemorrhagic deaths compared with other phenotypes. Taking into consideration the controversial reports of a survival benefit of TXA, and it being an antifibrinolytic agent, we hypothesized that TXA will be most beneficial in patients who have admission hyperfibrinolysis. In our analysis, the 24-hour mortality rate in patients who received TXA was 26% compared with 39% in the No-TXA group. For it to reach significance, we needed a minimum of 176 patients in each group. Moreover, the 30-day mortality rate in patients who received TXA was 45% compared with 45% in the No-TXA group. For it to reach significance, we needed to increase the power of the study to include a minimum of 1,565 patients in each group. Contrary to our hypothesis, we did not see any long-term survival benefit of TXA in such severely injured trauma patients. Similar reports were published by Cotton et al.7 in their single-center study. In their study, there was no difference in the unadjusted and adjusted mortality rate in severely injured trauma patients who had hyperfibrinolysis on admission, regardless of TXA administration. Moreover, Moore et al.16 reported higher rates of an unadjusted mortality rate in trauma patients who had admission hyperfibrinolysis. Although after adjustment, the mortality rate became similar in both groups; increasing the sample size would have achieved a significant difference as they analyzed only 64 patients with admission hyperfibrinolysis, of which only 10 patients received TXA.16
The CRASH-2 trial included trauma patients with suspected hemorrhage; however, only 50% of their population received blood transfusions.17 In our analysis, all patients received at least 1 unit of blood component, which was an inclusion criteria for the PROPPR trial.3 When we analyzed the difference in the transfusion requirements for both groups, patients who received TXA had a trend toward a higher blood product requirement significant for plasma only. This finding might be due to the fact that patients who received TXA lived longer and hence received more blood products. Similar reports were published by Cole et al.,23 who analyzed the role of TXA in a civilian setting. Moreover, Howard et al.22 and Morrison et al.18 reported higher blood product requirements in a combat casualty setting. On the other hand, Shiraishi et al.,24 in their multicenter propensity-matched analysis of all trauma patients admitted to trauma centers in Japan, reported similar transfusion requirements in patients who received TXA or those who did not.
In our analysis, the most common cause of death was exsanguination/hemorrhagic shock, followed by TBI of demonstrating severely injured trauma patients in need of a massive transfusion. Similarly, Harvin et al.25 reported hemorrhage as the most common cause of death in their analysis of trauma patients with admission hyperfibrinolysis. These findings are contrary to the national statistics that show TBI being the most common cause of death.26 Although patients who received TXA had a lower death rate from hemorrhage, but it did not reach statistical significance. Contrary to our results, Harvin et al.25 reported higher unadjusted rates of death from hemorrhage in the TXA group.
It is important to evaluate the safety of any drug used in a clinical setting. Regarding TXA, the literature shows an association of several complications, including venous thromboembolism, fibrinolytic shutdown, seizures, blurry vision, and AKI.27 Our results show that TXA administration is not associated with increased DVT or PE rates. Similar reports were published by the CRASH-2 collaborators and other researchers who studied severely injured trauma patients managed at an advanced trauma system.17,21,25 However, increased risk of VTE has been demonstrated in combat casualty by Howard et al.22 and Morrison et al.18 Interestingly, TXA administration was associated with higher rates of AKI, SIRS, and multiple organ failure; however, there was no difference in infectious complications or stroke. Cole et al.23 also analyzed the association of TXA with nonthrombotic complications. Contrary to our results, they reported no association of TXA with AKI or multiple organ failure. Moreover, there was no difference in rates of stroke or infections in both groups as well.
Interestingly, on subanalysis based on the ratio of blood product resuscitation, TXA administration in 1:1:2 group was associated with lower 18- and 24-hour mortality. However, there was no effect of TXA on mortality in patients who received transfusion in 1:1:1 ratio. It can be explained by the fact that patients in 1:1:1 transfusion group received first platelet pack in first cooler. But the patients in 1:1:2 transfusion group received first platelet pack with second cooler of blood products. This delay in platelet transfusion might be the reason for different results in both groups. The platelets are an important component of coagulation cascade in the body, and an early transfusion of platelets has been demonstrated to improve survival in patients with trauma.28 As the 1:1:2 group received delayed platelets, TXA administration might have caused early hemostasis and improved survival compared with those who did not receive TXA in 1:1:2 group.
This study is not without limitations, and the results should be interpreted in similar contexts. As a secondary review of a randomized clinical trial, it inherits limitations of a retrospective study design, including error caused by confounding variables and bias for patients. Moreover, it is a nonrandomized clinical trial, and the TXA administration was solely based on attending surgeons' discretion, as there is no clearly defined protocol. Another possible limitation is the low number of patients in each group; however, we performed a power analysis based on the previous literature, and the sample size calculated required fewer patients in each group. Trauma patients with hyperfibrinolysis on admission represent a small subset of the overall trauma patients, and the results cannot be generalized to all trauma population. Additionally, as the TXA group had higher 6-hour survival, it might have caused a survival bias in the analysis for complications. Despite these limitations, the PROPPR databank has been used to study severely injured trauma patients admitted to 12 Level 1 trauma centers.
Tranexamic acid was associated with increased 6-hour survival but does not improve long-term outcomes in severely injured trauma patients with hemorrhage who develop hyperfibrinolysis. Tranexamic acid administration was associated with higher rates of nonthrombotic complications. Further randomized clinical trials will identify the subset of trauma patients who may benefit from TXA.
M.K., B.J., F.J., T.O., J.H., M.S., E.B., and C.W. designed this study. M.K., B.J., F.J., M.S., C.W., E.B., and T.O. searched the literature. M.K., B.J., J.H., E.B., M.S, T.O., and C.W. collected the data. M.K., B.J., F.J., and T.O. analyzed the data. All authors participated in data interpretation and manuscript preparation.
The authors thank the PROPPR Study Group for allowing the them to utilize its data set.
Pragmatic, Randomized Optimal Platelet and Plasma Ratios Study Group:
Clinical Coordinating Center: John B. Holcomb, MD; Charles E. Wade, PhD; Deborah J. del Junco, PhD; Erin E. Fox, PhD; Nena Matijevic, PhD; Jeanette Podbielski, RN; Angela M. Beeler, BS.
Data Coordinating Center: Barbara C. Tilley, PhD; Sarah Baraniuk, PhD; Hongjian Zhu, PhD; Joshua Nixon, MS; Roann Seay, MS; Savitri N. Appana, MS; Hui Yang, MS; Michael O. Gonzalez, MS.
Core Laboratory: Lisa Baer, MS; Yao-Wei Willa Wang, MD; Brittany S. Hula, MS; Elena Espino, BS; An Nguyen, BS; Nicholas Pawelczyk, BS; Kisha D. Arora-Nutall, BS; Rishika Sharma, MD; Jessica C. Cardenas, PhD; Elaheh Rahbar, PhD; Tyrone Burnett, Jr., BS; David Clark, BS.
Resuscitation Outcomes Consortium: Gerald van Belle, PhD; Susanne May, PhD; Brian Leroux, PhD; David Hoyt, MD; Judy Powell, BSN, RN; Kellie Sheehan, BSN.
Systems Biology Committee: Alan Hubbard, PhD; Adam P. Arkin, PhD.
Transfusion Committee: John R. Hess, MD; Jeanne Callum, MD.
PROPPR Clinical Sites (listed in order of number of patients enrolled):
University of Texas Health Science Center at Houston: Bryan A. Cotton, MD, MPH; Laura Vincent, BSN, RN, CCRP; Timothy Welch; Tiffany Poole, DC; Evan G. Pivalizza, MD; Sam D. Gumbert, MD; Yu Bai, MD, PhD; James J. McCarthy, MD; Amy Noland, MD; Rhonda Hobbs, MT(ASCP)SBB.
University of Washington: Eileen M. Bulger, MD; Patricia Klotz, RN; Lindsay Cattin, BA; Keir J. Warner, BS; Angela Wilson, BA; David Boman, BA; Nathan White, MD, MS; Andreas Grabinsky, MD; Jennifer A. Daniel-Johnson, MBBS.
University of California, San Francisco: Mitchell Jay Cohen, MD; Rachael A. Callcut, MD, MSPH; Mary Nelson, RN, MPA; Brittney Redick, BA; Amanda Conroy, BA; Marc P. Steurer, MD, DESA; Preston C. Maxim, MD; Eberhard Fiebig, MD; Joanne Moore; Eireen Mallari, MT.
University of Cincinnati: Peter Muskat, MD; Jay A. Johannigman, MD; Bryce R. H. Robinson, MD; Richard D. Branson, MSc, RRT; Dina Gomaa, BS, RRT; Christopher Barczak, BS, MT(ASCP); Suzanne Bennett, MD; Patricia M. Carey, MD; Christopher N. Miller, MD; Helen Hancock, BS, MT(ASCP); Carolina Rodriguez, BA.
University of Southern California: Kenji Inaba, MD; Jay G. Zhu, MD; Monica D. Wong, MS; Michael Menchine, MD, MPH; Kelly Katzberg, MD, FACEP; Sean O. Henderson, MD; Rodney McKeever, MD; Ira A. Shulman, MD; Janice M. Nelson, MD; Christopher W. Tuma, BA, MT(ASCP), SBB; Cheryl Y. Matsushita, BS, MT(ASCP).
Shock, Trauma and Anesthesiology Research - Organized Research Center (STAR-ORC), R Adams Cowley Shock Trauma Center, University of Maryland Medical Center: Thomas M. Scalea, MD; Deborah M. Stein, MD, MPH; Cynthia K. Shaffer, MS, MBA; Christine Wade, BA; Anthony V. Herrera, MS; Seeta Kallam, MBBS; Sarah E. Wade, BS; Samuel M. Galvagno, Jr., DO, PhD; Magali J. Fontaine, MD, PhD; Janice M. Hunt, BS, MT(ASCP) SBB; Rhonda K. Cooke, MD.
University of Tennessee Health Science Center, Memphis: Timothy C. Fabian, MD; Jordan A. Weinberg, MD; Martin A. Croce, MD; Suzanne Wilson, RN; Stephanie Panzer-Baggett, RN; Lynda Waddle-Smith, BSN; Sherri Flax, MD.
Medical College of Wisconsin: Karen J. Brasel, MD, MPH; Pamela Walsh, AS, CCRC; David Milia, MD; Allia Nelson, BS, BA; Olga Kaslow, MD, PhD; Tom P. Aufderheide, MD, MS; Jerome L. Gottschall, MD; Erica Carpenter, MLS(ASCP).
University of Arizona: Terence O'Keeffe, MBChB, MSPH; Laurel L. Rokowski, RN, BSN, MKT; Kurt R. Denninghoff, MD; Daniel T. Redford, MD; Deborah J. Novak, MD; Susan Knoll, MS, MT(ASCP) SBB.
University of Alabama at Birmingham: Jeffrey D. Kerby, MD, PhD; Jean-Francois Pittet, MD (Anesthesia Chair); Patrick L. Bosarge, MD; Albert T. Pierce, MD; Carolyn R. Williams, RN, BSN, BSME; Shannon W. Stephens, EMTP; Henry E. Wang, MD, MS; Marisa B. Marques, MD.
Oregon Health and Science University: Martin A. Schreiber, MD; Jennifer M. Watters, MD; Samantha J. Underwood, MS; Tahnee Groat, MPH; Craig Newgard, MD, MPH; Matthias Merkel, MD, PhD; Richard M. Scanlan, MD; Beth Miller, MT(ASCP)SBB.
Sunnybrook Health Sciences Centre: Sandro Rizoli, MD, PhD; Homer Tien, MD; Barto Nascimento, MD, MSc, CTBS; Sandy Trpcic; Skeeta Sobrian-Couroux, RN, CCRP, BHA; Marciano Reis; Adic Pérez, MD; Susan E. Belo, MD, PhD; Lisa Merkley, BA, MLT, CBTS; Connie Colavecchia, BSc, MLT.
The authors declare no conflicts of interest.
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The investigators of the Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial performed a secondary analysis of the PROPPR database to determine if tranexamic acid (TXA) was beneficial in patients with admission hyperfibrinolysis. The authors found that TXA was associated with increased six hour survival in patients with hyperfibrinolysis, however, TXA did not improve 12-hour, 24-hour, or 30-day mortality. The two most frequently cited articles showing benefit of TXA in trauma patients, CRASH-2 and MATTERs, have been widely criticized for methodological flaws and heterogeneous patient populations. The current study attempts to address these flaws by including only patients who were transfused and who had hyperfibrinolysis at admission, presumably the population of patients who would benefit most from TXA. While studying a more homogeneous population of trauma patients who displayed hyperfibrinolysis and required transfusion, the current study found an improvement in six hour survival, similar to the benefits from TXA seen in CRASH-2 and MATTERs. The lack of benefit seen at longer intervals (12-hour, 24-hour, 30-day) may have been due to a small sample size studied in the very specific subset of the PROPPR population. While thromboembolic events after TXA would seem intuitive as TXA anti-fibrinolytic effects should lead to a hypercoagulable state, the current study found no difference in thromboembolic complications but did find a higher rate of non-thrombotic complications in the TXA group. The higher non-thrombotic complications in the TXA group included acute kidney injury, sepsis, and multisystem organ failure. This increase in non-thromboembolic complications may be related to the fact that the TXA group in the study received more units of plasma transfusion during their resuscitation. The mixed results of this publication add little clarity to the existing and conflicting literature surrounding the use of TXA in trauma patients. Despite the large number of studies published to date that have investigated the use of TXA, controversy remains as to specifically which trauma patients could benefit or be harmed from this therapy. Further well designed prospective, randomized studies are still needed to definitively determine the role of TXA in the care of trauma patients.
Carlos V.R. Brown, MD
Keywords:© 2018 Lippincott Williams & Wilkins, Inc.
Hyperfibrinolysis; resuscitation; tranexamic acid; trauma