Secondary Logo

Share this article on:

Tranexamic acid administration is associated with an increased risk of posttraumatic venous thromboembolism

Myers, Sara P., MD; Kutcher, Matthew E., MD; Rosengart, Matthew R., MD; Sperry, Jason L., MD; Peitzman, Andrew B., MD; Brown, Joshua B., MD; Neal, Matthew D., MD

Journal of Trauma and Acute Care Surgery: January 2019 - Volume 86 - Issue 1 - p 20–27
doi: 10.1097/TA.0000000000002061
AAST 2018 PODIUM PAPER
Editor's Choice

BACKGROUND Tranexamic acid (TXA) is used as a hemostatic adjunct for hemorrhage control in the injured patient and reduces early preventable death. However, the risk of venous thromboembolism (VTE) has been incompletely explored. Previous studies investigating the effect of TXA on VTE vary in their findings. We performed a propensity matched analysis to investigate the association between TXA and VTE following trauma, hypothesizing that TXA is an independent risk factor for VTE.

METHODS This retrospective study queried trauma patients presenting to a single Level I trauma center from 2012 to 2016. Our primary outcome was composite pulmonary embolism or deep vein thrombosis. Mortality, transfusion, intensive care unit and hospital lengths of stay were secondary outcomes. Propensity matched mixed effects multivariate logistic regression was used to determine adjusted odds ratio (aOR) and 95% confidence intervals (95% CI) of TXA on outcomes of interest, adjusting for prespecified confounders. Competing risks regression assessed subdistribution hazard ratio of VTE after accounting for mortality.

RESULTS Of 21,931 patients, 189 pairs were well matched across propensity score variables (standardized differences <0.2). Median Injury Severity Score was 19 (interquartile range, 12–27) and 14 (interquartile range, 8–22) in TXA and non-TXA groups, respectively (p = 0.19). Tranexamic acid was associated with more than threefold increase in the odds of VTE (aOR, 3.3; 95% CI, 1.3–9.1; p = 0.02). Tranexamic acid was not significantly associated with survival (aOR, 0.86; 95% CI, 0.23–3.25; p = 0.83). Risk of VTE remained elevated in the TXA cohort despite accounting for mortality (subdistribution hazard ratio, 2.42; 95% CI, 1.11–5.29; p = 0.03).

CONCLUSION Tranexamic acid may be an independent risk factor for VTE. Future investigation is needed to identify which patients benefit most from TXA, especially given the risks of this intervention to allow a more individualized treatment approach that maximizes benefits and mitigates potential harms.

LEVEL OF EVIDENCE Therapeutic, level III.

From the Department of General Surgery (S.P.M., M.R.R., J.L.S., A.B.P., J.B.B., M.D.N.), The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; and Division of Trauma and Critical Care (M.E.K.), The University of Mississippi Medical Center, Jackson, Mississippi.

Address for reprints: Matthew D. Neal, MD, F1271.2 PUH, 200 Lothrop St, Pittsburgh, PA 15213; email: nealm2@upmc.edu.

This article will be presented as a podium presentation at the 77th Annual Meeting of the AAST and Clinical Congress of Acute Care Surgery and 4th World Trauma Congress, September 26–29, 2018 in San Diego, CA.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.jtrauma.com).

Trauma remains a leading cause of mortality worldwide1 with approximately 30% to 40% of trauma deaths attributed to hemorrhage.2 Thus, hemorrhage control plays a key role in the prevention of trauma related deaths.3 Physiologic ramifications of hemorrhage may be exacerbated by trauma induced coagulopathy. This leads to clotting factor depletion, consumption of platelets and increased clot breakdown in critically injured patients.4 Consequently, there has been increasing interest in the use of hemostatic adjuncts to mitigate early mortality associated with significant bleeding after trauma. Unfortunately, many of these adjuncts are associated with common and serious complications, such as venous thromboembolic (VTE) disease, reported in up to 28% of patients following trauma.5,6 Prior experiences with agents, such as recombinant activated factor VII,7 serve as an admonition to fully investigate adverse thromboembolic events that may result from their administration.

Tranexamic acid (TXA), a synthetic lysine analogue, is an antifibrinolytic that acts both by competitively inhibiting the conversion of circulating plasminogen to plasmin, and, at high concentrations, noncompetitively inhibiting plasmin. The consequent prevention of clot dissolution, while beneficial for the hemorrhaging trauma patient, may potentially heighten risk of VTE by promoting thrombus.8 Previous investigations vary in their conclusions as to whether or not TXA is associated with an increased risk for VTE. The Clinical Randomization of Antifibrinolytic in Significant Hemorrhage 2 (CRASH-2) trial9 and the Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) study10 demonstrated that administration of TXA improved survival without a significant increase in vascular occlusive events. Of note, although differences in VTE among treated and untreated patients in the MATTERs study did not reach statistical significance, raw data demonstrated that pulmonary embolism (PE) and deep vein thrombosis (DVT) occurred more frequently in patients who received TXA than those who did not. A recent investigation of patients at US military combat support hospitals, on the other hand, found treatment with TXA to be an independent risk factor for VTE.11 Subsequent meta-analysis from six observational studies demonstrated a nonsignificant increase in the risk of VTE events associated with TXA administration.12 Significant differences in the heterogeneity of effect size between studies, details of protocols for diagnosis of VTE, and VTE prophylaxis indicate that further studies are necessary to generate high quality data with regard to the effect of TXA on VTE after traumatic injury. To address these issues, we investigated the association of TXA with VTE in the trauma population using a propensity matched cohort analysis approach designed to mitigate heterogeneity between and within groups hypothesizing that TXA administration is associated with an increased risk of VTE.

Back to Top | Article Outline

METHODS

Study Population

Adult patients presenting as trauma activations to a single quaternary referral center between January 2012 and December 2016 were eligible for inclusion. Patients taking prehospital anticoagulation, those with a known history of DVT or PE, or hereditary coagulopathy, and those who had received prehospital TXA as part of a separate trial protocol13 were excluded (Fig. 1). Timing of TXA administration and dose were obtained from trauma-bay, intraoperative, and anesthesia reports in the electronic medical record. Administration of TXA was at the discretion of the treating trauma surgeon and generally recommended by institutional guidelines when massive transfusion (MT) protocol is activated for a patient. This study was approved by the University of Pittsburgh Institutional Review Board (PRO17100418).

Figure 1

Figure 1

Data were retrospectively queried and abstracted from a prospectively collected database capturing all trauma patients. Supplemental injury data for study patients was obtained from institutional trauma registry and electronic health records. For each patient, data pertaining to demographics, reason for admission (i.e., penetrating versus blunt trauma), injury complex and severity (ISS), comorbidities and diagnoses, vital signs, medication history, admission laboratory and diagnostic data, reversal of anticoagulation (e.g., prothrombin complex concentrate, vitamin K, etc.), transfusion requirements, need for operative intervention, and outcomes were abstracted. As missing data did not exceed 5% for all variables collected, imputation methods were deemed unnecessary.

Back to Top | Article Outline

Propensity Score Matching

Propensity score matching was used to reduce selection bias since treatment with TXA was not randomly assigned. As TXA was given at the discretion of the treating clinician in absence of an institutional protocol to guide its administration, the propensity score model was generated to predict the likelihood of receiving this therapy based on clinical characteristics that plausibly influenced providers' decision to administer TXA. This model included age, sex, admission hemoglobin, admission lactate, admission INR, and first systolic blood pressure. Nearest neighbor matching was performed using a 1:1 ratio without replacement and caliper of 0.1 to construct of matched cohort of treatment patients (those receiving TXA) and control patients (those not receiving TXA).14 Balance of covariates used in estimating propensity scores was assessed using standardized differences.15 For a given variable, an absolute standardized difference less than 0.2 was accepted as good balance between TXA and control groups.

Back to Top | Article Outline

Statistical Analysis

The primary outcome was VTE, a composite including both DVT and pulmonary embolus. Venous thromboembolism was diagnosed by ultrasonography (DVT) and/or computed tomography angiography (PE). As our institution does not routinely screen for VTE, this imaging was prompted by clinical suspicion for VTE. Secondary outcomes included in-hospital mortality, transfusion requirement, intensive care unit (ICU) and total hospital length of stay, administration of hemostatic agents, and operative intervention.

Continuous variables were described using median and interquartile range (IQR) or mean and standard deviation (SD). Univariate analyses to determine the association between our exposures and outcomes of interest were performed using Wilcoxon signed-rank test. Survival was analyzed using a mixed effect logistic regression model adjusting for variables relevant to critical illness and survival including renal function, traumatic brain injury, blood product administration, ISS, need for ICU admission, hemodynamics, mechanism of injury, ventilator days, and race. Occurrence of VTE was analyzed using a separate mixed effects logistic regression model adjusting for body weight, renal function, hospital day on which VTE prophylaxis was initiated, type of VTE prophylaxis (i.e., none, subcutaneous heparin, enoxaparin, fondaparinux, other), hip/pelvis/long bone fracture, traumatic brain injury, spinal cord injury, tobacco use, reversal agents, cirrhosis, malignancy, and blood product administration (Supplementary Table 1, http://links.lww.com/TA/B258). A random effect was included for the pair indicator to account for the matched pair design. Model fit was determined by examining percent change in model coefficients after performing residual analysis and dropping outliers (Supplementary Table 2, http://links.lww.com/TA/B259). Discrimination of model predictors was verified by running a c-statistic prior to matching.

A competing risks regression analysis was performed to assess subdistribution hazard ratio (SHR) of VTE after accounting for mortality. Cumulative incidence was then graphed to represent distribution of VTE over time between treated and control patients.

Back to Top | Article Outline

RESULTS

Of the 21,931 patients who presented as trauma activations between January 2012 and December 2016, 217 patients were treated with TXA as an adjunct for hemorrhagic control within 3 hours16 of presentation (Fig. 1). Propensity score matching generated 189 well-matched pairs with absolute standardized differences for propensity score variables less than 0.2 (Fig. 2). Patients who received TXA weighed less, less frequently received VTE prophylaxis, more frequently used tobacco, and had higher rates of penetrating injury than patients who did not receive TXA (Table 1).

Figure 2

Figure 2

TABLE 1

TABLE 1

Back to Top | Article Outline

Association of TXA With VTE

The prevalence of VTE in the treated cohort was 15.3% (n = 29) compared to 7.4% (n = 14) in the untreated cohort. Of these, DVT represented 51.7% and 50.0% cases in the treated and untreated groups, respectively. After adjusting for differences in case mix, treatment with TXA was associated with more than threefold increased risk of VTE (adjusted odds ratio [aOR], 3.26; 95% CI, 1.3–9.1; p = 0.02, Table 2). Adjusting for the competing risk of death did not substantially alter these point estimates (SHR, 2.42; 95% CI, 1.11–5.29; p = 0.027). Cumulative incidence of VTE was higher among patients who received TXA compared with those who did not (Fig. 3).

TABLE 2

TABLE 2

Figure 3

Figure 3

Back to Top | Article Outline

Secondary Outcomes

Tranexamic acid was not associated with survival (aOR, 0.86; 95% CI 0.23–3.25, p = 0.83, Table 2). Venous thromboembolism prophylaxis was less frequently initiated for patients treated with TXA (57% vs. 74%; p < 0.001, Table 3). In unadjusted analysis, patients who received TXA experienced longer ICU length of stays (9.4 days vs. 6.5 days; p < 0.001) as well as overall hospital length of stays (18.2 days vs. 10.9 days; p < 0.001). In our study, 26 of the 29 patients who were treated with TXA and suffered VTE did not receive massive transfusion (MT), defined as greater than 10 units of red blood cells within 24 hours of admission. Of these 29 patients, 22 would have been predicted to require MT by their Assessment of Blood Consumption score.17 Among the 14 untreated patients who developed VTE, 2 required MT. Although patients receiving TXA more frequently required transfusion (89% vs. 69%, p < 0.001) there was no significant difference between treatment with reversal agents (p = 0.24). Untreated patients received fewer units of packed red blood cells, platelets, and fresh frozen plasma (Table 1). Median number of operations differed significantly between untreated and treated cohorts (Table 1).

TABLE 3

TABLE 3

Back to Top | Article Outline

DISCUSSION

This study is among the first to specifically address VTE as a primary outcome after administration of TXA in a civilian population. TXA was found to be an independent risk factor for VTE when comparing treated and untreated cohorts, which were matched based on readily available clinical characteristics that determine propensity to receive TXA therapy. Treatment with TXA was more frequently associated with mortality, transfusion requirement, increased ICU and hospital length of stay, and higher number of operative interventions during admission in univariate analyses. After adjusting for clinically relevant confounders of thromboembolic complications, which were prespecified based on existing literature, patient weight, presence of hip, pelvis, or leg fracture, and red blood cell transfusion were significantly associated with VTE. Mortality was not found to be significantly different between treated and untreated cohorts in an adjusted model.

Our findings diverge from the CRASH-2 trial, which differed in setting, population, and availability of interventions. Specifically, it has been argued that the limited prehospital care in middle- to low-income countries bestows uncertainty with regard to generalizability to our trauma systems.18 Patients eligible for the CRASH-2 study were those for whom the treating physician had uncertainty with regard to the benefit of TXA, further limiting applicability of this subpopulation to our cohort. The patients in our study, though less severely injured than those represented by the MATTERs study, may have sustained more significant injury than those in the CRASH-2 study as 89% of treated patients and 64% of untreated patients required transfusion in our investigation as compared to half of patients in CRASH-2. These differences represent concerns with regard to the applicability and predictability of previous studies that may affect the accuracy of both the mortality benefit and risk of VTE associated with TXA.19

Combat casualty studies have advanced our understanding of the effects of TXA. While others have demonstrated an association between treatment with TXA and VTE,10 critics have expressed concern with regard to the generalizability of these findings to the civilian trauma population.20 Differences in injury mechanism and severity may contribute to the higher incidence of both MT and VTE in military patients. Even in military populations, VTE occurrence varies widely with studies reporting rates as low as 1.8%8 and 4.0%,9 to as high as 15.6%.10 The MATTERs study demonstrated a crude association between TXA and VTE that was no longer significant after a multivariate logistic regression analysis. In our study, while 11.4% of all patients experienced VTE, only 7.4% of individuals who had not received TXA had DVT or PE. Though clinical guidelines aim to direct appropriate use of TXA, there is concern that increased use of TXA in patients who do not require MT may unnecessarily place patients at an increased risk of thrombotic complications. Similarly, in our study, the majority of the patients who were treated with TXA and suffered VTE did not receive MT. Although 76% of these patients would have been predicted to require MT by their Assessment of Blood Consumption score, it is not possible to determine from available data whether TXA administration prevented need for MT. Further investigations are needed to determine whether VTE rates are higher in the subset of patients who receive TXA preemptively but do not require MT.

Prior propensity matched cohort studies have attempted to address benefits and risks associated with TXA administration, though none have specifically investigated the effect of TXA on thromboembolic complications as a primary outcome. One such single-center study investigating a more severely injured subset of trauma patients than the CRASH-2 trial demonstrated that TXA increased transfusion requirement as well as mortality relative to propensity-matched controls who had not received treatment with TXA.21 Subgroup analysis indicated that TXA may confer survival benefit in patients who require less than eight units of blood transfusion or who do not require surgery. Others have suggested that this survival benefit from TXA may be inversely related to transfusion requirement.22–24 Fibrinolysis shutdown25 has been cited as a potential negative effect of the use of antifibrinolytics in severely injured patients. In our study, increased transfusion requirement and unadjusted mortality among those who received TXA compared with those who did not may be related to these processes. Thus, these studies and our data suggest more selective criteria are needed for the administration of TXA to maximize survival and reduce morbidity, especially in light of our findings that TXA increases risk of VTE. Along these lines, further investigations are necessary to elucidate whether the optimal time to administer TXA may be in the prehospital setting12,26 prior to initiation of transfusion or operative intervention. Additionally, risk of VTE may not be increased when limiting TXA therapy to the prehospital setting. In their propensity-matched cohort analysis, Wafaisade et al. found no increased risk of thromboembolism in civilian patients who had received TXA prior to hospital arrival.22

To date, previous investigations have not considered time-to-VTE in trauma populations. Data from nontrauma literature is insufficient and has used arbitrary cutoffs to designate early and late events.27,28 This study adds insight into differences in posttraumatic VTE distribution over time, which might inform criteria for early and late events. Based on the divergence pattern of cumulative incidence in VTE, the curves largely diverge in the second and third week postinjury, suggesting that risk of late, but not early VTE, may be increased in patients who receive TXA compared with those who had not. Further studies are needed to define chronological thresholds as well as clinical markers associated with temporal trends in VTE distribution. Once identified, a more individualized approach to thromboprophylaxis29,30 can be adopted for patients who initially required TXA and in whom hemostasis has been achieved.

Back to Top | Article Outline

Limitations

This study has limitations worth noting. Propensity matching was performed using prospectively collected data from our institution’s trauma database. This represents a tradeoff of limiting the number of included subjects in favor of reducing selection bias. These data were restricted and may not include other important clinical criteria that are factored into the decision to administer TXA. Although previous literature cites the benefits of administering TXA within a 3-hour window from time of injury,15 available data required that time of hospital presentation be used as a proxy for time of injury. As our institution is a tertiary referral center with a wide catchment area, time of injury and presentation may have differed markedly. During the last 18 months of the study period, a randomized trial protocol was underway that included prehospital and variable in-hospital TXA dosing when transported by a large regional air medical service, and these patients were excluded since treatment was blinded and patients could receive variable doses of TXA from none (placebo) to 3 g. Additional data regarding prehospital medication and blood product use that may have guided TXA administration were incomplete. We restricted our propensity model to variables available prior to TXA administration, thus there remained important differences between groups among in-hospital variables after matching that required further adjustment in multivariable models. Thromboelastography data, which may have more accurately assessed coagulopathy, hyperfibrinolysis, and TXA administration31 was limited and therefore not incorporated into our analysis. While our multivariate analysis was intended to adjust for confounding, biases may remain. The analysis cohort is small, limiting our power to detect a significant association between TXA and certain factors, including survival; this is particularly notable if the absolute survival advantage is only 1.5% as seen in CRASH-2. Finally, while it is a possibility that providers who were aware that a patient had received TXA may have had a higher suspicion of thromboembolic events, we do not believe that this was a significant source of surveillance bias. Previous studies on surveillance bias refer to screening practices in asymptomatic patients32,33 rather than symptomatic patients, such as those in our study. Although data are varied, since the existing CRASH2 and MATTERs studies (the TXA investigations par excellence) indicate no significant increase in VTE as a result of TXA administration, it is unlikely that a provider would increase their use of imaging studies for VTE diagnosis based solely on whether a patient received TXA.

Back to Top | Article Outline

CONCLUSION

Previous studies vary both in population of interest and findings with regard to the mortality benefit of TXA and risk of VTE. Our data demonstrates that TXA may be an independent risk factor for VTE development, but was not associated with a survival benefit in this single-center cohort study. Further investigation is needed to identify which injured patients have a survival advantage from TXA, especially given the risks of this intervention. Additionally, the utility of screening for VTE and measures to ensure that prophylaxis is administered rapidly and efficaciously in patients who are treated with TXA should be explored. Such studies will allow a more individualized treatment approach that maximizes benefits and mitigates potential harms.

Back to Top | Article Outline

AUTHORSHIP

Significant contributions were made by all listed authors. Specifically, M.D.N. and J.B.B. were responsible for conceptualization of this study. Data acquisition, analysis, and drafting of this article were performed by S.P.M. and J.B.B., M.D.N., M.R.R., J.L.S., and M.E.K. provided assistance in data interpretation, analysis, and critical review of this article.

Back to Top | Article Outline

DISCLOSURE

M.D.N. is an external scientific advisor for Janssen Pharmaceuticals. All other authors have no disclosures.

There are no sources of funding for this study.

M.D.N. and J.B.B. contributed equally as senior author to this publication.

Conflict of interest: M.D.N. is an external scientific advisor to Janssen Pharmaceuticals. Remaining authors have no disclosures.

Back to Top | Article Outline

REFERENCES

1. World Health Organization: The top 10 causes of death. Available at http://www.who.int/mediacentre/factsheets/fs310/en/. Accessed 19 Dec 2016.
2. Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma. 2006;60:S3–S11.
3. Gruen RL, Jurkovich GJ, McIntyre LK, Foy HM, Maier RV. Patterns of errors contributing to trauma mortality: lessons learned from 2,594 deaths. Ann Surg. 2006;244:371–380.
4. Madurska MJ, Sachse KA, Jansen JO, Rasmussen TE, Morrison JJ. Fibrinolysis in trauma: a review. Eur J Trauma Emerg Surg. 2018;44(1):35–44.
5. Geerts WH, Code KI, Jay RM, Chen E, Szalai JP. A prospective study of venous thromboembolism after major trauma. N Engl J Med. 1994;331(24):1601–1606.
6. Brill JB, Badiee J, Zander AL, Wallace JD, Lewis PR, Sise MJ, Bansal V, Shackford SR. The rate of deep vein thrombosis doubles in trauma patients with hypercoagulable thromboelastography. J Trauma Acute Care Surg. 2017;83(3):413–419.
7. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363(19):1791–1800.
8. Ng W, Jerath A, Wąsowicz M. Tranexamic acid: a clinical review. Anaesthesiol Intensive Ther. 2015;47(4):339–350.
9. CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, El-Sayed H, Gogichaishvili T, Gupta S, Herrera J, 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;376:23–32.
10. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) study. Arch Surg. 2012;147:113–119.
11. Johnston LR, Rodriguez CJ, Elster EA, Bradley MJ. Evaluation of military use of tranexamic acid and associated thromboembolic events. JAMA Surg. 2018;153(2):169–175.
12. Nishida T, Kinoshita T, Yamakawa K. Tranexamic acid and trauma-induced coagulopathy. J Intensive Care. 2017;5:2–7.
13. Brown JB, Neal MD, Guyette FX, Peitzman AB, Billiar TR, Zuckerbraun BS, Sperry JL. Design of the study of tranexamic acid during air medical prehospital transport (STAAMP) trial: addressing the knowledge gaps. Prehosp Emerg Care. 2015;19(1):79–86.
14. Sainani KL. Propensity scores: uses and limitations. PM R. 2012;4(9):693–697.
15. Rosenbaum PR, Rubin D. Constructing a control group using multivariate matching sampling methods that incorporate the propensity score. Am Stat. 1985;39(1):33–38.
16. Ramirez RJ, Spinella PC, Bochicchio GV. Tranexamic acid update in trauma. Crit Care Clin. 2017;33(1):85–99.
17. Nunez TC, Voskresensky IV, Dossett LA, Shinall R, Dutton WD, Cotton BA. Early prediction of massive transfusion in trauma: simple as ABC (Assessment of Blood Consumption)? J Trauma. 2009;66(2):346–352.
18. Cornelius BG, McCarty K, Hylan K, Cornelius A, Carter K, Smith KWG, Ristic S, Vining D, Cvek U, Trutschl M. Tranexamic acid: promise or panacea: the impact of air medical Administration of Tranexamic Acid on morbidity, mortality, and length of stay. Adv Emerg Nurs J. 2018;40(1):27–35.
19. Mitra B, Mazur S, Cameron PA, Bernard S, Burns B, Smith A, Rashford S, Fitzgerald M, Smith K, Gruen RL; PATCH-Trauma Study Investigators. Tranexamic acid for trauma: filling the ‘GAP’ in evidence. Emerg Med Australas. 2014;26:194–197.
20. Etchill EW, Fang R, Haut ER. Does tranexamic acid cause venous thromboembolism after trauma? JAMA Surg. 2018;153(2):175–176.
21. Valle EJ, Allen CJ, Van Haren RM, Jouria JM, Li H, Livingstone AS, Namias N, Schulman CI, Proctor KG. Do all trauma patients benefit from tranexamic acid? J Trauma Acute Care Surg. 2014;76(6):1373–1378.
22. Shiraishi A, Kushimoto S, Oromo Y, Matsui H, Hagiwara A, Murata K. On behalf of the Japanese observational study for coagulation and thombolysis in early trauma (J-OCTET). Effectiveness of early administration of tranexamic acid in patients with severe trauma. BJS. 2017;104:710–717.
23. Cole E, Davenport R, Willett K, Brohi K. Tranexamic acid use in severely injured civilian patients and the effects on outcomes: a prospective cohort study. Ann Surg. 2015;261:390–394.
24. Harvin JA, Peirce CA, Mims MM, Hudson JA, Podbielski JM, Wade CE, Holcomb JB, Cotton BA. The impact of tranexamic acid on mortality in injured patients with hyperfibrinolysis. J Trauma Acute Care Surg. 2015;78:905–909.
25. Moore HB, Moore EE, Gonzalez E, Chapman MP, Chin TL, Silliman CC, Banerjee A, Sauaia A. Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown: the spectrum of post-injury fibrinolysis and relevance to antifibrinolytic therapy. J Trauma Acute Care Surg. 2014;77:811–817.
26. Wafaisade A, Lefering R, Bouillon B, Böhmer AB, Gäßler M, Ruppert M; Trauma Register DGU. Prehospital administration of tranexamic acid in trauma patients. Crit Care. 2016;20:143–152.
27. McClendon J Jr, Smith TR, O'Shaughnessy BA, Sugrue PA, Thompson SE, Koski TR. Time to event analysis for the development of venous thromboembolism after spinal fusion ≥ 5 levels. World Neurosurg. 2015;84(3):826–833.
28. Tzeng CW, Curley SA, Vauthey J, Aloia TA. Distinct predictors of pre- versus post-discharge venous thromboembolism after hepatectomy: analysis of 7621 NSQIP patients. HPB (Oxford). 2013;15(10):773–780.
29. Costantini TW, Min E, Box K, Tran V, Winfield RD, Fortlage D, Doucet J, Bansal V, Coimbra R. Dose adjusting enoxaparin is necessary to achieve adequate venous thromboembolism prophylaxis in trauma patients. J Trauma Acute Care Surg. 2013;74(1):128–133.
30. Ko A, Harada MY, Barmparas G, Chung K, Mason R, Yim DA, Dhillon N, Margulies DR, Gewertz BL, Ley EJ. Association between enoxaparin dosage adjusted by anti-factor Xa trough level and clinically evident venous thromboembolism after trauma. JAMA Surg. 2016;151(11):1006–1013.
31. Chapman MP, Moore EE, Ramos CR, Ghasabyan A, Harr JN, Chin TL, Stringham JR, Sauaia A, Silliman CC, Banerjee A. Fibrinolysis greater than 3% is the critical value for initiation of antifibrinolytic therapy. J Trauma Acute Care Surg. 2013;75(6):961–967.
32. Haut ER, Schneider EB, Patel A, Streiff MB, Haider AH, Stevens KA, Chang DC, Neal ML, Hoeft C, Nathens AB, et al. Duplex ultrasound screening for deep vein thrombosis in asymptomatic trauma patients: a survey of individual trauma surgeon opinions and current trauma center practices. J Trauma. 2011;70(1):27–33.
33. Haut ER, Pronovost PJ. Surveillance bias in outcomes reporting. JAMA. 2011;305(23):2462–2463.
Back to Top | Article Outline

Discussion

Dr. Adrian A. Maung (New Haven, Connecticut): Good morning. I want to thank the Association for the opportunity to discuss this very interesting paper and congratulate Dr. Myers and her colleagues on a very well-presented study, as well as the acceptance of their paper into the Journal of Trauma.

Since the publication of the CRASH-2 trial in 2010, despite the relatively small absolute decrease in mortality, TXA has been viewed as a magical potion for patients in hemorrhagic shock. Yet, subsequent studies have raised concerns that there are potential side effects, including this paper.

Dr. Myers reports increased rates of VTE in patients who received TXA compared to patients identified by propensity score matching who did not receive TXA.

But this study does have several limitations, some of which have been already acknowledged in the presentation that I would like to discuss and point out further.

1) The propensity matching used very reasonably criteria that were known to the clinicians at the beginning when the patient arrived yet this created some important differences between the two groups, including higher rates of penetrating injury in the TXA group as well as higher level of patients who did not receive VTE prophylaxis at all in the TXA group.

So do you think these results would have been different if you had matched your groups based on injury severity, use of VTE prophylaxis, et cetera, or perhaps that’s a topic for another paper.

2) Pittsburgh is a very well-experienced, very well run trauma center but the rates of VTE prophylaxis were quite low and their rates of VTE were much higher compared to CRASH-2 or MATTER trials. How do you think this affected your results?

3) Did you examine the need for surgery, especially surgery required for bleeding control, between the two groups and how it differed?

And my last question is what is the take-home message? What do we do when we get home from San Diego and see that patient in hemorrhagic shock? Do we still give TXA? Should we be more vigilant about VTE prophylaxis? About VTE screening? What should we do?

Again, congratulations on a great study. Thank you.

Dr. Matthew Martin (San Diego, California): Nicely presented paper. I do have significant concerns, along with Adrian, about the data. One of the reasons you do propensity matching is to pseudo-randomize but your groups are so different on multiple factors that impact the VTE rate so I’m just a little unclear about how you then make the leap to TXA is the associated or causal factor?

Another important factor that we would need to know is what was the use of routine screening for DVT, and for PE? With a retrospective study it’s always a challenge to get at the true incidence of VTE unless there has been uniform and routine screening, particularly for DVT. And then trying to nail down any causal factors becomes highly unreliable and biased, such as jumping from TXA as causing the VTEs.

We also know that DVT and PE now are two different processes with actually different risk factors so did you look at them independently as opposed to the combined group of lumping them together? Thanks.

Dr. Krista L. Kaups (Fresno, California): Good morning. My question really relates very much to Dr. Martin’s question and this is the difficulty of a retrospective study is how were PE and – well, how was VTE diagnosed. Was this by ultrasound? By CT scan? Do you know how was this determined retrospectively? Thank you.

Dr. Nasim Ahmed (Neptune, New Jersey): My question to you about the propensity score analysis, when you matched that two groups and you said that was a good match, instead of doing a relative risk reduction or absolute risk reduction why did you do the regression analysis? Thank you.

Dr. Martin Schreiber (Portland, Oregon): Dr. Myers, Dr. Martin asked you how you will change management based on your findings. You showed no benefit and only negative outcomes. Will you stop giving TXA?

Dr. Sara P. Myers (Pittsburgh, Pennsylvania): I would like to begin by thanking Dr. Maung for his comments and questions. I will first address his question regarding the propensity matching methodology itself. We acknowledge that there are significant differences between treated and untreated cohorts. Other studies that have used propensity score methodology to address use of TXA have similar limitations. There have been, to my knowledge, four propensity score matched studies that address similar questions with regard to TXA administration. These investigations match on very different variables, ranging from 4 variables up to 20. It is certainly possible that, had the groups been matched on other parameters, the results may have been different. That having been said, I do not believe that matching on injury severity of VTE prophylaxis would be appropriate. Matching is meant to be done on variables that predict the propensity that a patient would receive TXA. In this sense, we would not have matched on injury severity score, which is retrospectively assessed, or VTE prophylaxis, which occurs after the fact. ISS and VTE prophylaxis may be confounders, which is why we adjusted for these in our regression model. As such, I would like to emphasize that the cohorts are different based on the variables that we were adjusting for in the regression but they were not different in the predictive factors that we used to match. Ultimately, prospective randomized studies are needed to determine which patients benefit most from TXA, especially given the potential risks of this intervention.

Dr. Maung’s second question relates to how our VTE prophylaxis and rates compared to the CRASH-2 and MATTERs trials, and how this may have affected our results. As I mentioned, there are concerns regarding the generalizability and applicability of these trials to the patients we treat as Trauma Surgeons in the United States. I concede that the rate of VTE prophylaxis was low. This may reflect changes in VTE prophylaxis practices over time, but when we revisited patient charts to abstract the rationale for withholding prophylaxis, we found that the majority of patients had either died or been discharged prior to VTE prophylaxis being initiated. Additionally, in the treated group, VTE occurred in 12% of the patients who didn’t receive thromboprophylaxis prior to thromboprophylaxis being started. In this subset of patients, thromboprophylaxis was delayed given concern for bleeding risk. The rates of VTE quoted in the literature vary depending on injury severity and patient population. Though our results differ from those in the CRASH-2 and MATTERs trial, this may, again, stem from the fact that our patient population was fundamentally different than in these two studies.

We did examine the need for surgery. Patients treated with TXA required significantly more operative intervention(s) for bleeding control than the untreated cohort.

Turning to Dr. Maung’s final question- what is the take-home message? The take-home message is that TXA may increase the risk for serious adverse events such as VTE without a concomitant survival benefit. While this may not be true for all patients, it is likely true for some. I believe that we need to identify the patients who maximally benefit from TXA. Individuals who do not benefit from the agent may be exposed to unnecessary risks associated with its administration. Either way, it is important to acknowledge that as a hemostatic adjunct, TXA may increase the risk of thrombosis. We should administer TXA when we believe it will be a life-saving intervention, as that is our priority, and remain vigilant that VTE may occur taking care to institute appropriate prophylaxis, and perhaps, screening as well.

Finally, I will address the question regarding our screening process. We did not have routine screening of either DVT or PE. All of the VTE were diagnosed based on a clinical suspicion. PE was diagnosed based on CTA primarily; individuals suspected of having a DVT received ultrasound.

I would like to end by thanking the audience and Dr. Maung for their comments and questions, and appreciate the opportunity to present our data.

Keywords:

Tranexamic acid; venous thromboembolism; deep vein thrombosis; pulmonary embolism

Supplemental Digital Content

Back to Top | Article Outline
© 2019 Lippincott Williams & Wilkins, Inc.