What Do We Know About Routine Use of Tranexamic Acid in Foot and Ankle Surgery?

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Tranexamic acid (TXA) has gained popularity in recent years in orthopedic lower extremity surgery due to the purported benefits of reduced intraoperative bleeding, lower wound complications, and lower risk of hematoma formation in the postoperative period.¹ But is this drug too good to be true?
 
Turns out, it may very well be too good to be true—or at least, surgeons should be very aware of the evidence and the risks of TXA. Before we dive deeper into the literature surrounding TXA, it is important to understand the mechanism of action. TXA is an antifibrinolytic agent that works by competitively interfering with plasminogen activation. When activated, plasminogen converts into plasmin, which is a blood clot fibrinolysis agent. Secondarily, it is a competitive inhibitor of tissue plasminogen activation (tPa).¹ It is important to note that it’s currently only approved by the Food and Drug Administration (FDA) for heavy menstrual bleeding and short-term prevention in patients with hemophilia, so use in surgical operations is currently off-label.² Another important thing to consider is that aprotinin, a similarly marketed drug, was pulled from the market due to concerns over increasing mortality, despite having better results across the board than TXA for surrogate outcomes, including decreasing blood loss.³
 
Decreasing perioperative blood loss can be important for patients, with increased blood loss leading to possible blood transfusions, elongated hospital stays, hypovolemia, and more.⁴ That being said, the average blood loss for foot and ankle surgery is typically low, even for procedures like total ankle arthroplasties.^5,6 However, the claims regarding TXA benefits extend beyond reducing perioperative blood loss. It purportedly decreases wound dehiscence and postoperative edema.
 
So, what's the catch? Well, the risk of deep vein thrombosis, increased risk of seizures, and pulmonary embolism cannot be overlooked.²
 
There is also the question of “Does the bleeding risk matter in foot and ankle surgery?” In many of these studies, blood loss may be slightly decreased, but there are no other changes in patient-oriented outcomes.¹ TXA has been studied across many specialties with a large number of randomized controlled trials. The larger, higher quality studies all point to TXA having no effect in regards to bleeding risk or need for transfusion, while smaller studies (which have a larger risk of potential bias) seem to show small benefit. Much of the foot and ankle–specific literature is unfortunately of low quality (level IV evidence) with a high risk of bias.⁸
 
A large multi-center study, the HALT-IT trial, evaluated TXA in gastrointestinal bleeds and compared to placebo, there was no change in mortality, rebleeding, surgery, need for transfusion, or total blood products transfused. One major difference was an increase in venous thromboembolic events (VTE), which was doubled compared to placebo.⁹ Another study, the MATTERs trial, showed that in significant wartime injuries, TXA did decrease mortality, but significantly increased VTEs.¹⁰ This led to Johnston and colleagues re-evaluating the data and evidence and suggested against routine use of TXA in wartime injuries due to concerns over major VTEs.¹¹
 
TXA is commonly utilized in lower extremity arthroplasties, particularly the hip and knee. This has become more popular, as these surgeries can lead to acute postoperative anemia and may require blood transfusions.¹² Therefore, the TXA is utilized to potentially decrease overall bleeding and lower the risk of needing a blood transfusion. Now, I’ve observed some podiatrists using this data as evidence that TXA should be used for distal lower extremity arthroplasties, like total ankle replacements (TAR). However, there are many key differences between knee and hip arthroplasties and total ankle replacements. Firstly, the amount of blood loss—hip and knee arthroplasties typically have around 1500cc or more of blood loss per case.⁴ TARs typically have 100–400cc.^5,6 Secondly, those procedures are weight-bearing immediately afterwards, which is shown to significantly decrease the risk of a lower extremity VTE.⁷ Thirdly, there is considerably more data available with more patients for hip and knee procedures versus foot and ankle.^4-6
 
There also isn’t great evidence that TXA even reduces blood loss in lower extremity arthroplasties, as Fillingham and colleagues explained, “network meta-analysis for primary TKA demonstrated that a single dose of IV TXA before incision reduced the risk of transfusion … however, there was no significant difference regarding blood loss.”¹³ Several authors, studying calcaneal fractures, TARs, and ambulatory foot and ankle procedures found no benefit in regards to intraoperative blood loss or wound complications.^14-16 In a meta-analysis, Mirghaderi and colleagues evaluated around 1000 patients and found that the half who received TXA reduced their 24-hour postoperative blood loss by 142 mL, which was statistically, but very unlikely clinically significant. However, the overall rate of postoperative anemia, blood transfusion, or wound complications were no different.¹ The same meta-analysis made the claim that there was no increase in VTE rate or risk; however, they only evaluated 232 patients per group, which is not enough statistical power to make that claim.
 
There are also claims of it enhancing wound healing abilities and decreasing the formation of hematomas, however these do not seem to be supported in large-scale trials.⁸

What Does the Evidence Truly Reveal?

Using TXA routinely to decrease blood loss in foot and ankle procedures is not well-supported based on current evidence. Even with the largest procedures done on the foot and ankle, the risk of transfusion or significant hemoglobin drop is incredibly low compared to more proximal procedures. Using an antifibrinolytic to decrease blood loss in procedures where blood loss is rarely, if ever, a significant adverse event while potentially increasing the risk of VTE, which can lead to a fatal event, seems to be missing the forest for the trees.

It is important to understand that many large foot and ankle surgeries are non-weight-bearing already, and adding a therapy to lessen the body’s ability to break down clots only furthers the potential for these emboli to form. While the data isn’t strong enough for a recommendation to use or not use, I think that more careful dissection should lead to decreased bleeding during procedures, therefore obviating the need for such adjunctive therapy. A very salient warning by Mirghaderi and colleagues is “We should interpret the results with caution due to publication bias, which tends to promote studies that demonstrate positive effects.”¹ While this blog is not a discussion on the merits of current scientific research and p values, it is wise to be skeptical and remember that one study of abstracts between 1990–2015 demonstrated that 96% contained at least 1 p value <0.05.¹⁷ Statistically insignificant data are much less likely to be published and this brings into question the possibility of “p-hacking,” attempting to find something in the data to report as “statistically significant.”¹⁸
 
There are many instances, even in recent history where very positive initial results regarding new therapies have turned out to be “too good to be true.” In my assessment, I think the recent enthusiasm and rise in popularity for TXA for foot and ankle surgeries should be met with caution until more high-quality data is available.
 
Dr. Ehlers is in private practice in Arvada, CO, and is an attending at the Highlands-Presbyterian/St. Luke’s Podiatric Residency Program. He finds interest in debunking medical myths and dogma.
 
References
1.    Mirghaderi S, Aliasin M, Salimi M, et al. The efficacy and safety of tranexamic acid in foot and ankle surgery: A systematic review and meta-analysis of comparative clinical studies. Foot and Ankle Surgery. 2023 January 29
2.    Chauncey JM, Wieters JS. Tranexamic Acid. [Updated 2023 Jul 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-
3.    Henry DA, Carless PA, Moxey AJ, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2011 Jan 19;(1):CD001886. doi: 10.1002/14651858.CD001886.pub3. Update in: Cochrane Database Syst Rev. 2011;(3):CD001886. PMID: 21249650.
4.    Newman JM, Webb MR, Klika AK, et al. Quantifying blood loss and transfusion risk after primary vs conversion total hip arthroplasty. J Arthroplasty. 2017 Jun;32(6):1902-1909. doi: 10.1016/j.arth.2017.01.038. Epub 2017 Feb 1. PMID: 28236548.
5.    Tan G, Xie LW, Yi SJ, Chen Y, Liu X, Zhang H. The efficacy and safety of intravenous tranexamic acid on blood loss during total ankle replacement: a retrospective study. Sci Rep. 2022 Jun 9;12(1):9542. doi: 10.1038/s41598-022-13861-3. PMID: 35680960; PMCID: PMC9184638.
6.    Ahn J, Lee HJ, Jeong BO. Assessment of perioperative total blood loss during total ankle arthroplasty. Foot Ankle Surg. 2022 Jul;28(5):564-569. doi: 10.1016/j.fas.2021.05.011. Epub 2021 May 24. PMID: 34049803.
7.    Saragas NP, Ferrao PNF, Saragas E, Jacobson BF. The impact of risk assessment on the implementation of venous thromboembolism prophylaxis in foot and ankle surgery. Foot Ankle Surg. 2014;20(2):85-89. doi:10.1016/j.fas.2013.11.002
8)    Morgenstern, J. Does TXA work for everything? For anything? First10EM, June 28, 2021. Available at: https://doi.org/10.51684/FIRS.79621
9.    Brenner A, Afolabi A, Ahmad SM, et al; HALT-IT Trial Collaborators. Tranexamic acid for acute gastrointestinal bleeding (the HALT-IT trial): statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial. Trials. 2019 Jul 30;20(1):467. doi: 10.1186/s13063-019-3561-7. PMID: 31362765; PMCID: PMC6668177.
10. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg. 2012 Feb;147(2):113-9. doi: 10.1001/archsurg.2011.287. Epub 2011 Oct 17. PMID: 22006852.
11. Johnston LR, Rodriguez CJ, Elster EA, Bradley MJ. Evaluation of military use of tranexamic acid and associated thromboembolic events. JAMA Surg. 2018 Feb 1;153(2):169-175. doi: 10.1001/jamasurg.2017.3821. PMID: 29071337; PMCID: PMC5838717.
12. Fillingham YA, Ramkumar DB, Jevsevar DS, et al. Tranexamic Acid Use in Total Joint Arthroplasty: The Clinical Practice Guidelines Endorsed by the American Association of Hip and Knee Surgeons, American Society of Regional Anesthesia and Pain Medicine, American Academy of Orthopaedic Surgeons, Hip Society, and Knee Society. J Arthroplasty. 2018 Oct;33(10):3065-3069. doi: 10.1016/j.arth.2018.08.002. Epub 2018 Aug 7. PMID: 30146350.
13. Fillingham YA, Ramkumar DB, Jevsevar DS, et al. The efficacy of tranexamic acid in total knee arthroplasty: a network meta-analysis. J Arthroplasty. 2018 Oct;33(10):3090-3098.e1. doi: 10.1016/j.arth.2018.04.043. Epub 2018 May 5. PMID: 29805106.
14. B H PP, Diskina D, Lin HM, Vulcano E, Lai YH. Use of tranexamic acid does not influence perioperative outcomes in ambulatory foot and ankle surgery-a prospective triple blinded randomized controlled trial. Int Orthop. 2021 Sep;45(9):2277-2284. doi: 10.1007/s00264-021-05131-0. Epub 2021 Jul 29. PMID: 34324042.
15. Steinmetz RG, Luick L, Tkach S, Falcon S, Stoner J, Hollabaugh K, Ringus V, Haleem AM. Effect of tranexamic acid on wound complications and blood loss in total ankle arthroplasty. Foot Ankle Int. 2020 Sep;41(9):1117-1121. doi: 10.1177/1071100720934889. Epub 2020 Jul 13. PMID: 32659136.
16. Xie B, Tian J, Zhou DP. Administration of tranexamic acid reduces postoperative blood loss in calcaneal fractures: a randomized controlled trial. J Foot Ankle Surg. 2015 Nov-Dec;54(6):1106-10. doi: 10.1053/j.jfas.2015.07.006. Epub 2015 Aug 24. PMID: 26310621.
17. Ioannidis JP. What have we (not) learnt from millions of scientific papers with p values? American Statistician. 73(sup1):20-25
18. Morgenstern J. EBM masterclass: What exactly is a P value? First10EM, October 11, 2021. Available at: https://doi.org/10.51684/FIRS.83454

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