60 – Does administration of tranexamic acid (TXA) to a patient undergoing orthopaedic procedures increase the risk of subsequent VTE?

Armin Arshi, Vasili Karas, George C. Babis, Jeffrey J. Mojica, Uzung Yoon, Yale A. Fillingham.

Response/Recommendation A: Administration of tranexamic acid (TXA) in patients undergoing orthopaedic procedures does not increase the risk of developing subsequent venous thromboembolism (VTE) in patients without prior VTE history.

Strength of Recommendation A: Strong.

Response/Recommendation B: Administration of TXA in patients undergoing orthopaedic procedures does not increase the risk of developing subsequent VTE in patients with prior VTE or equivalently elevated hypercoagulability risk.

Strength of Recommendation B: Moderate.

Rationale: TXA is an antifibrinolytic agent that blocks lysin-binding sites on plasminogen, thereby preventing fibrin-plasminogen interaction and facilitating clot stabilization¹. Administered intravenously (IV), orally, topically, or in IV-topical combinations, TXA has been shown to effectively decrease blood loss and mortality in the setting of major trauma and, over the past few decades, has seen reemerged interest in orthopaedic surgery, including adult reconstruction, orthopaedic trauma, and spine surgery^2–7. Nevertheless, given its potency as a fibrin clot stabilizer, theoretical concerns exist regarding elevated VTE risk following TXA administration.

At this time, strong evidence supports that TXA is not associated with elevated VTE risk in orthopaedic surgery. In their recent meta-analysis of 101 orthopaedic subspecialty studies, Taeuber et al., found that IV TXA did not significantly increase the risk of subsequent VTE (TXA: 3.6%, control: 2.7%, p = 0.64)⁸. Among subspecialties, TXA has been most well studied in the setting of total joint arthroplasty (TJA). Fillingham et al., meta-analysis demonstrated a lack of evidence to support higher VTE rates in patients receiving perioperative IV, topical, and oral TXA in primary TJA³. As a result of the mounting evidence of TXA administration not leading to an increased risk of VTE, the combined clinical practice guideline of the American Association of Hip and Knee Surgeons, the American Academy of Orthopaedic Surgeons, the American Society of Regional Anesthesia and Pain Medicine, and the Hip and Knee Societies provided a strong recommendation regarding the safe administration of TXA in patients without a history of VTE⁹. Several published randomized controlled trials (RCT) have demonstrated equivalent VTE risk in patients receiving TXA in hip, knee, and shoulder arthroplasty^10–12. No studies have demonstrated increased VTE risk associated with TXA. Routine TXA use is currently incorporated in all rapid recovery protocols in arthroplasty practices and has been proved safe and effective in reducing blood loss and the need for blood transfusions¹².

TXA administration has also been shown to reduce blood loss without increasing VTE risk in orthopaedic trauma. In a meta-analysis of RCT, Reale et al., demonstrated that VTE risk is not increased in patients receiving TXA for non-arthroplasty lower limb orthopedic procedures such as hip fractures and knee arthroscopy¹³. This is particularly relevant in hip fracture surgery where mortality risk is sharply affected by perioperative blood loss and transfusion requirements for fragile patients and thus TXA may be quite beneficial with prudent use^14,15. TXA use in spine surgery has also recently emerged, with an interest in its use for single-level fusion for degenerative spine conditions and adult deformity surgery where blood loss may be substantial^5,16. In their meta-analysis of RCT, Cheriyan et al., found that IV TXA administration did not increase the risk of VTE or local hematoma in patients undergoing cervical and lumbar spine surgery¹⁶. Reasonable theoretical concerns on the balance between blood loss and epidural hematoma formation exist.

Though most published studies on TXA specifically exclude patients with prior VTE, moderate quality data exists and supports this recommendation in high-risk orthopaedic patients with prior VTE or other hypercoagulable risk-equivalent medical conditions (e.g., atrial fibrillation, coronary artery disease [CAD], cerebrovascular accident, cancer). In a matched retrospective series of 1,262 patients with prior VTE undergoing primary TJA, Sabbag et al., found that the risk of VTE recurrence was not significantly greater in patients who received perioperative IV TXA administration¹⁷. When matched-comparison analysis was performed on the 31 patients in their cohort who experienced a recurrent VTE, IV TXA was not independently associated with increased risk. Using the American Society of Anesthesiologists (ASA) status ≥ 3 as a surrogate for high VTE risk, Fillingham et al., found in meta-regression that high-risk patients were at no higher risk of subsequent VTE following TXA administration³. This analysis is supported by a retrospective chart review of 38,220 TJA patients, where Porter et al., concluded that high-risk patients that receive TXA are not associated with an increase in adverse outcomes. Similar VTE risk profiles have been noted in orthopaedic patients with comorbid CAD and cancer patients undergoing endoprosthetic reconstruction for primary bone sarcoma or metastatic carcinoma to bone^18,19. The decision to utilize TXA must not be solely based on the theoretical risk of VTE but instead must weigh all risks and benefits to the medication. It is important to note that patients with higher comorbidity burden (e.g., prior VTE, CAD, ASA ≥ 3, malignancy) are known to have a higher risk of complication following significant blood loss and blood product transfusion and, as such, indirectly benefit from routine TXA usage where there is lack of evidence to suggest harm from TXA administration.

References:

1.        Ker K, Roberts I, Shakur H, Coats TJ. Antifibrinolytic drugs for acute traumatic injury. Cochrane Database Syst Rev. 2015;2015(5).

2.        Fillingham YA, Ramkumar DB, Jevsevar DS, et al. The Efficacy of Tranexamic Acid in Total Knee Arthroplasty: A Network Meta-Analysis. J Arthroplasty. 2018;33(10):3090-3098.e1.

3.        Fillingham YA, Ramkumar DB, Jevsevar DS, et al. The Safety of Tranexamic Acid in Total Joint Arthroplasty: A Direct Meta-Analysis. J Arthroplasty. 2018;33(10):3070-3082.e1.

4.        Fillingham YA, Ramkumar DB, Jevsevar DS, et al. The Efficacy of Tranexamic Acid in Total Hip Arthroplasty: A Network Meta-analysis. J Arthroplasty. 2018;33(10):3083-3089.e4.

5.        Peters A, Verma K, Slobodyanyuk K, et al. Antifibrinolytics Reduce Blood Loss in Adult Spinal Deformity Surgery: A Prospective, Randomized Controlled Trial. Spine (Phila Pa 1976). 2015;40(8):E443-E449.

6.        Jules-Elysee KM, Tseng A, Sculco TP, et al. Comparison of Topical and Intravenous Tranexamic Acid for Total Knee Replacement: A Randomized Double-Blinded Controlled Study of Effects on Tranexamic Acid Levels and Thrombogenic and Inflammatory Marker Levels. J Bone Joint Surg  Am  2019;101(23):2120-2128.

7.        Abdel MP, Chalmers BP, Taunton MJ, et al. Intravenous versus topical tranexamic acid in total knee arthroplasty: Both effective in a randomized clinical trial of 640 patients. J Bone Joint Surg  Am . 2018;100(12):1023-1029.

8.        Taeuber I, Weibel S, Herrmann E, et al. Association of Intravenous Tranexamic Acid With Thromboembolic Events and Mortality: A Systematic Review, Meta-analysis, and Meta-regression. JAMA Surg. 2021;156(6):e210884-e210884.

9.        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. J Arthroplasty. 2018;33(10):3065-3069.

10.      Abildgaard JT, McLemore R, Hattrup SJ. Tranexamic acid decreases blood loss in total shoulder arthroplasty and reverse total shoulder arthroplasty. J Shoulder Elb Surg. 2016;25(10):1643-1648.

11.      Carbone A, Poeran J, Zubizarreta N, et al. Administration of tranexamic acid during total shoulder arthroplasty is not associated with increased risk of complications in patients with a history of thrombotic events. J Shoulder Elb Surg. 2021;30(1):104-112.

12.      Wang D, Wang HY, Luo ZY, Pei FX, Zhou ZK, Zeng WN. Finding the Optimal Regimen for Oral Tranexamic Acid Administration in Primary Total Hip Arthroplasty: A Randomized Controlled Trial. J Bone Joint Surg  Am . 2019;101(5):438-445.

13.      Reale D, Andriolo L, Gursoy S, Bozkurt M, Filardo G, Zaffagnini S. Complications of Tranexamic Acid in Orthopedic Lower Limb Surgery: A Meta-Analysis of Randomized Controlled Trials. Biomed Res Int. 2021;2021.

14.      Arshi A, Lai WC, Iglesias BC, et al. Blood transfusion rates and predictors following geriatric hip fracture surgery. Hip Int. 2021;31(2):272-279.

15.      Xiao C, Zhang S, Long N, Yu W, Jiang Y. Is intravenous tranexamic acid effective and safe during hip fracture surgery? An updated meta-analysis of randomized controlled trials. Arch Orthop Trauma Surg. 2019;139(7):893-902.

16.      Cheriyan T, Maier SP, Bianco K, et al. Efficacy of tranexamic acid on surgical bleeding in spine surgery: A meta-analysis. Spine J. 2015;15(4):752-761.

17.      Sabbag OD, Abdel MP, Amundson AW, Larson DR, Pagnano MW. Tranexamic Acid Was Safe in Arthroplasty Patients With a History of Venous Thromboembolism: A Matched Outcome Study. J Arthroplasty. 2017;32(9):S246-S250. doi:10.1016/J.ARTH.2017.02.008

18.      Haase DR, Templeton KJ, Rosenthal HG, Sweeney KR. Tranexamic Acid in Patients With Cancer Undergoing Endoprosthetic Reconstruction: A Retrospective Review. J Am Acad Orthop Surg. 2020;28(6):248-255.

19.      Zak SG, Tang A, Sharan M, Waren D, Rozell JC, Schwarzkopf R. Tranexamic Acid Is Safe in Patients with a History of Coronary Artery Disease Undergoing Total Joint Arthroplasty. J Bone Joint Surg Am. 2021;103(10):900-904.