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What evidence supports the use of oral tranexamic acid for major orthopedic surgery?

Introduction

Blood loss is a prominent complication of major orthopedic surgery, and interventions aimed at preventing blood loss during these procedures and subsequent need for blood transfusion are common. Tranexamic acid injection has been used in this setting but safety concerns (including thrombosis) have prompted clinical interest in alternate methods of administration.1,2 These include topical or local (ie, intra-wound) application as well as oral administration, either alone or in combination with intravenous (IV) administration.1

A guideline focused on the use of tranexamic acid in total joint arthroplasty was released in 2018 with endorsement from the American Association of Hip and Knee Surgeons, the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Orthopaedic Surgeons, The Hip Society, and The Knee Society.1 At that time, a review of direct and indirect meta-analyses led these organizations to conclude that the efficacy of tranexamic acid in reducing perioperative blood loss and risk of transfusion is similar among these various routes of administration. Subsequently, additional randomized studies with oral tranexamic acid have been published.3-16 Therefore, this article will summarize the latest comparative data with oral tranexamic acid in patients undergoing hip and knee replacement procedures.

Literature review

Total knee replacement surgery

Table 1 provides dosage and major outcome results for 8 randomized controlled trials (RCT) in patients undergoing knee replacement that have been published since 2018.3-10 Some studies compared different routes of administration, one study compared oral tranexamic acid to oral aminocaproic acid, and a few studies compared different oral tranexamic acid dosing regimens. The only study that reported a significant difference in blood loss compared oral tranexamic acid in combination with IV tranexamic acid vs IV administration alone.6 Two other studies reported significant improvements with multiple oral doses of tranexamic acid compared to a single oral dose.5,9 No major safety concerns were reported in these trials.3-10

Table 1. Randomized controlled trials with oral tranexamic acid in patients undergoing total knee replacement.3-10
Study designInterventionsResults
King 20193Oral tranexamic acid 1 g x 3 doses (2 hours before surgery, 2 hours after surgery, and 6 hours after surgery) (n=31)

Topical tranexamic acid 3 g perioperatively + IV tranexamic acid 1 g 2 hours after surgery + oral tranexamic acid 1 g x 3 doses (same timing as the oral-only group) (n=33)

All patients received apixaban 2.5 mg BID x 15 days		·     No significant differences in mean Hgb change or total blood loss

·     Only 1 transfusion was needed (in the combination group)

·     No VTE occurred
Morales-Avalos 20194Oral tranexamic acid 1300 mg x 3 doses (2 hours before surgery, 6 hours after surgery, 12 hours after surgery) (n=46)

Oral aminocaproic acid 2 g x 3 doses (2 hours before surgery, 6 hours after surgery, 12 hours after surgery) (n=46)

All patients received prophylactic unfractionated heparin during hospitalization and aspirin 100 mg daily x 30 days		·     No significant differences in blood loss-related outcomes

·     Only 1 transfusion was needed (in the aminocaproic acid group)

·     No VTE occurred
Tang 20195Oral tranexamic acid 2 g x 1 (at 2 hours preoperatively) (n=50)

Oral tranexamic acid 2 g x 2 (at 2 and 4 hours postoperatively) (n=50)

Oral tranexamic acid 2 g x 4 (at 2 hours preoperatively, and 4, 10, and 16 hours postoperatively) (n=51)

All patients received prophylactic LMWH during hospitalization and rivaroxaban 10 mg daily x 10 days		·     Total blood loss was significantly less in the group that received 4 doses vs the other 2 groups (p<0.001 and p=0.027, respectively)

·     Decreases in Hgb and Hct were less in the group that received 4 doses vs the other 2 groups (p<0.05 for all comparisons)

·     No patients required a transfusion

·     Only 1 VTE occurred (in the single-dose group)
Wang 20196IV tranexamic acid 20 mg/kg x 2 (10 minutes before surgery and 3 hours after surgery) + oral tranexamic acid 1 g daily from POD1 to POD14 (n=60)

IV tranexamic acid 20 mg/kg x 2 (10 minutes before surgery and 3 hours after surgery) (n=60)

All patients received prophylactic LMWH during hospitalization and rivaroxaban 10 mg daily x 10 days		·     Total blood loss was significantly less in the IV + oral group vs the IV-only group (p=0.001)

·     Hgb and Hct on POD3 were significantly higher in the IV + oral group vs the IV-only group (both p=0.001) but values were similar on POD1 and POD14

·     2 patients in each group required transfusion

·     No symptomatic VTE occurred
Cao 20187IV tranexamic acid 20 mg/kg x 1 (5 to 10 minutes before surgery) + oral tranexamic acid 2 g x 3 (4, 10, and 16 hours after surgery) (n=59)

IV tranexamic acid 20 mg/kg x 1 (5 to 10 minutes before surgery) + IV tranexamic acid 1 g x 3 (6, 12, and 18 hours after surgery) (n=59)

All patients received prophylactic LMWH during hospitalization and rivaroxaban 10 mg daily x 10 days		·     No significant differences in total blood loss, Hgb, or Hct

·     No patients required transfusion

·     A similar number of patients in each group developed VTE
Wang 20188Oral tranexamic acid 2 g x 1 (2 hours before surgery) (n=63)

IV tranexamic acid 20 mg/kg x 1 (5 minutes before surgery) (n=63)

Intraarticular tranexamic acid 2 g during the procedure (n=63)

All patients received prophylactic LMWH during hospitalization and rivaroxaban 10 mg daily x 10 days		·     No significant differences in total blood loss or Hgb

·     Blood transfusion was needed in 2 patients in the oral group, 4 patients in the IV group, and 2 patients in the intraarticular group

·     Only 1 VTE occurred (in the IV group)
Wang 20189Oral tranexamic acid 2 g given 2 hours before surgery + intraarticular tranexamic acid 1.5 g during the procedure (n=50)

Oral tranexamic acid 2 g given 2 hours before surgery + 1 g given 3 hours after surgery + intraarticular tranexamic acid 1.5 g during the procedure (n=50)

Oral tranexamic acid 2 g given 2 hours before surgery + 1 g given 3 and 9 hours after surgery + intraarticular tranexamic acid 1.5 g during the procedure (n=50)

Oral tranexamic acid 2 g given 2 hours before surgery + 1 g given 3, 9, and 15 hours after surgery + intraarticular tranexamic acid 1.5 g during the procedure (n=50)

All patients received prophylactic LMWH during hospitalization and rivaroxaban 10 mg daily x 10 days		·     Patients who received oral tranexamic acid after surgery had significantly less blood loss and higher Hgb vs only preoperative tranexamic acid (all p<0.05)

·     Patients who received 2 or 3 tranexamic acid doses postoperatively had significantly less blood loss and higher Hgb vs 1 dose (all p<0.05)

·     No significant differences between the 2-dose and 3-dose groups

·     Only 1 transfusion was needed (in the only-preoperative tranexamic acid group)

·     No VTE occurred
Wang 201810Oral tranexamic acid 2 g given 2 hours before surgery, then oral tranexamic acid 1 g x 2 (6 and 12 hours after surgery) (n=75)

Intraarticular tranexamic acid 3 g during the procedure (n=75)

All patients received prophylactic LMWH during hospitalization and rivaroxaban 10 mg daily x 10 days		·     No significant difference in blood loss, Hgb, or Hct

·     A similar number of patients required transfusion in the oral (n=3) and intraarticular (n=4) groups

·     Only 1 VTE occurred (in the oral treatment group)
Abbreviations: BID=twice daily; Hct=hematocrit; Hgb=hemoglobin; IV=intravenous; LMWH=low molecular weight heparin; POD=postoperative day; VTE=venous thromboembolism.

Total hip replacement surgery

The 6 RCT with oral tranexamic acid in patients undergoing hip replacement procedures that have been published since 2018 are summarized in Table 2.11-16 Four of these trials compared different routes of tranexamic acid administration and found no significant differences in efficacy or safety between groups.11-16 Two trials compared different oral tranexamic dosing regimens (one as monotherapy, one in combination with topical tranexamic acid), and both reported significantly better outcomes with multiple oral doses versus a single dose.11,12 No major safety events occurred in these studies.11-16

Table 2. Randomized controlled trials with oral tranexamic acid in patients undergoing total hip replacement.11-16
Study designInterventionsResults
Cao 201911Oral tranexamic acid 2 g x 1 (2 hours before surgery) (n=51)

Oral tranexamic acid 2 g x 2 (2 hours before surgery and 4 hours after surgery) (n=51)

Oral tranexamic acid 2 g x 4 (2 hours before surgery and 4, 10, and 16 hours after surgery) (n=50)

All patients received prophylactic LMWH during hospitalization and rivaroxaban 10 mg daily x 10 days		·     Total blood loss was significantly less in the 4-dose group vs the other groups (both p<0.05)

·     Total blood loss was significantly less in the 2-dose group vs the 1-dose group (p<0.05)

·     Hgb and Hct levels were significantly higher in the 4-dose group vs the other groups (all p<0.05)

·     No blood transfusions were needed

·     Two VTEs occurred (1 each in the 1-dose and 4-dose groups)
Wang 201912Oral tranexamic acid 2 g given 2 hours before surgery + topical tranexamic acid 1 g during the procedure (n=50)

Oral tranexamic acid 2 g given 2 hours before surgery + 1 g given 3 hours after surgery + topical tranexamic acid 1 g during the procedure (n=50)

Oral tranexamic acid 2 g given 2 hours before surgery + 1 g given 3 and 9 hours after surgery + topical tranexamic acid 1 g during the procedure (n=50)

Oral tranexamic acid 2 g given 2 hours before surgery + 1 g given 3, 9, and 15 hours after surgery + topical tranexamic acid 1 g during the procedure (n=50)

All patients received prophylactic LMWH during hospitalization and rivaroxaban 10 mg daily x 10 days		·     Total blood loss was significantly less and Hgb levels were significantly higher in the 4-dose group vs the other groups (all p<0.05)

·     Total blood loss was significantly less and Hgb levels were significantly higher in the 3-dose and 4-dose groups vs the 2-dose group (all p<0.05)

·     Only 1 transfusion was needed (in the single-dose group)

·     No symptomatic VTE occurred
Cao 201813IV tranexamic acid 20 mg/kg x 1 (5 to 10 minutes before surgery) + oral tranexamic acid 2 g x 3 (4, 10, and 16 hours after surgery) (n=54)

IV tranexamic acid 20 mg/kg x 1 (5 to 10 minutes before surgery) + IV tranexamic acid 1 g x 3 (6, 12, and 18 hours after surgery) (n=54)

All patients received prophylactic LMWH during hospitalization and rivaroxaban 10 mg daily x 10 days		·     No significant difference in blood loss, Hgb, or Hct between groups

·     No blood transfusions were needed

·     Two VTEs occurred (both in the IV group)
Luo 201814Oral tranexamic acid 2 g given 2 hours before surgery (n=60)

IV tranexamic acid 20 mg/kg given 5 minutes before surgery (n=60)

Topical/local tranexamic acid 2 g during the procedure (n=60)

All patients received prophylactic LMWH during hospitalization and rivaroxaban 10 mg daily x 10 days		·     No significant difference in blood loss or Hgb between groups

·     A similar number of transfusions were needed in all groups

·     No VTEs occurred
Wu 201815Oral tranexamic acid 1 g x 3 (2 hours before surgery and 3 and 6 hours after surgery) (n=50)

IV tranexamic acid 1 g x 3 (10 minutes before surgery and 3 and 6 hours after surgery) (n=50)

All patients received prophylactic LMWH during hospitalization and rivaroxaban 10 mg daily x 10 days		·     No significant difference in blood loss, Hgb, or Hct between groups

·     A similar number of transfusions were needed in both groups

·     No VTEs occurred
Zhao 201816Oral tranexamic acid 20 mg/kg x 2 (2 hours before surgery and 3 hours after surgery) (n=40)

IV tranexamic acid 15 mg/kg x 2 (10 minutes before surgery and 3 hours after surgery) (n=40)

Placebo (n=40)

All patients received prophylactic LMWH during hospitalization and rivaroxaban 10 mg daily x 10 days		·     No significant difference in blood loss, Hgb, or Hct between tranexamic acid groups

·     A similar number of transfusions were needed in both tranexamic acid groups

·     No VTEs occurred
Abbreviations: Hct=hematocrit; Hgb=hemoglobin; IV=intravenous; LMWH=low molecular weight heparin; VTE=venous thromboembolism.

Literature evaluation

The most recent RCTs with oral tranexamic acid in patients undergoing total knee or hip replacement procedures were well-designed and consistently used double dummy medication administration to maintain blinding with administration via multiple routes.3-16 However, several factors may limit the applicability of these studies in practice. Many studies were conducted at individual hospitals in China, so results may be different at institutions with other surgical and perioperative protocols. For example, postoperative prophylaxis against venous thromboembolism was consistently used but with parenteral and oral anticoagulant doses that are different from standard postoperative dosing in the United States.17 Almost all of the studies used tranexamic acid doses that cannot be achieved with the oral tranexamic acid formulation that is commercially available in the United States (a 650 mg tablet) and dosage protocols varied among studies.3-16,18 Finally, the lack of statistical difference that was reported in most studies could be explained by small sample sizes and the inability to detect small differences between groups.3-16

The 2 largest meta-analyses that have been published since 2018 have not identified significant differences in bleeding outcomes between oral tranexamic acid and other routes of administration.18,19 An analysis of 9 RCTs in patients undergoing total hip arthroplasty found no difference between oral and IV or topical administration.18 Similarly, bleeding results were similar between IV and oral tranexamic acid groups in an analysis of 6 RCTs and 3 retrospective cohort studies in patients undergoing total knee or hip replacement procedures.19

 

Conclusion

Due to its ease of administration, few serious safety concerns, and support from major medical societies, oral tranexamic acid for hemostatic control in patients undergoing joint replacement procedures is likely to continue to be of interest in practice.1 The only oral tranexamic acid product that is available in the United States is indicated for the treatment of heavy menstrual bleeding, but numerous RCTs and meta-analyses support the efficacy of oral tranexamic acid administration in patients undergoing joint replacement procedures.3-16,20 The latest RCTs in this population support the guideline statement that there is no data to suggest a clinical benefit with one route of tranexamic acid administration over another.3-16 Oral tranexamic acid has been studied as monotherapy and in combination with IV or topical/local administration, and multiple oral doses may be more effective than single oral doses but data to support this conclusion are limited. Further evidence is needed to identify the most effective oral tranexamic acid dosing strategies and regimens following knee and hip replacement surgery.

References

  1. American Academy of Orthopaedic Surgeons. Tranexamic Acid in Total Joint Arthroplasty. http://www.orthoguidelines.org/topic?id=1024. Accessed January 17, 2020.
  2. Tranexamic acid injection [package insert]. E. Windsor, NJ: AuroMedics Pharma LLC; 2019.
  3. King L, Randle R, Dare W, Bernaitis N. Comparison of oral vs. combined topical/intravenous/oral tranexamic acid in the prevention of blood loss in total knee arthroplasty: A randomised clinical trial. Orthop Traumatol Surg Res. 2019;105(6):1073-1077.
  4. Morales-Avalos R, Ramos-Morales T, Espinoza-Galindo AM, et al. First comparative study of the effectiveness of the use of tranexamic acid against ε-aminocaproic acid via the oral route for the reduction of postoperative bleeding in TKA: a clinical rrial [published online ahead of print, 2019 Sep 6]. J Knee Surg. doi:10.1055/s-0039-1696722
  5. Tang Y, Wen Y, Li W, Li H, Yang Y, Liu Y. The efficacy and safety of multiple doses of oral tranexamic acid on blood loss, inflammatory and fibrinolysis response following total knee arthroplasty: A randomized controlled trial. Int J Surg. 2019;65:45-51.
  6. Wang HY, Wang L, Luo ZY, et al. Intravenous and subsequent long-term oral tranexamic acid in enhanced-recovery primary total knee arthroplasty without the application of a tourniquet: a randomized placebo-controlled trial. BMC Musculoskelet Disord. 2019;20(1):478.
  7. Cao G, Xie J, Huang Z, et al. Efficacy and safety of multiple boluses of oral versus intravenous tranexamic acid at reducing blood loss after primary total knee arthroplasty without a tourniquet: A prospective randomized clinical trial. Thromb Res. 2018;171:68-73.
  8. Wang D, Wang HY, Cao C, et al. Tranexamic acid in primary total knee arthroplasty without tourniquet: a randomized, controlled trial of oral versus intravenous versus topical administration. Sci Rep. 2018;8(1):13579.
  9. Wang D, Wang HY, Luo ZY, et al. Blood-conserving efficacy of multiple doses of oral tranexamic acid associated with an enhanced-recovery programme in primary total knee arthroplasty: a randomized controlled trial. Bone Joint J. 2018;100-B(8):1025-1032.
  10. Wang D, Zhu H, Meng WK, et al. Comparison of oral versus intra-articular tranexamic acid in enhanced-recovery primary total knee arthroplasty without tourniquet application: a randomized controlled trial. BMC Musculoskelet Disord. 2018;19(1):85.
  11. Cao G, Huang Q, Huang Z, et al. The efficacy and safety of multiple-dose oral tranexamic acid on blood loss following total hip arthroplasty: a randomized controlled trial. Int Orthop. 2019;43(2):299-305.
  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. Cao G, Huang Z, Xie J, et al. The effect of oral versus intravenous tranexamic acid in reducing blood loss after primary total hip arthroplasty: A randomized clinical trial. Thromb Res. 2018;164:48-53.
  14. Luo ZY, Wang HY, Wang D, Zhou K, Pei FX, Zhou ZK. Oral vs intravenous vs topical tranexamic acid in primary hip arthroplasty: a prospective, randomized, double-blind, controlled study. J Arthroplasty. 2018;33(3):786-793.
  15. Wu Y, Zeng Y, Hu Q, et al. Blood loss and cost-effectiveness of oral vs intravenous tranexamic acid in primary total hip arthroplasty: A randomized clinical trial. Thromb Res. 2018;171:143-148.
  16. Zhao H, Xiang M, Xia Y, Shi X, Pei FX, Kang P. Efficacy of oral tranexamic acid on blood loss in primary total hip arthroplasty using a direct anterior approach: a prospective randomized controlled trial. Int Orthop. 2018;42(11):2535-2542.
  17. Clinical Pharmacology [database online]. New York, NY: Elsevier; 2020. https://www.clinicalkey.com/pharmacology/. Accessed January 17, 2020.
  18. Xu Y, Sun S, Feng Q, et al. The efficiency and safety of oral tranexamic acid in total hip arthroplasty: A meta-analysis. Medicine (Baltimore). 2019;98(46):e17796.
  19. Han X, Gong G, Han N, Liu M. Efficacy and safety of oral compared with intravenous tranexamic acid in reducing blood loss after primary total knee and hip arthroplasty: a meta-analysis. BMC Musculoskelet Disord. 2018;19(1):430.
  20. Lysteda [package insert]. Parsippany, NJ: Ferring Pharmaceuticals Inc.; 2019.

Prepared by:
Heather Ipema, PharmD, BCPS
Clinical Assistant Professor
College of Pharmacy
University of Illinois at Chicago

February 2020

The information presented is current as December 11, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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