Antifibrinolytics in Total Hip Arthroplasty

Introduction

In a number of clinical trials, antifibrinolytic medications used perioperatively have been shown to reduce blood loss and transfusion rates in a variety of surgical subspecialties. (5-18) 

Background

Antifibrinolytic drugs can decrease the need for blood transfusion following surgical procedures. Two such drugs are epsilon aminocaproic acid (EACA) and tranexamic acid (TA).  Tranexamic acid has been studied more thoroughly in the orthopaedic literature and appears to be effective at decreasing blood loss and blood transfusion rates.  There has been some hesitancy in utilizing these medicines due to fear of adverse effects, primarily thromboembolic disease. 

Mechanism and Pharmacokinetics

EACA and TA are water soluble analogs of lysine; they block the lysine binding site of plasminogen and free plasmin (3,4). This effectively displaces plasminogen from the fibrin surface, leading to inhibition of fibrinolysis (3,4). 

Following intravenous (IV) administration, maximum plasma levels of TA and EACA are reached in 5-15 minutes and diffuse rapidly in synovial fluid and membrane; the half-life of these drugs in plasma is 1-3 hours (3).  They are excreted by glomerular filtration non-metabolized in their active form.  Thus, excretion is prolonged in patients with renal impairment(4). The 24-hour urine recovery rate in EACA is 71% after a single IV bolus.  Animal studies have shown a serum concentration of 1,000 mcg/mL reduces fibrinolytic activity by 98%, 250 mcg/mL by 90%, and 100 mcg/mL by 80% (4). EACA collects in soft tissues causing a continued inhibitory effect approximately 3 hours after its presence in the serum (4).  TA and EACA are compared in Table 1.

Table 1: Pharmacokinetics of TA and EACA

TA= tranexamic Acid; EACA= epsilon aminocaproic acid

Dosing and Efficacy

The amount and frequency of dosing is variable in the literature.  TA dosing ranges most frequently between 10-20 mg/kg; however, dosing as high as 150 mg/kg has been reported.  There does not yet appear to be a clear correlation between the dosage amount and clinical efficacy (5-18). The frequency of the dose given is even more variable, with some studies giving a single IV injection preoperatively, others both pre- and postoperatively, and still others a bolus followed by a slow infusion. 

The haemostatic effect of TA in arthroplasty patients has been investigated in many studies, with the majority showing a positive effect with higher postoperative hemoglobin levels and lower blood transfusion rates (5-18).  A retrospective review of a single 20 mg/kg TA dose given either before incision in total hip arthroplasty or before tourniquet release in total knee arthroplasty showed a reduction in transfusion rates from 13.5% to 3.6% and 13.1% to 2.0%, respectively (19).  In a randomized, prospective study by Johansson et al, 100 patients received either a single dose of 15 mg/kg or saline placebo before total hip arthroplasty, with average total blood loss of 0.97L in the TA group and 1.3L in the placebo group (p < 0.001) (11). The rate of transfusion decreased from 40% in the placebo group to 20% in the TA group (p < 0.009).  Postoperative drainage volume and drainage hemoglobin concentration were also significantly lower in the TA group.  According to the authors, this decrease in hemoglobin concentration in drainage makes drainage volume measurement alone inadequate to measure blood loss (11). A meta-analysis of 13 articles by Kagoma et al showed a 58% reduction in risk of transfusion with the use of antifibrinolytics in total hip arthroplasty. (26)

Limited studies have been conducted regarding the use of EACA in orthopedic surgery. In a prospective randomized study of 55 patients, Harley et al compared EACA to saline placebo in patients receiving total hip replacements.  They utilized a preoperative loading dose of 150 mg/kg followed by a 15 mg/kg/hr infusion for 5 hours.  This dose schedule is similar to that used in cardiovascular procedures. Patients receiving EACA showed a 27% significant reduction in blood loss and an 11% reduction in transfusion rates, although this was not statistically significant, potentially due to the small size of the treatment groups (1). There was no clinical evidence of thromboembolic disease in either group. 

Not every study has shown antithrombolytics to reduce blood loss. A study by Good et al demonstrated no decrease in hidden blood loss in patients who received TA, but still did identify a significant decrease in blood transfusion rates when compared to a saline placebo group (22).

Safety

While most studies have indicated no increased incidence in symptomatic DVT or pulmonary embolus (PE) (1,7,10,23,24), a few  studies have shown a non-statistically significant increased risk of DVT or PE.(19,26)  A meta-analysis of 27 studies reporting on venous thromboembolic complications revealed no absolute change in risk between patients receiving antifibrinolytics versus those receiving placebo.  The relative risk for patients receiving antifibrinolytics was 0.95, with a CI of 0.80 to 1.10.  However, the authors cautioned that the strength of these conclusions is limited due to the lack of systematic investigation and small numbers of events.

Most studies excluded patients with a recent heart attack or stroke and patients with a history of VTE disease or a genetic predisposition to clotting disease.

Recommendations

Perioperative use of TA in total hip arthroplasty seems to be safe and effective at reducing blood loss and transfusions.  A single 20-mg/kg dose just prior to incision or split to give a 10-mg/kg dose prior to incision and another 4 hours later appear to be reasonable until further research on optimal dosing is performed.   Exclusion criteria may include patients with a recent heart attack or stroke and patients with a history of VTE disease or a genetic predisposition to clotting disease. More data on the use of EACA in total hip arthroplasty is needed until its efficacy can be determined.

References

1. Harley BJ, Beaupre LA, Jones CA, Cinats JG, Guenther CR. The effect of epsilon aminocaproic acid on blood loss in patients who undergo primary total hip replacement: a pilot study.  Can J Surg 2002:45(3) 185-190.
2. Walzman M, Bonnar J. Effects of tranexamic acid on the coagulation and fibrinolytic systems in pregnancy complicated by placental bleeding. Arch Toxicol Suppl 1982;5:214-20.
3. Verstraete M. Clinical application of inhibitors of fibrinolysis. Drugs 1985;29:236-61.
4. Andersson L, Nilsson IM, Colleen S, Granstrand B, Melander B. Role of urokinase and tissue activator in sustaining bleeding and the management thereof with EACA and AMCA. Ann NY Acad Sci 1968;146:642-58.
5. Alvarez JC, Santiveri FX, Ramos I, Vela E, Puig L, Escolano F. Tranexamic acid reduces blood transfusion in total knee arthroplasty even when a blood conservation program is applied.  Transfusion. 2008;48:519--525.
6. Camarasa MA, Olle´ G, Serra-Prat M, Mart?´n A, Sa´nchez M, Rico´s P, Pe´rez A, Opisso L. Efficacy of aminocaproic, tranexamic acids in the control of bleeding during total knee replacement: a randomized clinical trial. Br J Anaesth. 2006;96:576--582.
7. Cid J, Lozano M. Tranexamic acid reduces allogeneic red cell transfusions in patients undergoing total knee arthroplasty: results of a meta-analysis of randomized controlled trials. Transfusion. 2005;45:1302--1307.
8. Claeys MA, Vermeersch N, Haentjens P. Reduction of blood loss with tranexamic acid in primary total hip replacement surgery.Acta Chir Belg. 2007;107:397--401.
9. Gill JB, Rosenstein A. The use of antifibrinolytic agents in total hip arthroplasty: a meta-analysis. J Arthroplasty. 2006;21:869--873.
10. Ho KM, Ismail H. Use of intravenous tranexamic acid to reduce allogeneic blood transfusion in total hip and knee arthroplasty: a meta-analysis. Anaesth Intensive Care. 2003;31:529--537.
11. Johansson T, Pettersson LG, Lisander B. Tranexamic acid in total hip arthroplasty saves blood and money: a randomized, doubleblind study in 100 patients. Acta Orthop. 2005;76:314--319.
12. Kagoma YK, Crowther MA, Douketis J, Bhandari M, Eikelboom J, Lim W. Use of antifibrinolytic therapy to reduce transfusion in patients undergoing orthopedic surgery: a systematic review of randomized trials. Thromb Res. 2009;123:687--696.
13. Lozano M, Basora M, Peidro L, Merino I, Segur JM, Pereira A, Salazar F, Cid J, Lozano L, Mazzara R, Macule F. Effectiveness and safety of tranexamic acid administration during total knee arthroplasty. Vox Sang. 2008;95:39--44.
14. Molloy DO, Archbold HA, Ogonda L, McConway J, Wilson RK, Beverland DE. Comparison of topical fibrin spray and tranexamic acid on blood loss after total knee replacement: a prospective, randomised controlled trial. J Bone Joint Surg Br. 2007;89:306--309.
15. Niskanen RO, Korkala OL. Tranexamic acid reduces blood loss in cemented hip arthroplasty: a randomized, double-blind study of 39 patients with osteoarthritis. Acta Orthop. 2005;76:829--832.
16. Orpen NM, Little C, Walker G, Crawfurd EJ. Tranexamic acid reduces early post-operative blood loss after total knee arthroplasty: a prospective randomised controlled trial of 29 patients. Knee. 2006;13:106--110.
17. Rajesparan K, Biant LC, Ahmad M, Field RE. The effect of an intravenous bolus of tranexamic acid on blood loss in total hip replacement. J Bone Joint Surg Br. 2009;91:776--783.
18. Zufferey P, Merquiol F, Laporte S, Decousus H, Mismetti P, Auboyer C, Samama CM, Molliex S. Do antifibrinolytics reduce allogeneic blood transfusion in orthopedic surgery? Anesthesiology. 2006;105:1034--1046.
19. Ralley FE, Berta D, Binns V, Howard J, Naudie DR. One Intraoperative Dose of Tranexamic Acid for Patients Having Primary Hip or Knee Arthroplasty. Clin Orthop Relat Res (2010) 468:1905--1911
20. Tanaka N, Sakahashi H, Sato E, et al. Timing of the administration of tranexamic acid for maximum reduction in blood loss in arthroplasty of the knee. J Bone Joint Surg Br 2001;83:702-5.
21. Benoni G, Bjorkman S, Fredin H. Application of pharmacokinetics data from healthy volunteers for the prediction of plasma concentrations of tranexamic acid in surgical patients. Clin Drug Invest 1995;10:280-7.
22. Good L, Peterson E, Lisander B.  Tranexamic acid decreases external blood loss but not hidden blood loss in total knee replacement. Br J Anaesth. 2003 May;90(5):596-9.
23. Zohar E, Fredman B, Ellis M, et al. A comparative study of the postoperative allogeneic blood-sparing effect of tranexamic acid versus acute normovolemic hemodilution after total knee replacement. Anesth Analg 1999;89:1382-7.
24. Zohar E, Fredman B, Ellis MH, et al. A comparative study of the postoperative allogeneic blood-sparing effects of tranexamic acid and of desmopressin after total knee replacement. Transfusion 2001;41:1285-9.
25. Slaughter TF, Greenberg CS:  Antithrombolytic drugs and perioperative hemostasis.  Am J Hematol 1997; 56:32-36.
26. Kagoma YK, Crowther MA, Douketis J, Bhandari M, Eikelboom J, Lim W. Use of antifibrinolytic therapy to reduce transfusion in patients undergoing orthopedic surgery: a systematic review of randomized trials. Thromb Res. 2009;123:687--696.
27. Ray M, Hatcher S, Whitehouse SL, Crawford S, Crawford R: Aprotinin and epsilon aminocaproic acid are effective in reducing blood loss after primary total hip arthroplasty: A prospective, randomized double-blind placebocontrolled study. J Thromb Haemost 2005;3:1421-1427.