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Official Journal of the Italian Society of Orthopaedics and Traumatology

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Epsilon-aminocaproic acid versus tranexamic acid in total knee arthroplasty: a meta-analysis study

Journal of Orthopaedics and Traumatology volume 20, Article number: 28 (2019) Cite this article

Abstract

Introduction

Total knee arthroplasty (TKA) surgery can be associated with significant blood loss. Among the problems associated with such blood loss is the need for transfusions of banked blood [1]. Transfusions not only have a financial consequence but also carry a small risk of disease transmission to the patient. Antifibrinolytics have been successfully used to reduce transfusion requirements in elective arthroplasty patients. The objective of this meta-analysis is to determine which of tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA) is more effective for reducing peri-operative blood loss, and lessening the need for blood transfusion following knee arthroplasty surgery.

Materials and methods

MEDLINE, Embase and CINAHL databases were searched for relevant articles published between January 1980 to January 2018 for the purpose of identifying studies comparing TXA and EACA for TKA surgery. A double-extraction technique was used, and included studies were assessed regarding their methodological quality prior to analysis. Outcomes analysed included blood loss, pre- and post-operative haemoglobin, number of patients requiring transfusion, number of units transfused, operative and tourniquet time, and complications associated with antifibrinolytics.

Results

Three studies contributed to the quantitative analysis of 1691 patients, with 743 patients included in the TXA group and 948 in the EACA group. Estimated blood loss was similar between the two groups [95% confidence interval (CI) −0.50, 0.04; Z = 1.69; P = 0.09]. There were no differences between the two groups regarding the percentage of patients requiring transfusion (95% CI 0.14, 4.13; Z = 0.31; P = 0.76). There was no difference in the pre- and post-operative haemoglobin difference between the two groups (95% CI −0.36, 0.24; Z = 0.38; P = 0.70). There was no difference in the average number of transfused units (95% CI −0.53, 0.25; Z = 0.71; P = 0.48). There was no difference in the operative (95% CI −0.35, 0.36; Z = 0.04; P = 0.97) or tourniquet time (95% CI −0.16, 0.34; Z = 0.72; P = 0.47). Similarly, there was no difference in the percentage of venous thromboembolism between the two groups (95% CI 0.17, 2.80; Z = 0.51; P = 0.61).

Conclusions

This study did not demonstrate TXA to be superior to EACA. In fact, both antifibrinolytic therapies demonstrated similar efficacy in terms of intra-operative blood loss, transfusion requirements and complication rates. Currently EACA has a lower cost, which makes it an appealing alternative to TXA for TKA surgery.

Level of evidence

3.

Introduction

Total knee arthroplasty (TKA) surgery can be associated with significant blood loss, which can be associated with a number of problems, including the requirement for blood transfusions [1]. Blood transfusions incur significant cost in terms of materials and technician and nursing staff and pose significant risk of adverse clinical outcomes. These risks include transfusion-related infections, intravascular haemolysis, transfusion-induced coagulopathy, renal impairment, immunologic incompatibility and even mortality [2]. In addition to its association with blood transfusion, excessive bleeding can impair the result of TKA surgery through haematoma, swelling, stiffness, prolonged use of drains, increased length of stay, delayed functional recovery and rehabilitation [3, 4].

Antifibrinolytics have already been successfully used to reduce transfusion requirements in elective arthroplasty patients. Tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA) are two agents that have been shown to reduce peri-operative surgical blood loss and transfusion requirements [5,6,7,8,9,10]. EACA is a lysine analog class of antifibrinolytic which has been widely used in cardiac procedures and has only recently been used in elective orthopaedic surgery [11, 12]. Whilst studies have demonstrated EACA to have a good efficacy and safety profile [13], TXA has been preferentially used in orthopaedics. This may in part be due to the familiarity of TXA to orthopaedic surgeons and anaesthetists and the fact that it was the first to be introduced onto the market. However, TXA appears to be considerably more expensive than its newer counterpart [14, 15].

The objective of this meta-analysis is to determine which of TXA or EACA has greater efficacy for reducing peri-operative blood loss and transfusion requirements associated with knee arthroplasty surgery. The secondary objective is to compare complication rates between the two drugs.

Materials and methods

A comprehensive search of the published literature in MEDLINE, Embase and CINAHL databases was performed for articles comparing EACA and TXA during total knee arthroplasty. The text words “aminocaproic acid”, “EACA”, “tranexamic acid”, and “TXA”, were used in combination with the medical subject headings “knee arthroplasty” and “knee replacement”. All included studies directly compared EACA and TXA for total knee arthroplasty. In addition, patients were of minimum age of 18 years, and comprised both sexes. Irrelevant articles and studies, which failed to meet inclusion criteria, such as reviews, evident from their titles and abstract, were excluded. Nonclinical studies, or those assessing other forms of arthroplasty such as hip, were excluded. Similarly, studies not directly comparing EACA with TXA were also excluded. Relevant articles referenced in these publications were obtained, and the “related article” function was used to widen the results. No language restriction was applied. All abstracts, comparative studies, and citations were searched comprehensively. This study conformed to QUOROM and PRISMA guidelines [16, 17]. A flowchart of the literature search is provided in Fig. 1. The quality of included trials was rated using the Scottish Intercollegiate Guidelines Network scoring system (Table 1) [18].

Fig. 1
figure 1

PRISMA flowchart of study selection

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Table 1 Methodological quality of prospective studies included, adapted from the Scottish Intercollegiate Guidelines Network
Full size table

We found three articles which met our inclusion criteria [19,20,21]. Each article was critically reviewed by two researchers (O.R., A.A.) using a double-extraction method for eligibility. Article extraction was performed independently, and any conflict resolved before final analysis.

Outcome measures were chosen if they were comparable to those from other papers. The primary outcome measures included blood loss and the amount of tranfusion required. Secondary objectives compared operative time, tourniquet time and complications between the two drug groups.

Statistical analyses were performed using Review Manager version 5.0 (The Nordic Cochrane Centre Copenhagen, Denmark). P-value less than 0.05 was chosen as the significance level for outcome measures. For continuous data, the inverse variance method was used for the combination of standardised mean differences (SMDs). Binary data were summarised as risk ratios (RR) and combined using the Mantel–Haenszel method. In each case, a heterogeneity test was performed and a random-effects model used for analyses for consistency and to deal with possible population heterogeneity. Forest plots were used for graphical representation. Funnel plots were not constructed, as they were deemed inappropriate for this number of studies.

Results

Three studies met the inclusion criteria. All three studies reported outcomes which were suitable for quantitative analysis. In total, data from 1691 patients were used in the analysis. There were 743 patients in the TXA group and 948 patients in the EACA group.

Estimated blood loss

Two studies contributed to the analysis of estimated blood loss [19, 20]. There was no significant heterogeneity between the two trials (df = 1; I2 = 10%; Q = 1.11; P = 0.29). There was no significant difference in estimated blood loss between TXA and EACA in these two studies (95% CI −0.50, 0.04; Z = 1.69; P = 0.09) (Fig. 2).

Fig. 2
figure 2

Estimated total blood loss

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Percentage of patients requiring transfusion

Three studies contributed to the analysis of the percentage of patients requiring transfusion [19,20,21]. There was no significant heterogeneity between the three trials (df = 1; I2 = 62%; Q = 2.61; P = 0.11). There was no significant difference in the percentage of patients requiring transfusion between TXA and EACA groups in these three studies (95% CI 0.14, 4.13; Z = 0.31; P = 0.76) (Fig. 3).

Fig. 3
figure 3

Percentage of patients requiring transfusion

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Difference between pre- and post-operative haemoglobin (Hb)

Two studies contributed to the analysis of difference between pre- and post-operative haemoglobin levels [20, 21]. There was no significant heterogeneity between these studies (df = 1; I2 = 48%; Q = 1.93; P = 0.16). There was no significant difference in the pre- and post-operative haemoglobin change between TXA and EACA groups (95% CI −0.36, 0.24; Z = 0.38; P = 0.70) (Fig. 4).

Fig. 4
figure 4

Difference in pre- and post-operative Hb

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Average number of transfused units

Whilst three studies reported on this outcome, only data from two studies were comparable in the analysis [20, 21]. There was some heterogeneity between these trials, justifying the use of a random-effects model (df = 1; I2 = 64%; Q = 2.78; P = 0.10). There was no significant difference in the average number of transfused units between TXA and EACA groups (95% CI −0.53, 0.25; Z = 0.71; P = 0.48) (Fig. 5).

Fig. 5
figure 5

Average no. of transfused units

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Operative time in minutes

Two studies contributed to the analysis of operative time [19, 20]. There was some heterogeneity between the two trials, justifying the use of a random-effects model (df = 1; I2 = 43%; Q = 1.77; P = 0.18). There was no significant difference in operative time between TXA and EACA groups (95% CI −0.35, 0.36; Z = 0.04; P = 0.97) (Fig. 6).

Fig. 6
figure 6

Operative time in minutes

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Tourniquet time in minutes

Two studies contributed to the analysis of tourniquet time [19, 20]. There was no significant heterogeneity between the two trials (df = 1; I2 = 0%; Q = 0.13; P = 0.72). There was no significant difference in tourniquet time between TXA and EACA groups (95% CI −0.16, 0.34; Z = 0.72; P = 0.47) (Fig. 7).

Fig. 7
figure 7

Tourniquet time in minutes

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Percentage of patients with VTE complications

Three studies contributed to the analysis of patients with VTE events [19,20,21]. There was no significant heterogeneity between the three trials (df = 1; I2 = 32%; Q = 1.47; P = 0.23). There was no significant difference in VTE events between TXA and EACA groups in these three studies (95% CI 0.17, 2.80; Z = 0.51; P = 0.61) (Fig. 8).

Fig. 8
figure 8

Percentage of patients with VTE events

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Discussion

Excessive intraoperative blood loss can predispose to hypotension and other cardiac, pulmonary and renal complications, with a subsequent knock-on adverse effect on peri-operative recovery. Excessive bleeding in the early post-operative period can be associated with haematoma formation, swelling, stiffness and wound complications, which may impair the long-term outcome of TKA surgery. In addition, post-TKA blood transfusions have been reported to cause acute lung injury, infections, immune suppression and hypersensitivity reactions [22].

The normal process of fibrinolysis involves the liquefaction of fibrin within blood clots. It consists of two steps: degradation of fibrin and activation of plasminogen [23]. Antifibrinolytic agents such as TXA and EACA decrease blood loss by attenuating this fibrinolytic process [6,7,8].

Specifically, TXA works by competitively binding to plasminogen lysine receptor sites, preventing formation of plasmin and its action in degrading fibrin. At high doses, it can also have a protective effect on platelets. EACA is a 6-aminohexanoic acid also belonging to the lysine class of antifibrinolytic agents. Thus, EACA is believed to work by a similar mechanism to TXA.

TXA has gained in popularity and is in routine use in many centres due to its efficacy in reducing transfusion risks and costs [24]. Many studies have demonstrated the benefits of TXA in reducing peri-operative blood loss and transfusion requirements. However, fewer studies have investigated EACA in elective orthopaedic surgery, and even fewer compare the two drugs head to head in large enough numbers to draw any meaningful conclusions [25,26,27]. Given that these drugs work in a similar way and have the same indications, it seems reasonable to perform a quantitative analysis of all studies comparing these two drugs, in order to gain statistical power and make more meaningful conclusions. To the best of the authors’ knowledge, this is the first meta-analysis comparing the outcomes and complications of TXA and EACA in elective TKA surgery.

In this meta-analysis of 1691 total knee arthroplasty patients, we found no statistical difference between TXA and EACA with regards to blood loss, transfusion requirements or VTE complication rates. These findings are in accordance with other recent reviews of these drugs in patients undergoing other orthopaedic procedures [28,29,30].

Clearly, EACA may prove to be a useful alternative in case of patient allergies to TXA. However, one study suggested that it should be considered as first-line therapy, given that EACA is more cost effective that its counterpart TXA. Whilst the singular difference in cost was only £26, the cumulative cost saving to a healthcare provider could be quite significant [22]. As it appears that the efficacy and complication rates of the two drugs are similar, it would seem reasonable for users to consider EACA favourably whilst it remains less expensive.

We acknowledge some limitations to this study. The studies included in the meta-analysis were of variable quality. However, following quantitative assessment, they were found to meet an acceptable standard prior to their inclusion. We also acknowledge the possibility of publication bias. This is difficult to account for with the number of studies included in this analysis, and readers should bear this in mind. In addition, there will have been some variability in transfusion protocols and population heterogeneity between studies. Thus, as a standard, we performed heterogeneity calculations to give clarity to the reader and used a random-effects model as standard to reduce any heterogeneity effects.

Whilst in individual studies, TXA and EACA were given at set times and set doses, these were different between studies. Whilst this creates some heterogeneity between studies, the slight difference between the dosage regimes will have little impact on the outcome variables, as all dosage regimes had similar outcomes across the studies.

This study is also limited by the fact we did not factor in cost-effectiveness analysis of the drugs used. This was because such data were not available from the published studies, and drug costs are likely to vary from region to region based on the healthcare system and whether cost reduction from bulk ordering can be achieved. We recommend that healthcare institutions investigate drug costs available to them when deciding which of these drugs to use.

Given the results of this study of 1691 patients, it can, however, be concluded that use of TXA and EACA was equally safe and effective as prophylaxis for excessive bleeding in TKA surgery. As EACA has lower cost, it may be seen as a suitable alternative first-line agent in order to reduce the financial burden on healthcare providers.

Availability of data and materials

Not applicable.

Abbreviations

TKA:

total knee arthroplasty

TXA:

tranexamic acid

EACA:

epsilon-aminocaproic acid

SMDs:

standardised mean differences

Hb:

haemoglobin

References

  1. Sculco TP (1998) Global blood management in orthopaedic surgery. Clin Orthop Relat Res 357:43–49

    Article  Google Scholar 

  2. Cardone D, Klein AA (2009) Perioperative blood conservation. Eur J Anaesthesiol 26(9):722–729

    Article  Google Scholar 

  3. Liu X, Zhang X, Chen Y, Wang Q, Jiang Y, Zeng B (2011) Hidden blood loss after total hip arthroplasty. J Arthroplasty 26(7):1100–1105

    Article  Google Scholar 

  4. Spahn DR, Cassut M (2000) Eliminating blood transfusion. New aspects and perspectives. Anesthesiology 93:242–255

    Article  CAS  Google Scholar 

  5. Huang Z, Kie X, Li L, Huang Q, Ma J, Shen B, Kraus VB, Pei F (2017) Intravenous and topical tranexamic acid alone are superior to tourniquet use for primary total knee arthroplasty: a prospective, randomized controlled trial. J Bone Joint Surg Am 99:2053–2061

    Article  Google Scholar 

  6. Blaine KP, Press C, Lau K, Sliwa J, Rao VK, Hill C (2016) Comparative effectiveness of epsilon-aminocaproic acid and tranexamic acid on postoperative bleeding following cardiac surgery during a national medication shortage. J Clin Anesth 35:516–523

    Article  CAS  Google Scholar 

  7. Li G, Sun TW, Luo G, Zhang C (2017) Efficacy of antifibrinolytic agents on surgical bleeding and transfusion requirements in spine surgery: a meta-analysis. Eur Spine J 26:140–154

    Article  Google Scholar 

  8. Sucher MG, Giordani M, Figoni A, Nedopil AJ (2016) Peri-operative blood-loss after total hip arthroplasty can be significantly reduced with topical application of epsilon-aminocaproic acid. Int Orthop 40:2013–2019

    Article  Google Scholar 

  9. Oremus K, Sostaric S, Trkulja V, Haspl M (2014) Influence of tranexamic acid on postoperative autologous blood retransfusion in primary total hip and knee arthroplasty: a randomized controlled trial. Transfusion 54:31–41

    Article  CAS  Google Scholar 

  10. Zufferey P, Merquiol F, Laporte S, Decousus H, Mismetti P, Auboyer C (2006) Do antifibrinolytic reduce allogeneic blood transfusion in orthopaedic surgery? Anaesthesiology 105:1034–1046

    Article  Google Scholar 

  11. Chauhan S, Gharde P, Bisoi A, Kale S, Kiran U (2004) A comparison of aminocaproic acid and tranexamic acid in adult cardiac surgery. Ann Card Anaesth 7:40–43

    PubMed  Google Scholar 

  12. Raghunathan K, Connelly NR, Kanter GJ (2011) Aminocaproic acid and clinical value in cardiac anesthesia. J Cardiothorac Vasc Anesth 25:16–19

    Article  CAS  Google Scholar 

  13. Harley BJ, Beaupre LA, Jones CA, Cinats JG, Guenther CR (2002) The effect of epsilon aminocaproic acid on blood loss in patients who undergo primary total hip replacement: a pilot study. Can J Surg 45:185–190

    PubMed  PubMed Central  Google Scholar 

  14. Tranexamic acid. Lexi-Drugs. Lexicomp. Wolters Kluwer Health Inc. Hudson, OH. http://online.lexi.com. Accessed 14 Dec 2015

  15. Aminocaporic acid. Lexi-Drugs. Lexicomp. Wolters Kluwer Health Inc. Hudson, OH. http://online.lexi.com. Accessed 14 Dec 2015

  16. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF (2000) Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. QUOROM Group. Br J Surg 87:1448–1454

    Article  CAS  Google Scholar 

  17. PRISMA. Transparent Reporting of Systematic Reviews and Meta-Analyses. 2009. http://www.prisma-statement.org/statement.htm. Accessed 2 Feb 2018

  18. SIGN. Meta-analysis methodology checklist. 2004. http://www.sign.ac.uk/guidelines/fulltext/50/checklist1.html. Accessed 22 Feb 2018

  19. Boese CK, Centeno L, Walters R (2017) Blood conservation using tranexamic acid is not superior to epsilon-aminocaproic acid after total knee arthroplasty. J Bone Jt Surg 99:1621–1628

    Article  Google Scholar 

  20. Camarasa MA, Olle G, Serra-Prat M, Martin A, Sanchez M, Ricos P, Perez A, Opisso L (2006) Efficacy of aminocaproic, tranexamic acids in the control of bleeding during total knee replacement: a randomized clinical trial. Br J Anaesth 96:576–582

    Article  CAS  Google Scholar 

  21. Churchill JL, Puca KE, Meyer E, Carleton M, Anderson MJ (2017) Comparing ∑-aminocaproic acid and tranexamic acid in reducing postoperative transfusions in total knee arthroplasty. J Knee Surg 30:460–466

    Article  Google Scholar 

  22. Henry DA, Carless PA, Moxey AJ (2013) Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 1:CD001886

    Google Scholar 

  23. Ortmann E, Besser MW, Klien AA (2013) Antifibrinolytic agents in current anaesthetic practice. Br J Anaesth 111:549–563

    Article  CAS  Google Scholar 

  24. Keating KM, Meding JB (2002) Perioperative blood management practices in elective orthopaedic surgery. J Am Acad Orthop Surg 10:393

    Article  Google Scholar 

  25. Churchill JL, Puca KE, Meyer E, Carleton M, Truchan RN, Anderson MJ (2016) Comparing ∑-aminocaproic acid and tranexamic acid in reducing postoperative transfusions in total hip arthroplasty. J Arthroplasty 31:2795–2799

    Article  Google Scholar 

  26. Falana O, Patel G (2014) Efficacy and safety of tranexamic acid versus aminocaproic acid in cardiovascular surgery. Ann Pharmcother 48:1563

    Article  CAS  Google Scholar 

  27. Guang L, Tian-Wei S, Gan L, Chao Z (2017) Efficacy of antifibrinolytic agents on surgical bleeding and transfusion requirements in spine surgery: a meta-analysis. Eur Spine J 26:140–154

    Article  Google Scholar 

  28. Huang F, Wu Y, Yin Z, Ma G, Chang J (2015) A systematic review and meta-analysis of the use of antifibrinolytic agents in total hip arthroplasty. Hip Int 25:502–509

    Article  Google Scholar 

  29. Aishryda S, Sarda P, Sukeik M, Nargol A, Blenkinsopp K, Mason JM (2011) Tranexamic acid in total knee replacement: a systematic review and meta-analysis. J Bone Joint Surg Br 93:1577–1585

    Article  Google Scholar 

  30. Kagoma YK, Crowther MA, Douketis J, Bhandari M, Elkelboom K, Lim W (2009) Use of antifibrinolytic therapy to reduce transfusion in patients undergoing orthopaedic surgery: a systematic review of randomized trials. Throm Res 123:687–696

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Bradford Teaching Hospitals NHS Foundation Trust, Duckworth Lane, Bradford, BD9 6RJ, UK

    Osman Riaz, Adeel Aqil, Samir Asmar, Raees Vanker, James Hahnel, Christopher Brew, Richard Grogan & Graham Radcliffe

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  1. Osman Riaz
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All authors contributed to the study. All authors read and approved the final manuscript.

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Riaz, O., Aqil, A., Asmar, S. et al. Epsilon-aminocaproic acid versus tranexamic acid in total knee arthroplasty: a meta-analysis study. J Orthop Traumatol 20, 28 (2019). https://doi.org/10.1186/s10195-019-0534-2

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