Comparison between epsilon-aminocaproic acid and tranexamic acid for total hip and knee arthroplasty: A meta-analysis

Abstract

Background:

The aim was to compare the efficacy and safety of epsilon-aminocaproic acid (EACA) and tranexamic acid (TXA) in total hip arthroplasty (THA) and total knee arthroplasty (TKA).

Methods:

Potential academic articles were identified from the Cochrane Library, Springer, PubMed, and ScienceDirect databases from inception to December 2019. Randomized controlled trials (RCTs) and non-RCTs involving EACA and TXA in THA or TKA were included. Pooled data were analyzed using RevMan 5.1.

Results:

Three RCTs and three non-RCTs met the inclusion criteria. The present meta-analysis reveals that EACA is associated with significantly more blood loss than TXA. No significant differences were identified in terms of blood transfusion rate, transfusion units, hemoglobin (Hb) level at discharge, operation time, length of hospital stay, deep venous thrombosis (DVT), or 30-day readmission.

Conclusions:

Compared with TXA, EACA led to more blood loss in patients undergoing THA or TKA. However, there was no significant difference in the blood transfusion rate, transfusion units, Hb level at discharge, operation time, length of hospital stay, DVT, or 30-day readmission between groups.

Keywords

aminocaproic acid arthroplasty blood loss meta-analysis tranexamic acid

Introduction

Epsilon-aminocaproic acid (EACA) and tranexamic acid (TXA) are synthetic amino acid derivatives that promote hemostasis by competitively blocking the lysine-binding site of plasminogen.^1,2 Both drugs are widely used to reduce blood loss and transfusion requirements in orthopedic, hepatic, and cardiac surgery.^2
–4 To date, the intravenous administration of TXA in total hip arthroplasty (THA) and total knee arthroplasty (TKA) has been well established in the literature.^5,6 Recently, several published studies have compared EACA with TXA in patients treated with THA and TKA.^7

–10 However, their results are not consistent. Moreover, some limitations exist in these previous studies, such as small sample sizes, inconclusive results, and inaccurate evaluations. Therefore, we conducted a large sample meta-analysis of randomized controlled trials (RCTs) and non-RCTs to compare the efficacy and safety of EACA and TXA in patients undergoing THA or TKA.

Methods

Search strategy

Potentially relevant published academic literature was identified from the PubMed, MEDLINE, Cochrane Library, Embase, and ScienceDirect databases from inception to December 2019. Secondary sources were identified from the references of the included studies. No studies were excluded on the basis of the language used. The keywords used for the search were “replacement OR arthroplasty,” “tranexamic acid,” and “aminocaproic acid” in combination with the Boolean operators AND or OR.

Selection criteria and quality assessment

The present meta-analysis included published RCTs and non-RCTs that compared EACA with TXA in patients undergoing primary THA or TKA. Two independent reviewers determined the suitability of the studies. A third reviewer resolved any disagreements. A quality assessment of the RCTs was conducted according to a modified generic evaluation tool described in the Cochrane Handbook for Systematic Review of Interventions.¹¹ The Methodological Index for Nonrandomized Studies (MINORS) form was used to assess non-RCTs.¹²

Data extraction

The data were extracted from the included literature by two independent researchers. For incomplete data, additional details were obtained by writing to the corresponding author of the included study. The following information were extracted: the first author’s name, publication year, intervening measures, outcome measures, sample size, and comparable baselines. Other relevant parameters were also extracted from individual studies.

Data analysis and statistical methods

RevMan 5.1 (The Cochrane Collaboration, Oxford, UK) was used to analyze the pooled data. The values of p were used to estimate the heterogeneity, and I² depended on the standard χ ² test. When I ² > 50%, p < 0.1 was considered to indicate significant heterogeneity, which indicated that a random-effects model should be used for the data analysis. When I² < 50%, p > 0.1 was considered to indicate no significant heterogeneity. Then, a fixed-effects model was used for the data analysis. When significant heterogeneity was found, a subgroup analysis was performed to identify the sources. The mean differences (MDs) and 95% confidence intervals (CIs) were determined for continuous outcomes. Dichotomous data were analyzed by the risk differences (RDs) and 95% CIs.

Results

Search results

A total of 196 studies were identified as potentially relevant literature reports. By scanning the titles and abstracts, 190 reports were excluded according to the eligibility criteria. No additional studies were obtained after reviewing the references. Ultimately, three RCTs and three non-RCTs^{7

–10,13,14} were eligible for data extraction and the meta-analysis. The search process is shown in Figure 1.

Figure 1.

Flowchart of the study selection process.

Risk of bias assessment

RCT quality was assessed based on the Cochrane Handbook for Systematic Review of Interventions (Figure 2). The RCTs stated clear inclusion and exclusion criteria. The included RCTs included adequate methodology of randomization, concealment of allocation, blinding, and intent-to-treatment analysis. No unclear bias was reported due to incomplete outcome data or selective outcomes. For the non-RCTs, the MINORS score was 20 for the retrospective controlled trials. The methodological quality assessment is illustrated in Table 1.

Figure 2.

Risk of bias summary for the RCTs. RCTs: randomized controlled trials.

Table 1.

Quality assessment for non-randomized trials.

Quality assessment for non-randomized trials	Churchill et al.⁹	Churchill et al.⁸	Lum et al.¹⁴
A clearly stated aim	2	2	2
Inclusion of consecutive patients	2	2	2
Prospective data collection	0	0	0
Endpoints appropriate to the aim of the study	2	2	2
Unbiased assessment of the study endpoint	2	2	2
A follow-up period appropriate to the aim of study	2	2	2
Less than 5% loss to follow-up	2	2	2
Prospective calculation of the sample size	0	0	0
An adequate control group	2	2	2
Contemporary groups	2	2	2
Baseline equivalence of groups	2	2	2
Adequate statistical analyses	2	2	2
Total score	20	20	20

Study characteristics

Demographic characteristics and details concerning the literature type of the included studies are summarized in Table 2. Statistically similar baseline characteristics were observed between both groups.

Table 2.

Characteristics of included studies.

Study	Operation	Intervention	Cases	Mean age	Female	Dosage	Prophylactic antithrombotic
Boese et al.⁷	TKA	EACA	96	66.12	71	2 g	Warfarin
Boese et al.⁷	TKA	TXA	98	64.97	69	14 g	Warfarin
Bradley et al.¹³	THA	EACA	44	59.2	21	5 g	Aspirin
	THA	TXA	46	61.3	27	1 g	Aspirin
	TKA	EACA	72	65.6	42	5 g	Aspirin
	TKA	TXA	73	64.7	50	1 g	Aspirin
Camarasa et al.¹⁰	TKA	EACA	32	73	28	10 mg/kg	LMWH
Camarasa et al.¹⁰	TKA	TXA	35	73	26	3 g	LMWH
Churchill et al.⁹	THA	EACA	711	64.7	392	5 g or 10 g	Surgeon’s discretion
Churchill et al.⁹	THA	TXA	445	65.1	263	1 g	Surgeon’s discretion
Churchill et al.⁸	TKA	EACA	820	63.9	527	5 g or 10 g	Surgeon’s discretion
Churchill et al.⁸	TKA	TXA	610	65.8	392	1 g	Surgeon’s discretion
Lum et al.¹⁴	THA	EACA	183	62.7	105	5 g	Aspirin/warfarin
Lum et al.¹⁴	TKA	TXA	204	65	100	3 g	Aspirin/warfarin

THA: total hip arthroplasty; TKA: total knee arthroplasty; EACA: epsilon-aminocaproic acid; TXA: tranexamic acid; LMWH: low-molecular-weight heparin.

Outcomes of the meta-analysis

It was possible to perform a meta-analysis with eight outcomes (Table 3). EACA was associated with significantly more blood loss than TXA (RD = 136.11, p = 0.004). There were no statistically significant differences between the EACA and TXA groups regarding blood transfusion rate (RD = 0.00, p = 0.94), transfusion units per patient (MD = −0.01, p = 0.71), hemoglobin (Hb) level at discharge (MD = 0.14, p = 0.26), operation time (MD = −1.02, p = 0.68), length of hospital stay (MD = 0.05, p = 0.60), deep venous thrombosis (DVT; RD = −0.00, p = 0.94), or 30-day readmission (RD = 0.00, p = 0.79).

Table 3.

Meta-analysis results.

Outcome	Studies	Groups (EACA/TXA)	Overall effect			Heterogeneity
Outcome	Studies	Groups (EACA/TXA)	Effect estimate	95% CI	p Value	I ² (%)	p Value
Total blood loss	4	244/252	136.11	60.19, 212.03	0.004	41	0.17
Discharge Hb level	4	1647/1174	0.14	−0.10, 0.37	0.26	76	0.007
Blood transfusion rate	4	1958/1511	0.00	−0.02, 0.02	0.94	67	0.006
Transfusion units per patient	3	1563/1090	−0.01	−0.03, 0.02	0.71	56	0.11
Operation time	2	128/133	−1.02	−5.92, 3.88	0.68	45	0.18
Length of hospital stay	5	1743/1272	0.05	−0.14, 0.24	0.60	79	0.0007
Deep venous thrombosis	5	1679/1209	−0.00	−0.01, 0.01	0.94	0	1.00
30-day readmission	2	1531/1055	0.00	−0.01, 0.02	0.79	0	0.95

Hb: hemoglobin; CI: confidence interval; EACA: epsilon-aminocaproic acid; TXA: tranexamic acid.

Discussion

The application of TXA has been confirmed to effectively reduce blood loss and transfusion rates in TKA and THA.^5,6 EACA has a similar mechanism of action to TXA, and several studies have assessed the efficacy of EACA in TKA and THA. However, it is controversial whether EACA is as effective for preventing blood loss as TXA in TKA and THA. Our meta-analysis was more systematic, comprehensive, and novel than the previous meta-analysis.¹⁵

Studies have shown that the total calculated blood loss ranges from 1000 ml to 2000 ml in primary TKA and THA, and 10–38% of patients require transfusions.¹⁶ There is a risk of transfusion-associated complications, such as induced infectious disease, hemolysis, and anaphylactic reactions, and blood transfusions also increase the economic burden.¹⁷ Our study showed greater blood loss in the EACA group than in the TXA group. These results are consistent with previous studies.^13,14 The pooled results indicated that the Hb levels at discharge in the EACA group were similar to those in the TXA group. The indications for blood transfusion were based on postoperative Hb levels and clinical symptoms of anemia. Although the transfusion indicators varied among the included studies, the present meta-analysis showed that the blood transfusion rate and the average transfusion units were not significantly different between the EACA and TXA groups.

The length of hospital stay is another element in determining the effectiveness of THA and TKA. Alshryda et al.¹⁸ reported that TXA decreased the length of hospital stay after TKA by 24%. Churchill et al.^8,9 compared the length of hospital stay between the EACA and TXA groups of patients who underwent THA and TKA. Their outcomes showed that the length of hospital stay was shorter in the EACA group. Recently, Boese et al.⁷ performed an RCT, and the results showed no statistically significant differences in the length of hospital stay between groups. Their results were consistent with the present meta-analysis. Moreover, the pooled results indicated that the 30-day all-cause readmission rate was similar for both the EACA and TXA groups. Taking these findings together, we concluded that EACA may be an acceptable alternative to TXA for preventing blood loss following TKA.

Postoperative DVT is a common complication in TKA and THA. DVT may develop into pulmonary embolism (PE) and result in death. Theoretically, TXA and EACA inhibit fibrinolytic activity and may increase the risk of DVT.¹⁹ Astedt et al.²⁰ found that intravenous TXA does not suppress fibrinolytic activity in the normal vein wall. Numerous studies^21,22 have confirmed the safety of TXA, without increases in the incidence of either DVT or PE. All included studies reported the use of postoperative anticoagulant therapy. In total, 8 of 1679 patients in the EACA group and 6 of 1209 patients in the TXA group reported clinical complications of DVT. The present meta-analysis showed that the use of EACA did not increase the risk of DVT compared with TXA.

Previous studies^23,24 indicated that the routine use of TXA was associated with lower mean total direct hospital costs after primary THA and TKA. Churchill et al.^8,9 reported that the medication acquisition cost for EACA averaged $2.70 per surgery compared with $39.58 per surgery for TXA. EACA is more economical than TXA and has a similar efficacy. Therefore, there is an advantage for patients undergoing TKA or THA to use an intravenous application of EACA.

Several potential limitations should be noted: (1) Only six studies were included, all of which had a relatively small sample size; (2) methodological weaknesses existed in studies, and some outcome parameters were not fully described, so we failed to perform a meta-analysis for those parameters; and (3) subgroup analysis was not performed because of the limited number of included studies, so we could not determine the source of heterogeneity.

Conclusion

Compared with TXA, EACA led to more blood loss in patients undergoing THA or TKA. However, there was no significant difference in blood transfusion rate, transfusion units, Hb level at discharge, operation time, length of hospital stay, DVT, or 30-day readmission between groups. More high-quality RCTs are required due to the limited quality of the evidence and amount of data currently available.

Footnotes

Acknowledgment

We thank the authors of the included studies.

Author contributions

Wen-bin Liu and Gui-Shi Li contributed equally to this work.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Fu-jiang Zhang

References

Levine

Haughom

Strong

, et al. Blood management strategies for total knee arthroplasty. J Am Acad Orthop Surg 2014; 22: 361–371.

Huang

Yin

, et al. A systematic review and meta-analysis of the use of antifibrinolytic agents in total hip arthroplasty. Hip Int 2015; 25: 502–509.

Falana

Patel

. Efficacy and safety of tranexamic acid versus aminocaproic acid in cardiovascular surgery. Ann Pharmacother 2014; 48: 1563–1569.

Makwana

Paranjape

Goswami

. Antifibrinolytics in liver surgery. Indian J Anaesth 2010; 54: 489–495.

Zhao

, et al. Combined use of intravenous and topical versus intravenous tranexamic acid in primary total knee and hip arthroplasty: a meta-analysis of randomised controlled trials. J Orthop Surg Res 2017; 12: 22.

Shang

Wang

Zheng

, et al. Combined intravenous and topical tranexamic acid versus intravenous use alone in primary total knee and hip arthroplasty: a meta-analysis of randomized controlled trials. Int J Surg 2016; 36: 324–329.

Boese

Centeno

Walters

. Blood conservation using tranexamic acid is not superior to epsilon-aminocaproic acid after total knee arthroplasty. J Bone Joint Surg Am 2017; 99: 1621–1628.

Churchill

Puca

Meyer

, et al. Comparing epsilon-aminocaproic acid and tranexamic acid in reducing postoperative transfusions in total knee arthroplasty. J Knee Surg 2017; 30: 460–466.

Churchill

Puca

Meyer

, et al. Comparison of epsilon-aminocaproic acid and tranexamic acid in reducing postoperative transfusions in total hip arthroplasty. J Arthroplasty 2016; 31: 2795–2799.

10.

Camarasa

Olle

Serra-Prat

, et al. 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.

11.

Handoll

Gillespie

, et al. The Cochrane Collaboration: a leading role in producing reliable evidence to inform healthcare decisions in musculoskeletal trauma and disorders. Indian J Orthop 2008; 42: 247–251.

12.

Slim

Nini

Forestier

, et al. Methodological index for non-randomized studies (MINORS): development and validation of a new instrument. ANZ J Surg 2003; 73: 712–716.

13.

Bradley

Ryan

Penrose

, et al. Tranexamic acid or epsilon-aminocaproic acid in total joint arthroplasty? A randomized controlled trial. Bone Joint J 2019; 101-B: 1093–1099.

14.

Lum

Manoukian

MAC

Pacheco

, et al.

Intravenous tranexamic acid versus topical aminocaproic acid: which method has the least blood loss and transfusion rates?

J Am Acad Orthop Surg Glob Res Rev 2018; 2: e072.

15.

Liu

Geng

Shi

, et al. Tranexamic acid versus aminocaproic acid for blood management after total knee and total hip arthroplasty: a systematic review and meta-analysis. Int J Surg 2018; 54: 105–112.

16.

Kopanidis

Hardidge

McNicol

, et al. Perioperative blood management programme reduces the use of allogenic blood transfusion in patients undergoing total hip and knee arthroplasty. J Orthop Surg Res 2016; 11: 28.

17.

Hart

Khalil

Carli

, et al. Blood transfusion in primary total hip and knee arthroplasty. Incidence, risk factors, and thirty-day complication rates. J Bone Joint Surg Am 2014; 96: 1945–1951.

18.

Alshryda

Sukeik

Sarda

, et al. A systematic review and meta-analysis of the topical administration of tranexamic acid in total hip and knee replacement. Bone Joint J 2014; 96-B: 1005–1015.

19.

Foreman

Chua

Harrigan

, et al. Antifibrinolytic therapy in aneurysmal subarachnoid hemorrhage increases the risk for deep venous thrombosis: a case-control study. Clin Neurol Neurosurg 2015; 139: 66–69.

20.

Astedt

Liedholm

Wingerup

. The effect of tranexamic acid on the fibrinolytic activity of vein walls. Ann Chir Gynaecol 1978; 67: 203–205.

21.

Gillette

DeSimone

Trousdale

, et al. Low risk of thromboembolic complications with tranexamic acid after primary total hip and knee arthroplasty. Clin Orthop Relat Res 2013; 471: 150–154.

22.

Nishihara

Hamada

. Does tranexamic acid alter the risk of thromboembolism after total hip arthroplasty in the absence of routine chemical thromboprophylaxis? Bone Joint J 2015; 97-B: 458–462.

23.

Gillette

Kremers

Duncan

, et al. Economic impact of tranexamic acid in healthy patients undergoing primary total hip and knee arthroplasty. J Arthroplasty 2013; 28: 137–139.

24.

Irisson

Hemon

Pauly

, et al. Tranexamic acid reduces blood loss and financial cost in primary total hip and knee replacement surgery. Orthop Traumatol Surg Res 2012; 98: 477–483.