Tranexamic acid versus epsilon-aminocaproic acid in total knee arthroplasty: a meta-analysis (Preprint)
Authors: Zheng Jr Yongbin 
Published: August 2021

BACKGROUND

At present, the effect of tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA) on total knee arthroplasty (TKA) remains controversial. Therefore, the aim of this meta-analysis is to compare the differences between the effects of TXA and EACA in TKA. We used electronic databases, including PubMed, EMbase, Medline, OVID, ScienceDirect, Cochran library, Google academic, Clinical trial and Chinese related databases, for literature-search to find any effect of TXA and EACA in TKA. The differences between groups were compared by odds ratio (OR), weighted mean difference (WMD) and 95% confidence interval (CI). A total of four studies, including 3 randomized controlled trials (RCT) and 1 cohort study, were involved in this meta-analysis, involving 1836 participants. Among these participants, 816 belonged to the TXA group and 1020 belonged to the EACA group. Meta-analysis indicated no difference in surgery time (WMD=0.01, 95% CI -0.35 to 0.36), total amount of blood loss (WMD=0.14, 95% CI -0.09 to 0.37), transfusion rate (OR=0.74, 95% CI 0.20 to 2.78), transfusion units per patient (SMD=-0.15, 95% CI -0.54 to 0.25), complications (OR=0.75, 95% CI 0.37 to 1.55) and length of stay (SMD=-0.01, 95% CI -0.11 to 0.08). Our results suggest that the effect of TXA is not superior to EACA in TKA. However, this conclusion still needs to be further confirmed by multicenter and large sample clinical trials.

OBJECTIVE

Total knee arthroplasty (TKA) is the most effective and widely used surgical method for the treatment of patients with advanced osteoarthritis[1,2,3]. For patients with significantly narrowed femoral and tibial gaps in the lower extremity knee joint and severely worn cartilage layer accompanied by extremity deformities, TKA has a meaningful effect. TKA could not only relieve the patient’s arthritis pain, but also provide a safe and effective treatment for the recovery of knee joint function [4,5]. At present, with the acceleration of the aging of the population, the number of people affected by arthritis is increasing, and the number of patients receiving TKA is also growing.

It is well known that during TKA process, there might be a large amount of blood loss, resulting in an increased rate of blood transfusion [6,7]. The disadvantage of blood transfusion is that it may cause severe immune response, intravascular hemolysis, disease transmission, acute renal failure and coagulopathy [8,9,10,11], resulting in prolonged hospital stay, increased risk of infection at the surgical site, and even death. To reduce intraoperative blood loss and blood transfusion rates, medical researchers have developed several clinical strategies, including hypotension control [12], administration of local anesthesia[13] and erythropoietin[14], lowering the blood transfusion threshold[15], and utilizing antifibrinolytic agents[16].

Antifibrinolytic agents are usually used in clinical practice to enhance hemostasis and could effectively reduce the amount of bleeding during TKA process, thereby reducing the incidence of blood transfusion and postoperative complications [17]. Tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA) are commonly used antifibrinolytic agents. Previous studies have revealed that both TXA and EACA could decrease the amount of blood loss and transfusion rate in TKA process, thereby improving the patient's prognosis [18,19,20]. However, there is still controversy regarding the efficacy of TXA and EACA in TKA. Camarasa[21] and Boese[22] found that TXA and EACA had no statistical difference in reducing the bleeding volume and blood transfusion rate during TKA process. However, evidence from a cohort study demonstrated that although EACA was comparable to TXA in reducing blood loss and length of hospital stay, EACA has a lower cost [23]. On the other hand, a recent randomized controlled trial (RCT) found that EACA was associated with increased perioperative blood loss compared to TXA in TKA process [24].

To resolve above controversy, our study used a meta-analysis method to compare the effectiveness of TXA and EACA in TKA, and provide a theoretical basis for clinical treatment.

METHODS

This study has been approved by the ethics committee of Beihua University.

RESULTS

Literature search process
A total of 375 related literatures were initially obtained. After reading the title, abstract and full text, four studies were finally included in this meta-analysis, including three RCTs and one cohort study, involving 1836 participants. Among them, 816 participants belonged to the TXA group and 1020 belonged to the EACA group. The flow chart of literature retrieval is shown in Figure 1, and the basic features of the included literature are presented in Table 1.

Literature quality evaluation
The quality evaluation of the three RCTs is shown in Figure 2. NOS score of the cohort study was 7 score.

Surgery time
Two studies involving 261 participants described surgery time. Among them, 133 participants were in the TXA group and 128 were in the EACA group. Meta-analysis showed that compared with TXA, EACA did not significantly reduce surgery time (WMD = 0.01, 95% CI -0.35 to 0.36, I2=44.4%) (Figure 3), suggesting no difference between the effect of TXA and EACA on surgery time.

Total blood loss
Three studies involving 399 participants described total blood loss. Among them, 203 participants were in the TXA group and 196 were in the EACA group. Comprehensive analysis demonstrated that compared with TXA, EACA did not remarkably reduce total blood loss (WMD = 0.14, 95% CI -0.09 to 0.37, I2=23.1%) (Figure 4), indicating that TXA is not superior in efficacy to EACA in reducing total blood loss.

Transfusion rate
Three studies involving 1642 participants described transfusion rates. Among them, there were 718 participants in the TXA group and 924 participants in the EACA group. Of the patients in the TXA group, 25 received transfusion treatment, while 28 of 924 patients in the EACA group received transfusion treatment. Meta-analysis indicated that compared with TXA, EACA did not notably reduce transfusion rate (OR=0.74, 95% CI 0.20 to 2.78, I2=40.2%) (Figure 5).

Transfusion units per patient
Two studies involving 1497 participants described transfusion units per patient. Among them, 645 participants were in the TXA group and 852 were in the EACA group. The results of meta-analysis displayed that compared with TXA, EACA did not significantly reduce the transfusion units per patient (SMD = -0.15, 95% CI - 0.54 to 0.25, I2=64.9%) (Figure 6). Considering only two studies were included, we did not conduct sensitivity analysis. The obvious heterogeneity may be caused by different research types.

Complications
Two studies involving 339 participants described the complications. Among the participants, there were 171 in the TXA group and 168 in the EACA group. Complications occurred in 15 patients in the TXA group and 19 patients in the EACA group. Summary analysis demonstrated that compared with TXA, EACA did not reduce the incidence of complications (OR=0.75, 95% CI 0.37 to 1.55, I2=0.0%) (Figure 7).

Length of stay
Three studies involving 1766 participants described the length of stay. Among the participants, 778 were in the TXA group and 988 were in the EACA group. The results of meta-analysis indicated that compared with TXA, EACA did not decrease the length of stay (SMD=-0.01, 95% CI -0.11 to 0.08, I2=0.0%) (Figure 8).

CONCLUSIONS

Our results suggest that the effect of TXA is not superior to EACA in TKA. However, this conclusion still needs to be further confirmed by multicenter and large sample clinical trials.