What is the ideal route of administration of tranexamic acid in total knee arthroplasty? A meta-analysis based on randomized controlled trials

Introduction

Total knee arthroplasty (TKA) was a common method for the treatment of elderly patients with end-stage knee osteoarthritis. However, average blood loss after TKA has been noted to range from 500–1,500 mL, resulting in about 40–50% of the patients undergoing TKA unavoidably experience postoperative anemia (1,2).

In the past two decades, the role of Tranexamic acid (TXA) in TKA has been a concern and the application of TXA also been studied a lot to limit the rate of blood loss and transfusion (3-5). Previous studies have indicated that TXA was related to the significant reduction of blood loss and transfusion demand (6,7). In addition, previous studies also indicated that oral and intravenous TXA had similar hemostatic effect (8,9). And relevant studies have shown that patients receiving combined topical and intravenous TXA benefit more than patients receiving a single route of TXA (10,11). In particular, surgeons have been worried about the occurrence of venous thromboembolism (VTE) in high-risk patients using TXA. Recently, some new randomized controlled trials (RCTs) have been carried out to study this problem. Therefore, we conducted this meta-analysis to discuss the efficacy and safety of different TXA administration methods with regard to blood loss, postoperative hemoglobin (HB) level, the incidence of VTE and blood transfusion.

This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (available at http://dx.doi.org/10.21037/apm-20-1857) (12).

Methods

Literature search strategy

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This meta-analysis does not require the approval of the ethics committee. Literature search was conducted by using the electronic databases PubMed, Medline, Web of Science and Embase (last search was updated on March 31, 2020). The following keywords were used to search the data base: (“TKA” OR “Total knee arthroplasty”) AND (“tranexamic acid” OR “TXA”) AND (“randomized controlled trials” OR “RCT”). The included literatures must be written in English.

Inclusion and exclusion criteria

Inclusion criteria: (I) RCTs; (II) patients: underwent TKA (III) groups including topical TXA, intravenous TXA, oral TXA or combination; (IV) complete outcome data. Reviews, case reports, biochemical studies, letters, and conference abstracts were excluded.

Data extraction

All data were extracted by two independent researchers according to the criteria. A data extraction table was provided including the year of publication, first author’s name, simple sizes, mean ages, male (%), comparison types, Intravenous regimen, topical regimen, oral regimen, surgery, tourniquet use, calculation method of blood loss, time of postoperative evaluation of Hb, evaluation method of VTE and the indications of blood transfusion.

Study quality assessment

Study quality assessment was conducted by using the Cochrane Collaboration’s tool to assess the risk of bias. This tool was conducted by the following 6 items: sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, incomplete outcome data, selective outcome reporting, and other sources of bias. The results were classified into three grades: “low risk, middle risk, and high risk”.

Statistical analysis

The relative risks (RRs) with 95% confidence intervals (CIs) were calculated to analysis dichotomous outcomes. The mean differences (MD) with 95% CIs were calculated to analysis dichotomous outcomes. The P value of Q statistic test and I² statistic were used to assess statistical heterogeneity (13). A random effects model was applied If I²<50% and P value lower than 0.10. Subgroup analysis was carried out according to the following variables: surgery (bilateral TKA or unilateral TKA), topical dose (≥3 or <3 g), intravenous dose (≥3 or <3 g), tourniquet (use or not use), region (Asia, Europe or North America). Publication bias was assessed by using funnel plot. Sensitivity analysis determines the impact on heterogeneity testing by eliminating each study in turn, and evaluates the stability of the overall results. All statistical analyses were conducted in Review Manager Software (RevMan version 5.3, the Cochrane Collaboration, Copenhagen, Denmark).

Results

Characteristics of the included studies

A total of 420 records were retrieved from the database, and 180 remained after eliminating duplicate documents. Then, 109 records were screened by titles, and 40 records were excluded after reviewing the abstracts. We reviewed the full text of the remaining 69 records and excluded 41 citations for reasons such as reviews, not RCTs and without sufficient data (Figure 1). Finally, we identified 28 RCTs studies in this meta-analysis and involved a total of 4,200 participants. Study quality assessment and other features of the included studies were shown in Tables 1,2.

Figure 1 Flowchart of the literature search and selection for the present study.

Table 1 Study characteristics and patient demographic details
Full table

Table 2 Study characteristic
Full table

Topical versus intravenous route

Blood loss

Twelve studies involving 1,260 patients that reported blood loss were included. No significant difference was observed in the total blood loss (MD, 11.55; 95% CI, −10.23 to 33.34; P=0.30; I²=28.0%; fixed effect model) between intravenous TXA administration and topical administration (Figure 2A).

Figure 2 Forest plot between intravenous and topical tranexamic acid (A) blood loss. (B) Hemoglobin level. (C) venous thrombotic events rate. (D) transfusion rate.

Postoperative HB level

Twelve studies involving 1,309 patients that reported postoperative HB level were included. The data showed that the topical TXA administration had significant increased postoperative HB level compared with the intravenous TXA administration (MD, −0.37; 95% CI, −0.47 to −0.26; P<0.001; I²=34.0%; fixed effect model) (Figure 2B).

VTE rate

Nine studies involving 1,547 patients that reported VTE rate were included. No significant difference was observed in the VTE rate (RR, 1.43; 95% CI, 0.81 to 2.54; P=0.22; I²=0%; fixed effect model) between topical TXA administration and intravenous administration (Figure 2C).

Transfusion rate

Fourteen studies involving 1,536 patients that reported transfusion rate were included in the analysis. No significant difference was observed in the transfusion rate (RR, 1.04; 95% CI, 0.64 to 1.69; P=0.88; I²=7%; fixed effect model) between intravenous TXA administration and topical administration (Figure 2D).

Oral vs. intravenous or topical

Blood loss

Four studies that reported blood loss were included in this analysis. Two studies involving 191 patients compared oral TXA with intravenous TXA and two studies involving 267 patients compared oral TXA with topical TXA. No significant difference was observed in the total blood loss between oral TXA administration and intravenous or topical administration (vs. intravenous: MD, −27.61; 95% CI, −129.69 to 74.47; P=0.60; vs. topical: MD, −73.01; 95% CI, −166.71 to 20.69; P=0.13) (Figure 3A).

Figure 3 Forest plot between oral and intravenous or topical tranexamic acid (A) blood loss. (B) Hemoglobin level. (C) transfusion rate.

Postoperative HB level

Five studies that reported postoperative HB level were included in this analysis. Three studies involving 471 patients compared oral TXA with intravenous TXA and two studies involving 267 patients compared oral TXA with topical TXA. No significant difference was observed in the postoperative HB level between oral TXA administration and intravenous or topical administration (vs. intravenous: MD, −0.02; 95% CI, −0.07 to 0.12, P=0.61; vs. topical: MD, 0.21; 95% CI, −0.09 to 0.52; P=0.67) (Figure 3B).

Transfusion rate

Four studies reported transfusion rate were included in this analysis. Two studies involving 191 patients compared oral TXA with intravenous TXA and two studies involving 267 patients compared oral TXA with topical TXA. No significant difference was observed in the transfusion rate between oral TXA administration and intravenous or topical administration (vs. intravenous: RR, 0.61; 95% CI, 0.15 to 2.48; P=0.49; vs. topical: RR, 0.81; 95% CI, 0.35 to 1.87; P=0.62) (Figure 3C).

Combined vs. single route

Blood loss

Fourteen studies were included in this analysis. Nine studies involving 1,188 patients compared combined TXA route with intravenous TXA and five studies involving 774 patients compared combined TXA route with topical TXA. The results showed that the combined route had significantly decreased total blood loss (MD, −199.58; 95% CI, −181.68 to −57.49; P<0.001; I²=86%) compared with the single regimen. Compared with the intravenous (MD, −134.00; 95% CI, 228.10 to −39.89; P<0.05) or topical route (MD, −93.52; 95% CI, −157.44 to −29.59; P<0.05), combined group showed significantly difference in total blood loss (Figure 4A).

Figure 4 Forest plot between combined administration and single administration of tranexamic acid (A) blood loss. (B) Hemoglobin level. (C) Venous thrombotic events rate. (D) Transfusion rate.

Postoperative HB level

Nine studies reported postoperative HB level were included in this analysis. Five studies involving 585 patients compared combined TXA route with intravenous TXA and four studies involving 674 patients compared combined TXA route with topical TXA. The results showed that the combined route significantly increased postoperative HB level (MD, 0.54; 95% CI, 0.45 to 0.64; P<0.001; I²=71%) compared with the single regimen. Either compared with the intravenous (MD, 0.74; 95% CI, 0.61 to 0.87; P<0.05) or topical route (MD, 0.31; 95% CI, 0.16 to 0.45; P<0.05) showed significantly difference on postoperative HB level (Figure 4B).

Transfusion rate

Six studies involving 799 patients reported transfusion rate were included in this analysis. No significant difference was observed in the transfusion rate (RR, 0.62; 95% CI, 0.26 to 1.48; P=0.28; I²=3%) between combined TXA administration and single administration (Figure 4C).

VTE rate

Eight studies involving 1,128 patients reported on VTE rate were included in this analysis. No significant difference was observed in the VTE rate (RR, 0.81; 95% CI, 0.57 to 1.15; P=0.24; I²=0%) between combined TXA administration and single administration (Figure 4D).

Sensitivity analysis and publication bias analysis

Sensitivity analysis was also conducted to determine the impact on heterogeneity and evaluate the stability of the overall results by eliminating each study in turn. Our sensitivity analysis results show that our analysis was stable and reliable. We also conducted subgroup analysis and the results showed that surgery (bilateral TKA or unilateral TKA), region (Asia, Europe or North America), topical dose (≥3 or <3 g), intravenous dose (≥3 or <3 g), tourniquet (use or not use) had no impact on the overall effect of the analysis. Funnel plot was performed to evaluate the publication bias of literature. The results suggested that there was no evidence of publication bias in the meta-analyses.

Discussion

TXA was widely used in primary TKA and the efficacy of TXA in reducing blood loss and transfusion rate has been reported in many studies, but the ideal route of administration has been controversial (36). At present, there is no unified standard for the administration of TXA, the most commonly method of TXA is intravenous injection and intra-articular topical injection, and some scholars think that the combination of the two can have a better effect (11,35). Some scholars also think that oral administration of TXA can achieve the same effect and is more economical (18,23). As there are many updated RCT studies comparing the administration of TXA, we carried out this meta-analysis to find the safest and effective method of using TXA in primary TKA.

The most important finding of this study was that the combined use of topical and intravenous administration of TXA is more beneficial than intravenous, topical or oral routes only. The results of this study suggested that the combined use of topical and intravenous administration of TXA reduced blood loss and preserved higher postoperative HB level than intravenous, topical or oral routes. In addition, there was no significant difference in the total blood loss, blood transfusion rate and VTE rate after single administration of TXA. The only difference is that the postoperative HB level of topical TXA administration was significantly increased compared with the intravenous TXA administration. Although many studies have shown that intravenous or topical TXA administrations have the same effect (24,33,34), our findings suggest that topical injection of TXA can be seen as a more effective route of single administration of TXA. There was no significant difference in blood loss and postoperative HB level between oral TXA and intravenous TXA or local TXA, which means that oral TXA can also be used as a method of clinical choice, and has more economic and convenient advantages. However, one meta-analyses have shown that topical and intravenous administration are equally effective in reducing blood loss and blood transfusion rate during TKA (6). Considering topical administration was a simple, surgeon-directed method, we believe topical administration of TXA could be an alternative of combined administration.

The use of topical or intravenous TXA in the setting of primary total joint arthroplasty has become routine practice because it has been shown to provide a clinical benefit and cost savings (40). However, there are still concerns about the safety of intravenous and oral TXA and the risk of thromboembolism in high-risk groups with a history of thromboembolism, acute myocardial infarction or ischemic cerebrovascular accident. Considering these safety issues, topical TXA can be a safe route of administration to reduce postoperative bleeding without increasing VTE associated with knee surgery (30). Our study confirmed that different administration did not significantly affect the incidence of postoperative VTE rate. It can be considered that the combination administration of TXA can bring the greatest benefits to patients without increasing the VTE rate.

The heterogeneity of this study was small, but we still do subgroup analysis. In our meta-analysis, we found that subgroups had no significant effect on the overall effect of the analysis. We believed that TXA had a good effect on reducing blood loss in both bilateral TKA and unilateral TKA and among different races, TXA can also play a good effect. There are still many disputes about the best amount of TXA, but this meta-analysis did not compare the amount of TXA in different groups. Subgroup analysis showed that there was no significant difference between the high-dose group and the low-dose group, indicating that the use of low-dose TXA was equivalent to the use of high-dose TXA in reducing blood loss, but the optimal dose of TXA still needs further study. Some studies have shown that TXA can play a good role in hemostasis in TKA without tourniquet (10,14,15), so as to reduce the influence of tourniquet on postoperative rehabilitation. The subgroup of use tourniquet or not showed no statistically significant difference between the two groups.

There have been some meta-analyses on the efficacy and safety of TXA (6,7,9). These studies have shown that intravenous, topical and oral TXA were effective and safe routes, among which intravenous TXA is the most common. Compared to these meta-analysis, our study has some unique advantages. First, all included studies were RCTs. In our meta-analysis, the latest research has been included, and a large amount of researches have been included, which enhances the persuasiveness of the research. Second, a number of subgroups including surgery, region, TXA dose and tourniquet were analyzed to find out the relevant factors. The final results showed that subgroups had no significant effect on the overall efficacy of the analysis. Admittedly, there were a few limitations in the current study that should not be ignored. First, although the administrations of using TXA were compared, the optimal dosage of TXA was not considered in this study. Second, because of the low incidence of blood transfusion and VTE, more samples are needed to improve the statistical ability. Thirdly, the calculation method of total blood loss was not uniform, the calculation formula of different authors was not consistent, and the factors of postoperative drainage tube were not considered.

Conclusions

This meta-analysis indicates that combined administration of TXA in primary TKA can significantly decrease total blood loss, postoperative HB drop compared with intravenous, topical or oral TXA alone. Oral administration of TXA is similar to intravenous or topical TXA use alone. No matter which administration, there is no significant difference between the postoperative transfusion rate and VTE rate.

Acknowledgments

Funding: This study was funded by National Natural Science Foundation of China (grant numbers 81972130, 81703896, 81972107, 82072494 and 81902203), the National Key Research and Development Program of China (grant number 2017YFC0108102), and the Capital Health Research and Development of Special (grant number 2020-2-4067).

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at http://dx.doi.org/10.21037/apm-20-1857

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/apm-20-1857). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This meta-analysis does not require the approval of the ethics committee.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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