A Single Preoperative Dose and an Additional Dose of Tranexamic Acid in Total Knee Arthroplasty: a Meta-analysis

Objective: To review the ecacy and safety of a single preoperative dose and an additional postoperative dose of tranexamic acid (TXA) in reducing blood loss in total knee arthroplasty (TKA). Methods: PubMed, Embase, Cochrane Library and Web of Science were searched for randomized controlled trials (RCTs) in March 2021. Postoperative blood loss, transfusion rate, and deep vein thrombosis (DVT) incidence were studied. Data were analyzed using Review Manager 5.3 software and Stata 14.0 software. Results: Intravenous (IV) TXA twice provided lower postoperative blood loss compared with placebo group (P(cid:0)0.001) and IV TXA once group (P=0.007), but a higher postoperative blood loss as compared with combined TXA (P(cid:0)0.001). IV TXA twice provided lower transfusion rate compared with placebo group (P(cid:0)0.001). No signicant difference was found in terms of DVT incidence (P(cid:0)0.05). There was no signicant publication bias for postoperative blood loss, transfusion rate, and DVT incidence. Conclusion: When it comes to IV TXA in TKA, a single preoperative dose and an additional dose of TXA may be a better and more feasible way for blood control than a single preoperative dose.


Introduction
Total knee arthroplasty (TKA) is one of the most commonly performed orthopedic surgery, which is associated with a series of postoperative complications including blood loss [1,2]. Intraoperative and postoperative bleeding is one of the main complications in TKA, and various blood-conserving strategies have been used in TKA. Hyper brinolysis following surgery is a major contributor to perioperative blood loss in TKA [3]. Tranexamic acid (TXA), a commonly used anti brinolytic agent, inhibits brinolysis by blocking the lysine-binding site of plasminogen and has become the method of choice for controlling blood loss [4,5]. Several studies have shown that intravenous (IV)[6-8], intra-articular (IA) [9][10][11] or oral [12][13][14] application of TXA can successfully reduce blood loss and transfusion rate in primary TKA without increasing the risk of thrombosis. But the most effective administration route of TXA remains controversial.
Recently, a meta-analysis [15] assessed the e cacy and safety of the e cacy and safety of a single dose of IV TXA given preoperatively. and it showed that preoperative IV TXA reduced perioperative blood loss and transfusion requirements in a variety of surgical disciplines without increasing the risk of thromboembolic events.
One RCT [7] showed that with the same total dose of TXA, the preoperative dose and an additional dose of TXA (IV TXA twice) were superior to a single preoperative dose of TXA (IV TXA once) in reducing blood loss in TKA. So this study aimed to assess the effect of a single preoperative dose and an additional postoperative dose of tranexamic acid more comprehensively. Postoperative blood loss, transfusion rate, and complication such as DVT incidence were the e cacy and safety points, respectively.

Search Strategy
The literature search using Embase, Cochrane Library, PubMed, and Web of Science databases until May 2021 were conducted. The search strategy included key search terms: ("tranexamic acid" or "TXA" or "TA") and ("total knee arthroplasty" or "total knee replacement" or "TKA" or "TKR"). and ("randomized controlled trial" or "RCT"). Besides, the reference lists of previously published randomized trials, review articles, and meta-analyses were manually searched for additional eligible studies. Related articles and reference lists were searched to avoid original miss. Duplicate records were removed electronically and manually. Eligibility Criteria All citations were downloaded into Endnote X9. Two reviewers (LT and ZL) performed study selection independently, with disagreements solved through discussions and by consulting a third reviewer (HL) if necessary. The inclusion criteria for these studies were performed as follows: (1) Studies on patients with TKA; (2) RCTs; (3) IV TXA twice as intervening measure; (4) Studies reporting postoperative blood loss, transfusion rate, or DVT incidence. The exclusion criteria were: (1) Secondary analyses, including some pooled analyses; (2) Studies published not in English; (3) Abstract, case reports, letters, editorials, conference articles, or insu cient data.

Quality Assessment
The Cochrane risk of bias assessment tool was used to determine the methodological quality of included RCTs [16]. A total of six domains were evaluated: random sequence generation, allocation concealment, participant blinding, outcome assessor blinding, incomplete outcome data and selective reporting. Each domain was assigned a judgment of low risk of bias, high risk of bias or unclear risk of bias. The judgments for each domain were made by strictly following the Cochrane Handbook V.5.1.0, Chapter 8.5.

Data Extraction
The following data were extracted: (1) Characteristics of the 24 trials selected showing general surgical information; (2) Outcome measures including postoperative blood loss, transfusion rate, and DVT incidence; (3) For continuous outcomes, we extracted the mean and standard deviation (SD). For dichotomous outcomes, we extracted the total numbers and the numbers of events in both groups.

Statistical Analysis
Heterogeneity among studies was tested using the Q statistic (P<0.05 was considered heterogeneous) and I 2 statistic (I 2 >50% was considered heterogeneous). If there was no signi cant heterogeneity among studies, a xed-effects model was used; otherwise, a randomeffects model was used [17]. The effect of publication bias was investigated by Egger's test [18]. Mean difference (MD) was calculated for continuous outcomes, and risk ratio (RR) was calculated for dichotomous outcomes. Statistical analyses were conducted using Review

Study Characteristics and Quality Assessment
A total of 1754 potentially relevant articles were identi ed from the databases. After removal of duplicates, 1251 articles were screened for relevance in terms of the title and abstract. And then 109 articles were read the full text and 26 articles were reserved, in which 24 of them possibly eligible for inclusion. Two studies were excluded for reasons of "No available data" (Details are shown in Fig. 1). The remaining 24 RCTs were included in this meta-analysis. The characteristics of the ten included studies were summarized and showed in Table 1. The quality assessment of RCTs is presented in Fig. 2.

Meta-analysis of Postoperative Blood Loss
Postoperative blood loss data were provided by 16 included studies (Fig. 3)

Meta-analysis of Transfusion Rate
Transfusion rate data were provided by 22 included studies (Fig. 4). Our meta-analysis indicated that patients receiving IV TXA twice had signi cantly lower transfusion rate as compared to the placebo group (RR=0.27, 95% CI 0.21 to 0.34, P<0.001; I 2 =43.0%, P=0.03). No signi cant differences in were observed in IV TXA twice and topical TXA or IV once or topical TXA group.
Meta-analysis of DVT Incidence 18 randomized studies reported DVT incidence and no signi cant differences were observed (Fig. 5).

Publication bias
Egger's test was used to assess the potential publication bias of postoperative blood loss, transfusion rate, and DVT incidence studies included in this meta-analysis. The P values from Egger's test indicated that there was no signi cant publication bias for postoperative blood loss, transfusion rate, and DVT incidence (P=0.936, P=0.224 and P =0.705, respectively).

Discussion
Allogenic blood transfusions after TKA carried signi cant potential risks, which should be avoided as well as possible, so TXA should be applied. IV application of TXA has been con rmed as effectively decreasing postoperative blood loss and transfusion rate in TKA patients [19,20]. However, there is no clear consensus on the optimal regimen of IV application of TXA. Administering one pre-operative dose and one subsequent post-operative dose is one of the most common IV application practices. The interval of doses is usually three hours, which is because TXA has a plasma half-life of three hours. This is the rst meta-analysis to identify the e cacy and safety of a single preoperative dose and an additional dose of IV TXA in TKA.
This study showed that IV TXA twice could reduce postoperative blood loss than the placebo group and IV TXA once group, which was consistent with those of previous studies [7,21]. There is a difference existing between single dose and multiple doses, and two doses of TXA may be the optimal regimen for blood loss. IV TXA twice had a higher postoperative blood loss as compared with the IV TXA once and topical/oral group, which may due to the total TXA dose. The e cacy of TXA was positively correlated with total dose, and the use of TXA at two intervals could maintain the exposure level of tranexamic acid to systemic circulation in order to achieve a better effect of reducing postoperative bleeding after TKA.
In three RCTs included, IV TXA twice with subsequent TXA was more effective than IV TXA twice group. Wang et al [22] compared IV 20mg/kg TXA twice with IV 20mg/kg TXA twice and subsequent long-term oral TXA for 14 days, nding the latter produced less blood loss and less swelling and ecchymosis without increasing the risk of complications. Takuya et al [23] compared IV 1g TXA twice with IV 1g TXA twice and intra-articular (IA) 1g TXA, showing IV and IA TXA regimen signi cantly reduced perioperative blood loss compared with only IV TXA. Lee et al [24] compared IV 10mg/kg TXA twice with IV 10mg/kg TXA twice and IA 1g TXA, concluding that combined IA TXA administration further reduces blood loss after TKA in comparison to IV use alone. IV TXA twice with subsequent TXA, either oral or IA, and either long or short term, bleeding could be better controlled.
In addition, IV TXA twice had a similar e cacy with topical TXA in terms of reducing postoperative blood loss. One study [25] indicated that topical 1g TXA and IV 10 mg/kg TXA once have similar safety and e cacy for reducing perioperative blood loss in TKA. Gomez-Barrena et al concluded[26] that a single topical dose of 3g of TXA was not inferior to two 15mg/kg IV TXA doses. We thought IV TXA twice and topical TXA achieved equal control of blood loss. TXA applied locally before wound closure targeted the bleeding, which could reduce the signi cant increase in local brinolysis associated with tourniquet release [27].
IV TXA twice had signi cantly lower transfusion rate as compared to the placebo group. No signi cant differences in were observed between IV TXA twice and TXA control group in terms of transfusion rate. No signi cant differences in were observed in terms of DVT incidence. When the patients determined to apply TXA during the perioperative period, IV TXA twice could be used without without safety concerns. Egger's test indicated that there was no signi cant publication bias for postoperative blood loss, transfusion rate, and DVT incidence. Therefore, the results of this study were relatively stable.
The authors acknowledge that the current study has several limitations. Firstly, the sample of IV TXA twice in this study was small.
Secondly, we only pooled DVT complication. Finally, there may be high quality non-English studies that could have in uenced the outcomes of our meta-analysis, but were excluded due to the selection criteria. A longer follow-up period is required to compare the safety pro le and functional outcome differences.

Conclusion
When it comes to IV TXA in TKA, a single preoperative dose and an additional dose of TXA may be a better and more feasible way for blood control than a single preoperative dose.

Declarations
The authors declared that they had no known competing nancial interests or personal relationships that could have appeared to in uence the work reported in this paper. All methods in the included studies of this meta-analysis were carried out in accordance with relevant guidelines and regulations.
Ethics approval and consent to participate Not applicable.