The Efficacy and Safety of Tranexamic Acid Combined with Rivaroxaban in Prevention of Clinical Events in Patients after Total Knee/ Hip Arthroplasty: A Meta-analysis CURRENT STATUS:

Purpose To evaluate the efficacy and safety clinical events in patients after TKA/THA through meta-analysis of randomized controlled trials. Materials and Methods In total, 16 (23 trial comparisons) contained 2179 In general, 1257 patients (57.7%) were to experimental group whereas 922 patients (42.3%) were randomized to control group. The result showed that TXA combined with rivaroxaban significantly reduce TBL, BTV, BTR and the incidence of MB compared to the control group; there were no significant differences in NMB between experimental group and control group. This meta-analysis reveals that TXA combined with rivaroxaban can significantly reduce TBL, BTV, the incidence of blood transfusion and the compared to the which proved that its and following keywords and MeSH terms used: (“total knee arthroplasty” OR “total hip arthroplasty”) AND “tranexamic acid” AND “rivaroxaban”. Additional relevant studies were retrieved from reviews, meta-analyses, and other literature. Two authors screened and double-reviewed the retrieved studies.


Background
In recent years, total knee arthroplasty (TKA) has become an important method for the clinical treatment of severe knee joint diseases, while total hip arthroplasty (THA) is also widely used in the treatment of end-stage femoral head necrosis, hip ankylosis and other hip related diseases [1]. As the techniques of TKA and THA become more and more mature, one of the biggest problems that afflict these two types of surgery are the large amount of blood loss during the perioperative period and the need for blood transfusion after operation [2]. Therefore, the prevention and treatment of perioperative complications and postoperative rehabilitation on the success or failure of the operation and to ensure the postoperative recovery of patients cannot be ignored [3].
TXA is a commonly used hemostatic drug in clinic, which can competitively prevent and inhibit the binding of fibrin with fibrinogen and fibrinolytic enzyme, and then play a hemostatic effect, several studies have confirmed that the use of TXA before and during THA/TKA can effectively reduce blood loss [4]. However, there may be a risk of keeping venous blood in a hypercoagulable state at the same time [5,6]. Patients undergoing major orthopedic surgery, especially lower limb joint replacement, are inherently at high risk of venous thromboembolism (VTE). Both the American Academy of Orthopedic Surgeons (AAOS) and the American College of Chest Physicians (ACCP) have developed new evidence-based guidelines for venous thromboembolic prophylaxis after total joint arthroplasty [7,8].
Low molecular weight heparin (LMWH) is still commonly used in anticoagulant, but LMWH needs to be adjusted when it is used, and subcutaneous injection leads to poor compliance of patients after discharge. Rivaroxaban is a direct oral anticoagulant, which is used to prevent VTE in THA/TKA [9]. At the same time, rivaroxaban is given orally without adjusting the dose. Despite its clinical efficacy in VTE prophylaxis, orthopedic surgeons are still skeptical regarding the routine use of rivaroxaban in knee and hip surgery and, in particular, the increased risk of bleeding complications [10].
Therefore, how to balance antifibrinolysis and anticoagulation is a challenge. Some studies have pointed out that we should guard against the risk of postoperative VTE associated with antifibrinolytic drugs and the risk of bleeding caused by anticoagulant drugs [5,6]. There are also studies suggest that TXA has a short half-life in plasma and its antifibrinolytic effect only lasts for 3-4 hours [11], or according to others, up to 6-8 hours [12]. This time interval is well shorter than, or may just coincide with, the initiation of anticoagulant administration to patients after joint replacement surgery. In theory, therefore, no "contradiction" in the combined use of such agents exists, the added use of TXA does not increase rates of thromboembolic events after total joint replacement surgery [13][14][15]. The application of TXA combined with rivaroxaban is relatively few and lacks clinical significance. The purpose of this study was to explore the efficacy and safety of TXA combined with rivaroxaban in patients with THA or TKA to provide more options for the clinical application of anticoagulants.

Search strategy
Two researchers searched for published articles comparing the efficacy and safety of TXA combined with rivaroxaban in patients with THA or TKA following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The RCTs were systematically searched in the databases such as the Cochrane Library, Embase, PubMed, Google Scholar, Baidu Scholar, CNKI and VIP with no restrictions on language or publication date from inception to 16 May 2019. The following keywords and MeSH terms were used: ("total knee arthroplasty" OR "total hip arthroplasty") AND "tranexamic acid" AND "rivaroxaban". Additional relevant studies were retrieved from reviews, metaanalyses, and other literature. Two authors screened and double-reviewed the retrieved studies.
Where disputes were encountered, they were resolved by consulting a third author. In this metaanalysis, all data were extracted from previously published studies, thus no patient consent and ethical approval were required.

Inclusion And Exclusion Criteria
The following inclusion criteria were used: (1) Studies that assessed the efficacy and safety of TXA combined with rivaroxaban in patients with THA or TKA; (2) The study was a randomized controlled trial (RCT); (3) The study subjects were patients undergoing THA or TKA (both primary and revision cases); (4) General information (e.g. gender, age, disease type) of the experimental group and the control group was not statistically different at baseline; (5) At least one of the evaluated groups was based on TXA combined with rivaroxaban; (6) TXA and rivaroxaban had no limitation in usage and dose; (7) Included articles provide sufficient data for analysis; (8) Language was limited to English or Chinese.
The following exclusion criteria were used: (1) Nonclinical trials, case reports or series; (2) Animal experiments; (3) Semi-randomized controlled trials or non-randomized trials; (4) Articles with incorrect or incomplete data, or articles whose data could not be extracted; (5) Studies that compared the efficacy and safety of TXA versus rivaroxaban in patients after THA or TKA.

Endpoints
The primary endpoints for this study were total blood loss (TBL), blood transfusion volume (BTV) and blood transfusion rate (BTR). The secondary endpoints for this study were hidden blood loss (HBL), intraoperative blood loss (IBL), postoperative drainage, (activated partial thromboplastin time) APTT, (fibrinogen) FG, (hemoglobin) Hb and (prothrombin time) PT. The safety endpoints included major bleeding (MB), non-major bleeding (NMB) (including clinically relevant non-major bleeding, minor bleeding, any overt bleeding, etc) and venous thromboembolism (VTE).

Data Extraction
Two authors independently reviewed the contents of the retrieved studies. The primary endpoints were extracted by two authors and verified by a third author. The data extracted included the following primary information: first author's name, year of publication, test type/region, sample size, sex ratio, average age, body mass index (BMI), intervention, operative type, follow-up time and endpoints measured in each study. If the contents of the studies needed clarification, the first author of the study was contacted. Disagreements were resolved through consensus or by consulting a third author.

Risk-of-bias Assessments
The methodological quality of the included studies was estimated independently by two authors based on The Cochrane Risk of Bias criteria. Each quality item was graded as low risk, high risk, or no clear risk. The seven items used to assess bias in each trial included the randomization sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases.

Statistical analysis
Stata (version 12.0, Stata Corp, College Station, Texas) was used to analyze and pool the individual research results. Pooled results were recorded as risk ratios (RR) Standard mean difference (SMD) and 95% confidence intervals (CI) with two-sided P-values. P-values < 0.05 were considered to be statistically significant. Heterogeneity was evaluated using the I 2 test. The heterogeneity was considered to be small when I 2 < 50% and substantial when I 2 > 50%. The fixed effect model was used when I 2 < 50%, while the random effect model was used when I 2 > 50%. A funnel plot was generated to examine the publication bias and to explore the sources of heterogeneity if more than ten studies were included to assess this endpoint. Subgroup analysis was performed according to the administration, operative type, follow-up period and dosage of TXA.

Studies Retrieved and Characteristics
A total of 3298 relevant studies were enrolled according to PRISMA guidelines. The titles and abstracts of the studies were screened to exclude irrelevant studies. Then, we further eliminated the unfit studies by reading the full text of the articles. Finally, 16 studies [12,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] (23 trial comparisons) were included according to the inclusion and exclusion criteria and they had a total of 2179 patients as shown in Fig. 1. In general, 1257 patients (57.7%) were randomized to experimental group whereas 922 patients (42.3%) were randomized to control group. All studies included in this meta-analysis were RCTs. The basic characteristics of the individuals from the trials are described in Table 1.

Secondary Endpoints
The result showed that compared to the control group, TXA combined Rivaroxaban could significantly There was no significant difference between the TXA combined Rivaroxaban and the control group on FG (SMD: -0.12, 95% CI -0.32 to 0.07, I 2 = 0.0%).
There was no significant difference between the TXA combined Rivaroxaban and the control group on

Publication Bias And Sensitivity Analysis
The funnel plot showed that there was bias among retrieved articles as shown in Supply Fig. 1-7. The results of the sensitivity analysis were shown in Supply Fig. 8-10.

Discussion
THA/TKA is one of the operations with large blood loss in orthopedic surgery [31]. TXA, a hemostatic, is often used to prevent perioperative bleeding in TKA/THA [32]. However, the antifibrinolytic effect of TXA may increase the risk of DVT [33]. Anticoagulant drugs should be given within 6-12 hours after the application of TXA [34]. As a direct oral anticoagulant, rivaroxaban has been used clinically for more than a decade, and its antithrombotic effect has been widely recognized [35]. Applying TXA and rivaroxaban at the same time in clinic is contradictory, so the efficacy and safety of TXA combined with rivaroxaban in the prevention of clinical events in patients undergoing TKA/THA are still controversial [36].
Nowadays, there are many meta-analyses to study TXA in patients after THA/TKA. They all concluded that TXA was effective after THA/TKA. Grandhi et al [37], Wei et al [14], Dong et al [38], and Kuo et al [39] conducted meta-analyses to evaluate the effectiveness and safety of aminocaproic acid for reducing blood loss in total knee and hip arthroplasty; Li et al [40], Chen et al [41] and Yang et al [42] conducted meta-analyses to comprise the efficacy and safety of topical, system and intravenous tranexamic acid usage in total knee and hip arthroplasty; Zhang et al [43] and Han et al [44] conducted meta-analyses to compared the efficacy and safety of oral compared with intravenous tranexamic acid in reducing blood loss after primary total knee and hip arthroplasty. However, they only focused on the administration of TXA itself, but did not analysed other influencing factors. Yu et al [45] and Wu et al [46] compared tranexamic acid plus diluted-epinephrine versus tranexamic acid alone for blood loss in total joint arthroplasty, but they only retrieved several studies and only focused on blood loss and transfusion rate. As a result, whether TXA combined with anticoagulant are effective and safe enough to apply in clinical is still inconsistent. When evaluating the primary endpoints, we found that the results were highly heterogeneous, so we did sensitivity analyses to decompose it. The results showed that after excluding Wu et al 's article [30], the overall effect of TBL has been greatly affected; after excluding Wang et al 's article [18], the overall effect of NMB has been greatly affected; the heterogeneity of BTV cannot be explore by sensitivity analysis, which may be caused by the lack of studies. In the study of Wu et al [46] were different, which may be due to the different wound size, operation time and the severity of primary disease. In the follow-up time subgroup analysis, the results showed that except that the 3month group had no effect on TBL, each group could reduce TBL and BTR. This may be due to the imbalance in the number of people in each subgroup. In the dosage of TXA subgroup analysis, the results showed that except that other group had no effect on TBL, each group could reduce TBL and BTR. Because the dosage of TXA included in the article is different, we only distinguish it from the clinical commonly used 1 g and 2 g, and combine the other doses into one group, so different doses may be the main reason for the invalidity of other group.
The potential clinical implications of this meta-analysis are as follows: (1)  We used the outcome events reported in the retrieved studies to integrate the results of this metaanalysis. Therefore, it is difficult to assess the effect of these baseline characteristics on the results.

Conclusion
This meta-analysis reveals that TXA combined with rivaroxaban can significantly reduce TBL, BTV, the incidence of blood transfusion and the incidence of MB compared to the control group, which proved that its efficacy and safety are trustworthy.

Funding
None.  Comparison of BTV between the experimental group and the control group. SMD= standardized mean difference Comparison of BTR between the experimental group and the control group. RR= Risk Ratio Figure 5 Comparison of TBL and BTR between the experimental group and the control group.

Authors
(subgroup analysis) SMD= standardized mean difference RR= Risk Ratio Incidence of adverse reaction between the experimental group and the control group. RR=

Risk Ratio
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