Combined intravenous and topical tranexamic acid versus intravenous use alone in primary total knee and hip arthroplasty: A meta-analysis of randomized controlled trials

Combined intravenous and topical tranexamic acid versus intravenous use alone in primary total knee and hip arthroplasty: A meta-analysis of randomized controlled trials

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Accepted Manuscript Combined intravenous and topical tranexamic acid versus intravenous use alone in primary total knee and hip arthroplasty: A meta-analysis of randomized controlled trials Jie Shang, Haibo Wang, Bai Zheng, Min Rui, Yehua Wang PII:

S1743-9191(16)31042-1

DOI:

10.1016/j.ijsu.2016.11.033

Reference:

IJSU 3223

To appear in:

International Journal of Surgery

Received Date: 22 July 2016 Revised Date:

9 November 2016

Accepted Date: 10 November 2016

Please cite this article as: Shang J, Wang H, Zheng B, Rui M, Wang Y, Combined intravenous and topical tranexamic acid versus intravenous use alone in primary total knee and hip arthroplasty: A meta-analysis of randomized controlled trials, International Journal of Surgery (2016), doi: 10.1016/ j.ijsu.2016.11.033. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Combined intravenous and topical tranexamic acid versus intravenous use alone in primary total knee and hip arthroplasty:A meta-analysis of

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Randomized Controlled Trials

Jie Shang, first author, Department of Orthopedic Surgery, XuZhou Medical University Affiliated

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Hospital, XuZhou Medical University, XuZhou JiangSu Province, China, 221000

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Haibo Wang, co-first author, Department of Orthopedic Surgery, XuZhou Medical University Affiliated Hospital, XuZhou Medical University, XuZhou JiangSu Province, China, 221000

Bai Zheng, Department of Orthopedic Surgery, XuZhou Medical University Affiliated Hospital, XuZhou Medical University, XuZhou JiangSu Province, China, 221000

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Min Rui, Department of Orthopedic Surgery, XuZhou Medical University Affiliated Hospital, XuZhou Medical University, XuZhou JiangSu Province, China, 221000

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Yehua Wang, corresponding author, Department of Orthopedic Surgery, XuZhou Medical University Affiliated Hospital, XuZhou JiangSu Province,China, 221000, E-mail:

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[email protected]

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Combined intravenous and topical tranexamic acid versus intravenous use alone in primary total knee and hip arthroplasty:A meta-analysis of

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Randomized Controlled Trials Abstract

Objective: The tranexamic acid (TXA) can reduce surgical perioperative blood loss.

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However, the optimal regimen of tranexamic acid remains controversial. The purpose of this meta-analysis was to compare the efficacy and safety of combined intravenous and topical

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tranexamic acid versus intravenous use alone in primary total knee and hip arthroplasty

Methods: PubMed, EMbase, Cochrane library and OVID were searched. Eligible randomized controlled trials (RCTs) evaluating combined intravenous and topical TXA versus

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intravenous alone in primary total knee and hip arthroplasty were included. The relative risk (RR) or the mean difference (MD) for dichotomous or continuous data was calculated respectively, and heterogeneity was analyzed by chi-square and I2 tests.

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Results: A total of five RCTs met the inclusion criteria were included. The meta-analysis indicated that there was statistically significant difference favoring the combined group in

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total blood loss(MD=-160.90, 95% CI[-201.26,-120.54]), P<0.00001), hemoglobin drop (MD=-0.41, 95% CI[-0.73,0.08], P=0.01), transfusion requirements(RR=0.29, 95% CI[0.12,0.70], P=0.006) and length of hospital stays (MD=-0.21, 95%CI[-0.40,-0.02], P=0.03).

Both

groups

showed

similar

outcomes

complications(RR=0.84, 95% CI[0.26,2.70], P=0.76).

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regarding

thromboembolic

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Conclusions: Based on our study, Combined use of intravenous and topical TXA is more effective than intravenous TXA alone in primary total knee or hip arthroplasty without

patients are needed in future studies.

Keywords

Combined use

meta-analysis

total knee arthroplasty

total hip

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arthroplasty

tranexamic acid

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increasing the risk of thromboembolic complications. Further high quality studies with more

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1. Introduction

Total knee arthroplasty (TKA) and total hip arthroplasty (THA) have been successful interventions for patients to relief pain and improve functions. One of the major concerns with joint arthroplasty is its potential for marked perioperative blood loss, which may impede the

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rehabilitation in early period after operation. It is estimated that the expected blood loss following total knee arthroplasty is a mean of 1,500 mL, followed by a concomitant decline in hemoglobin of 3 g/dL [1]. Likewise, it is reported blood loss in THA ranges from 1,188 to

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1,651 ml [2]. In an effort to blood preservation, a transfusion with allogeneic blood has been

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employed. However, blood is a scarce resource and transfusion is not without risk [3]. A cost-effective strategy to reduce the need for transfusion with few or no side effects would be a major medical advance.

Tranexamic acid (TXA) is an antifibrinolytic agent that is a synthetic analog of the amino acid lysine; by blocking lysine-binding sites on plasminogen molecules and thereby inhibiting the interaction of plasma fibrin, it exerts its antifibrinolytic effect [4]. So TXA can enhance hemostasis, 2

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potentially reduce blood loss during surgery and, therefore, transfusion requirements. Previous studies have reported either intravenous (IV) or topical (TA) administration of TXA with

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satisfactory results in reducing blood loss and transfusion requirement in joint arthroplasty [5-8]. Recent studies have found that another method, the combined use of intravenous and topical tranexamic acid, achieved better clinical outcomes than either regimen alone [9-15]. This

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meta-analysis was conducted to evaluate combined use of intravenous and topical tranexamic acid

versus intravenous alone in primary total knee and hip arthroplasty in terms of: 1) reduction in

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2. Materials and Methods

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blood loss and the transfusion rate, 2) the safety of combined method.

This systematic review and meta-analysis was performed according to PRISMA Statement Criteria [16].

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2.1 Search strategy

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The databases of PubMed、Embase、Cochrane library and OVID were searched for the relevant randomized controlled trials from the time of the establishment of these databases to 2016, using the following search terms: (1) Arthroplasty, Replacement, Knee (Medical Subject Headings), (2) Total Knee Arthroplasty, (3) Total Knee Replacement, (4) Arthroplasties, Replacement, Hip (Medical Subject Headings), (5) Total Hip Replacement, (6) Total Hip Arthroplasty, (7) Tranexamic Acid, (8) intra articular, (9) topical, (10)intravenous. The authors also manually 3

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searched reference lists of the review papers and Google Scholar for further relevant studies.

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2.2 Inclusion criteria

All published randomized, controlled trials comparing combined use of IV and topical TXA with intravenous alone in primary total knee or hip arthroplasty were considered for inclusion

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without language restriction. Nonrandomized, controlled trials were not considered for

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inclusion. The included participants should be adult patients who underwent the primary TKA or THA, and participants in both groups were comparable in preoperative variables.

2.3 Data Extraction and Bias Risk Assessment

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Two review authors extracted information from all eligible publications independently. First author, publication year, study location, demographic data on the participants, information

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about the TKA or THA procedure and outcomes were all collected. The methodological quality was evaluated using the following items recommended by the Cochrane Handbook

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version 5.1.0: (1) random sequence generation; (2)allocation concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessment; (5)incomplete outcome data;

(6)selective reporting; (7)other bias. Each item was evaluated by “Yes”, “No”, or “Unclear”: “Yes” - low risk of bias, “No” - high risk of bias, “Unclear” - lack of information or unclear risk of bias[17]. Any disagreement in assessments was resolved by discussing with a third author to reach a consensus. 4

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2.4 Statistical Analysis

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The Cochrane software Review Manager version 5.3.0 was used for meta-analysis. Mean

difference(MD) and 95% confidence interval (CI) were used for continuous outcomes, and

odds ratios (OR) and 95%CI was calculated to test the overall effects for dichotomous

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outcomes. Significance was set at P<0.05. Statistical heterogeneity was tested by chi-square

test and I2 statistic (I2 > 50% or p < 0.10). The effect estimates would be performed using a

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fixed-effect model when heterogeneity was absent; otherwise, a random-effects model would have been adopted.

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3. Results

3.1 Search Results and Characteristics of Included Studies

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Fig. 1 showed the flow chart of literature screening. Of the initial 158 potentially relevant studies identified, five randomized controlled trials met the inclusion criteria were included in the

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meta-analysis. Three of the studies [11-13] were conducted in patients with total knee arthroplasty and the other two [14, 15] were in patients with total hip arthroplasty. These studies ranged from 2014 to 2016, covering 603 patients. Both groups were statistically comparable in the number of patients, age and gender. The characteristics of individual randomized, controlled trials are presented in Tables 1 and 2.

Fig. 1 Flow chart of literature screening 5

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2.2 Risk of Bias in Included Studies

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Fig. 2 presents the risk of bias of the included studies. Two studies [11,14] did not report the method of randomization while one study [11] did not report the blinding. Three studies [11,13,14] used sealed envelopes for allocation concealment. Besides, there were patients lost

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to follow-up in one study [13].

2.3 Results of meta-analysis

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2.3.1 Meta-analysis of total blood loss

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Fig. 2 Risk of bias summary.

Five studies [11-15] provided data on total blood loss. There was no statistical heterogeneity between studies (P=0.17; I2=37%). Using a fixed-effects model, the result indicated the total blood

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loss in the combined group was significantly less than that in IV group (MD=-160.90, 95% CI[-201.26,-120.54]), P<0.00001) (Fig. 3).

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Fig. 3 Forest plot of total blood loss

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2.3.2 Meta-analysis of hemoglobin drop

The drop in hemoglobin after surgery was provided in three [11,12,14] studies. There was significant statistical heterogeneity between studies (P=0.0004; I2=87%). With a random-effects 6

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model, the meta-analysis of the hemoglobin drop illustrated a statistically significant difference between the combined group and the IV group (MD=-0.41, 95% CI[-0.73,-0.08], P=0.01) (Fig. 4).

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Fig. 4 Forest plot of hemoglobin drop

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2.3.3 Meta-analysis of transfusion requirements

Five studies [11-15] provided data on transfusion requirements. There was no statistical

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heterogeneity between studies (P=0.64; I2=0%). Using a fixed-effects model, the summarized results indicated the combined group achieve a lower risk in transfusion requirements compared with IV group (RR=0.29, 95% CI[0.12,0.70], P=0.006) (Fig. 5).

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Fig. 5 Forest plot of transfusion requirements

2.3.4 Meta-analysis of thromboembolic complications

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Regarding thromboembolic complications, five randomized, controlled trials [11-15] were available for meta-analysis. There was no statistical heterogeneity between studies (P=0.76;

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I2=0%). With a fixed-effects model, the meta-analysis illustrated there was no statistically

significant difference between the groups in the number of patients with DVT or PE (RR=0.84, 95% CI[0.26,2.70], P=0.76) (Fig. 6).

Fig. 6 Forest plot of thromboembolic complications

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2.3.5 Meta-analysis of length of hospital stays

Three studies [11,14,15] compared length of hospital stays between the combined and IV group.

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There was no statistical heterogeneity in this outcome between the two groups(P=0.53, I2=0%), thus a fixed-effects model was used. The pooling results showed the combined group had a less length of hospital stays than IV group (MD=-0.21, 95% CI[-0.40,-0.02], P=0.03) (Fig. 7).

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Fig. 7 Forest plot of length of hospital stays

4. Discussion

While tranexamic acid has been long used in TKA or THA, the most effective and safe regime is still controversial. A previous meta-analysis [18] about intravenous and topical TXA was

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conducted, its results revealed similar outcomes in efficacy and safety between the two groups. Recently, the combined use of IV-TXA and local TXA, has been put under the spotlight, showing satisfactory results [14]. To evaluate the efficacy and safety of the combined regime of TXA, we

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conducted the meta-analysis. A total of five randomized controlled trials with 603 patients were

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included in our study. The results of current study indicated that combined use of intravenous and topical TXA leads to a significantly reduction in total blood loss, hemoglobin drop and transfusion rates compared to IV alone without sacrificing its safety. Interestingly, the combined group also shows an advantage in length of hospital stays over the IV group, which may be related to a faster recovery early after surgery.

Blood management remains a topic in joint replacement. With substantial blood loss, an 8

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allogeneic blood transfusion is often required to improve the hematocrit and the hemoglobin levels. However, this procedure is frequently associated with risks of allergic reaction, hemolytic

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transfusion reactions, anaphylaxis, and transmission of infections [19]. Thus, blood loss prevention has a major influence on total knee and hip replacement costs through decreases in morbidity and mortality [20]. The current meta-analysis suggested that the combined group

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achieved better outcomes in reducing total blood loss than IV group, as well as the reduction in hemoglobin drop. Additionally, in our study, the results showed that 5 of 301 patients in the

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combined group required transfusion compared with 20 of 302 patients in the IV group(1.66% VS 6.62%). Besides, two studies [11,15] reported that the transfusion units was less in combined group than the IV group. By pooling these data together, analyses revealed that combined use of IV and topical TXA had a significant advantage over IV alone in terms of transfusion rate.

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TXA is a lysine analog procoagulant that acts by inhibiting fibrinolysis, the prominent adverse effects of procoagulants include thrombotic complications associated with excessive blood coagulation [21]. Regarding the safety of the two regimes, we compared the

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thromboembolic complications including deep vein thrombosis (DVT) and pulmonary embolism

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(PE). The pooled analyses indicated the safety of combined administration of tranexamic acid. In fact, many previous clinical studies [5,7,22-24] have proved the safety of TXA in TKA or THA that different regimes and doses didn’t increase the incidence of DVT and PE regardless TXA carries a potential risk of thrombosis theoretically. In a meta-analysis [26], Shemshaki et al. reported that there was no statistically significant difference in the incidence of venous thromboembolic events associated with the use of TXA between TXA group and control group

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(5.79% vs. 4.65%). In a systematic review conducted by Kim and his colleagues, they revealed that all included studies confirmed the safety of TXA use in terms of symptomatic DVT and PE,

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regardless a variety of doses, timings, and routes for TXA administration [26].

The current study had several potential limitations. The first limitation is the relatively small

number of included studies. Secondly, although all the included studies were RCTs, the random

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sequence generation, allocation concealment and blinding were absent in some studies, which

might lead to the risks of methodological bias. Huang et al. [11] and Xie et al. [14] did not report

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the method of randomization in their articles. However, when we excluded the two studies, the analysis showed that the results were stable compared with the original results. Thirdly, clinical heterogeneity may be induced by different operative procedures, types of the prosthesis, blood transfusion protocol. These differences could lead to bias in the pooled results. Fourthly, some

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outcome parameters, such as hemoglobin drop, are not given as the mean and standard deviation, thus the data could not be fully used. Fifthly, the doses and timings of TXA in included studies are various. For example, for systemic administrations of TXA, Jain et al. [12] applied a preoperative

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and postoperative dose of IV TXA in the combined group, while Nielsen et al. [13] gave one dose

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of IV TXA just preoperatively.

In conclusion, this meta-analysis shows that combined use of IV and topical TXA leads to an

advantage over IV alone in reducing total blood loss, hemoglobin drop and transfusion rates without increasing the risk of thromboembolic complications. Due to the limit eligible studies, further high quality RCTs with more patients needed in future research to validate the efficacy and

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Studies

Country

Patients (n)

Mean age (yrs)

Combination

IV

Combination

Gender(M/F) IV

Combination

IV

China

92

92

65.4±8.7

64.7±9.5

37/55

30/62

Jain 2016 [12]

India

59

60

68.27±8.66

70.0±6.56

20/39

24/36

Nielsen 2016 [13]

Denmark

30

30

65.5±7.8

63.2±8.6

13/17

15/15

Xie 2016 [14]

China

70

70

60.54±10.96

59.53±11.50

22/48

20/50

Zeng 2016 [15]

China

50

50

53.64±14.75

54.00±12.55

29/21

24/26

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Huang 2014 [11]

Table 1 Characteristics of included 5 RCTs showing general patient information M/F male/female

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IV intravenous

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TKA

Jain 2016 [12]

TKA

Nielsen 2016 [13]

TKA

Xie 2016 [14]

THA

Zeng 2016 [15]

THA

Combination

IV

1.5g TXA IV + 1.5g TXA/50ml NS TA 15mg/kg TXA/100ml IV + 2g TXA TA 1g TXA IV + 3g TXA/100ml NS TA

3g TXA IV

1g TXA IV + 2g TXA/150ml NS TA 15mg/kg TXA IV + 200mg TXA/20ml NS acetabulum bath + 200mg TXA/20ml NS femoral canal + 600mg TXA/60ml NS TA

1.5g TXA IV

15mg/kg TXA IV 1g TXA IV + 100ml NS TA

15mg/kg IV

TXA

Transfusion protocol

Surgical approach

Hb < 70 g/L or Hb 70~100 g/L with symptomatic anemia Hb < 70 g/L or 70~80 g/L with symptomatic anemia Hb <7.5 g/dL or Hb reduce >25% with symptoms of anemia Hb < 70 g/L or Hb 70~100 g/L with symptomatic anemia Hb < 70 g/L or any anemia-related organ dysfunction

MSI+MP

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Huang 2014 [11]

Intervention

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Surgery

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Studies

Table 2 Characteristics of included 5 RCTs showing general surgical information TKA total knee arthroplasty, THA total hip arthroplasty, Hb hemoglobin, TXA tranexamic acid, IV intravenous, TA topical, NS normal saline, MSI midline skin incision, MP medial parapatellar approach,

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MV midvastus approach, SV subvastus approach

Mini-SV MSI+MP

Posterolateral Posterolateral

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Tranexamic acid can reduce blood loss in TKA and THA. The combined group leads to an advantage over IV alone in reducing blood loss. The combined group has lower transfusion rates than IV alone.

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Combined use of TXA will not increase the risk of thromboembolic complications.

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2. 3.