Comparison of topical versus intravenous tranexamic acid in primary total knee arthroplasty: A meta-analysis of randomized controlled and prospective cohort trials

Comparison of topical versus intravenous tranexamic acid in primary total knee arthroplasty: A meta-analysis of randomized controlled and prospective cohort trials

THEKNE-01983; No of Pages 7 The Knee xxx (2014) xxx–xxx Contents lists available at ScienceDirect The Knee Review Comparison of topical versus int...

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THEKNE-01983; No of Pages 7 The Knee xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

The Knee

Review

Comparison of topical versus intravenous tranexamic acid in primary total knee arthroplasty: A meta-analysis of randomized controlled and prospective cohort trials Hao Wang 1, Bin Shen ⁎, Yi Zeng 2 Department of Orthopaedics, West China Hospital, Sichuan University, 37# Guoxue Road, Chengdu 610041, China

a r t i c l e

i n f o

Article history: Received 8 August 2014 Received in revised form 10 September 2014 Accepted 17 September 2014 Available online xxxx Keywords: Tranexamic acid Topical Intravenous Total knee arthroplasty Meta-analysis

a b s t r a c t Background: There has been much debate and controversy about the optimal regimen of tranexamic acid in primary total knee arthroplasty. The purpose of this study was to undertake a meta-analysis to compare the efficacy of topical and intravenous regimen of tranexamic acid in primary total knee arthroplasty. Methods: A systematic review of the electronic databases PubMed, CENTRAL, Web of Science, and Embase was undertaken. All randomized controlled trials and prospective cohort studies evaluating the effectiveness of topical and intravenous tranexamic acid during primary total knee arthroplasty were included. The focus of the analysis was on the outcomes of blood loss, transfusion rate, and thromboembolic complications. Subgroup analysis was performed when possible. Results: Of 328 papers identified, six trials were eligible for data extraction and meta-analysis comprising 679 patients (739 knees). We found no statistically significant difference between topical and intravenous administration of tranexamic acid in terms of blood loss, transfusion requirements and thromboembolic complications. Conclusions: Topical tranexamic acid has a similar efficacy to intravenous tranexamic acid in reducing both blood loss and transfusion rate without sacrificing safety in primary total knee arthroplasty. Level of Evidence: II © 2014 Elsevier B.V. All rights reserved.

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . . . . . . . 2.1. Search strategy . . . . . . . . . . . . . . . . . 2.2. Eligibility criteria . . . . . . . . . . . . . . . . 2.3. Data extraction . . . . . . . . . . . . . . . . . 2.4. Outcome measures . . . . . . . . . . . . . . . 2.5. Study quality . . . . . . . . . . . . . . . . . . 2.6. Statistical analysis . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Search results . . . . . . . . . . . . . . . . . . 3.2. Quality assessment . . . . . . . . . . . . . . . 3.3. Results of meta-analysis . . . . . . . . . . . . . 3.3.1. Total drain output . . . . . . . . . . . . 3.3.2. Total blood loss . . . . . . . . . . . . . 3.3.3. Maximum postoperative hemoglobin drop . 3.3.4. Blood units transfused per patient . . . . 3.3.5. Blood transfusion requirements . . . . . . 3.3.6. Thromboembolic complications . . . . . . 3.3.7. Subgroup analysis . . . . . . . . . . . .

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⁎ Corresponding author. Tel.: +86 13881878767; fax: +86 28 85423438. E-mail addresses: [email protected] (H. Wang), [email protected]mail.com (B. Shen), [email protected] (Y. Zeng). 1 Tel.: +86 15882450246. 2 Tel.: +86 13688069779.

http://dx.doi.org/10.1016/j.knee.2014.09.010 0968-0160/© 2014 Elsevier B.V. All rights reserved.

Please cite this article as: Wang H, et al, Comparison of topical versus intravenous tranexamic acid in primary total knee arthroplasty: A metaanalysis of randomized..., Knee (2014), http://dx.doi.org/10.1016/j.knee.2014.09.010

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H. Wang et al. / The Knee xxx (2014) xxx–xxx

4. Discussion . . . . . . . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . Appendix A. The search string of our research . . . . . . . PubMed database . . . . . . . . . . . . . . . . . . . CENTRAL, Web of Science, Embase, Ovid Medline databases References . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Total knee arthroplasty (TKA) is one of the most common operations in orthopedic practice, associated with large amounts of postoperative blood loss and significant rates of transfusion. The reported amounts of blood loss have ranged from 1450 to 1790 mL [1–3], necessitating allogeneic blood transfusion in 10% to 38% of patients [4,5]. However, blood transfusion is certainly not a zero-risk procedure. On the contrary, it has potential hazards including hemolysis, infection, immunosuppression, transfusion-related acute lung injury and even death [6,7]. Tranexamic acid (TXA) is a synthetic antifibrinolytic agent that binds to the lysine binding site of plasminogen and blocks the binding of plasminogen to the fibrin surface. Thus, plasminogen activation is prevented and fibrinolysis is delayed [8]. By this process, TXA is believed to be able to help the body retain blood clots more effectively and therefore reduces bleeding. Large clinical studies [9,10] and several meta-analyses [11,12] have confirmed that intravenous (IV) administration of TXA could effectively reduce blood loss and transfusions in TKA without increasing the risk of DVT. However, concerns remain over the risk of thromboembolic complications after systemic administration [13]. In light of the safety concerns with the IV-TXA, there has been a growing interest in the topical use of TXA for prevention of bleeding in major orthopedic procedures. Compared with IV-TXA, the topical application leads to 70% lower systemic absorption, and therefore may be a safer alternative to giving it systemically [14]. Besides, the topical application has the advantages of being easy to administer, providing a maximum concentration of TXA at the bleeding site, and inducing partial microvascular hemostasis by stopping fibrin clot dissolution in the affected area. Cumulative studies of topical administration of TXA [15–17], showed reliable evidence that it was effective in reducing total blood loss and blood transfusion rate compared with the placebo. However, it is still controversial whether topical TXA could attain similarly good results in reducing bleeding and transfusions as IV-TXA. Thus, we carried out a meta-analysis to investigate whether there were any differences when comparing topical TXA and IV-TXA in terms of: 1) blood loss results including total drain output, total blood loss and maximum postoperative hemoglobin (Hb) drop; 2) blood units transfused per patient and transfusion requirements; and 3) thromboembolic complications including deep venous thrombosis (DVT) and pulmonary embolism (PE). 2. Materials and methods The methods adopted for this review were based on the recommended PRISMA checklist guidelines [18].

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arthroplasty OR total knee replacement OR TKA OR TKR) AND tranexamic acid. The bibliographies of identified articles, including relevant reviews and meta-analyses were manually searched for potential eligible reports. In addition, the Google database was used to look for additional trials. There were no restrictions in terms of the date or language of publication. 2.2. Eligibility criteria Study selection was performed according to the following inclusive criteria: (1) randomized controlled trials (RCTs) or prospective cohort studies (PCSs); (2) participants underwent primary TKA; (3) interventions including topical (intra-articular) and IV-TXA; and (4) reported outcomes, including postoperative total drain output, total blood loss, maximum postoperative Hb drop, blood units transfused per patient, the number of patients receiving blood transfusion, the incidence of DVT and PE. Studies with cadaver and artificial models were excluded, or if patients were with bleeding disorders. 2.3. Data extraction After exclusion of duplicates, two reviewers (HW and YZ) independently screened the titles and abstracts of identified papers. Most citations could be excluded on the basis of information provided by their respective title or abstract. Otherwise, the full article was obtained and carefully scrutinized by the two reviewers. If necessary, we attempted to contact the author of the original reports to obtain further details. Any disagreement between them was resolved by consensus. The following data were extracted: (1) demographic data of participants including age, gender, indication for TKA, location of study, length of follow-up and whether they underwent unilateral or bilateral TKA; (2) general surgical information including the surgical approach, method of administration, transfusion criteria and whether it was conventional TKA (Con-TKA) or computer-assisted TKA (CAS-TKA); and (3) the number of patients receiving blood transfusion, blood units transfused per patient, blood loss results including total drain output, total blood loss, maximum postoperative Hb drop, thromboembolic complications including DVT and PE. 2.4. Outcome measures The primary outcome was the proportion of patients who were transfused with allogeneic blood, autologous blood or both. The secondary outcomes were the amount of blood loss. Thromboembolic complications were also reviewed to check the safety of topical and IV-TXA. Subgroup analysis was performed based on the study type (RCT or PCS), surgical protocol (CAS-TKA or Con-TKA), and timing of drain clamping (short-time, b 2 h or long-time, ≥2 h).

2.1. Search strategy 2.5. Study quality We searched electronic databases including PubMed, CENTRAL (Cochrane Controlled Trials Register), Web of Science, and Embase for relevant studies published between the time of the establishment of these databases and 21 July 2014. The following search strategy was used to maximize search specificity and sensitivity: (total knee

Two reviewers (HW, YZ) rated the quality of the eligible studies independently. Study quality was judged by using the Jadad five point scale for RCTs and the NEWCASTLE–OTTAWA quality assessment scale for other studies. The Jadad five point scale contained two questions

Please cite this article as: Wang H, et al, Comparison of topical versus intravenous tranexamic acid in primary total knee arthroplasty: A metaanalysis of randomized..., Knee (2014), http://dx.doi.org/10.1016/j.knee.2014.09.010

H. Wang et al. / The Knee xxx (2014) xxx–xxx

each on randomization and masking and one question on the reporting of dropouts and withdrawals. The total score was five [19]. For the NEWCASTLE–OTTAWA quality assessment scale, we assessed the studies included based on three aspects: the selection of the study groups (zero–four points), the comparability of the groups (zero–two points), and the ascertainment of either the exposure or outcome of interest (zero–three points). The total score was nine. Discrepancies were resolved by consensus after discussion, and a third reviewer was consulted if necessary. 2.6. Statistical analysis

Identification

Dichotomous outcomes (transfusion rate, complication rates) were expressed as risk ratios (RR) with 95% confidence (CIs). Continuous outcomes (total drain output, total blood loss, maximum Hb drop, and blood units transfused per patient) were expressed as the mean differences (MD) and respective 95% CIs. Statistical significance was set at p b 0.05 to summarize findings across the trials, as outcomes of the meta-analysis were assessed with RevMan 5.2 software (The Nordic Cochrane Center, The Cochrane Collaboration). Statistical heterogeneity was tested using the chi-squared test and I2 statistic. The chi-squared test b 0.1 was considered suggestive of statistical heterogeneity. Heterogeneity was also assessed by the I2 statistic, which describes the percentage of total variation across studies that is due to heterogeneity rather than chance [20]. An I2 statistic value of N 50% was considered to indicate substantial heterogeneity [21]. Depending on the heterogeneity, a meta-analysis was performed using fixed effect or random effect

Records identified through database searching (n = 328)

3

models. When there was no statistical evidence of heterogeneity, a fixed effect model was adopted; otherwise, a random effect model was chosen. Publication bias was tested using funnel plots. 3. Results 3.1. Search results Fig. 1 shows details of the identification of the studies, their inclusion and exclusion. In the initial search we identified 328 potentially relevant studies. Of these, we included six clinical trials with 679 patients (739 knees) in the meta-analysis. Classification of the remaining studies resulted in a total of five RCTs [10,22–25] and one PCS [26]. One report included four IV groups (based on different doses and timing of intravenously applied), compared with a topical group [25] and one report included two topical groups (based on different doses of topically applied), compared with an IV group [10]. These groups were analyzed separately resulting ultimately in 10 component studies for the metaanalysis. Of the included studies, all articles were in English and published after 2012. The characteristics of the studies that were included are shown in Tables 1 and 2. All participants in the six studies were adults. The mean age of the patients in the studies ranged from 64.8 years [23] to 69.5 years [22]. The dose of topical TXA ranged from 1 g [26] to 3 g [10,22,25] and the IV-TXA ranged from single-dose [10,23,24,26] to triple-dose [22]. All patients were diagnosed osteoarthritis and had undergone primary TKA. 3.2. Quality assessment The quality scores of the six trials are summarized in Table 1. The total scores of the five RCTs included show that the quality of the three trials is high (Jadad score ≥ 3), with a minimum of two points [22,24] and a maximum of four points [23,25]. Two were lower quality randomized control trials, due to a lack of information on the blinding of participants and personnel. According to the NEWCASTLE–OTTAWA quality assessment scale, one PCS scored eight points which meant that the included trials had high quality.

Additional records identified through other sources (n = 0)

Eligibility

Screening

Records after duplicates removed (n = 328)

Records screened (n = 328)

Full-text articles assessed for eligibility (n = 24)

Records screened (n = 304)

Full-text articles excluded, with reasons (n = 18)

Included

Studies included in qualitative synthesis (n = 6)

Studies included in quantitative synthesis (meta-analysis) (n = 6) Fig. 1. Flow chart showing study identification, inclusion and exclusion.

Please cite this article as: Wang H, et al, Comparison of topical versus intravenous tranexamic acid in primary total knee arthroplasty: A metaanalysis of randomized..., Knee (2014), http://dx.doi.org/10.1016/j.knee.2014.09.010

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H. Wang et al. / The Knee xxx (2014) xxx–xxx

Table 1 Characteristics of the six trials selected showing general patient information. Author/s

Year of publication

Maniar RN [25] Seo JG [24] Hegde C [26] Sarzaeem MM [10] Soni A [22] Patel JN [23]

2012 2013 2013 2014 2014 2014

Patients (n)

Age (Y)

Topical

IV

Topical

IV

Male

Gender Female

40 50 30 100 40 47

160 50 30 50 40 42

67.4 67.5 65.48 67.8 69.45 64.8

67.45 66.8 66.57 66.9 69.05 64.9

42 11 – 20 36 23

158 89 – 130 44 66

Country

Diagnosis

Unilateral TKA (no. patients)

FU (months)

Study

Quality score

India South Korea India Ran India USA

OA(200) OA(100) – OA(150) OA(80) OA(89)

All All None All All All

3 2 – – 1.5 4.6

RCT RCT PCS RCT RCT RCT

4 2 8 3 2 4

Abbreviations: IV, intravenous; FU, follow-up; OA, osteoarthritis; RCT, randomized controlled trial; PCS, prospective cohort study. 3.3. Results of meta-analysis

risk of transfusion requirements between the groups (RR 1.02, 95% CI 0.70 to 1.49) in the absence of statistical heterogeneity (p = 0.31, I2 = 15%) (Fig. 2).

3.3.1. Total drain output A total of eight component studies (689 patients) provided data on total drain output. There was no statistically significant difference between the groups with respect to the total drain output (MD 21.91, 95% CI −85.01 to 128.82). Nevertheless, these results should be interpreted with caution due to the presence of significant statistical heterogeneity (p b 0.001, I2 = 94%). 3.3.2. Total blood loss A total of five component studies (420 patients) provided data on total blood loss. There was moderate statistical heterogeneity between studies (p = 0.09, I2 = 51%). The meta-analysis of the total blood loss illustrated no statistically significant difference in the topical group compared with the IV group (MD −14.36, 95% CI −92.02 to 63.30). 3.3.3. Maximum postoperative hemoglobin drop A total of six component studies (529 patients) provided data on maximum postoperative Hb drop. Pooling the data revealed no statistically significant difference in maximum postoperative Hb drop between the topical and IV groups (MD 0.43, 95% CI −0.25 to 1.11). However, there was significant statistical heterogeneity among the studies (p b 0.001, I2 = 95%). 3.3.4. Blood units transfused per patient A total of three component studies (260 patients) provided data on blood units transfused per patient. Pooling the data revealed that topical TXA significantly decreased blood units transfused per patient compared with the IV-TXA (MD −0.40, 95% CI −0.75 to −0.05). 3.3.5. Blood transfusion requirements A total of nine component studies (789 patients) provided data on the number of patients who needed transfusion. In the topical group, transfusions were found in 44 of 397 patients (11.1%), and in the IV group they were found in 43 of 392 patients (11.0%). The summarized estimate of effect size indicated no statistically significant difference in the

3.3.6. Thromboembolic complications All component studies (849 patients) provided data on thromboembolic complications. In nine of them no symptomatic DVT and in all of them no symptomatic PE had been documented in both topical and IV groups. One study [24] documented three DVT cases among 50 patients of the topical group while no DVT case among 50 IV group patients (RR = 7.00, 95% CI 0.37 to 132.10). 3.3.7. Subgroup analysis To eliminate the heterogeneity, six trials were under subgroup analysis based on the study type (RCT or PCS). The subgroup based on surgical protocol and timing of drain clamping was only performed for transfusion rate, as for the remaining outcomes it was not feasible due to either lack of available data or presence of significant statistical heterogeneity. The primary significant result of this review was transfusion rate. In subgroup analysis of different study types, all the nine component studies were RCTs. In subgroup analysis of surgical protocol, five component studies reported the results of CAS-TKA, four component studies reported Con-TKA. In subgroup analysis of different timing of drain clamping, three component studies were assigned to the short-time (b2 h) subgroup while five component studies were assigned to the long-time (≥2 h) subgroup. There was no significant difference in all analyses except one, confirming that the incidence of transfusion was not much different between the groups. Table 3 shows the results of the meta-analysis and subgroup analysis of the cumulative data from these six clinical trials.

4. Discussion Our analysis showed that, in the overall comparison or subgroup analysis, there were no statistically significant differences in blood loss, transfusion requirements and thromboembolic complications when comparing topical TXA and IV-TXA in primary TKA.

Table 2 Characteristics of the six trials selected showing general surgical information. Author/s

Intervention

Technique used

Surgical protocol

Pneumatic tourniquet

Transfusion criteria

Thromboprophylaxis

One dose as IO Two doses as IOPO Two doses as POIO Three doses as POIOPO One dose as post-operative

CAS-TKA

Yes

Hb b 8.5 g/dL Hb b 10.0 g/ dL + symptoms

LMWH

CAS-TKA

Yes

-

IA after the wound closure, no drain

One dose as pre-operative

CAS-TKA

Yes

1.5 g TXA: IA injected through the drain after wound closure 3 g TXA: 5 min TA before suturing, clamp drain 1 h then fully open 5 min TA before tourniquet release, clamp drain 2 h then fully open 2 min TA before tourniquet release, with drain

One dose as post-operative

Con-TKA

Yes

Hb b 8.0 g/dL Hb b 10.0 g/ dL + symptoms HB b 7 g/dL HB b9 g/dL + heart disease Hb b 7.0 g/dL Hb b 10.0 g/ dL + symptoms

Three doses as POIOPO One dose as IO

Con-TKA

Yes

Hb b 8.0 g/dL

LMWH

Con-TKA

Yes

Hb b 8.0 g/ dL + symptoms

LMWH

Topical group

IV group

Maniar RN [25]

3 g TXA/ 100 mL NS

10 10 10 10

Seo JG [24]

1.5 g TXA/ 100 mL NS

1.5 g TXA/100 mL NS

IA while suturing, with nonclamp drain

Hegde C [26]

1 g TXA/ 10 mL NS

1 g TXA/10 mL NS

Sarzaeem MM [10]

1.5 g TXA/ 100 mL NS 3.0 g TXA/ 100 mL NS 3 g TXA/ 100 mL NS 2 g TXA/ 100 mL NS

1.5 g TXA/100 mL NS

Soni A [22] Patel JN [23]

mg/kg mg/kg mg/kg mg/kg

∗ ∗ ∗ ∗

one dose two doses two doses three doses

10 mg/kg ∗ three doses 10 mg/kg ∗ one dose

Topical group

IV group

5 min TA before tourniquet release, clamp drain 2 h then fully open





Abbreviations: TXA, tranexamic acid; NS, normal saline; TA, topical application; IA, intra-articular; min, minute; h, hour; IO, intraoperative intravenous dose; POIO, pre- and intraoperative intravenous doses; IOPO, intra- and postoperative intravenous doses; POIOPO, all three doses; Con-TKA, conventional total knee arthroplasty; CAS-TKA, computer-assisted total knee arthroplasty; Hb, hemoglobin; LMWH, low molecular weight heparin.

Please cite this article as: Wang H, et al, Comparison of topical versus intravenous tranexamic acid in primary total knee arthroplasty: A metaanalysis of randomized..., Knee (2014), http://dx.doi.org/10.1016/j.knee.2014.09.010

H. Wang et al. / The Knee xxx (2014) xxx–xxx

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Fig. 2. The meta-analysis of six trials included showed that there was no statistical significance between topical and IV-TXA in terms of the transfusion rate (RR 1.02, 95% CI 0.70 to 1.49).

TKA may cause significant perioperative bleeding because of the large exposed surface of cancellous bone and activation of local fibrinolysis which is further enhanced by tourniquet release at the end of the procedure [27]. Thus, many TKA patients, particularly those aged N65 years, are at risk for anemia. Postoperative anemia can be an important problem that is associated with adverse effects, including increased mortality and morbidity [28] and a longer hospital stay due to the associated need for blood transfusion [29,30]. TXA was introduced with the aim of reducing postoperative bleeding and transfusion rate. The application of IV-TXA in orthopedic surgery has been well established in the literature [9,31]. Compared with the IV-TXA in TKA, topical TXA was considered to be of less systemic absorption and better local effect. Thus, a growing number of studies have focused on the topical application of TXA in TKA and the results are promising [15,16].

However, there is no consensus regarding the most effective regimen for TXA administration. So this study comparing topical with IV-TXA in primary TKA was considered. We want to see if topical TXA could have advantages over IV application measures. To our knowledge, this is the first one to date evaluating the efficacy and safety of topical application of TXA in primary TKA compared with the IV-TXA. In this study, total drain output and total blood loss were not significantly reduced in the topical group. Maximum postoperative Hb drop in the topical group was decreased by approximately 0.43 g/dL. However, the difference did not reach significance. Besides, topical application of TXA reduced the units of blood transfusion per patient by a mean volume of − 0.40 units (95% CI − 0.75 to − 0.05) compared with the IV group. It seems that the observed magnitude does not reach the level of major clinical importance. In addition, 44 of 397 patients

Table 3 The results of meta-analyses and subgroup analyses in 6 trials. Variables

Total drain outputa All study RCT study PCS study Total blood lossa All studies RCT study PCS study Maximum postoperative hemoglobin dropa All studies RCT study PCS study Blood units transfused per patienta All studies RCT study PCS study Transfusion requirementsb All studies RCT study PCS study Surgical protocol CAS-TKA Con-TKA Clamped drain Short time Long time DVTb b PE

Studies (n)

Patients (n)

p-Value

Incidence Mean difference (95% CI) or risk ratio (95% CI)

Heterogeneity p-value (I2)

Model

8 8 0

689 689 –

0.69 0.69 –

21.91 [−85.01, 128.82] 21.91 [−85.01, 128.82] –

b 0.001 (94%) b 0.001 (94%) –

Random Random –

5 5 0

420 420 –

0.72 0.72 –

−14.36 [−92.02, 63.30] −14.36 [−92.02, 63.30] –

0.09 (51%) 0.09 (51%) –

Random Random –

6 5 1

529 469 60

0.22 0.06 0.0007

0.43 [−0.25, 1.11] 0.65 [−0.04, 1.33] −0.66 [−1.04, −0.28]

b 0.001 (95%) b 0.001 (94%) –

Random Random Fixed

3 2 1

260 200 60

0.03 – 0.03

−0.40 [−0.75, −0.05] – −0.40 [−0.75, −0.05]

– – –

Fixed – Fixed

9 9 0

789 789 –

0.92 0.92 –

1.02 [0.70, 1.49] 1.02 [0.70, 1.49] –

0.31 (15%) 0.31 (15%) –

Fixed Fixed –

5 4

420 369

0.19 0.02

0.75 [0.49, 1.15] 3.41 [1.22, 9.51]

0.75 (0%) 0.43 (0%)

Fixed Fixed

3 5 10 10

300 400 849 849

0.40 0.76 0.19 –

2.86 [0.25, 33.12] 0.92 [0.55, 1.55] 7.00 [0.37, 132.10] –

0,02 (75%) 0.83 (0%) – –

Random Fixed Fixed –

Abbreviations: Con-TKA, conventional total knee arthroplasty; CAS-TKA, computer-assisted total knee arthroplasty; RCT, randomized controlled trial; PCS, prospective cohort study. a The values are presented as mean difference (MD) and 95% confidence interval (95% CI). b The values are presented as risk ratio (RR) and 95% confidence interval (95% CI).

Please cite this article as: Wang H, et al, Comparison of topical versus intravenous tranexamic acid in primary total knee arthroplasty: A metaanalysis of randomized..., Knee (2014), http://dx.doi.org/10.1016/j.knee.2014.09.010

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H. Wang et al. / The Knee xxx (2014) xxx–xxx

(11.1%) in the topical group and 43 of 392 patients (11.0%) in the IV group underwent transfusion, suggesting that topical TXA did not significantly reduce the risk of transfusion. Thus, topical TXA was not clinically superior to IV TXA in reducing blood loss and the transfusion requirements. Subgroup analysis based on the study type illustrated no statistically significant difference in all analysis except one between the groups with respect to total drain output, total blood loss, maximum Hb drop, and transfusion requirements. Theoretically, compared with Con-TKA, CAS-TKA should be reduced blood loss because intramedullary femoral guide was not necessary [32]. In this subgroup analysis, the need for transfusion significantly differed between CAS-TKA (RR, 0.75; 95% CI 0.49 to 1.15) and Con-TKA (RR, 3.41; 95% CI 1.22 to 9.51). The IV TXA seems to play a bigger role in reducing transfusion requirements than topical TXA. Given the small numbers of patients involved, these findings require further confirmation. With regard to drain clamping time, prolonged clamping (RR, 0.92; 95% CI 0.55 to 1.55) reduced blood loss more successfully than clamping for a short duration (RR, 2.86; 95% CI 0.25 to 33.12), although the difference was not significant. Besides, the topical TXA was more effective than IV, when the drain champing time was prolonged. This phenomenon may be explained by the longer tissue contact time of TXA in the prolonged clamping subgroup. Furthermore, clamping of drainage tubes prevents immediate blood loss and promotes blood clot formation in a time-dependent manner. Theoretically, TXA carries a risk of thrombosis, although this has not been proven clinically. Our analysis did not demonstrate increased risks of DVT or PE. In our study, only three DVT cases in the topical group were reported by Seo et al. [24]. Nonetheless, uncertainty still remains because of the difference of DVT and PE screening. Many studies have evaluated only symptomatic DVT and PE. The number of asymptomatic DVT and PE events needs to be evaluated as well. Furthermore, the small numbers of patients involved also prevented us from drawing an accurate conclusion. Considering the above factors, these findings require further confirmation. In eligible studies of this meta-analysis, four IV TXA administration protocols existed including intraoperative intravenous dose (IO group), pre- and intraoperative intravenous dose (POIO group), intraand postoperative intravenous dose (IOPO group), and all three doses (POIOPO group). However, subgroup analysis was not performed for TXA regimen due to either varied dose and times of IV TXA or lack of available data. Maniar et al. [25] conducted an RCT that compared topical TXA with four IV TXA administration protocols. They found that triple-dose regimen of POIOPO produced maximum effective reduction of drain loss and total blood loss. They also concluded that topical TXA was much effective than a single-dose regimen of IV TXA. However, an RCT conducted by Soni et al. [22] found a different result. They compared topical with triple intravenous dose of POIOPO regimens and concluded that topical TXA was equally effective as triple intravenous dose regimen in reducing blood loss during total knee arthroplasty surgery. To clarify this issue, further studies with a larger sample size are required to figure out whether POIOPO regimen is better than topical application. Considering the similar effect between the two regimens and the advantage of topical administration, topical application may be a more rational choice. This meta-analysis has some limitations. Firstly, there was significant heterogeneity among studies when blood loss was evaluated. Variations in methodology and applicative techniques among the trials may have accounted for such heterogeneity. In order to eliminate heterogeneity, subgroup analysis was performed appropriately. Secondly, functional outcomes or quality of life outcome measures could not be addressed in our analysis because of lack of relevant data. Finally, most trials included in our analysis excluded high-risk patients, such as patients with cardiovascular disease, previous DVT events and renal dysfunction. Thus, we should explain the result with caution. In addition, this prevented us from reaching a conclusive conclusion about the safety of TXA.

5. Conclusions Our meta-analysis of currently available evidence indicates that compared with IV-TXA, topical application of TXA had comparative effectiveness on reducing both blood loss and transfusion rate without sacrificing safety in primary TKA. However, studies with more patients and better-designed methods are needed to establish the optimal regimen of TXA in primary TKA. Funding No funding or benefits have been received in the preparation of this manuscript. Conflict of interest statement There are no conflicts of interest to declare. All authors contributed substantially to the study and writing of the manuscript. Each of the authors has read and concurs with the content of the final manuscript. Appendix A. The search string of our research PubMed database #1 #2 #3 #4 #5 #6 #7 #8 #9 #10

Arthroplasty, Replacement, Knee [Mesh] Total Knee Arthroplasty [All Fields] Total Knee Replacement [All Fields] TKA [All Fields] TKR [All Fields] #1 OR #2 OR #3 OR #4 OR #5 Tranexamic Acid [Mesh] Tranexamic Acid [All Fields] #7 OR #8 #6 AND #9

CENTRAL, Web of Science, Embase, Ovid Medline databases #1 #2 #3 #4 #5 #6 #7

Total Knee Arthroplasty Total Knee Replacement TKA TKR #1 OR #2 OR #3 OR #4 Tranexamic Acid #5 AND #6

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Please cite this article as: Wang H, et al, Comparison of topical versus intravenous tranexamic acid in primary total knee arthroplasty: A metaanalysis of randomized..., Knee (2014), http://dx.doi.org/10.1016/j.knee.2014.09.010