Comparison of intravenous versus topical tranexamic acid in primary total hip and knee arthroplasty: An updated meta-analysis

Comparison of intravenous versus topical tranexamic acid in primary total hip and knee arthroplasty: An updated meta-analysis

Thrombosis Research 153 (2017) 28–36 Contents lists available at ScienceDirect Thrombosis Research journal homepage: www.elsevier.com/locate/thromre...

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Thrombosis Research 153 (2017) 28–36

Contents lists available at ScienceDirect

Thrombosis Research journal homepage: www.elsevier.com/locate/thromres

ETRO Corner Review Article

Comparison of intravenous versus topical tranexamic acid in primary total hip and knee arthroplasty: An updated meta-analysis Jinwei Xie, Qinsheng Hu 1, Qiang Huang, Jun Ma, Yiting Lei, Fuxing Pei ⁎ Department of Orthopaedic Surgery and Dermatology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, PR China

a r t i c l e

i n f o

Article history: Received 3 November 2016 Received in revised form 26 February 2017 Accepted 9 March 2017 Available online 10 March 2017 Keywords: Total hip arthroplasty Total knee arthroplasty Tranexamic acid Enhanced recovery after surgery

a b s t r a c t Background: The appropriate route for administering tranexamic acid in primary total hip (THA) and knee arthroplasty (TKA) remains controversial. The purpose of this meta-analysis was to compare the efficacy and safety of topical or intravenous tranexamic acid. Methods: PubMed, EMBASE, and the Cochrane Library databases were systematically searched for randomized controlled trials (RCTs) comparing topical and intravenous tranexamic acid following primary THA or TKA. Primary outcomes were transfusion frequency and maximum drop in hemoglobin. Other parameters included total blood loss (TBL), hidden blood loss, drainage volume, hemoglobin level on postoperative day 1 (POD 1), deep vein thrombosis (DVT), pulmonary embolism (PE), wound complications and other adverse events. Data were analyzed using Rev Man 5.2. Results: A total of 18 RCTs involving TKA and 4 RCTs involving THA, corresponding to approximately 2260 patients, were included in the meta-analysis. No significant difference between topical and intravenous tranexamic acid was found in transfusion requirement (RR 1.14, 95%CI 0.87 to 1.50, p = 0.35). The maximum drop in hemoglobin was significantly smaller in the intravenous group than in the topical group (MD 0.33 g/dL, 95%CI 0.07 to 0.58, p = 0.01); similar results were observed for the subset of studies involving THA (MD 0.49 g/dL, 95%CI 0.28 to 0.70, p b 0.001) and the subset involving TKA (MD 0.30 g/dL, 95%CI 0.02 to 0.59, p = 0.04). The topical and intravenous groups did not differ significantly in TBL, drainage volume, hemoglobin level on POD 1, DVT, PE, wound complications or other adverse events. Conclusion: The available evidence indicates similar transfusion requirements and safety for topical and intravenous tranexamic acid in THA and TKA. However, intravenous injection seems to be associated with a smaller maximum drop in hemoglobin. © 2017 Elsevier Ltd. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . . . . . 2.1. Literature search . . . . . . . . . . . . . . . 2.2. Study selection criteria . . . . . . . . . . . . 2.3. Quality assessment of included studies . . . . . 2.4. Outcome measures . . . . . . . . . . . . . . 2.5. Statistical analysis . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . 3.1. Search results . . . . . . . . . . . . . . . . 3.2. Study characteristics and quality assessment . . 3.3. Meta-analysis of the requirement for transfusion 3.4. Meta-analysis of maximum hemoglobin drop . . 3.5. Meta-analysis of blood loss . . . . . . . . . . 3.6. Meta-analysis of hemoglobin level on POD 1 . .

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⁎ Corresponding author at: Department of Orthopaedic Surgery, West China Hospital, Sichuan University, 37#Guoxue Road, 610041, PR China. E-mail address: [email protected] (F. Pei). 1 Qinsheng Hu, co-first author, the author contributed to this paper equally.

http://dx.doi.org/10.1016/j.thromres.2017.03.009 0049-3848/© 2017 Elsevier Ltd. All rights reserved.

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3.7. DVT and PE . . . . . . . . . . . . . . . . 3.8. Wound complications . . . . . . . . . . . 3.9. Other adverse events and functional outcomes 4. Discussion . . . . . . . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . Conflict of interests . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

2.2. Study selection criteria

Primary total hip arthroplasty (THA) and total knee arthroplasty (TKA) are among the most common and effective elective orthopedic procedures. The demand for these surgeries is increasing as the population ages; by 2030 in the US alone, demand for primary TKA is projected to grow by 673% to 3.48 million, and demand for THA is projected to grow by 174% to 572,000 procedures [1]. Since THA and TKA are often performed in older patients with complex comorbidities, the concept of enhanced recovery after surgery (ERAS) is often implemented to reduce morbidity, accelerate convalescence and shorten hospital stay [2]. One of the cornerstones of ERAS in THA and TKA is blood management, since substantial perioperative blood loss can occur because of hyper-fibrinolysis induced by surgical trauma and enhanced by tourniquet use. The synthetic fibrinolysis inhibitor tranexamic acid is one of the most effective alternatives to blood management for reducing perioperative blood loss and allogeneic blood transfusion requirements without sacrificing safety [3–4]. Tranexamic acid can be delivered intravenously [5–6], topically [7– 8] or combined application [9,32], and the most appropriate method of administration, dosage and duration remain controversial. Our own work has suggested that the combination of intravenous and topical application can lead to smaller drop in hemoglobin, less blood loss, less postoperative knee pain, and less knee swelling, as well as shorten hospital stay and increase short-term satisfaction following THA and TKA [9,32]. However, it is unclear how intravenous and topical routes of tranexamic acid administration compare with each other. One metaanalysis [10] of five randomized controlled trials (RCTs) and one prospective cohort study, involving a total of 328 patients who underwent TKA, found no difference between the two routes of administration in terms of blood loss, hemoglobin drop, transfusion requirement or thromboembolic complications. However, an RCT from our group [32] found that intravenous administration was associated with a smaller maximum hemoglobin drop, though the transfusion requirement and blood loss were similar between intravenous and topical routes. In order to gain a comprehensive understanding of how the efficacy and safety of tranexamic acid compare between intravenous and topical routes, we performed an updated meta-analysis of the literature. Outcomes of interest were the transfusion requirement, maximum hemoglobin drop, blood loss, deep venous thrombosis, pulmonary embolism, wound complications and other adverse events.

We retrieved all RCTs that compared topical tranexamic acid with intravenous tranexamic acid in patients after primary THA or TKA, and that reported adequate data on target outcomes. Studies were excluded if (1) their quality was too low or (2) outcomes information was insufficient even after contacting the authors. After exclusion of duplicates, one reviewer screened titles and abstracts to discard those that were clearly ineligible. We then obtained the full text of the remaining references, and the full text was reviewed to assess whether the studies should be included based on the predefined selection criteria. Disagreements were resolved by discussion.

2. Materials and methods 2.1. Literature search We searched the following electronic databases: PubMed (1966 to September 2016), Cochrane Central Register of Controlled Trials (September 2016), Embase (1974 to September 2016) and Web of Science (1995 to September 2016). The following search string was used: (total knee arthroplasty OR total knee replacement) OR (total hip arthroplasty OR total hip replacement) AND (tranexamic acid) AND (TXA). We further screened the reference lists of citations for additional eligible studies. No limitations were placed on language or publication type.

2.3. Quality assessment of included studies Following the criteria in the Cochrane Handbook for Systematic Reviews of Interventions, two reviewers independently assessed study quality and risk of bias, including assessment of random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting and other sources of bias. Each study was judged to be at low, high or unclear risk of bias in each domain. Likelihood of bias was scored using the modified Jadad scale [11]. Studies scoring 4 or more out of a total possible of 8 were considered to be of high quality. Discrepancies were resolved by consensus, and a third reviewer was consulted if necessary. 2.4. Outcome measures We compared intravenous and topical tranexamic acid in terms of hemostatic effect and safety. Primary outcomes were the proportion of patients transfused with allogenic blood and the maximum drop in hemoglobin, defined as the difference between the preoperative level and the lowest postoperative level. Secondary outcomes were total blood loss (TBL), hidden blood loss, drainage volume, hemoglobin level on postoperative day 1 (POD 1), deep vein thrombosis (DVT) pulmonary embolism (PE), wound complications and other adverse events. When reported, functional outcomes and length of hospital stay were also compared. The following data were extracted from the included trials: general information (authors, publication year, location of study), participants (number, age, gender ratio, BMI, preoperative hemoglobin level, transfusion protocol), tranexamic acid dose and route of administration, and outcome measures. All data were extracted on an intention-totreat basis. Missing data were obtained from corresponding authors when possible. 2.5. Statistical analysis Meta-analysis was performed according to the PRISMA statement [12], and statistical analysis was performed using Review Manager 5.2 (The Cochrane Collaboration, Oxford, UK) with a significance threshold of p b 0.05. For dichotomous data, risk ratios (RRs) and 95% confidence intervals (95%CIs) were calculated. For continuous data, mean differences (MDs) and 95%CIs were calculated. The chi-squared test and I2 statistic were used to test for the presence of statistical heterogeneity,

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which was defined as present when p b 0.10 or I2 N 50%. When heterogeneity was absent, meta-analysis was performed using a fixed-effects model; otherwise, a random-effects model was used. 3. Results 3.1. Search results Fig. 1 shows the steps of study selection, in which 249 potentially relevant citations were screened, 217 were excluded as irrelevant or duplicates on the basis of their titles and abstracts, and the remaining 32 were read in full. After excluding 10 publications for failing to meet the inclusion criteria, 22 trials [13–34] involving 2260 patients were included in the meta-analysis. 3.2. Study characteristics and quality assessment Of the 22 studies, 18 involved TKA [13–30] and 4 involved THA [31– 34]. One study [17] involved four intravenous groups with different

dosing regimes and one topical group, and another trial [22] involved two topical groups with different doses and one intravenous group. All studies were published in English between 2012 and 2016, except one study published in French [29]. Key characteristics of all studies are shown in Tables 1 and 2. Sample size of included trials ranged from 20 to 203, and mean age of participants ranged from 55.7 to 72.5 years. All but one TKA study [23] involved surgeries performed under tourniquet; in all but two studies [24,34], a drainage tube was used in all surgeries, and this drainage tube was clamped, except in one study [26]. Topical tranexamic acid dose ranged from 1 g [15] to 3 g [13], and the number of injections of intravenous tranexamic acid ranged from one [13] to four [16]. All patients in the included studies received chemical DVT prophylaxis such as low-molecular-weight heparin, aspirin or factor Xa inhibitor. Table 3 summarizes the methodological quality and the risk of bias of the included studies. All 22 trials were relatively well designed; modified Jadad scores were at least 4. Randomization was performed in all 22 trials, and the method was mentioned in all except 2 trials [13–14]. Details of blinding were clearly reported in 11 studies, and allocation

Fig. 1. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow diagram of literature selection.

J. Xie et al. / Thrombosis Research 153 (2017) 28–36

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Table 1 Characteristics of included trials showing general patient information. Studies

Country

Patients (T/I)

Age (years, T/I)

Gender (M/F)

BMI (kg/m2, T/I)

Pre-Hb (d/dL, T/I)

FU (months)

Keyhani 2016 [13] Öztaş 2015 [14] Aguilera 2012 [15] Maniar 2012 [16] Digas 2015 [17] Gomez-B 2014 [18] Uğurlu 2016 [19] Patel 2014 [20] Soni 2014 [21] Sarzaeem 2014 [22] Tzatzairis 2016 [23] May 2016 [24] Aggarwal 2015 [25] Drosos 2016 [26] Chen 2016 [27] Seo 2012 [28] Çavuşoğlu 2015 [29] Goyal 2016 [30] Zhang 2016 [31] Xie 2016 [32] Wei 2014 [33] North 2016 [34]

Iran Turkey Spain India Greece Spain Turkey US India Iran Greece US India Greece Singapore Korea Turkey Australia China China China US

40/40 30/30 50/50 160/40 30/30 39/39 42/40 47/42 40/40 100/50 40/40 62/69 35/35 30/30 50/50 50/50 20/20 83/85 25/25 70/70 102/101 69/70

67/68.4 67.1/68.6 72.5/72.5 67.4/67.3 71/70 70.1/71.8 70.6/69.4 64.8/64.9 69.5/69.1 68.1/66.9 69.1/69.6 63.0/65.0 55.7/58.8 71.1/69.3 65/65 67.5/66.8 – 66.7/68.8 44.3/44.5 62.2/59.5 60.2/63.6 65.7/64.1

49/31 9/51 30/70 42/158 9/51 27/51 20/62 23/66 36/44 27/86 16/64 29/102 25/45 12/48 25/75 11/89 – 80/88 27/23 45/95 129/74 77/62

31.3/32.7 32.4/30.6 30.9/30.2 30.9/29.4 – 30.4/30.2 31.1/30.8 32.7/35.8 – 32.3/31.6 32.6/32.6 33.8/33.8 27.3/26.3 33.4/32.8 28/28 27.8/28.1 – 30.3/31.0 23.5/24.3 24.5/24.2 25.3/24.2 31.1/31.1

13.7/13.1 12.7/12.6 13.6/13.9 – 13.5/13.3 14.5/14.5 13.3/13.4 13.4/13.4 12.0/11.9 – 13.5/13.6 13.5/13.2 11.9/12.4 14.5/13.6 13.4/13.2 11.5/11.3 12.9/13.5 14.1/14.0 13.0/12.7 13.2/13.3 – 13.2/13.4

– 3 2 3 12 1 – – 1.5 – 1.5 1 6 1 1 2 – 1 12 3 3 1

Abbreviations: T, Topical group; I, Intravenous group; M, male; F, female; FU, follow-up.

concealment was reported in 19 of 22 RCTs (86%). A funnel plot (Fig. 2) showed trials scattered symmetrically around the pooled RR, indicating low risk of publication bias. 3.3. Meta-analysis of the requirement for transfusion A total of 22 studies (2260 patients) provided data on the number of patients who needed allogeneic blood transfusion. Transfusions were needed in 94 of 1214 patients (7.7%) in the topical group, compared to 82 of 1216 patients (6.7%) in the intravenous group. Risk of a transfusion was similar between the two groups (RR 1.14, 95%CI 0.87 to 1.50, p = 0.35), and the pooled data did not show statistical heterogeneity (p = 0.48, I2 = 0%) (Fig. 3). Subgroup analyses based on type of surgery (THA or TKA), topical dose (b2 g or ≥2 g) or intravenous dose (single or ≥2) were performed. In no cases were significant differences observed between topical and intravenous tranexamic acid (Table 4). Meanwhile, because of the heterogeneity between studies, we performed a sensitivity analysis based on the risk of bias. Similar results were obtained when we examined only studies at low risk of bias (defined as studies with a modified Jadad score N 6) (RR 1.06, 95%CIs 0.68 to 1.64, p = 0.80), the same as those with high risk of bias (RR = 1.14, 95%CI = 0.87 to 1.50, p = 0.35). 3.4. Meta-analysis of maximum hemoglobin drop A total of 11 studies (1215 patients) provided data on maximum drop in hemoglobin. Pooling the data revealed a significant difference between the two groups (MD 0.33 g/dL, 95%CI 0.07 to 0.58, p = 0.01). There was significant heterogeneity among the studies (p b 0.001, I2 = 92%), which was eliminated by conducting subgroup analysis based on type of surgery. The results showed that intravenous administration was associated with significantly smaller maximum hemoglobin drop in THA (MD 0.49 g/dL, 95%CI 0.28 to 0.70, p b 0.001) and TKA (MD 0.30 g/dL, 95%CI 0.02 to 0.59, p = 0.04). 3.5. Meta-analysis of blood loss A total of 12 studies (1321 patients) provided data on TBL. Given the presence of significant heterogeneity among studies (p b 0.001, I2 = 81%), a random-effects meta-analysis model and subgroup analyses

were used. TBL was similar between the topical and intravenous groups (MD −23.62 mL, 95%CI −92.70 to 45.47, p = 0.50), and subgroup analysis confirmed this result separately for TKA (MD -50.77 mL, 95%CI − 128.21 to 26.67, p = 0.20) and THA (MD 71.43 mL, 95%CI − 43.29 to 186.16, p = 0.22). A total of 13 studies (1289 patients) provided data on drainage volume. Given the presence of significant heterogeneity among studies (p b 0.001, I2 = 97%), a random-effects meta-analysis model was used. Pooling data revealed no significant difference between the treatment groups (MD 2.20 mL, 95%CI −42.79 to 47.19, p = 0.92). Drainage volume was also similar between the two groups in subgroup analysis based on time of tube clamping. 3.6. Meta-analysis of hemoglobin level on POD 1 Relevant data were obtained from 14 studies (1267 patients). Although topical tranexamic acid was associated with higher hemoglobin on POD 1 than intravenous drug (MD 0.08 g/dL), this difference did not achieve statistical significance (95%CI −0.13 to 0.29, p = 0.46) or clinical relevance. Similar results were obtained in subgroup analysis based on type of surgery. 3.7. DVT and PE A total of 21 studies (2190 patients) reported data on the occurrence of DVT. No statistical heterogeneity was detected among studies (p = 0.88, I2 = 0%), so a fixed-effects meta-analysis model was used. The two groups were similar in the frequency of postoperative DVT (RR 2.02, 95%CI 0.99 to 4.15, p = 0.05). Since several studies in our metaanalysis did not include follow-up [13,19,20,22,29], we performed a sensitivity analysis in which we included only studies with follow-up. In this case, risk of DVT was significantly higher in the topical group (RR 2.14, 95%CI 1.01 to 4.51, p = 0.05). Across all 22 studies, only 4 PE (0.2%) were reported in two studies [24,34]. In the RCT of 131 patients who underwent TKA [24], 2 of 69 patients who received intravenous tranexamic acid developed PE, and 1 of 62 patients who received topical tranexamic acid developed PE. In a double-blind RCT involving 139 patients [34], 1 of 70 patients in the intravenous group developed PE. Rate of PE was similar between topical and intravenous groups in the two RCTs.

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Table 2 Characteristics of included trials showing general surgical information. Studies

Surgery Pneumatic tourniquet

Drainage

Interventions

Transfusion criteria

DVT prophylaxis

DVT screen

Keyhani 2016 [13]

K

Yes

Clamped for 2 h

Hb b 8 g/dL

LMWH

Ultrasound

Öztaş 2015 [14]

K

Yes

Clamped for 30 min

Hb b 8 g/dL

LMWH

Clinical

Aguilera 2012 [15]

K

Yes

Clamped for 1 h

Hb b 8 g/dL



Clinical

Maniar 2012 [16]

K

Yes

Clamped for 2 h

Hb b 8.5 g/dL, 8.5–10 g/dL with anemic symtoms.

LMWH

Clinical

Digas 2015 [17]

K

Yes

Clinical

K

Yes

Hb b 8.5 g/dL without CHD, or b 9.5 g/dL with CHD. Hb b 8 g/dL, 8–10 g/dL with anemic symtoms.

LMWH

Gomez-B 2014 [18]

Clamped for 3 h Clamped for 2 h

LMWH

Clinical

Uğurlu 2016 [19]

K

Yes

Clamped for 1 h

Hb b 8 g/dL or N8 g/dLwith anemic symptoms

LMWH

Clinical

Patel 2014 [20]

K

Yes

Yes

Hb b 8 g/dL with anemic symptoms

LMWH

Clinical

Soni 2014 [21]

K

Yes

Clamped for 2 h

Hb b 8 g/dL

LMWH

Clinical

Sarzaeem 2014 [22]

K

Yes

Clamped for 1 h

Hb b 8 g/dL, 8–10 g/dL with anemic symtoms.





Tzatzairis 2016 [23] May 2016 [24]

K

No

Hb b 10 g/dL

LMWH

Clinical

K

Yes

Clamped for 1 h No drain

Hb b 7 g/dL, 7–10 g/dL with anemic symtoms.

LMWH

Clinical

Aggarwal 2015 [25]

K

Yes

Clamped for 2 h

Hct b 25%, or Hb b 8 g/dL.

Aspirin

Clinical

Drosos 2016 [26] Chen 2016 [27]

K

Yes

No clamp



Yes

Yes

Hb b 10 g/dL with anemic symtoms. Hb b 8 g/dL, 8–10 g/dL with anemic symtoms.



K

LMWH

Clinical

Seo 2012 [28]

K

Yes

Yes



K

Yes

Yes





K

Yes/No

Closed

Hb b 8 g/dL, 8–10 g/dL with anemic symtoms. Hb b 10 g/dL with anemic symtoms. Hb b 7 g/dL, 7–10 g/dL with anemic symtoms.



Çavuşoğlu 2015 [29] Goyal 2016 [30]

LMWH or Aspirin

Clinical

Zhang 2016 [31]

H



Ultrasound

H



Hb b 8 g/dL, 8–10 g/dL with anemic symtoms. Hb b 7 g/dL, 7–10 g/dL with anemic symtoms.

LMWH

Xie 2016 [32]

Closed for 3 h. Clamped for 30 min.

LMWH

Ultrasound

Wei 2014 [33]

H



Clamped for 30 min.

Hb b 9 g/dL

LMWH

Ultrasound

North 2016 [34]

H



No drain

T: 1.5 g/50 mL irrigated before closure, 1.5 g/50 mL injected to joint after closure via tube. I: 0.5 g TXA given at the end of surgery. T: 2.0 g TXA injected after closure. I: 15 mg/kg 1 h before inflation, 10 mg/kg 1 h after deflation infusion. T: 1.0 g/10 mL was applied by syringespray to the following surfaces after cementing implants. I: 1 g TXA given before inflation and another 1 g after deflation. T: 3.0 g/100 mL irrigated before deflation for at least 5 min. I: 10 mg/kg 15 min before deflation; 10 mg/kg 15 min before deflation, another dose 3 h later; 10 mg/kg 20 min before inflation and 10 mg/kg 15 min before deflation; 10 mg/kg 20 min before inflation, 10 mg/kg 15 min before deflation, 10 mg/kg 3 h later. T: 2.0 g TXA injected after closure via drainage tube. I: 15 mg/kg TXA given 15 min before deflation. T: 1.5 g/50 mL TXA irrigated the wound for 5 min, another 50 mL injected to the joint. I: 15 mg/kg TXA given 15 min before deflation. T: 1.5 g TXA/50 mL NS irrigated the wound, another 50 mL injected to the joint. I: 20 mg/kg TXA injected 15 min before inflation. T: 2.0 g TXA/100 mL irrigated the joint prior to the tourniquet release for at least 2 min. I: 10 mg/kg TXA injected 10 min before deflation. T: 3.0 g/100 mL NS irrigated after cementing implant and before tourniquet release for at least 5 min. I: 11 mg/kg 20 min before inflation, 15 mg/kg 15 min before deflation, another 10 mg/kg 3 h later. T: 3.0 g TXA/100 mL NS irrigated before suturing for 5 min; or 1.5 g/100 mL NS injected via tube. I: 0.5 g TXA injected i.v after closure. T: 1.0 g TXA/100 mL NS applied after closure. I: 1.0 g/100 mL injected before incision. T: 2 g TXA/50 mL NS was injected after capsular closure via 20-gauge hypodermic needle. I: 1.0 g TXA was given before inflation and another 1.0 g was given after closure. T: 15 mg/kg TXA in 100 mL NS irrigated for 10 min before wound closure. I: 15 mg/kg TXA 30 min before tourniquet deflation, and repeated after 2 h. T: 1.0 g TXA/30 mL NS applied topically. I: 1.0 g i.v. T: 1.5 g was given as an IA wash after cementing the prostheses. I: 1.5 g was given i.v over 20 min after cementing the prostheses. T: 1.5 g/100 mL irrigated the joint. I: 1.5 g/100 mL NS after closure. T: 2.0 g TXA injected via drainage. I: 2.0 g/100 mL NS injected 15 min before closure. T: 3.0 g/30 mL TXA infiltrated via drainage tube. I: 1.0 g injected before incision of deflation, another two doses of 1.0 g TXA after surgery at 8 h interval. T: 1.0 g TXA/100 mL NS injected via drainage. I: 1.0 g TXA injected 15 min prior to incision. T: 3.0 g TXA/150 mL NS, 50 mL for acetabulum; 50 mL for femoral canal; 50 mL for joint irrigation. I: 1.5 g TXA injected 15 min prior to incision. T: 3.0 g TXA/100 mL NS, 20 mL for acetabulum; 20 mL for femoral canal; 60 mL for joint irrigation. I: 3.0 g TXA injected 10 min prior to incision. T: 2.0 g TXA applied to the wound for 5 min. I: 2.0 g/100 mL NS, 50 mL injected 10 min prior to incision, the second during the fascial closure.

Hb b 7 g/dL, or b8 g/dL with anemic symptoms.

LMWH or Rivaroxaban or Aspirin

Clinical

Abbreviation: K, knee; H, hip; T, topical; I, intravenous. Hb, hemoglobin; DVT, deep venous thrombosis; LMWH, low molecular weight heparin.

J. Xie et al. / Thrombosis Research 153 (2017) 28–36

33

Table 3 Quality assessment of selected studies (“Unclear”, lack of information or uncertainty over the potential bias). Studies

Random sequence generation

Allocation concealment

Blinding

Incomplete outcome data

Selective reporting

Other bias

Jadad score (0–8)

Keyhani 2016 [13] Öztaş 2015 [14] Aguilera 2012 [15] Maniar 2012 [16] Digas 2015 [17] Gomez-B 2014 [18] Uğurlu 2016 [19] Patel 2014 [20] Soni 2014 [21] Sarzaeem 2014 [22] Tzatzairis 2016 [23] May 2016 [24] Aggarwal 2015 [25] Drosos 2016 [26] Chen 2016 [27] Seo 2012 [28] Çavuşoğlu 2015 [29] Goyal 2016 [30] Zhang 2016 [31] Xie 2016 [32] Wei 2014 [33] North 2016 [34]

Unclear Unclear Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low

Unclear Unclear Low Low Low Low Low Low Low Low Low Low Low Low Low Low Unclear Low Low Low Low Low

Unclear Unclear Low Unclear Unclear Low Unclear Low Unclear Unclear Low Low Low Unclear Low Unclear High Low Unclear Low Low Low

Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low

Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low

Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low Low

5 4 8 6 6 8 6 7 6 6 7 8 8 6 8 6 5 8 6 7 8 8

3.8. Wound complications A total of 18 RCTs provided relevant data on wound complications, including infection, necrosis, dehiscence, and oozing. No statistical heterogeneity was detected among the studies (p = 0.82, I2 = 0%), so a fixed-effects model was used. Pooled results showed similar risk of wound complications in the two groups (RR 1.13, 95%CI 0.72 to 1.77, p = 0.59).

3.9. Other adverse events and functional outcomes Among all 22 studies, three studies [20,23,34] reported a total of 4 cases of myocardial infarction, 2 cases of acute kidney injury, 1 death, and 1 case of deep infection. In one study [34], 3 patients who underwent THA developed non-ST elevation myocardial infarction: 1 in the intravenous group and 2 in the topical group (p = 0.619). In another RCT [20], 1 case of acute kidney injury was reported in each treatment group, and both patients recovered after discharge without further complications. In that same study, one case of myocardial infarction was reported in the topical group, and the patient was discharged without further complications; in addition, 1 death occurred when an 83-year-old patient with multiple co-morbidities in the topical group died during physical therapy on POD 1. Only three studies [22,25,27]

Fig. 2. Funnel plot of transfusion requirement demonstrates minimal publication bias.

reported functional outcomes, including KSS, WOMAC score, VAS pain score, wound score, range of motion and limb swelling. 4. Discussion This meta-analysis indicates that, based on the available evidence, the intravenous and topical routes of administration of tranexamic acid during primary THA or TKA are associated with similar TBL, drainage volume, hidden blood loss, transfusion requirement and incidence of DVT, PE, wound complications and other adverse events. However, the intravenous route is associated with significantly smaller maximum hemoglobin drop, which was one of the primary outcomes of the metaanalysis. Subgroup analyses showed that these results were observed for THA and TKA. Tranexamic acid, an analog of the amino acid lysine, inhibits fibrinolysis by competitively inhibiting plasminogen activation and plasmin binding to fibrin. Tranexamic acid has been used in total joint arthroplasty for a long time with positive clinical results. For example, a large retrospective study [35] involving 872,416 patients in 51 US hospitals showed that intravenous tranexamic acid reduced the rate of allogeneic blood transfusion by 65% (7.7% vs 20.1% without tranexamic acid), as well as the occurrence of thromboembolic complications by 25% (0.6% vs 0.8%). Nevertheless, many clinicians are hesitant to administer tranexamic acid intravenously out of concerns about the risk of thromboembolic complications after systemic administration. This has spurred growing interest in the topical application of tranexamic acid for preventing bleeding in major orthopedic surgeries. A systematic review and meta-analysis [36] of 14 RCTs comparing patients who received topical tranexamic acid or not in primary THA and TKA found that topical use led to significantly lower transfusion rates in THA (RR 2.56, p = 0.004) and TKA (RR 4.51, p b 0.001), while rates of thromboembolic events were similar between the two groups. Those authors further compared, albeit indirectly, the topical and intravenous routes of administration and concluded that the topical route was superior. How the two routes compare with each other has been controversial: the large number of head-to-head comparisons [13–34] has given conflicting results. Therefore we performed the present meta-analysis to analyze available evidence comprehensively. In our meta-analysis, the rate of transfusion was slightly less for the intravenous route (6.7%) than for the topical route (7.7%), but the difference was not statistically significant (RR 1.14, p = 0.35). Subgroup analyses showed similar results for the two types of surgery and different

34

J. Xie et al. / Thrombosis Research 153 (2017) 28–36

Fig. 3. Forest plots showing the effect of topical versus intravenous tranexamic acid on transfusion rate (RR 1.14, 95% CIs 0.87 to 1.50). IO, intraoperative intravenous dose; POIO, pre- and intraoperative intravenous doses; IOPO, intra- and postoperative intravenous doses; POIOPO, all three doses.

dosages of tranexamic acid. Some studies in the literature have explored potential differences between different injection routes of administration. In one RCT [28], 1.5 g tranexamic acid was administered intravenously or intra-articularly, and TBL, transfusion requirement and hemoglobin drop were compared. Topical administration was associated with lower blood loss (426 ± 197 mL vs 528 ± 227 mL) and transfusion rate (20% vs 34%). Another RCT [22] compared the intravenous route with irrigation and joint injection via a drain; intravenous injection led to a smaller hemoglobin drop and a smaller number of blood units transfused, but injection via a drain led to less postoperative drainage. And the sensitivity analysis also showed the same results when studies at high risk of bias were excluded. We observed trends in our meta-analysis suggesting that in THA, intravenous tranexamic acid can lead to smaller TBL (MD 71.43 mL, 95%CI −43.29 to 186.16, p = 0.22), while in TKA, topical tranexamic acid can lead to smaller TBL (MD − 50.77 mL, 95%CI − 128.21 to 26.67, p = 0.20). These trends are consistent with observed changes in hemoglobin level on POD 1 in the two groups. It is possible that during THA, intravenous injection of tranexamic acid may inhibit fibrinolysis from the initial stages, whereas topical administration may inhibit it only at the primary site of bleeding [37]. In TKA, because of the use of a tourniquet, intraoperative blood loss is negligible. Clamping the drainage tube can prolong the contact time between topically applied tranexamic acid and knee joint tissue, allowing it to inhibit the breakdown of fibrin clots and reduce blood loss [32]. Total drainage volume was similar for the topical and intravenous routes in our meta-analysis (MD 2.20 mL, 95%CI −42.79 to 47.19), but subgroup analysis carried out because of the significant heterogeneity (I2 = 97%) indicated that clamping time N 2 h can lead to lower drainage volume in the topical group. This phenomenon may be explained by longer time of contact between tissue and tranexamic acid. Furthermore, clamping the drainage tube prevents immediate blood loss and promotes blood clot formation in a time-dependent manner [38].

Hidden blood loss is estimated to make up approximately 50% of TBL [39] and is therefore an important parameter to consider. Hidden blood loss consists of losses from tissue extravasation, residual blood in the knee joint and hemolysis. Unfortunately, only two studies [15,32] in our analysis reported data on hidden blood loss. One study [15] compared a topical dose of 1 g tranexamic acid with an intravenous dose of 2 g tranexamic acid in patients undergoing TKA. Hidden blood loss was lower in the intravenous group (685.02 mL vs 851.6 mL), although this difference did not achieve statistical significance. Our own group [32] has reported a similar trend for primary THA (482.25 mL vs 496.97 mL). Further study is needed to address this question. The purpose of blood management is to reduce perioperative blood loss and hemoglobin drop, maintain higher postoperative hemoglobin levels and accelerate functional recovery after surgery. Hemoglobin levels decrease after surgery and reach a trough on postoperative days 3–4 because of hidden blood loss [40–41]. Therefore the maximum hemoglobin drop is usually calculated on these postoperative days. In our meta-analysis, the maximum hemoglobin drop was smaller with intravenous tranexamic acid (MD 0.33 g/dL, 95%CI 0.07 to 0.58), and subgroup analysis showed this blood-saving effect in THA (MD 0.49 g/dL, 95%CI 0.28 to 0.70) and TKA (0.30 g/dL, 95%CI 0.02 to 0.59). This result may be particularly important for ensuring rapid recovery of anemic patients. At the same time, it should be interpreted with caution because of significant heterogeneity among the studies (I2 = 92%) and limited clinical relevance for patients with higher preoperative hemoglobin levels. Further work is needed to verify that route of tranexamic acid administration can significantly influence the maximum hemoglobin drop. While tranexamic acid carries with it the potential for triggering thrombosis, this has not been shown empirically, and several studies have even shown that tranexamic acid reduces the risk of thromboembolic events [35,42–43]. The current meta-analysis showed no significant difference between intravenous and topical routes of tranexamic

J. Xie et al. / Thrombosis Research 153 (2017) 28–36

35

Table 4 Results of meta-analysis and subgroup analyses stratified by type of surgery.

Variables Transfusion rate All studies Surgery type THA TKA Topical dose b2g ≥2g IV dose Single dose ≥ 2 doses Maximum Hb drop All studies Surgery type THA TKA Total blood loss All studies Surgery type THA TKA Drainage volume Clamp time b2h ≥2h Hb on POD 1 All studies Surgery type THA TKA DVT Wound complications LOH

Studies (n)

Patients (n)

p-Value

Incidence RR/MDs (95%CI)

Heterogeneity p-Value (I2)

Model

22

2260

0.35

1.14 (0.87 to 1.50)

0.48 (0%)

Fixed

4 18

532 1720

0.50 0.48

1.22 (0.68 to 2.19) 1.12 (0.82 to 1.52)

0.78 (0%) 0.31 (12%)

Fixed Fixed

5 17

360 1000

0.59 0.19

0.84 (0.44 to 1.60) 1.22 (0.90 to 1.65)

0.14 (42%) 0.59 (0%)

Fixed Fixed

16 6

1583 677

0.18 0.47

1.24 (0.91 to 1.69) 1.27 (0.67 to 2.39)

0.54 (0%) 0.48 (0%)

Fixed Fixed

11

1215

0.01

0.33 (0.07 to 0.58)

b0.001 (92%)

Random

2 9

279 936

b0.001 0.04

0.49 (0.28 to 0.70) 0.30 (0.02 to 0.59)

0.59 (0%) b0.001 (93%)

Fixed Random

12

1321

0.50

−23.62 (−92.70 to 45.47)

b0.001 (81%)

Random

3 9 13

482 839 1289

0.22 0.20 0.92

71.43 (−43.29 to 186.16) −50.77 (−128.21 to 26.67) 2.20 (−42.79 to 47.19)

0.05 (66%) b0.001 (79%) b0.001 (97%)

Random Random Random

5 8

532 757

0.08 0.16

71.68 (−7.87 to 151.24) −37.84 (−91.23 to 15.54)

b0.001 (96%) b0.001 (95%)

Random Random

14

1267

0.46

0.08 (−0.13 to 0.29)

b0.001 (69%)

Random

2 12 21 18 9

189 1078 2190 1850 960

0.63 0.17 0.05 0.59 0.59

−0.24 (−1.21 to 0.74) 0.14 (−0.06 to 0.33) 2.02 (0.99 to 4.15) 1.13 (0.72 to 1.77) 0.03 (−0.08 to 0.15)

0.03 (78%) 0.003 (61%) 0.88 (0%) 0.82 (0%) 0.07 (49%)

Random Random Fixed Fixed Fixed

Abbreviation: RR, risk ratio, a RR N 1 favours intravenous tranexamic acid, a RR b 1 favours topical tranexamic acid; MDs, mean differences; THA, total hip arthroplasty; TKA, total knee arthroplasty; Hb, hemoglobin; POD 1, postoperative day 1; DVT, deep venous thrombosis; LOH, length of hospital stay.

acid administration in terms of DVT and PE. Nevertheless, several studies in the meta-analysis did not follow up with patients after discharge, which may lead to underestimation of the true incidence of DVT. Sensitivity analysis in which we excluded studies with no follow-up showed topical administration to be associated with significantly higher risk of DVT. Further work is needed to clarify these results. In fact, future studies should look specifically at patients at high risk of vascular occlusive events, since such patients were excluded from the studies in our meta-analysis; in these studies, patients were routinely given chemical prophylaxis. In our institution, intravenous tranexamic acid is a routine part of blood management, except for patients at high risk of thromboembolic events. Tranexamic acid appears to be safe for most patients like those in the studies in our meta-analysis. Relatively few adverse events were reported, including four cases of myocardial infarction, two cases of acute kidney injury, one death and one deep infection, and these do not appear to be linked to tranexamic acid [20,23,34]. We analyzed several other outcomes, including wound complications and functional recovery, but we were often limited by incomplete data reporting in the studies. Joint irrigation with tranexamic acid may increase tension on the wound, thus increasing the risk of wound complications. In our meta-analysis, wound complications were less frequent in the intravenous group than in the topical group (3.4% vs 3.5%), although this difference was not significant. Only two studies [22,27] in our meta-analysis reported data on limb swelling. One study [22] found that topical administration of tranexamic acid via a drain tube significantly increased joint swelling. Another study [27]

did find thigh girth to be similar between intravenous and topical groups on postoperative day 4; however, the thigh girth, especially on postoperative days 1–3 was not reported, which was more important for pain management and functional recovery. Nearly none of the studies in our analysis provided data on patient-reported outcomes, which are important for ERAS-based joint arthroplasty [44]. Future studies should examine these outcomes. On the other hand, the application of tourniquet and drainage has been questioned under modern perioperative blood management [45], and the topical TXA should be further studied. The present meta-analysis has several strengths over previous systematic reviews [38,46–47] because it contains more RCTs, it applied stricter inclusion and exclusion criteria, and it included more functional outcomes as well as wound complications. However, the meta-analysis also has limitations. There was substantial heterogeneity in the metaanalyses of several outcomes, and heterogeneity was present even in some subgroup analyses. In addition, data reporting was incomplete in many studies, and functional outcomes reported in some studies could not be meta-analyzed because of differences in how investigators defined the outcomes and performed their assessments.

5. Conclusion This update of the available evidence indicates that topical and intravenous routes of tranexamic acid administration show similar ability to reduce transfusion requirements and blood loss without sacrificing

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safety in both THA and TKA. However, intravenous injection is associated with a smaller maximum drop in hemoglobin. Conflict of interests None of the authors has financial or personal relationships with other people or organizations that could inappropriately influence this work. Acknowledgements We thank Xiaowei Feng from the Affiliated Hospital of North Sichuan Medical College for providing language help and writing assistance. This research was funded by the National Health and Family Planning Commission of the People's Republic of China (program 201302007). References [1] S. Kurtz, K. Ong, E. Lau, F. Mowat, M. Halpern, Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030, J. Bone Joint Surg. Am. 89 (4) (2007) 780–785. [2] H. Kehlet, Fast-track hip and knee arthroplasty, Lancet 381 (9878) (2013) 1600–1602. [3] J. Xie, J. Ma, P. Kang, et al., Does tranexamic acid alter the risk of thromboembolism following primary total knee arthroplasty with sequential earlier anticoagulation? A large, single center, prospective cohort study of consecutive cases, Thromb. Res. 136 (2) (2015) 234–238. [4] C.M. Duncan, B.P. Gillette, A.K. Jacob, et al., Venous thromboembolism and mortality associated with tranexamic acid use during total hip and knee arthroplasty, J. Arthroplast. 30 (2) (2015) 272–276. [5] C. Wang, P. Kang, J. Ma, et al., Single-dose tranexamic acid for reducing bleeding and transfusions in total hip arthroplasty: a double-blind, randomized controlled trial of different doses, Thromb. Res. 141 (2016) 119–123. [6] S. Alshryda, P. Sarda, M. Sukeik, et al., Tranexamic acid in total knee replacement: a systematic review and meta-analysis, J. Bone Joint Surg. (Br.) 93 (12) (2011) 1577–1585. [7] C. Yue, P. Kang, P. Yang, et al., Topical application of tranexamic acid in primary total hip arthroplasty: a randomized double-blind controlled trial, J. Arthroplast. 29 (12) (2014) 2452–2456. [8] S. Alshryda, M. Sukeik, P. Sarda, et al., A systematic review and meta-analysis of the topical administration of tranexamic acid in total hip and knee replacement, J. Bone Joint Surg. 96-B (8) (2014) 1005–1015. [9] Z. Huang, J. Ma, B. Shen, F. Pei, Combination of intravenous and topical application of tranexamic acid in primary total knee arthroplasty: a prospective randomized controlled trial, J. Arthroplast. 29 (12) (2014) 2342–2346. [10] H. Wang, B. Shen, Y. Zeng, Comparison of topical versus intravenous tranexamic acid in primary total knee arthroplasty: a meta-analysis of randomized controlled and prospective cohort trials, Knee 21 (6) (2014) 987–993. [11] Z. Huang, J. Ma, F. Pei, et al., Meta-analysis of temporary versus no clamping in TKA, Orthopedics 36 (7) (2013) 543–550. [12] A. Liberati, D.G. Altman, J. Tetzlaff, et al., The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration, BMJ 339 (2009) b2700. [13] S. Keyhani, A.A. Esmailiejah, M.R. Abbasian, F. Safdari, Which route of tranexamic acid administration is more effective to reduce blood loss following total knee arthroplasty? Arch Bone Jt Surg. 4 (1) (2016) 65–69. [14] S. Öztaş, A. Öztürk, Y. Akalin, et al., The effect of local and systemic application of tranexamic acid on the amount of blood loss and allogeneic blood transfusion after total knee replacement, Acta Orthop. Belg. 81 (4) (2015) 698–707. [15] X. Aguilera, M.J. Martínez-Zapata, P. Hinarejos, et al., Topical and intravenous tranexamic acid reduce blood loss compared to routine hemostasis in total knee arthroplasty: a multicenter, randomized, controlled trial, Arch. Orthop. Trauma Surg. 135 (7) (2015) 1017–1025. [16] R.N. Maniar, G. Kumar, T. Singhi, et al., Most effective regimen of tranexamic acid in knee arthroplasty: a prospective randomized controlled study in 240 patients, Clin. Orthop. Relat. Res. 470 (9) (2012) 2605–2612. [17] G. Digas, I. Koutsogiannis, G. Meletiadis, et al., Intra-articular injection of tranexamic acid reduce blood loss in cemented total knee arthroplasty, Eur. J. Orthop. Surg. Traumatol. 25 (7) (2015) 1181–1188. [18] E. Gomez-Barrena, M. Ortega-Andreu, N.G. Padilla-Eguiluz, et al., Topical intra-articular compared with intravenous tranexamic acid to reduce blood loss in primary total knee replacement: a double-blind, randomized, controlled, noninferiority clinical trial, J. Bone Joint Surg. Am. 96 (23) (2014) 1937–1944. [19] M. Uğurlu, M.A. Aksekili, C. Çağlar, et al., Effect of topical and intravenously applied tranexamic acid compared to control group on bleeding in primary unilateral total knee arthroplasty, J. Knee Surg. 2 (2016 May) (Epub ahead of print). [20] J.N. Patel, J.M. Spanyer, L.S. Smith, et al., Comparison of intravenous versus topical tranexamic acid in total knee arthroplasty: a prospective randomized study, J. Arthroplast. 29 (8) (2014) 1528–1531.

[21] A. Soni, R. Saini, A. Gulati, et al., Comparison between intravenous and intra-articular regimens of tranexamic acid in reducing blood loss during total knee arthroplasty, J. Arthroplast. 29 (8) (2014) 1525–1527. [22] M.M. Sarzaeem, M. Razi, G. Kazemian, M.E. Moghaddam, et al., Comparing efficacy of three methods of tranexamic acid administration in reducing hemoglobin drop following total knee arthroplasty, J. Arthroplast. 29 (8) (2014) 1521–1524. [23] T.K. Tzatzairis, G.I. Drosos, S.E. Kotsios, et al., Intravenous vs topical tranexamic acid in total knee arthroplasty without tourniquet application: a randomized controlled study, J. Arthroplast. 31 (11) (2016) 2465–2470. [24] J.H. May, G.R. Rieser, C.G. Williams, et al., The assessment of blood loss during total knee arthroplasty when comparing intravenous vs intracapsular administration of tranexamic acid, J. Arthroplast. 31 (11) (2016) 2452–2457. [25] A.K. Aggarwal, N. Singh, P. Sudesh, Topical vs intravenous tranexamic acid in reducing blood loss after bilateral total knee arthroplasty: a prospective study, J. Arthroplast. 31 (7) (2016) 1442–1448. [26] G.I. Drosos, A. Ververidis, C. Valkanis, et al., A randomized comparative study of topical versus intravenous tranexamic acid administration in enhanced recovery after surgery (ERAS) total knee replacement, J. Orthop. 13 (3) (2016) 127–131. [27] J.Y. Chen, P.L. Chin, I.H. Moo, et al., Intravenous versus intra-articular tranexamic acid in total knee arthroplasty: a double-blinded randomised controlled noninferiority trial, Knee 23 (1) (2016) 152–156. [28] J.G. Seo, Y.W. Moon, S.H. Park, et al., The comparative efficacies of intra-articular and IV tranexamic acid for reducing blood loss during total knee arthroplasty, Knee Surg. Sports Traumatol. Arthrosc. 21 (8) (2013) 1869–1874. [29] A.T1. Çavuşoğlu, T. Ayanoğlu, E. Esen, et al., Is intraarticular administration of tranexamic acid efficient and safe as systemic administration in total knee arthroplasty? Single center, randomized, controlled trial, Eklem Hastalik. Cerrahisi 26 (3) (2015) 164–167. [30] N. Goyal, D.B. Chen, I.A. Harris, et al., Intravenous vs intra-articular tranexamic acid in total knee arthroplasty: a randomized, Double-Blind Trial. J Arthroplasty. 32 (1) (2017) 28–32. [31] Y. Zhang, L. Zhang, X. Ma, et al., What is the optimal approach for tranexamic acid application in patients with unilateral total hip arthroplasty? Orthopade 45 (7) (2016) 616–621. [32] J. Xie, J. Ma, C. Yue, et al., Combined use of intravenous and topical tranexamic acid following cementless total hip arthroplasty: a randomised clinical trial, Hip Int. 26 (1) (2016) 36–42. [33] W. Wei, B. Wei, Comparison of topical and intravenous tranexamic acid on blood loss and transfusion rates in total hip arthroplasty, J. Arthroplast. 29 (11) (2014) 2113–2116. [34] W.T. North, N. Mehran, J.J. Davis, et al., Topical vs intravenous tranexamic acid in primary total hip arthroplasty: a double-blind, Randomized Controlled Trial. J Arthroplasty. 31 (5) (2016) 1022–1026. [35] J. Poeran, R. Rasul, S. Suzuki, et al., Tranexamic acid use and postoperative outcomes in patients undergoing total hip or knee arthroplasty in the United States: retrospective analysis of effectiveness and safety, BMJ 349 (2014) g4829. [36] S. Alshryda, M. Sukeik, P. Sarda, et al., A systematic review and meta-analysis of the topical administration of tranexamic acid in total hip and knee replacement, Bone Joint J. 96-B (8) (2014) 1005–1015. [37] C.D. Krohn, R. Sørensen, J.E. Lange, R. Riise, S. Bjørnsen, F. Brosstad, Tranexamic acid given into the wound reduces postoperatve blood loss by half in major orthopaedic surgery, Eur. J. Surg. Suppl. 588 (588) (2003) 57–61. [38] K. Chareancholvanich, P. Siriwattanasakul, R. Narkbunnam, C. Pornrattanamaneewong, Temporary clamping of drain combined with tranexamic acid reduce blood loss after total knee arthroplasty: a prospective randomized controlled trial, BMC Musculoskelet. Disord. 13 (124) (2012). [39] L. Good, E. Peterson, B. Lisander, Tranexamic acid decreases external blood loss but not hidden blood loss in total knee replacement, Br. J. Anaesth. 90 (5) (2003) 596–599. [40] Q. Zhou, Y. Zhou, H. Wu, et al., Changes of hemoglobin and hematocrit in elderly patients receiving lower joint arthroplasty without allogeneic blood transfusion, Chin. Med. J. 128 (1) (2015) 75–78. [41] Z.Y. Huang, F.X. Pei, J. Ma, et al., Comparison of three different tourniquet application strategies for minimally invasive total knee arthroplasty: a prospective non-randomized clinical trial, Arch. Orthop. Trauma Surg. 134 (4) (2014) 561–570. [42] A. Godier, I. Roberts, B.J. Hunt, Tranexamic acid: less bleeding and less thrombosis? Crit. Care 16 (3) (2012) 135. [43] H. Shemshaki, S.M. Nourian, N. Nourian, et al., One step closer to sparing total blood loss and transfusion rate in total knee arthroplasty: a meta-analysis of different methods of tranexamic acid administration, Arch. Orthop. Trauma Surg. 135 (4) (2015) 573–588. [44] H. Tang, H. Du, Q. Tang, et al., Chinese patients' satisfaction with total hip arthroplasty: what is important and dissatisfactory? J. Arthroplast. 29 (12) (2014) 2245–2250. [45] S. Zhang, B. Xu, Q. Huang, et al., Early removal of drainage tube after fast-track primary total knee arthroplasty, J. Knee Surg. 24 (2016 Oct) (Epub ahead of print). [46] Y.S. Shin, J.R. Yoon, H.N. Lee, S.H. Park, D.H. Lee, Intravenous versus topical tranexamic acid administration in primary total knee arthroplasty: a meta-analysis, Knee Surg. Sports Traumatol. Arthrosc. 14 (2016 Jul) (Epub ahead of print). [47] J. Li, Z. Zhang, J. Chen, Comparison of efficacy and safety of topical versus intravenous tranexamic acid in total hip arthroplasty: a meta-analysis, Medicine (Baltimore) 95 (36) (2016), e4689.