Combination of Intravenous and Topical Application of Tranexamic Acid in Primary Total Knee Arthroplasty: A Prospective Randomized Controlled Trial

Combination of Intravenous and Topical Application of Tranexamic Acid in Primary Total Knee Arthroplasty: A Prospective Randomized Controlled Trial

    Combination of intravenous and topical application of tranexamic acid in primary total knee arthroplasty: a prospective randomized co...

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    Combination of intravenous and topical application of tranexamic acid in primary total knee arthroplasty: a prospective randomized controlled trial ZeYu Huang, Jun Ma, Bin Shen, FuXing Pei PII: DOI: Reference:

S0883-5403(14)00394-5 doi: 10.1016/j.arth.2014.05.026 YARTH 54022

To appear in:

Journal of Arthroplasty

Received date: Revised date: Accepted date:

1 May 2014 20 May 2014 31 May 2014

Please cite this article as: Huang ZeYu, Ma Jun, Shen Bin, Pei FuXing, Combination of intravenous and topical application of tranexamic acid in primary total knee arthroplasty: a prospective randomized controlled trial, Journal of Arthroplasty (2014), doi: 10.1016/j.arth.2014.05.026

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ACCEPTED MANUSCRIPT Combination of intravenous and topical application of tranexamic acid in primary total knee arthroplasty: a prospective randomized

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controlled trial

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ZeYu Huang1, Jun Ma1†, Bin Shen1, FuXing Pei1*

1. Department of Orthopaedics, West China Hospital, Sichuan University, 37# Wainan Guoxue Road, Chengdu, 610041, People’s Republic of China

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*Corresponding author: FuXing Pei Department of Orthopaedics, West China hospital, Sichuan University, 37# Wainan Guoxue Road, Chengdu, 610041, People’s Republic of China. Telephone number: +86- 028-85422430 Fax number: +86-028-85423848 †Jun

Ma contributed equally to this work.

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E-mail: [email protected]

ZeYu Huang: Tel number:+86-13551068719 [email protected] Jun Ma: Tel number:+86-18980605921

[email protected]

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Bin Shen: Tel number:+86-13881878767 [email protected]

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ACCEPTED MANUSCRIPT Combination of intravenous and topical application of tranexamic acid in primary total knee arthroplasty: a prospective randomized

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controlled trial Abstract

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The objective of this study was to determine the efficacy and safety of combined intravenous and topical application of tranexamic acid (TXA) in unilateral total knee arthroplasty (TKA) compared with

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the intravenous TXA (IV-TXA). One hundred and eighty-four patients from a single surgical team were enrolled. Participants received either 3g of IV-TXA (IV-Group) or 1.5g topical TXA combined with 1.5g IV-TXA (Combined Group). The results revealed that compared with the 3g IV-TXA, adding 1.5g

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topical TXA to 1.5g IV-TXA in unilateral TKA can have the similar effectiveness in reducing

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transfusion rate and total blood loss without sacrificing safety. What is most important is that by adding topical TXA, patients can gain a smaller maximum decline of hemoglobin (Hb) (p=0.031), less

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drainage volume (p=0.011), less postoperative knee pain, less knee swelling, shorter length of hospital

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stays (p=0.016) and higher short-term satisfaction (p=0.039). Keywords: tranexamic acid; transfusion rate; blood loss; total knee arthroplasty; knee swelling

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ACCEPTED MANUSCRIPT Introduction Total knee arthroplasty (TKA) is considered as one of the most successful orthopedic surgical

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interventions. Intraoperative and postoperative bleeding is one of the major complications following this procedure [1]. The total blood loss varies in the published literatures due to differences in surgical

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technique, a lack of standardized definition of blood loss and differences in measuring blood loss. According to a previous study [2], the total blood loss associated with unilateral primary TKA can

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reach 2000mL, which is approximate 40% percent of the body’s total blood volume. There is no doubt that this may have a significant influence on morbidity and mortality [3]. Thus alternative measures including tourniquets [1], reinfusion drains [4] and drain clamping [5] have been introduced. However,

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none of these techniques reduce bleeding in the first instance.

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Tranexamic acid (TXA) is an antifibrinolytic agent that acts by blocking the lysine binding sites on plasminogen molecules, inhibiting the formation of plasmin. By this process, TXA is believed to be

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able to help the body retain blood clots more effectively and therefore reduces bleeding.

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Although there were still some controversies, large clinical studies [6,7] and several meta-analyses [8,9] have confirmed that IV-TXA could effectively reduce blood loss and transfusions in TKA without increasing the risk of DVT. Compared with IV-TXA, the topical application has the advantages of being easy to administer, providing a maximum concentration of TXA at the bleeding site, and is associated with 70% lower systemic absorption of TXA [10,11]. Thus, recently topical application of TXA has been put under the spotlight. Cumulative studies of topical administration of TXA [12-16], showed reliable evidence that it significantly reduces the total blood loss and the need for transfusion varies between 10% to 15%. Yet, no study has investigated the combination of intravenous and topical application of TXA in primary TKA. By undertaking this study, we want to address the following 3

ACCEPTED MANUSCRIPT questions: (1) Can the combination application of TXA reduce the blood loss further? (2) Are there any other benefits patients can gain from the combination application? (3) Is it safe to combine the two

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applications? Materials and Methods

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This prospective, randomized controlled study was approved by the Institutional Review Board of West China Hospital of SiChuan University (No. 201302008). All patients, aged 18 years and older,

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who were scheduled for a primary TKA for end-stage osteoarthritis were eligible for inclusion in the trial. Exclusion criteria included revisions, bilateral procedures, flexion deformity≥30°, varus/valgus deformity≥30°, contraindications for the use of TXA and coagulation disorders. Informed consent

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was obtained from all the recruited patients.

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Recruited patients were randomized to either an intravenous group (IV-Group) or a combined application group (Combined Group). Randomization was blind and performed with the use of sealed

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envelopes in a 1:1 ratio opened just prior to surgery. All the surgeries were performed by one surgical

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team, composed of four senior orthopedic surgeons, and conducted under general anesthesia. TKA was performed in the standard way, using a midline skin incision, a standard medial parapatellar approach and a measured resection technique. A tourniquet was applied to all the patients from both groups with a strategy of inflating before the incision and deflating after the closure of the incision under control at 100mmHg above systolic pressure. In the IV-Group, 3g TXA was administered before inflation of the tourniquet. In the Combined Group, a solution of 1.5g TXA dissolved in 50mL normal saline was irrigated in the wound after implantation of the components and 1.5g IV-TXA was administered before inflation of the tourniquet. The wound was closed in layers and a pressure dressing made from a soft roll and crepe bandage was applied. All the drainage of both groups remained clamped for thirty 4

ACCEPTED MANUSCRIPT minutes after the tourniquet was released and removed in the next morning. Half dose of low-molecular weight heparin (LMWH) (0.2mL 2000IU) was started 6 h postoperatively and repeated at 24-h

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intervals with a full dose (0.4mL 4000IU) in the subsequent days. Besides, an intermittent foot slope pump system was used as a routine practice to prevent deep-vein thrombosis (DVT). After the

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discharge, 10mg rivaroxaban was administered orally to the patients for 10 days. Doppler ultrasound was used to diagnose the deep vein thrombosis (DVT) at different time points (POD1, POD3, the time

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of discharge, 1- and 3-month follow-up). Hb and hematocrit level were tested preoperatively and on postoperative days one, three and five routinely. The length of hospital stays and complications were recorded carefully.

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We compared the total blood loss (calculated using the modified Gross formula [17]), hidden

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blood loss, maximum decline (defined as the difference between the pre-operative hemoglobin(Hb) level drawn closest to the time of the surgery and the minimal Hb level drawn postoperatively during

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the hospitalization and prior to any blood transfusion) and transfusion rate between the two groups.

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Patients were transfused for symptomatic anemia (defined as lightheadedness, presyncope, fatigue precluding participation the therapy, palpitations, or shortness of breath not due to other causes) with hemoglobin (Hb) between 70g/L and 100g/L or any Hb below 70g/L. Swelling ratio, the length of hospital stays, patient satisfaction, perioperative visual analog scale (VAS), deep vein thrombosis (DVT) events, pulmonary embolism (PE) events and other complications were also compared. The knee circumference, including the upper and lower pole of patella, was measured according to the method described by our previous study [1]. The swelling ratio was defined as the circumference of the operative limb divided by the circumference of the contralateral limb. At the time of the discharge, all the patients completed a satisfaction questionnaire regarding the outcomes of the surgery. Satisfaction 5

ACCEPTED MANUSCRIPT was rated on a 7-point scale, ranging from extremely dissatisfied to extremely satisfied [18]. All data management and statistical analysis were performed with SPSS version 18.0 software

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(SPSS Inc., Chicago, IL, USA). Independent t-tests were used for continuous variables such as maximum decline, BMI, age, etc. Person chi-square test or Fisher exact test were used to analyze the

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categorical variables. The level of significance was set at p<0.05. Results

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During the recruitment period from July 2013 to October 2013, 228 patients were scheduled to have a primary unilateral TKA because of OA in the West China Hospital. Of them all, twenty-five patients were ineligible and nineteen patients declined participation. The remaining 184 eligible

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participants were recruited and formed the study cohort; ninety-two were randomized to the IV-Group

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and ninety-two to the Combined Group (Fig.1). The two groups were comparable at baseline (Table 1). No significant differences were observed between groups in terms of total blood loss or hidden

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blood loss, which means the combination application of TXA can’t further reduce the total blood loss

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or hidden blood loss. An average of 36mL decreased drainage volume was detected in the Combined Group (364±86 mL VS 328±104 mL; p=0.011). The maximum decline of Hb was significantly lower in the Combined Group compared with that of the IV-Group (25.6±5.3 g/L VS 27.3±5.5 g/L; p=0.031) (Table 2). However, as to the transfusion rate there was no statistically significant difference between the two groups. The mean duration of the surgery was 4 minutes longer in the Combined Group than in the IV-Group. Significant reduction in length of hospital stays was observed in the Combined Group compared with the IV-Group (6.9±0.9 d VS 7.2±0.8 d; p=0.016). All these outcomes were showed in Table 2. Postoperative pain declined daily. The Combined Group had slightly less postoperative pain 6

ACCEPTED MANUSCRIPT (Figure 2). The difference was significant on Postoperative Day 2 and 3 (p=0.023, p=0.038; respectively). The severity of the knee swelling was significantly less in the Combined Group on

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Postoperative Day 2, 3 and 4 (p=0.043, p=0.030, p=0.049; respectively). When it comes to the satisfaction at the time of discharge, a total of 76 patients from the IV-Group felt satisfied with the

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surgical outcomes while a total of 86 patients from the Combined Group felt satisfied (p=0.039) (Table 2). So we can tell that by combing the topical TXA with IV-TXA, patients can gain additional benefits

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such as a smaller maximum decline of Hb, less drainage volume, less postoperative knee pain, less knee selling, shorter length of hospital stays and higher short-term satisfaction. DVT was detected in one patient of the IV-Group on postoperative day 3 by means of ultrasound

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examination. No PE events were found in any patients (Table 3). One patient in each group developed

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superficial infection and was controlled with dressing changes and antibiotics. Wound secretion was found in 7 patients from the IV-Group and 5 patients in the Combined Group (p=0.767) (Table 3). Thus,

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it is safe to use a total dose of 3g combined intravenous and topical application of TXA in patients

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treated with unilateral TKA. Discussion

The application of IV TXA in orthopedic surgery has been well established in the literature [7,19-21]. Camarasa et al.[7] reported 10mg/kg IV-TXA used before the tourniquet was deflated and 3h later in unilateral TKA could lower the total blood loss from 1784mL to 1099mL and reduce the transfusion rate from 38.3% to 7.5%. In another study performed by Good et al.[19], they observed decreased external blood loss but not hidden blood loss after TKA in patients treated with IV-TXA. They also reported that TXA could decrease drainage volume by about 50% to 385mL. In our study, we used a total dose of 3g IV-TXA in the IV-Group and observed similar reduced total blood loss, 7

ACCEPTED MANUSCRIPT transfusion rate and drainage volume. Recently, more and more studies have focused on the topical application of TXA in the TKA and the results are promising [10,14,15]. Compared with the IV-TXA in

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TKA, topical TXA was considered to be of less systemic absorption and better local effect. However, topical TXA was effective in reducing the blood transfusion rate compared with the placebo, it does not

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appear to be as effective as IV-TXA according to a meta-analysis done by Alshryda et al. [12]. We were not sure whether topical TXA could attain similarly good results in the reducing bleeding and

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transfusions as IV-TXA. So the new strategy of TXA use, the combined used strategy was considered. We want to see if this kind of strategy could have advantages of both application measures. To our knowledge, this is the first time it has been studied.

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The results of this high-quality randomized controlled trial revealed that compared with the IV

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application of TXA, a total dose of 3g combined intravenous and topical application of TXA had comparative effectiveness on reducing both total blood loss and transfusion rate. The combination

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application of TXA could reduce the mean maximum decline of Hb from 27.3g/L to 25.6g/L and

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reduce drainage volume by about 36mL without increasing the risk of DVT, PE and other complications in TKA. The most important finding of this study was that we observed significant reduced postoperative knee pain, severity of knee swelling and improved short-term patients’ satisfaction by combing the topical TXA with IV-TXA. These additional benefits of combination application of TXA are seldom reported by other studies. Though there are many studies [6,7,10,11,22] on both IV and topical TXA in TKA, the methods and effect of both IV and topical TXA application are still controversial [10,22] . A RCT conducted by Wong et al. found significant differences in Hb loss and blood loss between the IV groups and the placebo group, and a trend towards lower transfusion rates in the 3g group, with no differences in 8

ACCEPTED MANUSCRIPT thromboembolic complications between the groups [10]. So we decided to give a total dose of 3g TXA to all the patients in this study. However, unlike most studies on topical TXA in TKA, we used a

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1.5g/50mL solution in the Combined Group. This decision was made based on the following two reasons: first, according to a meta-analysis conducted by our center, we found that a high-concentration

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(≥20mg/mL) topical TXA was much more important than a high total dose (≥2g) in reducing the transfusion rate. Second, previous studies have proven that the knee articular cavity was much smaller

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than that of Caucasian [23,24]. And according to our daily practice, a 50mL solution is more suitable than a 100mL solution for the knee articular cavity of Chinese people. Through our study, we could see that the effect of a total dose of 3g combined intravenous and topical application of TXA was

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satisfactory. It had the same effect as the 3g IV-TXA in reducing the transfusion rate and was much

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better in reducing the maximum decline of Hb. The reason for why the benefit of reduced maximum decline of Hb doesn’t show in the field of transfusion rate is that an advantage of 1.7g/L can hardly

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have any effect on the transfusion rate.

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Ishida et al. [25] conducted a RCT that compared 2000mg/20mL topical TXA with a placebo, they found topical TXA could reduce not only blood loss but also knee joint swelling. After further analysis, they attributed the reduced knee joint swelling to the diminished hidden blood loss in the joint. However, in our study we observed significant differences between the two groups in terms of the drainage volume other than the hidden blood loss. The explanations for this phenomenon are as follows: In this study, the Combined Group had a better and quicker topical hemostatic effect than the IV-TXA because of the higher local concentration of TXA. So, much more postoperative blood loss in IV-Group was calculated in the form of drainage volume. Thus, that accounted for why we observed the higher drainage volume in the IV-Group. As to the hidden blood loss, it is well accepted that the hidden blood 9

ACCEPTED MANUSCRIPT loss, to a large extent, represents extravasation of red cells just after tourniquet release [19]. At this time, the haemostasis may be by vascular and primary haemostatic mechanism, before fibrinolysis has any

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effect. Haematoma in the joint and thigh could be limited by tissue pressure so that extravasation would not differ much between the two groups. As Bergin et al. [26] reported, the postoperative blood loss

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had an incentive relationship with the postoperative inflammation and could be used as a standard to evaluate the surgical trauma. So, we hold the view that the greater severity of the knee swelling in the

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patients from the IV-Group was caused by the inflammatory signaling cascade induced the increased postoperative blood loss. This could also explain why the patients in the IV-Group had a significantly higher VAS score on postoperative day 2 and 3, which was also the peak period of the postoperative

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inflammation [1]. As for the length of hospital stays, we found it was shorter in the Combined Group.

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The possible reason for this phenomenon is that the patients could be more aggressively mobilized. It was unnecessary for the patients to avoid physical therapy because of less pain. Thus, the patients in

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the Combined Group could reach the standard of discharge much earlier.

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In this study, we also compared the patient satisfaction of surgical outcomes between the two groups. At the time of discharge, there were 16 patients in the IV-Group and 6 patients in Combined Group who didn’t feel satisfied. Of all the unsatisfied patients in the IV-Group, 12 attributed it to the knee pain, 1 attributed to the superficial infection and 3 attributed to the wound secretion. While in the Combined Group only 3 patients complained of knee pain, 1 patient complained of superficial infection and 2 patients complained of wound secretion. The main cause of the patient dissatisfaction from the IV-Group was knee pain. So we believed the improvement in the patient satisfaction was an accidental benefit of the local superiority of the Combined Group. We performed the lower extremity venous ultrasonography for every patient at the time of 10

ACCEPTED MANUSCRIPT hospitalization, 1- and 3-month follow-up. We didn’t see a significant increase in DVT or PE events in our study. The reasons might be as follows: First, in order to reduce the risk of DVT, we moved the

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usage of the LMWH 2 hours ahead to 6 hours after the operation. Second, a regular protocol of thrombosis prevention, including medical and physical approaches, was followed well in the patients of

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both groups even after the discharge. Furthermore, early rehabilitation activities which can reduce the risk of thromboembolism were encouraged in the physical therapy process of our center. What is more,

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according to the study of Lee [27], Asians are less likely to develop DVT than Caucasians. The current study had the following strengths: First, it was a randomized controlled trial which was carefully and strictly designed and performed. So the bias was miniature. Second, the transfusion

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protocol was explicit, which made the result of the transfusion rate convincing. Third, we used Gross

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formula to evaluate the amount of total blood loss based on the hematocrit level, and the formula was proven to be more accurate than clinical methods [28,29]. Fourth, ultrasound examination was routine

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for every patient. And according to the Barnes et al.’s study [30], the duplex scanning had an accuracy

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of 97% compared with venography as the golden standard. So our result of detecting DVT by using ultrasound is reliable. Additionally, we repeated this examination during the hospital duration and 3-month follow-up, thought to be long enough to identify known adverse events. Some limitations of the current study warrant further discussion. First and foremost, we didn’t calculate the sample size needed before the study. However, according to our previous study [31], a power of 80% to detect a significant difference (p<0.05, two-side) of maximum decline of Hb, 29 patients were needed for each group. And based on Alshryda et al.’s study [12], 144 patients (seventy-two in each group) were expected to detect the difference of transfusion rate at a 5% level of significance. So we believe our sample size was enough for these parameters. Second, clinical 11

ACCEPTED MANUSCRIPT functional outcomes such as range of motion and HSS score are not reported. We will be following up on these clinical functional outcomes with the patients enrolled in this study for at least 2 years. In

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addition, the combined method increased the duration of surgery by about four minutes, which might theoretically make the risk of infection higher. However, in fact, the results of our study showed the

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rate of infection and other complications were very low. We didn’t think these limitations would affect the results seriously.

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Conclusion

In conclusion, compared with the 3g IV application of TXA, adding 1.5g topical TXA to 1.5g IV-TXA in unilateral TKA can have similar effectiveness in reducing transfusion rate and total blood

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loss without sacrificing safety. What is most important is that by adding topical TXA, patients can gain

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a smaller maximum decline of Hb, less drainage volume, less postoperative knee pain, less knee selling,

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shorter length of hospital stays and higher short-term satisfaction.

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ACCEPTED MANUSCRIPT Acknowledgments No benefits in any form have been received or will be received from a commercial party related

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directly or indirectly to the subject of this article.

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Source of Funding

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This research was funded by the China Health Ministry Program (201302007).

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ACCEPTED MANUSCRIPT Figure legends Figure 1 Flow diagram of patients involved

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Figure 2 The postoperative VAS pain score. POD1=postoperative day 1; POD2=postoperative day 2; POD3=postoperative day 3; POD4=postoperative day 4. The asterisks indicate values that were

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significantly different between the groups.

Figure 3 The postoperative swelling ratio (%).POD1=postoperative day 1; POD2=postoperative day

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2; POD3=postoperative day 3; POD4=postoperative day 4. The asterisks indicate values that were

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significantly different between the groups.

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32. Figure 1

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Figure 3

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ACCEPTED MANUSCRIPT Table 1 Preoperative Demographics

64.7±9.5

Male sex

30 (32.6%)

BMI* (Kg/m2)

25.2±2.9

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Age* (yr)

Combined Group (n=92)

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IV-Group (n=92)

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65.4±8.7

0.578

37 (40.2%)

0.358

SC

Demographics

0.507

2.2±0.5

2.1±0.5

0.327

41/51

50/42

0.238

135.6±8.7

136.1±9.2

0.706

39.3±4.7

39.6±5.2

0.613

207±44.0

205±46.5

0.700

1.00±0.18

0.99±0.18

0.499

28.2±2.3

28.3±1.6

0.706

98.8±19.2

98.3±17.8

0.797

Preop. VAS score*

7.0±2.7

7.2±1.3

0.471

Preop. HSS score*

55.4±11.6

53.6±12.0

0.291

Upper pole of patella*

36.9±3.2

36.3±2.7

0.138

Lower pole of patella*

32.7±2.3

32.2±2.7

0.152

MA NU

24.9±3.2

ASA grade* Surgical site (right/left)

Preop. Hct* (%)

ED

Preop. Hb* (g/L)

Preop. INR*

CE

APTT* (sec)

PT

Preop. platelet count* (×109/L)

AC

Preop. ROM* (deg)

Prep. Knee circumference(cm)

*The values are given as Mean ± Standard Deviation. Abbreviations: BMI, body mass index; ASA, American Society of Anesthesiologists; Hb, hemoglobin; Hct, hematocrit; INR, International Normalized Ratio; APTT, activated partial thromboplastin time; 21

ACCEPTED MANUSCRIPT VAS, Visual Analogue Scale; HSS, Hospital for Special Surgery.

AC

CE

PT

ED

MA NU

SC

RI P

T

P values calculated using independent t-test, Person chi-square or Fisher exact test.

22

ACCEPTED MANUSCRIPT Table 2 Intraoperative and Postoperative Demographics

Duration of the surgery* (min)

72±8.8

Total blood loss* (mL)

957±285

Drainage volume* (mL)

364±86

Combined Group (n=92)

T

IV-Group (n=92)

P

RI P

Demographics

0.006‡

328±104

0.011‡

593±311

539±321

0.250

4 (4.3%)

3 (3.3%)

1

10

6

0.522

27.3±5.5

25.6±5.3

0.031‡

7.2±0.8

6.9±0.9

0.016‡

Extremely satisfied

31

39

Very satisfied

45

47

10

3

Transfusion rate* (%) Units transfused (IU)

ED

Maximum decline* (g/L)

PT

Length of hospital stays* (days)

867±374

0.067

SC

MA NU

Hidden blood loss* (mL)

76±9.8

AC

CE

Satisfaction Level†

Somewhat satisfied

0.039‡

Neither satisfied nor dissatisfied

5

3

Somewhat dissatisfied

1

0

Very dissatisfied

0

0

*The values are given as Mean ± Standard Deviation. ‡

Significantly different.



Comparison of satisfied (defined as extremely or very satisfied) versus not satisfied (defined as

somewhat satisfied, neither satisfied nor dissatisfied, somewhat dissatisfied, or very dissatisfied) 23

ACCEPTED MANUSCRIPT

AC

CE

PT

ED

MA NU

SC

RI P

T

between groups.

24

ACCEPTED MANUSCRIPT Table 3 Complications

DVT

1

PE

0

Superficial infection

1

Combined Group (n=92)

T

IV-Group (n=92)

RI P

Complications

1

0

1

1

1

0

0

1

0

0

1

7

5

0.767

SC

0

MA NU

Deep infection Hematoma Wound secretion

P

ED

Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism.

PT

Wound secretion was analyzed by Pearson chi-square test while others were analyzed by Fisher’s exact

AC

CE

test.

25