In recent years there has been an increasing awareness

Chinese Journal of Traumatology 2013;16(2):67-76. 67. Original articles Use of intravenous tranexamic acid in total knee arthroplasty: a meta-analysis of randomized controlled trials FU De-jie, CHEN Cheng, GUO Lin, YANG Liu* Abstract Objective: The effect of tranexamic acid (TA) on patients receiving total knee arthroplasty (TKA) has been reported in many small clinical trials. But single trials are not sufficient enough to clarify the effectiveness and safety of TA. So, we carried out a meta-analysis of randomized controlled trials to investigate the efficacy and safety of the intravenous use of TA in TKA. Methods: Literatures were retrieved in Cochrane Library, OVID, PubMed, EMBASE, CNKI and Wanfang Data. All the related literatures were checked by two independent investigators and only the high quality randomized controlled trials were enrolled. Relevant data were analyzed using RevMan 5.1 to compare the difference of blood loss, transfusion and complications between TA group and control group. Results: There were 353 related literatures and only 22 randomized controlled trials met the inclusion criteria. The use of TA in TKA significantly reduced total blood loss by a mean of 435.41 ml (95% CI 300.62-570.21, P<0.01), postoperative blood loss by a mean of 406.69 ml (95% CI 333.16-480.22, P<0.01). TA also significantly lowered the transfusion rate (risk difference 0.30, 95% CI 0.21-0.39, P<0.01) and transfusion volume (mean difference 0.95 unit, 95% CI 0.53-1.37, P<0.01). The risks between TA group and control group in developing deep vein thrombosis and pulmonary embolism were not statistically significant. Conclusion: TA is beneficial for patients undergoing TKA, which can significantly reduce total blood loss, postoperative blood loss, transfusion rate, and transfusion volume. Meanwhile TA is recommended to reduce deep vein thrombosis and pulmonary embolism following TKA. Key words: Tranexamic acid; Arthroplasty; Knee; Blood loss, surgical; Meta-analysis Chin J Traumatol 2013;16(2):67-76 In recent years there has been an increasing awareness of the potential risks in allogenic blood transfusion, such as viral transmission, organic lesion and ABO incompatibility. 1,2 Total knee arthroplasty (TKA) is associated with marked blood loss, so how to avoid blood transfusion has long been a concern among clinicians. 3,4 Apparently, minimizing peri- and postoperative blood loss is the most direct way to avoid allogenic blood transfusion. Several techniques, such as autologous blood transfusion, intraoperative blood saving etc, have been adopted to reduce the need for allogenic blood transfusion. DOI: 10.3760/cma.j.issn.1008-1275.2013.02.001 Centre for Joint Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China (Fu DJ, Chen C, Guo L, Yang L) *Corresponding author: Tel: 86-23-68765280, Fax: 86-23-65464006, Email: jointsurgery@163.com Nowadays, tourniquet is routinely used in TKA. It not only reduces blood loss during operation but also makes a clear operation area. However, it should be emphasized that the use of tourniquet activates the local fibrinolytic system and greatly increases blood loss after operation. 5 Tranexamic acid (TA) is an analogue of lysine, 6 which has powerful antifibrinolytic potency through blocking the lysine-binding sites of plasminogen molecule and is mainly used in bleeding caused by acute or chronic, localized or systemic accentuation of fibrinolysis. Early in 1988, some investigators suggested giving TA before the release of tourniquet for its effectiveness on reducing blood loss after TKA. 7 From then on, a series of clinical trials have been done to verify this assumption. However, the use of TA still remains controversial.

. 68. Chinese Journal of Traumatology 2013;16(2):67-76 In this study, we retrieved the clinical randomized controlled trials (RCTs) concerning the use of TA on patients who undergo a TKA. The purpose of this metaanalysis is to evaluate the effect and safety of TA in patients receiving TKA. METHODS Inclusion and exclusion criteria Articles met the following criteria were included: (1) RCTs in any language; (2) patients who had undergone TKA regardless of age, sex, type or size of prosthesis used and surgical techniques; (3) intravenous use of TA for treatment group and placebo or no treatment for control group; (4) the evaluation of primary outcome by perioperative blood loss including intraoperative, postoperative and total blood loss, while the secondary outcome by the proportion of patients who needed blood transfusion, the amount of blood transfused per patient, and complications such as the incidence of deep vein thrombosis (DVT), pulmonary embolism (PE), etc. Exclusion criteria included: (1) RCTs of low quality; (2) simultaneous bilateral primary TKA or revision TKA; (3) original data being not enough for a meta-analysis. Search strategy The searching was carried out in the major medical databases including Cochrane Library (CENTRAL, 1948 to December 2012), OVID (1993 to December 2012), PubMed (1966 to December 2012), EMBASE (1966 to December 2012), CNKI (1994 to December 2012), and Wanfang Data (1982 to December 2012). No language restrictions were set. The reference lists were also checked for possible eligible articles. The keywords used for retrieve included Antifibrinolytics, Tranexamic acid, Cyklokapron, Total knee arthroplasty, Total knee replacement, TKA and TKR. Study selection and data extraction Two authors independently conducted the search strategy to select qualified references. The titles and abstracts of the references were read. If there was a doubt, the full text would be reviewed for clarification. The two authors respectively decided whether the article met the inclusion criteria. Disagreement between the two authors was resolved by a senior author. When necessary, the authors of the eligible trials were contacted to obtain missing information. Evaluation of methodological quality of included studies Two authors independently assessed the methodological quality of included studies. In this study, we used the tools for assessing quality and risk of bias from Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. 8 Disagreement was resolved by a senior author. Statistical analysis Statistical Software Review Manager (Version 5.1 for Windows, Cochrane Collaboration) was used for meta-analysis. Continuous variables were expressed as mean plus standard deviation (SD), and the outcomes were analyzed by mean difference (MD) with 95% confidence interval (CI). Dichotomous variables were expressed as proportions or risks, and the outcomes were analyzed by a risk difference (RD) with 95% CI. Significance levels for statistical tests were set at P<0.05. Heterogeneity was tested for all the included articles. Chi-squared test was used to estimate heterogeneity. P value was set at 0.1, and the quantity of heterogeneity was measured by I 2. If there was significant heterogeneity (P<0.1 and I 2 >50%), a random effect model was used; if not, a fixed effect model was used. When necessary, subgroup analysis was carried out to explore the source of heterogeneity. Data which could not be incorporated to the meta-analysis were analyzed descriptively. RESULTS Literature search and study characteristics The primary search found 353 potentially relevant articles (Figure 1). After reading the titles and abstracts, 309 articles were excluded. The full texts of the remaining 44 articles were read conscientiously, and at last 27 RCTs met the inclusion criteria. Among them, five trials were further excluded because TA was used through knee joint injection in two trials, placebo or blank control group was not set in two trials, and patients accepted concurrent bilateral TKA in the remaining trial. Finally, 22 studies with a total of 1 361 patients were included into this meta-analysis. 9-30 Most trials were small but well designed and had generally high quality (Figure 2). Key information of the 22 publications included in the meta-analysis was shown in Table 1.

Chinese Journal of Traumatology 2013;16(2):67-76. 69. Table 1. Characteristics of included studies Author and year Cases (TA/C) Usage of TA DVT Transfusion prophylaxis Control trigger Hiippala 1995 9 28 (15/13) 15 mg/kg before tourniquet deflation Benoni 1996 10 86 (43/43) 10 mg/kg before tourniquet deflation then 10 mg/kg after 3 h Hb<85 g/l Hiippala 1997 11 77 (39/38) 15 mg/kg before tourniquet deflation, 2 additional doses of 10 mg/kg after 3-4 h and 6-7 h Jansen 1999 12 42 (21/21) 15 mg/kg 30 min before tourniquet deflation, then repeated PCV<26% every 8 h for 3 d Ido 2000 13 43 (21/22) 1 g just before tourniquet release and then 1 g 3 h after operation Ellis 2001 14 20 (10/10) 15 mg/kg 30 min before tourniquet deflation, then 10 mg/kg/h Hct<27% infusion for 12 h Engel 2001 15 24 (12/12) 15 mg/kg before tourniquet deflation, then 10 mg/kg after 3 h Tanaka 2001 16 99 (73/26) 10 mg/kg before surgery, 10 mg/kg 10 min before tourniquet deflation Veien 2002 17 30 (15/15) 10 mg/kg before tourniquet deflation, repeated 3 h later Hct<28% Good 2003 18 51 (27/24) 10 mg/kg before tourniquet deflation, repeated 3 h later Hb<90 g/l Zohar 2004 19 40 (20/20) 15 mg/kg 15 min before tourniquet deflation, then 10 mg/kg/h Hct<28% infusion for 12 h Camaras 2006 20 95 (35/60) 10 mg/kg before tourniquet deflation, repeated 3 h later Hb<80 g/l Orpen 2006 21 29 (15/14) 15 mg/kg at cement mixing commenced Hb<90 g/l Molloy 2007 22 100 (50/50) 500 mg 5 min before tourniquet deflation, repeated 3 h later Aspirin Hct<25% Zhang 2007 23 102 (51/51) 1 g before tourniquet deflation, repeated 3 h later Alvarez 2008 24 95 (46/49) 10 mg/kg 30 min before tourniquet deflation, then 1 mg/kg/h Hb<90 g/l infusion for 6 h Kakar 2009 25 24 (12/12) 10 mg/kg before tourniquet deflation, then 1 mg/kg/h until wound closure or Hb<80 g/l Charoencholvanich 2011 26 100 (50/50) 10 mg/kg 10 min before tourniquet deflation, repeated 3 h later Ankle pump exercise Gautam 2011 27 40 (20/20) 10 mg/kg 0.5 h before tourniquet deflation, then 2 mg/kg after 3 h Hb<80 g/l or Hct<30% McConnell 2012 28 44 (22/22) 10 mg/kg at induction of anesthesia Aspirin Chareancholvanich 2012 29 120 (60/60) 10 mg/kg 10 min before tourniquet deflation, then 10 mg/kg 3 h Ankle postoperatively pump exercise Lee 2012 30 72 (36/36) 10 mg/kg before tourniquet deflation, repeated 6 h later Hb<80 g/l C=control; =not available; Hb=hemoglobin; Hct=hematocrit; PCV=packed cell volume; =low-molecular-weight heparin.

. 70. Chinese Journal of Traumatology 2013;16(2):67-76 353 records identified through database searching 309 records excluded on the basis of titles, abstracts or duplicates 44 full-text articles assessed for eligibility 22 full-text articles excluded, with reasons Not RCT: 17 Not intravenous TA: 2 No placebo control: 2 Simultaneous bilateral TKA: 1 primary TKA. Osteoarthritis was the main diagnosis, followed by rheumatoid arthritis. Thirteen trials used spinal anesthesia, 9-11,15,17,18,20,22,24-27,29 one used a combination of general and regional anesthesia, 28 five used general anesthesia 12,14,19,21,30 and the remaining three did not mention this information. 13,16,23 was used in sixteen trials as placebo 9-12,14,16,18,20,21,23-27,29,30 and control patients in the other six studies did not receive any treatment. 13,15,17,19,22,28 TA was used once in three trials 9,21,28 and used repeatedly in nineteen trials. 10-20,22-27,29,30 Eighteen trials mentioned a transfusion trigger 9-12,14,15,17-22,24-27,29,30 except for four studies. 13,16,23,28 To prevent DVT, fourteen trials used low-molecular-weight heparin, 9-12,14,15,17-21,23,24,30 two used aspirin, 22,28 two performed a mechanical ankle pump exercise regimen, 26,29 and four did not mention any preventative measures. 13,16,25,27 22 studies included in this meta-analysis Figure 1. Flow diagram of study selection. Total blood loss Fifteen trials described total blood loss of TKA (Figure 3), including 453 patients in TA group and 478 patients in control group. TA significantly reduced total blood loss of TKA (P<0.01, MD=435.41 ml, 95% CI 300.62-570.21). There was significant heterogeneity (P<0.01, I 2 =94%) in the trials, so a random effect model was used. Intraoperative blood loss Intraoperative blood loss was recorded in 4 trials which included 124 patients in TA group and 121 patients in control group. TA did not significantly reduce intraoperative blood loss of TKA (P=0.62, Figure 4) and there was no heterogeneity between trials (P=0.51, I 2 =0). Postoperative blood loss Eight trials involving 638 patients described postoperative blood loss. TA significantly reduced postoperative blood loss compared with control group (P<0.01, MD=406.69 ml, 95% CI 333.16-480.22). But heterogeneity was significant between trials (P=0.001, I 2 =71%, Figure 5). Figure 2. Quality of included RCTs. Totally there were 693 patients in TA group and 668 patients in control group. The number of patients in these trials ranged from 20 to 120. All the patients received Blood transfusion rate Blood transfusions were recorded in 19 trials (Figure 6), including 609 patients in TA group and 583 patients in control group. Among them, there were 172 patients in TA group and 318 patients in control group requiring transfusion. TA significantly reduced the proportion of patients who needed transfusion (P<0.01, RD=0.30, 95% CI 0.21-0.39). Heterogeneity still existed between trials (P<0.01, I 2 =80%).

Chinese Journal of Traumatology 2013;16(2):67-76. 71. Blood transfusion volume The units of blood transfused to patients were recorded in 15 trials (Figure 7), including 495 patients in TA group and 470 patients in control group. The MD cannot be calculated in three trials because the patients in TA group did not receive any blood. TA significantly reduced blood transfusion volume compared with control group (P<0.01, MD=0.95 unit, 95% CI 0.53-1.37). However, there was significant heterogeneity between these trials (P<0.01, I 2 =96%). Incidence of DVT In 21 trials, data on DVT were available. Studies included 683 and 658 patients in TA group and control group respectively (Figure 8). Among them, 47 patients in TA group and 27 in control group developed DVT. There was no statistical difference between TA group and control group (P=0.77) and no heterogeneity between trials either (P=1.00, I 2 =0). Incidence of PE In 13 trials data were available on patients outcome (Figure 9). In TA group, no PE was reported. In control group, 3 patients out of 460 developed PE. There was no statistical difference in the risk of developing PE between TA group and control group (P=0.44). There was no heterogeneity between trials either (P=1.00, I 2 =0). Other complications Besides thromboembolic episodes, some other complications were found. Three studies reported 6 cases of infection, 5 in TA group and 1 in control group. 10,18,22 Hematoma was reported in three studies, including 9 patients in TA group and 6 in control group. 10,26,29 Secretions occurred in the wounds of 5 patients, 3 from TA group and 2 from control group. In TA group, one patient with a history of ischemic heart disease suffered from myocardial infarction and recovered after prompt therapy. 9 One patient was hospitalized for 11 days because of heart attack 4 weeks after TKA. 11 Three days after TKA, one patient in TA group suffered from chest pain and showed hypotension. 10 In one trial, 11 one patient from TA group who had 30 years history of rheumatoid arthritis suffered from pneumonia and respiratory failure 4 days after operation and another developed pneumonia 4 weeks after operation; one patient from control group suddenly died 15 days after operation and the cause of death was certified as PE. Three patients in TA group had mild nausea 16 and a few patients complained of nausea and vomiting. 13 In the telephone follow-up, one patient from TA group died of aggravation of prior pulmonary fibrosis 3 months after surgery. 20 Figure 3. Forest plot diagram of TA versus control on total blood loss. Favours TA. Figure 4. Forest plot diagram of TA versus control on intraoperative blood loss. No statistical difference.

. 72. Chinese Journal of Traumatology 2013;16(2):67-76 Figure 5. Forest plot diagram of TA versus control on postoperative blood loss. Favours TA. Figure 6. Forest plot diagram of TA versus control on blood transfusion rate. Favours TA. Figure 7. Forest plot diagram of TA versus control on blood transfusion volume. Favours TA.

Chinese Journal of Traumatology 2013;16(2):67-76. 73. Figure 8. Forest plot diagram of TA versus control on incidence of DVT. No statistical difference. Figure 9. Forest plot diagram of TA versus control on incidence of PE. No statistical difference. DISCUSSION TA could reversibly occupy the lysine-binding sites of the plasminogen molecule and has powerful antifibrinolytic potency. It has been widely used in many kinds of therapies. Besides orthopedic surgery, it has been used in pediatric urinary tract surgery, 31 ruptured intracranial aneurysms, 32 oral surgery, 33 gynecologic surgery, 34 caesarian section, 35 upper gastrointestinal hemorrhage, 36 cardiac surgery, 37 and so on. The trial Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage 2 (CRASH-2) showed that TA can significantly reduce the all-cause mortality as a result of bleeding. 38 Cap et al 39 suggested that TA should be incorporated into trauma clinical practice guidelines and treatment protocols. In 2008, 615 050 total knee replacements were performed in the United States adult population, 134% more than in 1999. 40 The number of patients receiving TKA increases nowadays, which largely raises the risks of allogenic blood transfusion and heavily burdens the pub-

. 74. Chinese Journal of Traumatology 2013;16(2):67-76 lic health system. TA is cheap and very efficacious in reducing blood loss. Therefore, it is a very promising drug to lower these risks. According to the results of our meta-analysis, TA can significantly reduce total blood loss and postoperative blood loss. TA reduced the proportion of patients who needed transfusion by 30% and the decreased average volume of blood transfusion researched 0.95 unit. TA also did not raise the risks of DVT or PE. But significant heterogeneity existed between trials. Heterogeneity could result from many factors, such as different types of prosthesis, surgical techniques, TA usage, tourniquet usage and types of anesthesia. We carried out a subgroup analysis on blood transfusion rate according to the type of anesthesia, use of transfusion protocols, TA dose (high dose >3 000 mg ) and whether the patient received. Results were accordant to the original analysis. Except for TA dose, other factors could not explain the source of heterogeneity: heterogeneity did not exist in the high dose subgroup (P=0.79, I 2 =0), but existed in the low dose subgroup (P<0.01, I 2 =80%). Complications associated with TA use have been reported. Concerning the occasional thromboembolic events, most of doctors are reluctant to use TA in TKA. However, with many prospective random clinical trials being carried out, the safety of TA has been further confirmed. Intravenous administration of TA was approved by the Food and Drug Administration (FDA) in 1986 for prevention or reduction of bleeding in patients with hemophilia undergoing dental procedures. And in 2009 the FDA approved its oral use to control heavy menstrual cyclic bleeding. In the CRASH-2 study, 36 there was no significant difference between TA group and control group on incidence of DVT and PE. In our study, 47 patients in TA group and 27 patients in control group developed DVT. However, there was no significant difference (P=0.77) between two groups either, which was consistent with the result of CRASH-2. Three patients developed PE events, and they were all from control group unexpectedly. The difference between TA and control group was also not statistically significant (P=0.44). Then, from the result of our meta-analysis, TA did not increase risks of DVT or PE. We presume that use of TA mainly resists the fibrinolytic effect caused by tourniquet and generally has little influence on the normal fibrinolytic system. Thereby, TA does not obviously cause thromboembolic events. However, clinical trials are requisite to certify this hypothesis. Additionally, most of the reported thromboembolic events are detected by clinical examinations and Doppler ultrasound. Few studies perform a routine screening for thromboembolic complications as the study of Tanaka et al s 16, in which all the patients receive bilateral radioisotope venography and a standard perfusion lung scan imaging between 7 and 14 days after surgery. We insist on routine screening for thromboembolic complications after surgery in future trials. There are also many other meta-analysis articles that investigate the effect of TA in TKA. Ho and Ismail 41 studied the effect of TA in total hip arthroplasty (THA) and TKA. Data were analyzed without distinguishing TKA and THA. This might be a source of heterogeneity. Cid and Lozano 42 carried out a meta-analysis focused on the effects of TA in TKA. But only 9 trials were included in the study and the quality of some trials is very low. The result of their meta-analysis also showed that TA is effective to reduce the proportion of patients who need transfusion. However, they did not mention the blood loss as well as the complications. Zufferey et al 43 and Kagoma et al 44 performed another two metaanalysis articles. They both assessed the effect of antifibrinolytics on blood loss and blood transfusion rate in orthopedic surgery. But all antifibrinolytics were assessed in a single group or one of them was analyzed in many kinds of orthopedic surgeries. Yang et al 45 and Alshryda et al 46 also did similar researches, but the usage of TA included intravenous and topical administration. In our study, most of the trials are of high quality, which makes the conclusions drawn from this metaanalysis more reliable. We focused on the efficacy of TA in TKA only to reduce heterogeneity caused by other types of orthopedic surgery. Blood loss was analyzed separately by total, intraoperative and postoperative time period. Besides, we only included trials in which TA is used intravenously, and those that do not set placebo or blank controls are excluded. There are still many limitations in our analysis. (1) Some of the included studies have an obvious defect, i.e. the collection of autologous blood before surgery. It can be a confusing factor for the determination of blood loss based on decrease of hemoglobin, especially when the

Chinese Journal of Traumatology 2013;16(2):67-76. 75. blood collection program is not standard. (2) We mainly analyze the effect and safety of TA used in TKA. However, the recovery of joint function and quality of life after surgery are also very important for patients. Because few trials report these aspects, data are not enough for analysis. Many studies record the number of patients who develop DVT and PE, but the methods and time of follow-up are different, so the results are less comparable. Complications should be examined in larger clinical trials. (3) We searched for trials in the major medical databases and did not search for gray literature, such as special topic report, unpublished documents, government reports and other conventional or unconventional literature. So, publication bias might exist. 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