Official Journal of the British Blood Transfusion Society
Transfusion Medicine
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ORIGINAL ARTICLE
The effectiveness and safety of tranexamic acid in total hip or knee arthroplasty: a meta-analysis of 2720 cases Z. Wei & M. Liu Department of Trauma, Union Medicine Centre of Tianjin, Tianjin, China Received 4 June 2014; accepted for publication 5 May 2015
SUMMARY Aims: To evaluate the safety and efficacy of tranexamic acid (TXA) in total knee arthroplasty (TKA) and total hip arthroplasty (THA). The specific endpoints assessed in this meta-analysis include the total blood loss, the incidence rate of deep vein thrombosis (DVT) and pulmonary embolisms (PE), the number of patients requiring at least 1 U of red blood cell following surgery. Background: The prevalence of THA and TKA is increasing and both are usually accompanied by considerable blood loss. TXA has been reported to reduce total blood loss in many orthopaedic surgeries. TXA administration continues to be a controversial topic in the literature about joint arthroplasty, and many studies have reported substantial doubt with respect to its benefits and safety. Methods/materials: We conducted a meta-analysis that combined all data from available randomised controlled trials, regardless the methods of TXA administration, which included administrated intravenously, intra-articularly, topically or orally. Finally, available data from the 39 included trials were pooled for analysis. Then, mean differences with 95% confidence intervals (CIs) was calculated for continuous outcomes and relative risks with 95% CIs for dichotomous outcomes. Results: This meta-analysis suggests that the administration of TXA significantly reduced blood loss and the need for allogeneic blood transfusion, without apparent increased risk of DVT or PE thromboembolic complications. Conclusion: To our knowledge, this meta-analysis is more powerful and persuasive than any other published before. It suggests that the use of TXA reduced the risk of blood loss and the need for allogeneic blood transfusion significantly, without apparent increased risk of DVT or PE complications.
Correspondence: Minghui Liu, MM, Department of Trauma, Union Medicine Centre of Tianjin, 190 Jieyuan West Road, Tianjin 300121, China. Tel.: +86 22 27557265; fax: +86 22 27557265; e-mail: [email protected]
© 2015 British Blood Transfusion Society
Key words: meta-analysis, total hip arthroplasty, total knee arthroplasty, tranexamic acid. Total knee arthroplasty (TKA) and total hip arthroplasty (THA) is increasing and both are usually accompanied by considerable blood loss, which may lead to acute anaemia and related complications (Álvarez et al., 2008; Dhillon et al., 2011), thereby increasing the risk of blood transfusion for patients (Charoencholvanich & Siriwattanasakul, 2011). However, allogeneic blood transfusion is an expensive and scarce resource, and is not a risk-free therapeutic method. Undoubtedly, allogeneic transfusions may increase health care costs (Hiippala et al., 1997), as well as increase the patient’s risk for post-operative infection, such as hepatitis, cytomegalovirus, human immunodeficiency virus (HIV), Epstein-Barr virus (Tobias, 2004; Bursi et al., 2009). Tranexamic acid (TXA) is a synthetic production of the lysine, which competitively blocks the lysine binding sites on plasminogen to inhibit activation of plasminogen and interfere with fibrinolysis. TXA has been used widely in kinds of blood, such as gastrointestinal bleeding, cardiac surgery and liver transplantation as well as in orthopaedic surgery. TXA may be administered via kinds of methods, such as intravenous (iv), orally, topically in the surgical fields or intra-articular. It was reported that TXA reduced volume of blood loss in many kinds of orthopaedic surgery, such as spinal surgery as well as total hip or knee joint arthroplasty (Ralley et al., 2010; Wong et al., 2010). However, some studies have questioned the effectiveness and safety of TXA, by demonstrating that its use could not significantly reduce volume of blood loss and elevated the risk of thromboembolic complications such as deep vein thrombosis (DVT) and pulmonary embolisms (PE) (Rosencher et al., 2008; Ozier & Schlumberger, 2006). The main purpose of this meta-analysis was to compare the clinical results of TXA with the results of control groups following THA or TKA. To evaluate the clinical efficacy and safety of TXA, we performed this meta-analysis that combined all the data from available randomised controlled trials (RCTs). We hypothesised that TXA in both THA and TKA could significantly reduce volume of blood loss following surgery without an increased risk of DVT and PE. First published online 29 May 2015 doi: 10.1111/tme.12212
152 Z. Wei and M. Liu
MATERIALS AND METHODS
Statistical analysis
Literature search
Hip and knee arthroplasty data were calculated independently for our interested outcome measures. revman 5.2 software was employed to pool the included data for analysis. For each continuous data, we calculated mean differences (MDs) with 95% confidence intervals (CIs); and we calculated relative risks (RRs) with 95% CIs for dichotomous data. According to the heterogeneity between studies, we pooled the interested outcome data of comparable groups of trials using random-effect models (DerSimonian–Laird method) or the fixed-effect models (Mantel–Haenszel test). The I 2 value is a measure of the percentage of variation in the data that is as a result of heterogeneity as opposed to chance. The heterogeneity level among different studies was assessed using the I 2 statistic results. A random-effect model was employed when there was significant heterogeneity between studies included (P < 0·10; I 2 > 50%). A fixed-effect model was used for pooling and analysing when there was no significant heterogeneity.
We searched for the published available results of relevant trials in the PubMed (January 2000 to December 2013), Cochrane Library (Issue 2, 2011), ScienceDirect Online (January 2000 to December 2013), Ovid (January 2000 to December 2013), ISI Web of Knowledge (January 2000 to December 2013), several transfusion journals (Transfusion, Transfusion and apheresis science, Blood Transfusion, Transfusion medicine, Transfusion medicine reviews) and orthopaedic journals (Transfusion, Transfusion and apheresis science, Blood Transfusion, Transfusion medicine, Transfusion medicine reviews). The search terms used included ‘randomised controlled trials’, ‘RCTs’, ‘tranexamic acid’, ‘TXA’, ‘TEA’, ‘total hip replacement’, ‘total knee replacement’, ‘total hip arthroplasty’, ‘total knee arthroplasty’ and ‘total joint arthroplasty’. When it was necessary, the authors of the included articles were contacted for original data.
Inclusion and exclusion criteria We retrieved all related RCTs that compared the TXA group with the control group in patients undergoing total joint arthroplasty, including total knee or hip arthroplasty. Properly trials were eligible for inclusion if (i) the study involved the comparison of a TXA treatment group to a control group who received either a placebo or no treatment at all; (ii) studies included at least one of the outcome measures; (iii) the data points was presented as the mean ± standard deviation (SD); (iv) we obtained the original information from the authors of the included articles when data were shown as the medians and/or ranges. Studies were excluded from the analysis if (i) the patients received revision replacement of the joint; (ii) all data were shown as the medians and/or ranges, and we could not obtain the original information by any way; (iii) patients had received any other strategy to decrease blood loss peri-operation or post-operation; (iv) studies were published in language other than English.
Assessment of study quality Quality of included RCTs was estimated according to the method in the Cochrane Reviewer’s Handbook 5.0 (Higgins & Green, 2011). To make sure accuracy, the interested information was extracted by two reviewers independently. In cases of different opinions, conflicts were resolved by consensus of alls senior reviewers.
RESULTS Literature search Using our search terms, the primary literature search yielded 609 potentially relevant references. Most of these studies, however, did not fit our inclusion criteria and excluded from the analysis. Finally, 39 studies (13 for THA, 22 for TKA, 4 for both THA and TKA) were identified as available for data extraction and meta-analysis (Álvarez et al., 2008; Ekback et al., 2000; Ido et al., 2000; Benoni et al., 2001; Ellis et al., 2001; Tanaka et al., 2001; Veien et al., 2002; Good et al., 2003; Husted et al., 2003; Garneti & Field, 2004; Lemay et al., 2004; Yamasaki et al., 2004; Zohar et al., 2004; Johansson et al., 2005; Niskanen & Korkala, 2005; Yamasaki et al., 2005; Camarasa et al., 2006; Orpen et al., 2006; Claeys et al., 2007; Molloy et al., 2007; Kakar et al., 2009; Kazemi et al., 2010; Wong et al., 2010; Charoencholvanich & Siriwattanasakul, 2011; Ishida et al., 2011; MacGillivray et al., 2011; Malhotra et al., 2011; Clave et al., 2012; Imai et al., 2012; McConnell et al., 2012; Raviraj et al., 2012; Roy et al., 2012; Alipour et al., 2013; Dahuja et al., 2013; Gautam et al., 2013; Georgiadis et al., 2013; Konig et al., 2013; Martin et al., 2013; Oremus et al., 2014). These 39 studies were randomised adequately and consensus was reached by discussion (Fig. 1). All studies included in this meta-analysis were English-language.
Quality of the trials Outcome measures The primary interested outcome indexes in this meta-analysis include the total volume of blood loss following surgery and the incidence of DVT and PE. The secondary interested outcome measures include the number of patients requiring allogeneic red blood cells.
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In total, 2720 patients were included in our analysis from these 39 trials; 1422 patients received TXA administration and 1298 patients served as control group; 921 patients and 1799 patients received THA and TKA operation, respectively (Table 1). The quality of the RCTs included in this meta-analysis is showed in Tables 2 and 3, for THA and TKA, respectively.
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Fig. 1. The PRISMA flowchart diagram for review.
Outcome measures Total blood loss. A total of 9 THA studies and 13 TKA studies, respectively, compared the total volume of blood loss (including both the intra-operative and post-operative blood loss) in the TXA group with a control group. Therefore we included these studies as the data of the meta-analysis in Fig. 2a and b. For THA, no significant heterogeneity was detected between the studies (P = 0.14; I 2 = 34%), though, a fixed-effect model was used to analysis. The pooled result manifested a statistical significance between treatment groups in total volume of blood loss (MDs, −318.49; 95% CIs, −398.04 to 238.94; P < 0.00001) (Fig. 2a, b). For TKA, heterogeneity was significant between the studies (P < 0.00001; I 2 = 95%), a random-effect model was employed. The pooled result showed a significant difference between TXA group and control group in total blood loss (MDs, −321.78; 95% CIs, −413.25 to −213.08; P < 0.00001) (Fig. 2b). Both in hip and
© 2015 British Blood Transfusion Society
knee arthroplasty, the pooled results favored the experimental group. Deep vein thrombosis (DVT). A total of 15 THA studies and 21 TKA studies were included in the analysis of DVT and we pooled the results in Fig. 3a and b. Without significant heterogeneity among the data, (heterogeneity test: P = 0.66; I 2 = 0% and P = 0.23; I 2 = 30%, respectively; fixed-effect analysis), the pooled results indicated no significant difference in DVT between the treatment groups, (RRs, 0.63; 95% CIs, 0.20 to 2.01; P = 0.43) in THA and (RRs, 0.57; 95% CIs, 0.26 to 1.24; P = 0.15) in TKA (Fig. 3a and b). It showed that the incidence of DVT in the TXA group and the control group was NOT statistically significant. Pulmonary embolisms (PE). We pooled the results of the included trials in Fig. 4a and b. We found no significant heterogeneity between studies both in THA (P = 0.95; I 2 = 0%)
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LMWH, Low molecular weight heparin.
iv iv iv iv iv iv iv iv iv iv iv Topical Topical iv Topical iv Oral iv iv iv iv iv iv iv Topical Topical Topical iv + oral
Oremus et al. (2014) Garneti & Field (2004) Clave et al. (2012) McConnell et al. (2012) Ido et al. (2000) Gautam et al. (2013) Malhotra et al. (2011) Imai et al. (2012) Raviraj et al. (2012) Yamasaki et al. (2005) MacGillivray et al. (2011) Georgiadis et al. (2013) Konig et al. (2013) Dahuja et al. (2013) Martin et al. (2013) Orpen et al. (2006) Alipour et al. (2013) Claeys et al. (2007) Kazemi et al. (2010) Good et al. (2003) Camarasa et al. (2006) Ellis et al. (2001) Tanaka et al. (2001) Veien et al. (2002) Wong et al. (2010) Roy et al. (2012) Ishida et al. (2011) Charoencholvanich & Siriwattanasakul (2011) Molloy et al. (2007) Álvarez et al. (2008) Kakar et al. (2009) Zohar et al. (2004) iv iv iv iv
iv iv iv iv iv iv iv
Method of TXA
Yamasaki et al. (2004) Lemay et al. (2004) Husted et al. (2003) Benoni et al. (2001) Ekback et al. (2000) Johansson et al. (2005) Niskanen & Korkala (2005)
Study
Table 1. Study characteristics of the 39 included studies
1 g 5 min prior to operation 10 mg kg−1 prior to surgery. 1 mg kg−1 h−1 infusion until wound closure 10 mg kg−1 for 10 min, 15 min prior to incision + 1 mg kg−1 h−1 for 10 h 10 mg kg−1 for 5–10 min, immediately before operation 10 mg kg−1 before incision + 1 mg kg−1 h−1 for 10 h 15 mg/kg before operation 3 doses of 10 mg kg. First over 5–10 min before operation. 2nd + 3rd, 8 + 16 h after operation 1 g prior to operation + 1 g 3 h after operation 10 mg kg−1 before operation 1 g prior to operation + 1 g per 3 h/7 h/12 h after operation 10 mg kg−1 before operation 1 g prior to operation + 1 g 3 h after operation 10 mg kg−1 before deflation of tourniquet + 10 mg kg−1 4 h after first dose 15 mg kg−1 15 min prior to operation 1 g before operation 10 mg kg−1 before deflation of tourniquet + 10 mg kg−1 3 h after first dose 1 g 5 min before incision 10 mg kg−1 before deflation of tourniquet + 10 mg kg−1 3 h after first dose 2.0 g topically in 75 mL saline 3.0 g topically in 100 mL saline 15 mg kg−1 before deflation of tourniquet + 15 mg−1 kg−1 1/8 h after first dose for 2 days 3.0 g topically in 100 mL saline 15 mg kg−1 at time cement mixing commenced 1 g 2 h before deflation of tourniquet + 1/6 h after first dose for 18 h 15 mg kg−1 before operetation 15 mg kg−1 before operation 10 mg kg−1 before deflation of tourniquet + 10 mg kg−1 3 h after first dose 10 mg kg−1 before deflation of tourniquet + 10 mg kg−1 3 h after first dose 15 mg kg−1 before tourniquet deflation + 10 mg kg−1 h−1 until 12 h after deflation. 20 mg kg−1 before tourniquet deflation 10 mg kg−1 before deflation of tourniquet + 10 mg kg−1 3 h after first dose 1.5 g in saline 500 mg/5 mL through two intra-articular drain 2000 mg/20 mL via intra-articular drain. 10 mg kg−1 before inflation of tourniquet + 10 mg kg−1 3 h after operation + 1.5 g oral for 5 days 500 mg 5 min prior to deflation of tourniquet + 500 mg 3 h later 10 mg kg−1 before deflation tourniquet + 1 mg kg−1 h−1 for 3 h 10 mg kg−1 before tourniquet inflation + 1 mg kg−1 h−1 until wound closure 15 mg kg−1 before tourniquet deflation + 10 mg kg−1 h−1 for 12 h
Dose of TXA
None Saline Saline None
Saline Saline Saline Saline Saline Saline Saline Saline Saline None Saline Saline Saline Saline Saline Saline Saline Saline Saline Saline Saline
Saline Saline Saline Saline Saline None
None Saline Saline Saline Saline Saline Saline
Control
Aspirin Bemiparin None Enoxaparin
None stocking + pumps Riraroxaban Oral aspirin Unclear Unclear LMWH Unclear LMWH None None LMWH Unclear Unclear Unclear LMWH Enoxaparin LMWH Enoxaparin Fragmin Dalteparin Enoxaparin none LMWH LMWH LMWH Heparin sodium None
None Dalteparin LMWH LMWH LMWH Fragmin Dalteparin
DVT prophylaxis
Knee Knee Knee Knee
H&K Hip Hip Knee H&K Knee Hip Hip Knee Hip Knee Knee Knee Knee H&K Knee Knee Hip Hip Knee Knee Knee Knee Knee Knee Knee Knee Knee
Hip Hip Hip Hip Hip Hip Hip
Joint
154 Z. Wei and M. Liu
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Table 2. Quality evaluation of included Trials for THA Study Yamasaki et al. (2004) Lemay et al. (2004) Husted et al. (2003) Benoni et al. (2001) Ekback et al. (2000) Johansson et al. (2005) Niskanen & Korkala (2005) Oremus et al. (2014) Garneti & Field (2004) Clave et al. (2012) Ido et al. (2000) Malhotra et al. (2011) Imai et al. (2012) Martin et al. (2013) Claeys et al. (2007) Kazemi et al. (2010) Konig et al. (2013) Total
Number (T/C)
Random
Concealment
Blingding
Follow-up
Grade
20/20 20/19 20/20 18/20 20/20 47/53 19/20 20/22 25/25 37/33 20/20 25/25 26/22 25/25 20/20 32/32 91/40 485/436
Y Y Y Y Y Y Y Y Y Y U Y Y Y Y Y Y
Y Y Y Y Y Y Y Y Y U U Y Y Y Y Y U
Y Y Y Y Y Y Y Y Y Y U Y Y Y Y Y U
4W 3M NR 6W 3W 6–8 W NR 3M NR 3M NR NR NR 1W NR NR NR
A A B A A A B A B B C A A A B B C
M, month; NR, no report; T/C, Trial group/Control group; U, unclear; W, week; Y, yes.
Table 3. Quality evaluation of included Trials for TKA Study Oremus et al. (2014) McConnell et al. (2012) Ido et al. (2000) Gautam et al. (2013) Raviraj et al. (2012) Yamasaki et al. (2005) MacGillivray et al. (2011) Georgiadis et al. (2013) Konig et al. (2013) Dahuja et al. (2013) Martin et al. (2013) Orpen et al. (2006) Alipour et al. (2013) Good et al. (2003) Camarasa et al. (2006) Ellis et al. (2001) Tanaka et al. (2001) Veien et al. (2002) Wong et al. (2010) Roy et al. (2012) Ishida et al. (2011) Charoencholvanich & Siriwattanasakul (2011) Molloy et al. (2007) Álvarez et al. (2008) Kakar et al. (2009) Zohar et al. (2004) Total
Number (T/C)
Random
Concealment
Blinding
Follow-up
Grade
29/27 22/22 21/22 14/13 88/87 21/21 20/20 50/51 130/29 60/60 25/25 15/14 26/27 27/24 35/60 10/10 22/26 15/15 31/35 25/25 50/50 60/60 50/50 46/49 25/25 20/20 937/862
Y Y U Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
Y Y U U Y U Y Y U U Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
Y Y U Y Y Y Y Y U U Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
3M NR NR NR 30 W 6M NR 2W NR NR 1M 15 days 2W NR NR NR NR NR 6W NR NR NR 6W 6W NR 3M
A B C B A B A A C C A A A A A A A A A A A A A A A B
M, month; NR, no report; T/C, Trial group/Control group; U, unclear; W, week; Y, yes.
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156 Z. Wei and M. Liu
(a)
(b)
Fig. 2. (a and b) The MDs and 95% CIs for the volume of total blood loss among patients treated with vs without TXA for THA and TKA, respectively. It indicated that total blood loss in the TXA group was significantly lower than that in the control group.
and TKA (P = 0.95; I 2 = 0%) and thus compared the data with fixed-effect model. The pooled result showed no significant difference between the treatment groups, (RRs, 1.65; 95% CIs, 0.40–6.82; P = 0.49) (Fig. 4a) and (RRs, 1.63; 95% CIs, 0.43–6.12; P = 0.47) (Fig. 4b) for THA and TKA, respectively. It showed that there was NO statistical significance about the incidence of PE compared the TXA group with the control group.
Blood transfusion. The number of patients requiring at least 1 U of allogeneic red blood cells was compared between TXA group and control group following the joint arthroplasty surgery. There was no significant heterogeneity between the studies, so a fixed-effect model was used in both THA and TKA. The pooled result indicated a statistical significance between two treatment groups in the rate of patients requiring at least 1 U of allogeneic red blood cells, (RRs, 0.50; 95% CIs, 0.35–0.65; P < 0.00001) and (RRs, 0.53; 95% CIs, 0.45–0.63; P < 0.00001) for THA and TKA, respectively (Fig. 5a and b). The pooled results showed that TXA group required allogeneic blood transfusions less than control group.
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DISCUSSION TKA or THA is usually accompanied by considerable blood loss and regularly results in a postoperative requirement for allogeneic blood transfusion. Because of the disadvantages of blood transfusion such as the risk of incompatibility-related transfusion fatalities and transfusion-associated infections, a continuing effort is made to reduce blood loss (Haien et al., 2013). Thus, anti-fibrinolytic drugs, such as epsilon aminocaproic acid, aprotinin, fibrin spray as well as TXA have been used to decrease volume of blood loss following surgery (Kagoma et al., 2009). When compared to other antifibrinolytic drugs, TXA has been shown to be less expensive (Ralley et al., 2010). However, TXA administration continues to be a controversial issue in the orthopaedic literature, and many studies have also reported doubts with respect to its benefits. The theoretical risk with TXA is thrombosis (Ozier & Schlumberger, 2006; Rosencher et al., 2008). Clave et al. (2012) found no DVT or clinically symptomatic PE during hospital stay or at 3 months follow-up after primary THA. Their study design excluded patients at high-risk of thromboembolic or ischemic complications, and only low-risk
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(a)
(b)
Fig. 3. (a and b) The RRs and 95% CIs for the incidence of DVT among patients treated with vs without TXA for THA and TKA, respectively. The result revealed no significant difference between the treatment groups.
patients underwent the concomitant oral anti-Xa thromboprophylaxis. This introduced a systematic underestimation of thromboembolic risk by excluding high-risk cases, which was an important study limitation. Oremus et al.’s study demonstrated that the addition of TXA to a restrictive blood transfusion protocol significantly reduced
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postoperative external blood loss. And it also decreased the number and volume of postoperative autologous blood retransfusions rendering the routine use of a postoperative cell salvage system in patients undergoing primary THA or TKA. It also demonstrated that thromboembolic events in the TXA group was lower than in the placebo group, although the difference was
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158 Z. Wei and M. Liu
(a)
(b)
Fig. 4. (a and b) The RRs and 95% CIs for the incidence of PE among patients treated with vs without TXA for THA and TKA, respectively. The result revealed no significant difference between the treatment groups both in THA and TKA.
not significantly different (Oremus et al., 2014). As a result, it showed that TXA was not only effective but also safe in THA. In Imai et al.’s study, it found that blood loss of intra-operation in the TXA group was significantly lower than in the control group (Imai et al., 2012). It also demonstrated that the incidences of DVT were not statistically significance between the two groups,
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3 of 26 patients and 3 of 22 in TXA and control group, respectively. Consistent with the Oremus’s result, it demonstrated that TXA was an effective and safe strategy for decreasing blood loss following THA. In another RCT, 175 patients (n = 88 TXA vs 87 control) completed the study (Raviraj et al., 2012). Both the average blood
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(a)
(b)
Fig. 5. (a and b) The RRs and 95% CIs for the numbers of patients requiring at least 1 U of allogeneic RBCs among patients treated with vs without TXA. The pooled results demonstrated that TXA group required allogeneic blood transfusions less than control group both in THA and TKA.
loss and allogenic blood transfusion requirement in the TXA group were significantly less than the control group (P = 0.0001). The peri-operative complications and hospital stay was not significantly different in the two groups. As a results, it was recommended that the routine use of this drug reduced postoperative blood loss in THA in this study. Consistently, Good et al. (2003) also reported that TXA decreased total blood loss and reduced transfusion drastically, but did not increase the clinical symptoms of DVT. In contrast, MacGillivray et al. (2011) showed that 10 mg kg−1 of TXA was sufficient enough to lead to a lesser allogenic transfusion requirement (P < 0.01) in TKA. But 1 patients
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out of 20 in TXA group developed non-life-threatening PE diagnosed by spiral computed tomography (CT) after an episode of chest pain. In(Garneti & Field (2004)) trial, no statistically significance was found in the volume of internal and external blood loss in the two groups (1443 ± 809 mL in the TXA group vs 1340 ± 665 mL in the placebo group, P = 0.822). However, a greater number of patients required transfusion in the TXA group than in the placebo group and one patient in the TXA group was confirmed a PE. These results showed that TXA was neither effective nor safe. Consequently, they did not support the use of TXA routinely in primary THA.
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160 Z. Wei and M. Liu Wong et al. (2010) concluded that topical application of TXA directly into the surgical wound reduced postoperative bleeding by 20–25% and resulted in 16–17% higher postoperative haemoglobin levels compared with placebo, with no clinically important increase in complications. In another prospective controlled trial (Georgiadis et al., 2013), it demonstrated that administration of topical TXA in primary TKA decreased total blood loss (940.2 ± 327.1 vs 1293.1 ± 532.7 mL, P < 0.001) and postoperative transfusion (0/20 vs 4/20). Differently, thromboembolic rates was higher in the control group (DVT 4 vs 9, P = 0.231; and PE 1 vs 2, P = 1.0, TXA vs control, respectively), although the exact mechanism under it was unclear. Numerous literatures had evaluated the use of TXA in total joint surgery and had shown various opinions in reducing blood loss and kinds of complications. However, any single clinical trials lack sufficient statistical power to determine the safety and effectiveness of TXA in THA or TKA. Consequently, we performed this meta-analysis of RCTs from 2000 to November 2013 to investigate the safety and effectiveness of TXA administration in relation to reducing blood loss and transfusion requirement as well as incidence of complications in total joint arthroplasty. During the course of our study for searching literature and analysing the data, other meta-analysis on TXA for joint arthroplasty were published in 2013, which included the study by Gandhi et al. (2013), Panteli et al. (2013), Tan et al. (2013), Zhou et al. (2013). All of these published meta-analysis concluded exclusively that the clinical importance of effect should be interpreted with caution and more prospective RCTs with larger sample sizes were needed in the future. Our analysis included relatively latest literature, which was published from 2000 to 2013. Among of them, 12 studies were published after 2012 and 7 were published in 2013. However, among these four published meta-analysis, no included studies were published in 2013. Only two, one, three and three literatures were published in 2012 in Gandhi’s, Tan’s, Zhou’s and Panteli’s, respectively. Therefore the latest literature brought novelty for our analysis. A total of 2720 participants were included in our meta-analysis, while only 1114, 1030 and 397 patients were included in Tan’s, Zhou’s and Panteli’s, respectively. The sample size of our meta-analysis was larger than any other of the four. Both sufficient sample size and novel literature data strengthened the power to a great extent in our meta-analysis. Although the conclusion was consistent with other’s, it was more powerful and persuasive than other’s. Therefore, we reported the relatively latest findings in this field. In this meta-analysis we concluded all the available RCTs about TXA in THA or TKA, regardless the methods of TXA administration, which included administrated intravenously, intra-articularly, topically or orally (Huang et al., 2014). The subgroup-analysis showed that there was no significant differences between the different methods of administration, so it was reasonable to pool all the data of eligibility together for further analysis. Differently from THA, pneumatic tourniquet use could allow a dry surgical field and significantly decreased intra-operative
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blood loss in TKA. However, tourniquet employment was not riskless methods. Several previous studies had shown that even a short-term tourniquet application could enhance local fibrinolytic activity several times above the basal level (Kruithof et al., 1987). Under this context, we pooled eligible data of THA and TKA separately for meta-analysis in this study. This meta-analysis demonstrated that the use of TXA could effectively reduce total blood loss, intra-operative blood loss, postoperative drainage volume, the requirement of allogeneic blood transfusion, as well as the change of hematocrit for patients undergoing primary THA or TKA. Furthermore, TXA did not increase the prevalence of DVT or PE, compared patients who received TXA with those received placebo based on this meta-analysis. These results were consistent with the meta-analyses in THA by Sukeik et al. (2011). With regards to dose, it depends on the methods of TXA administration. Both in THA and TKA, different regimens were used by the trials ranging from 10 to 20 mg kg−1 (maximum 1 g) of TXA, followed or not by 10–20 mg kg−1 for 3–12 h afterwards, for intravenously and orally; or ranging from 250 mg to 3 g in 5–100 mL of saline for intra-articularly and topically. In many studies, it appeared to be safe and effective in these doses. For example, Imai et al. (2012) reported that 1 g TXA 10 min before surgery and 6 h after the first administration was most effective for the reduction of blood loss during THA. With regards to the best administration time, it depends on the kinds of arthroplasty. For THA, TXA was administrated 5–20 min prior to operation or incision for 10–20 min. For TKA, the best time for TXA administration was 5–20 min prior to deflation tourniquet or closure the wound. Benoni et al. (2001) showed that the administration of TXA at the end of THA operations did not reduce postoperative blood loss, and this might be attributed to an inadequate timing of the drug. Sukeik et al. (2011) concluded from a meta-analysis that the preoperative use of TXA reduced both intra-operative and postoperative blood loss following THA.
LIMITATION Firstly, limitations of this meta-analysis include the small sample size of each primary study and the significant heterogeneity in total blood loss and transfusion requirements. Secondly, only English language literatures included in this meta-analysis, there may be publication bias. Thirdly, some included trials excluding high-risk factors such as patients with a history of cardiovascular disease, the safety of TXA in high-risk patients should be explained cautiously.
CONCLUSION To our knowledge, this meta-analysis is more powerful and persuasive than any other published before. It suggests that the use of TXA reduced the risk of blood loss and the need for allogeneic blood transfusion significantly, without apparent increased risk of DVT or PE complications. TXA is an effective and safe drug
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The effectiveness and safety of tranexamic acid in total hip or knee arthroplasty for THA or TKA. However, larger, high-quality randomised control trials are required to strengthen this conclusion before recommending TXA widespread use in total joint arthroplasty.
ACKNOWLEDGEMENTS
Alipour, M., Tabari, M., Keramati, M., Zarmehri, A.M. & Makhmalbaf, H. (2013) Effectiveness of oral Tranexamic acid administration on blood loss after knee artroplasty: a randomized clinical trial. Transfusion and Apheresis Science, 49, 574–577. Álvarez, J.C., Santiveri, F.X., Ramos, I., Vela, E. & Puig, L. (2008) Tranexamic acid reduces blood transfusion in total knee arthroplasty even when a blood conservation program is applied. Transfusion, 48, 519–525. Benoni, G., Fredin, H., Knebel, R. & Nilsson, P. (2001) Blood conservation with tranexamic acid in total hip arthroplasty. A randomized, double-blind study in 40 primary operations. Acta Orthopaedica Scandinavica, 72, 442–448. Bursi, F., Barbieri, A., Politi, L., Di Girolamo, A. & Malagoli, A. (2009) Peri-operative red blood cell transfusion and outcome in stable patients after elective major vascular surgery. European Journal of Vascular and Endovascular Surgery, 37, 311–318. Camarasa, M.A., Ollé, G., Serra-Prat, M., Martín, A. & Sánchez, M. (2006) Efficacy of aminocaproic, tranexamic acids in the control of bleeding during total knee replacement: a randomized clinical trial. British Journal of Anaesthesia, 96, 576–582. Charoencholvanich, K. & Siriwattanasakul, P. (2011) Tranexamic acid reduces blood loss and blood transfusion after TKA: a prospective randomized controlled trial. Clinical Orthopaedics and Related Research, 469, 2874–2880. Claeys, M.A., Vermeersch, N. & Haentjens, P. (2007) Reduction of blood loss with Tranexamic acid in primary total Hip replacement surgery. Acta Chirurgica Belgica, 107, 397–401. Clave, A., Fazilleau, F., Dumser, D. & Lacroix, J. (2012) Efficacy of tranexamic acid on blood loss after primary cementless total hip replacement with rivaroxaban thromboprophylaxis: a case-control study in 70 patients.
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and statistical analysis: M. l.. Data acquisition, data analysis, manuscript preparation, manuscript editing and manuscript review: Z. W.
CONFLICT OF INTEREST
Guarantor of integrity of the entire study, study concepts, study design, definition of intellectual content, literature research
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The authors have no competing interests.
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ORIGINAL ARTICLE
The effectiveness and safety of tranexamic acid in total hip or knee arthroplasty: a meta-analysis of 2720 cases Z. Wei & M. Liu Department of Trauma, Union Medicine Centre of Tianjin, Tianjin, China Received 4 June 2014; accepted for publication 5 May 2015
SUMMARY Aims: To evaluate the safety and efficacy of tranexamic acid (TXA) in total knee arthroplasty (TKA) and total hip arthroplasty (THA). The specific endpoints assessed in this meta-analysis include the total blood loss, the incidence rate of deep vein thrombosis (DVT) and pulmonary embolisms (PE), the number of patients requiring at least 1 U of red blood cell following surgery. Background: The prevalence of THA and TKA is increasing and both are usually accompanied by considerable blood loss. TXA has been reported to reduce total blood loss in many orthopaedic surgeries. TXA administration continues to be a controversial topic in the literature about joint arthroplasty, and many studies have reported substantial doubt with respect to its benefits and safety. Methods/materials: We conducted a meta-analysis that combined all data from available randomised controlled trials, regardless the methods of TXA administration, which included administrated intravenously, intra-articularly, topically or orally. Finally, available data from the 39 included trials were pooled for analysis. Then, mean differences with 95% confidence intervals (CIs) was calculated for continuous outcomes and relative risks with 95% CIs for dichotomous outcomes. Results: This meta-analysis suggests that the administration of TXA significantly reduced blood loss and the need for allogeneic blood transfusion, without apparent increased risk of DVT or PE thromboembolic complications. Conclusion: To our knowledge, this meta-analysis is more powerful and persuasive than any other published before. It suggests that the use of TXA reduced the risk of blood loss and the need for allogeneic blood transfusion significantly, without apparent increased risk of DVT or PE complications.
Correspondence: Minghui Liu, MM, Department of Trauma, Union Medicine Centre of Tianjin, 190 Jieyuan West Road, Tianjin 300121, China. Tel.: +86 22 27557265; fax: +86 22 27557265; e-mail: [email protected]
© 2015 British Blood Transfusion Society
Key words: meta-analysis, total hip arthroplasty, total knee arthroplasty, tranexamic acid. Total knee arthroplasty (TKA) and total hip arthroplasty (THA) is increasing and both are usually accompanied by considerable blood loss, which may lead to acute anaemia and related complications (Álvarez et al., 2008; Dhillon et al., 2011), thereby increasing the risk of blood transfusion for patients (Charoencholvanich & Siriwattanasakul, 2011). However, allogeneic blood transfusion is an expensive and scarce resource, and is not a risk-free therapeutic method. Undoubtedly, allogeneic transfusions may increase health care costs (Hiippala et al., 1997), as well as increase the patient’s risk for post-operative infection, such as hepatitis, cytomegalovirus, human immunodeficiency virus (HIV), Epstein-Barr virus (Tobias, 2004; Bursi et al., 2009). Tranexamic acid (TXA) is a synthetic production of the lysine, which competitively blocks the lysine binding sites on plasminogen to inhibit activation of plasminogen and interfere with fibrinolysis. TXA has been used widely in kinds of blood, such as gastrointestinal bleeding, cardiac surgery and liver transplantation as well as in orthopaedic surgery. TXA may be administered via kinds of methods, such as intravenous (iv), orally, topically in the surgical fields or intra-articular. It was reported that TXA reduced volume of blood loss in many kinds of orthopaedic surgery, such as spinal surgery as well as total hip or knee joint arthroplasty (Ralley et al., 2010; Wong et al., 2010). However, some studies have questioned the effectiveness and safety of TXA, by demonstrating that its use could not significantly reduce volume of blood loss and elevated the risk of thromboembolic complications such as deep vein thrombosis (DVT) and pulmonary embolisms (PE) (Rosencher et al., 2008; Ozier & Schlumberger, 2006). The main purpose of this meta-analysis was to compare the clinical results of TXA with the results of control groups following THA or TKA. To evaluate the clinical efficacy and safety of TXA, we performed this meta-analysis that combined all the data from available randomised controlled trials (RCTs). We hypothesised that TXA in both THA and TKA could significantly reduce volume of blood loss following surgery without an increased risk of DVT and PE. First published online 29 May 2015 doi: 10.1111/tme.12212
152 Z. Wei and M. Liu
MATERIALS AND METHODS
Statistical analysis
Literature search
Hip and knee arthroplasty data were calculated independently for our interested outcome measures. revman 5.2 software was employed to pool the included data for analysis. For each continuous data, we calculated mean differences (MDs) with 95% confidence intervals (CIs); and we calculated relative risks (RRs) with 95% CIs for dichotomous data. According to the heterogeneity between studies, we pooled the interested outcome data of comparable groups of trials using random-effect models (DerSimonian–Laird method) or the fixed-effect models (Mantel–Haenszel test). The I 2 value is a measure of the percentage of variation in the data that is as a result of heterogeneity as opposed to chance. The heterogeneity level among different studies was assessed using the I 2 statistic results. A random-effect model was employed when there was significant heterogeneity between studies included (P < 0·10; I 2 > 50%). A fixed-effect model was used for pooling and analysing when there was no significant heterogeneity.
We searched for the published available results of relevant trials in the PubMed (January 2000 to December 2013), Cochrane Library (Issue 2, 2011), ScienceDirect Online (January 2000 to December 2013), Ovid (January 2000 to December 2013), ISI Web of Knowledge (January 2000 to December 2013), several transfusion journals (Transfusion, Transfusion and apheresis science, Blood Transfusion, Transfusion medicine, Transfusion medicine reviews) and orthopaedic journals (Transfusion, Transfusion and apheresis science, Blood Transfusion, Transfusion medicine, Transfusion medicine reviews). The search terms used included ‘randomised controlled trials’, ‘RCTs’, ‘tranexamic acid’, ‘TXA’, ‘TEA’, ‘total hip replacement’, ‘total knee replacement’, ‘total hip arthroplasty’, ‘total knee arthroplasty’ and ‘total joint arthroplasty’. When it was necessary, the authors of the included articles were contacted for original data.
Inclusion and exclusion criteria We retrieved all related RCTs that compared the TXA group with the control group in patients undergoing total joint arthroplasty, including total knee or hip arthroplasty. Properly trials were eligible for inclusion if (i) the study involved the comparison of a TXA treatment group to a control group who received either a placebo or no treatment at all; (ii) studies included at least one of the outcome measures; (iii) the data points was presented as the mean ± standard deviation (SD); (iv) we obtained the original information from the authors of the included articles when data were shown as the medians and/or ranges. Studies were excluded from the analysis if (i) the patients received revision replacement of the joint; (ii) all data were shown as the medians and/or ranges, and we could not obtain the original information by any way; (iii) patients had received any other strategy to decrease blood loss peri-operation or post-operation; (iv) studies were published in language other than English.
Assessment of study quality Quality of included RCTs was estimated according to the method in the Cochrane Reviewer’s Handbook 5.0 (Higgins & Green, 2011). To make sure accuracy, the interested information was extracted by two reviewers independently. In cases of different opinions, conflicts were resolved by consensus of alls senior reviewers.
RESULTS Literature search Using our search terms, the primary literature search yielded 609 potentially relevant references. Most of these studies, however, did not fit our inclusion criteria and excluded from the analysis. Finally, 39 studies (13 for THA, 22 for TKA, 4 for both THA and TKA) were identified as available for data extraction and meta-analysis (Álvarez et al., 2008; Ekback et al., 2000; Ido et al., 2000; Benoni et al., 2001; Ellis et al., 2001; Tanaka et al., 2001; Veien et al., 2002; Good et al., 2003; Husted et al., 2003; Garneti & Field, 2004; Lemay et al., 2004; Yamasaki et al., 2004; Zohar et al., 2004; Johansson et al., 2005; Niskanen & Korkala, 2005; Yamasaki et al., 2005; Camarasa et al., 2006; Orpen et al., 2006; Claeys et al., 2007; Molloy et al., 2007; Kakar et al., 2009; Kazemi et al., 2010; Wong et al., 2010; Charoencholvanich & Siriwattanasakul, 2011; Ishida et al., 2011; MacGillivray et al., 2011; Malhotra et al., 2011; Clave et al., 2012; Imai et al., 2012; McConnell et al., 2012; Raviraj et al., 2012; Roy et al., 2012; Alipour et al., 2013; Dahuja et al., 2013; Gautam et al., 2013; Georgiadis et al., 2013; Konig et al., 2013; Martin et al., 2013; Oremus et al., 2014). These 39 studies were randomised adequately and consensus was reached by discussion (Fig. 1). All studies included in this meta-analysis were English-language.
Quality of the trials Outcome measures The primary interested outcome indexes in this meta-analysis include the total volume of blood loss following surgery and the incidence of DVT and PE. The secondary interested outcome measures include the number of patients requiring allogeneic red blood cells.
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In total, 2720 patients were included in our analysis from these 39 trials; 1422 patients received TXA administration and 1298 patients served as control group; 921 patients and 1799 patients received THA and TKA operation, respectively (Table 1). The quality of the RCTs included in this meta-analysis is showed in Tables 2 and 3, for THA and TKA, respectively.
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The effectiveness and safety of tranexamic acid in total hip or knee arthroplasty
153
Fig. 1. The PRISMA flowchart diagram for review.
Outcome measures Total blood loss. A total of 9 THA studies and 13 TKA studies, respectively, compared the total volume of blood loss (including both the intra-operative and post-operative blood loss) in the TXA group with a control group. Therefore we included these studies as the data of the meta-analysis in Fig. 2a and b. For THA, no significant heterogeneity was detected between the studies (P = 0.14; I 2 = 34%), though, a fixed-effect model was used to analysis. The pooled result manifested a statistical significance between treatment groups in total volume of blood loss (MDs, −318.49; 95% CIs, −398.04 to 238.94; P < 0.00001) (Fig. 2a, b). For TKA, heterogeneity was significant between the studies (P < 0.00001; I 2 = 95%), a random-effect model was employed. The pooled result showed a significant difference between TXA group and control group in total blood loss (MDs, −321.78; 95% CIs, −413.25 to −213.08; P < 0.00001) (Fig. 2b). Both in hip and
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knee arthroplasty, the pooled results favored the experimental group. Deep vein thrombosis (DVT). A total of 15 THA studies and 21 TKA studies were included in the analysis of DVT and we pooled the results in Fig. 3a and b. Without significant heterogeneity among the data, (heterogeneity test: P = 0.66; I 2 = 0% and P = 0.23; I 2 = 30%, respectively; fixed-effect analysis), the pooled results indicated no significant difference in DVT between the treatment groups, (RRs, 0.63; 95% CIs, 0.20 to 2.01; P = 0.43) in THA and (RRs, 0.57; 95% CIs, 0.26 to 1.24; P = 0.15) in TKA (Fig. 3a and b). It showed that the incidence of DVT in the TXA group and the control group was NOT statistically significant. Pulmonary embolisms (PE). We pooled the results of the included trials in Fig. 4a and b. We found no significant heterogeneity between studies both in THA (P = 0.95; I 2 = 0%)
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LMWH, Low molecular weight heparin.
iv iv iv iv iv iv iv iv iv iv iv Topical Topical iv Topical iv Oral iv iv iv iv iv iv iv Topical Topical Topical iv + oral
Oremus et al. (2014) Garneti & Field (2004) Clave et al. (2012) McConnell et al. (2012) Ido et al. (2000) Gautam et al. (2013) Malhotra et al. (2011) Imai et al. (2012) Raviraj et al. (2012) Yamasaki et al. (2005) MacGillivray et al. (2011) Georgiadis et al. (2013) Konig et al. (2013) Dahuja et al. (2013) Martin et al. (2013) Orpen et al. (2006) Alipour et al. (2013) Claeys et al. (2007) Kazemi et al. (2010) Good et al. (2003) Camarasa et al. (2006) Ellis et al. (2001) Tanaka et al. (2001) Veien et al. (2002) Wong et al. (2010) Roy et al. (2012) Ishida et al. (2011) Charoencholvanich & Siriwattanasakul (2011) Molloy et al. (2007) Álvarez et al. (2008) Kakar et al. (2009) Zohar et al. (2004) iv iv iv iv
iv iv iv iv iv iv iv
Method of TXA
Yamasaki et al. (2004) Lemay et al. (2004) Husted et al. (2003) Benoni et al. (2001) Ekback et al. (2000) Johansson et al. (2005) Niskanen & Korkala (2005)
Study
Table 1. Study characteristics of the 39 included studies
1 g 5 min prior to operation 10 mg kg−1 prior to surgery. 1 mg kg−1 h−1 infusion until wound closure 10 mg kg−1 for 10 min, 15 min prior to incision + 1 mg kg−1 h−1 for 10 h 10 mg kg−1 for 5–10 min, immediately before operation 10 mg kg−1 before incision + 1 mg kg−1 h−1 for 10 h 15 mg/kg before operation 3 doses of 10 mg kg. First over 5–10 min before operation. 2nd + 3rd, 8 + 16 h after operation 1 g prior to operation + 1 g 3 h after operation 10 mg kg−1 before operation 1 g prior to operation + 1 g per 3 h/7 h/12 h after operation 10 mg kg−1 before operation 1 g prior to operation + 1 g 3 h after operation 10 mg kg−1 before deflation of tourniquet + 10 mg kg−1 4 h after first dose 15 mg kg−1 15 min prior to operation 1 g before operation 10 mg kg−1 before deflation of tourniquet + 10 mg kg−1 3 h after first dose 1 g 5 min before incision 10 mg kg−1 before deflation of tourniquet + 10 mg kg−1 3 h after first dose 2.0 g topically in 75 mL saline 3.0 g topically in 100 mL saline 15 mg kg−1 before deflation of tourniquet + 15 mg−1 kg−1 1/8 h after first dose for 2 days 3.0 g topically in 100 mL saline 15 mg kg−1 at time cement mixing commenced 1 g 2 h before deflation of tourniquet + 1/6 h after first dose for 18 h 15 mg kg−1 before operetation 15 mg kg−1 before operation 10 mg kg−1 before deflation of tourniquet + 10 mg kg−1 3 h after first dose 10 mg kg−1 before deflation of tourniquet + 10 mg kg−1 3 h after first dose 15 mg kg−1 before tourniquet deflation + 10 mg kg−1 h−1 until 12 h after deflation. 20 mg kg−1 before tourniquet deflation 10 mg kg−1 before deflation of tourniquet + 10 mg kg−1 3 h after first dose 1.5 g in saline 500 mg/5 mL through two intra-articular drain 2000 mg/20 mL via intra-articular drain. 10 mg kg−1 before inflation of tourniquet + 10 mg kg−1 3 h after operation + 1.5 g oral for 5 days 500 mg 5 min prior to deflation of tourniquet + 500 mg 3 h later 10 mg kg−1 before deflation tourniquet + 1 mg kg−1 h−1 for 3 h 10 mg kg−1 before tourniquet inflation + 1 mg kg−1 h−1 until wound closure 15 mg kg−1 before tourniquet deflation + 10 mg kg−1 h−1 for 12 h
Dose of TXA
None Saline Saline None
Saline Saline Saline Saline Saline Saline Saline Saline Saline None Saline Saline Saline Saline Saline Saline Saline Saline Saline Saline Saline
Saline Saline Saline Saline Saline None
None Saline Saline Saline Saline Saline Saline
Control
Aspirin Bemiparin None Enoxaparin
None stocking + pumps Riraroxaban Oral aspirin Unclear Unclear LMWH Unclear LMWH None None LMWH Unclear Unclear Unclear LMWH Enoxaparin LMWH Enoxaparin Fragmin Dalteparin Enoxaparin none LMWH LMWH LMWH Heparin sodium None
None Dalteparin LMWH LMWH LMWH Fragmin Dalteparin
DVT prophylaxis
Knee Knee Knee Knee
H&K Hip Hip Knee H&K Knee Hip Hip Knee Hip Knee Knee Knee Knee H&K Knee Knee Hip Hip Knee Knee Knee Knee Knee Knee Knee Knee Knee
Hip Hip Hip Hip Hip Hip Hip
Joint
154 Z. Wei and M. Liu
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Table 2. Quality evaluation of included Trials for THA Study Yamasaki et al. (2004) Lemay et al. (2004) Husted et al. (2003) Benoni et al. (2001) Ekback et al. (2000) Johansson et al. (2005) Niskanen & Korkala (2005) Oremus et al. (2014) Garneti & Field (2004) Clave et al. (2012) Ido et al. (2000) Malhotra et al. (2011) Imai et al. (2012) Martin et al. (2013) Claeys et al. (2007) Kazemi et al. (2010) Konig et al. (2013) Total
Number (T/C)
Random
Concealment
Blingding
Follow-up
Grade
20/20 20/19 20/20 18/20 20/20 47/53 19/20 20/22 25/25 37/33 20/20 25/25 26/22 25/25 20/20 32/32 91/40 485/436
Y Y Y Y Y Y Y Y Y Y U Y Y Y Y Y Y
Y Y Y Y Y Y Y Y Y U U Y Y Y Y Y U
Y Y Y Y Y Y Y Y Y Y U Y Y Y Y Y U
4W 3M NR 6W 3W 6–8 W NR 3M NR 3M NR NR NR 1W NR NR NR
A A B A A A B A B B C A A A B B C
M, month; NR, no report; T/C, Trial group/Control group; U, unclear; W, week; Y, yes.
Table 3. Quality evaluation of included Trials for TKA Study Oremus et al. (2014) McConnell et al. (2012) Ido et al. (2000) Gautam et al. (2013) Raviraj et al. (2012) Yamasaki et al. (2005) MacGillivray et al. (2011) Georgiadis et al. (2013) Konig et al. (2013) Dahuja et al. (2013) Martin et al. (2013) Orpen et al. (2006) Alipour et al. (2013) Good et al. (2003) Camarasa et al. (2006) Ellis et al. (2001) Tanaka et al. (2001) Veien et al. (2002) Wong et al. (2010) Roy et al. (2012) Ishida et al. (2011) Charoencholvanich & Siriwattanasakul (2011) Molloy et al. (2007) Álvarez et al. (2008) Kakar et al. (2009) Zohar et al. (2004) Total
Number (T/C)
Random
Concealment
Blinding
Follow-up
Grade
29/27 22/22 21/22 14/13 88/87 21/21 20/20 50/51 130/29 60/60 25/25 15/14 26/27 27/24 35/60 10/10 22/26 15/15 31/35 25/25 50/50 60/60 50/50 46/49 25/25 20/20 937/862
Y Y U Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
Y Y U U Y U Y Y U U Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
Y Y U Y Y Y Y Y U U Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
3M NR NR NR 30 W 6M NR 2W NR NR 1M 15 days 2W NR NR NR NR NR 6W NR NR NR 6W 6W NR 3M
A B C B A B A A C C A A A A A A A A A A A A A A A B
M, month; NR, no report; T/C, Trial group/Control group; U, unclear; W, week; Y, yes.
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156 Z. Wei and M. Liu
(a)
(b)
Fig. 2. (a and b) The MDs and 95% CIs for the volume of total blood loss among patients treated with vs without TXA for THA and TKA, respectively. It indicated that total blood loss in the TXA group was significantly lower than that in the control group.
and TKA (P = 0.95; I 2 = 0%) and thus compared the data with fixed-effect model. The pooled result showed no significant difference between the treatment groups, (RRs, 1.65; 95% CIs, 0.40–6.82; P = 0.49) (Fig. 4a) and (RRs, 1.63; 95% CIs, 0.43–6.12; P = 0.47) (Fig. 4b) for THA and TKA, respectively. It showed that there was NO statistical significance about the incidence of PE compared the TXA group with the control group.
Blood transfusion. The number of patients requiring at least 1 U of allogeneic red blood cells was compared between TXA group and control group following the joint arthroplasty surgery. There was no significant heterogeneity between the studies, so a fixed-effect model was used in both THA and TKA. The pooled result indicated a statistical significance between two treatment groups in the rate of patients requiring at least 1 U of allogeneic red blood cells, (RRs, 0.50; 95% CIs, 0.35–0.65; P < 0.00001) and (RRs, 0.53; 95% CIs, 0.45–0.63; P < 0.00001) for THA and TKA, respectively (Fig. 5a and b). The pooled results showed that TXA group required allogeneic blood transfusions less than control group.
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DISCUSSION TKA or THA is usually accompanied by considerable blood loss and regularly results in a postoperative requirement for allogeneic blood transfusion. Because of the disadvantages of blood transfusion such as the risk of incompatibility-related transfusion fatalities and transfusion-associated infections, a continuing effort is made to reduce blood loss (Haien et al., 2013). Thus, anti-fibrinolytic drugs, such as epsilon aminocaproic acid, aprotinin, fibrin spray as well as TXA have been used to decrease volume of blood loss following surgery (Kagoma et al., 2009). When compared to other antifibrinolytic drugs, TXA has been shown to be less expensive (Ralley et al., 2010). However, TXA administration continues to be a controversial issue in the orthopaedic literature, and many studies have also reported doubts with respect to its benefits. The theoretical risk with TXA is thrombosis (Ozier & Schlumberger, 2006; Rosencher et al., 2008). Clave et al. (2012) found no DVT or clinically symptomatic PE during hospital stay or at 3 months follow-up after primary THA. Their study design excluded patients at high-risk of thromboembolic or ischemic complications, and only low-risk
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(a)
(b)
Fig. 3. (a and b) The RRs and 95% CIs for the incidence of DVT among patients treated with vs without TXA for THA and TKA, respectively. The result revealed no significant difference between the treatment groups.
patients underwent the concomitant oral anti-Xa thromboprophylaxis. This introduced a systematic underestimation of thromboembolic risk by excluding high-risk cases, which was an important study limitation. Oremus et al.’s study demonstrated that the addition of TXA to a restrictive blood transfusion protocol significantly reduced
© 2015 British Blood Transfusion Society
postoperative external blood loss. And it also decreased the number and volume of postoperative autologous blood retransfusions rendering the routine use of a postoperative cell salvage system in patients undergoing primary THA or TKA. It also demonstrated that thromboembolic events in the TXA group was lower than in the placebo group, although the difference was
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158 Z. Wei and M. Liu
(a)
(b)
Fig. 4. (a and b) The RRs and 95% CIs for the incidence of PE among patients treated with vs without TXA for THA and TKA, respectively. The result revealed no significant difference between the treatment groups both in THA and TKA.
not significantly different (Oremus et al., 2014). As a result, it showed that TXA was not only effective but also safe in THA. In Imai et al.’s study, it found that blood loss of intra-operation in the TXA group was significantly lower than in the control group (Imai et al., 2012). It also demonstrated that the incidences of DVT were not statistically significance between the two groups,
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3 of 26 patients and 3 of 22 in TXA and control group, respectively. Consistent with the Oremus’s result, it demonstrated that TXA was an effective and safe strategy for decreasing blood loss following THA. In another RCT, 175 patients (n = 88 TXA vs 87 control) completed the study (Raviraj et al., 2012). Both the average blood
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(a)
(b)
Fig. 5. (a and b) The RRs and 95% CIs for the numbers of patients requiring at least 1 U of allogeneic RBCs among patients treated with vs without TXA. The pooled results demonstrated that TXA group required allogeneic blood transfusions less than control group both in THA and TKA.
loss and allogenic blood transfusion requirement in the TXA group were significantly less than the control group (P = 0.0001). The peri-operative complications and hospital stay was not significantly different in the two groups. As a results, it was recommended that the routine use of this drug reduced postoperative blood loss in THA in this study. Consistently, Good et al. (2003) also reported that TXA decreased total blood loss and reduced transfusion drastically, but did not increase the clinical symptoms of DVT. In contrast, MacGillivray et al. (2011) showed that 10 mg kg−1 of TXA was sufficient enough to lead to a lesser allogenic transfusion requirement (P < 0.01) in TKA. But 1 patients
© 2015 British Blood Transfusion Society
out of 20 in TXA group developed non-life-threatening PE diagnosed by spiral computed tomography (CT) after an episode of chest pain. In(Garneti & Field (2004)) trial, no statistically significance was found in the volume of internal and external blood loss in the two groups (1443 ± 809 mL in the TXA group vs 1340 ± 665 mL in the placebo group, P = 0.822). However, a greater number of patients required transfusion in the TXA group than in the placebo group and one patient in the TXA group was confirmed a PE. These results showed that TXA was neither effective nor safe. Consequently, they did not support the use of TXA routinely in primary THA.
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160 Z. Wei and M. Liu Wong et al. (2010) concluded that topical application of TXA directly into the surgical wound reduced postoperative bleeding by 20–25% and resulted in 16–17% higher postoperative haemoglobin levels compared with placebo, with no clinically important increase in complications. In another prospective controlled trial (Georgiadis et al., 2013), it demonstrated that administration of topical TXA in primary TKA decreased total blood loss (940.2 ± 327.1 vs 1293.1 ± 532.7 mL, P < 0.001) and postoperative transfusion (0/20 vs 4/20). Differently, thromboembolic rates was higher in the control group (DVT 4 vs 9, P = 0.231; and PE 1 vs 2, P = 1.0, TXA vs control, respectively), although the exact mechanism under it was unclear. Numerous literatures had evaluated the use of TXA in total joint surgery and had shown various opinions in reducing blood loss and kinds of complications. However, any single clinical trials lack sufficient statistical power to determine the safety and effectiveness of TXA in THA or TKA. Consequently, we performed this meta-analysis of RCTs from 2000 to November 2013 to investigate the safety and effectiveness of TXA administration in relation to reducing blood loss and transfusion requirement as well as incidence of complications in total joint arthroplasty. During the course of our study for searching literature and analysing the data, other meta-analysis on TXA for joint arthroplasty were published in 2013, which included the study by Gandhi et al. (2013), Panteli et al. (2013), Tan et al. (2013), Zhou et al. (2013). All of these published meta-analysis concluded exclusively that the clinical importance of effect should be interpreted with caution and more prospective RCTs with larger sample sizes were needed in the future. Our analysis included relatively latest literature, which was published from 2000 to 2013. Among of them, 12 studies were published after 2012 and 7 were published in 2013. However, among these four published meta-analysis, no included studies were published in 2013. Only two, one, three and three literatures were published in 2012 in Gandhi’s, Tan’s, Zhou’s and Panteli’s, respectively. Therefore the latest literature brought novelty for our analysis. A total of 2720 participants were included in our meta-analysis, while only 1114, 1030 and 397 patients were included in Tan’s, Zhou’s and Panteli’s, respectively. The sample size of our meta-analysis was larger than any other of the four. Both sufficient sample size and novel literature data strengthened the power to a great extent in our meta-analysis. Although the conclusion was consistent with other’s, it was more powerful and persuasive than other’s. Therefore, we reported the relatively latest findings in this field. In this meta-analysis we concluded all the available RCTs about TXA in THA or TKA, regardless the methods of TXA administration, which included administrated intravenously, intra-articularly, topically or orally (Huang et al., 2014). The subgroup-analysis showed that there was no significant differences between the different methods of administration, so it was reasonable to pool all the data of eligibility together for further analysis. Differently from THA, pneumatic tourniquet use could allow a dry surgical field and significantly decreased intra-operative
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blood loss in TKA. However, tourniquet employment was not riskless methods. Several previous studies had shown that even a short-term tourniquet application could enhance local fibrinolytic activity several times above the basal level (Kruithof et al., 1987). Under this context, we pooled eligible data of THA and TKA separately for meta-analysis in this study. This meta-analysis demonstrated that the use of TXA could effectively reduce total blood loss, intra-operative blood loss, postoperative drainage volume, the requirement of allogeneic blood transfusion, as well as the change of hematocrit for patients undergoing primary THA or TKA. Furthermore, TXA did not increase the prevalence of DVT or PE, compared patients who received TXA with those received placebo based on this meta-analysis. These results were consistent with the meta-analyses in THA by Sukeik et al. (2011). With regards to dose, it depends on the methods of TXA administration. Both in THA and TKA, different regimens were used by the trials ranging from 10 to 20 mg kg−1 (maximum 1 g) of TXA, followed or not by 10–20 mg kg−1 for 3–12 h afterwards, for intravenously and orally; or ranging from 250 mg to 3 g in 5–100 mL of saline for intra-articularly and topically. In many studies, it appeared to be safe and effective in these doses. For example, Imai et al. (2012) reported that 1 g TXA 10 min before surgery and 6 h after the first administration was most effective for the reduction of blood loss during THA. With regards to the best administration time, it depends on the kinds of arthroplasty. For THA, TXA was administrated 5–20 min prior to operation or incision for 10–20 min. For TKA, the best time for TXA administration was 5–20 min prior to deflation tourniquet or closure the wound. Benoni et al. (2001) showed that the administration of TXA at the end of THA operations did not reduce postoperative blood loss, and this might be attributed to an inadequate timing of the drug. Sukeik et al. (2011) concluded from a meta-analysis that the preoperative use of TXA reduced both intra-operative and postoperative blood loss following THA.
LIMITATION Firstly, limitations of this meta-analysis include the small sample size of each primary study and the significant heterogeneity in total blood loss and transfusion requirements. Secondly, only English language literatures included in this meta-analysis, there may be publication bias. Thirdly, some included trials excluding high-risk factors such as patients with a history of cardiovascular disease, the safety of TXA in high-risk patients should be explained cautiously.
CONCLUSION To our knowledge, this meta-analysis is more powerful and persuasive than any other published before. It suggests that the use of TXA reduced the risk of blood loss and the need for allogeneic blood transfusion significantly, without apparent increased risk of DVT or PE complications. TXA is an effective and safe drug
© 2015 British Blood Transfusion Society
The effectiveness and safety of tranexamic acid in total hip or knee arthroplasty for THA or TKA. However, larger, high-quality randomised control trials are required to strengthen this conclusion before recommending TXA widespread use in total joint arthroplasty.
ACKNOWLEDGEMENTS
Alipour, M., Tabari, M., Keramati, M., Zarmehri, A.M. & Makhmalbaf, H. (2013) Effectiveness of oral Tranexamic acid administration on blood loss after knee artroplasty: a randomized clinical trial. Transfusion and Apheresis Science, 49, 574–577. Álvarez, J.C., Santiveri, F.X., Ramos, I., Vela, E. & Puig, L. (2008) Tranexamic acid reduces blood transfusion in total knee arthroplasty even when a blood conservation program is applied. Transfusion, 48, 519–525. Benoni, G., Fredin, H., Knebel, R. & Nilsson, P. (2001) Blood conservation with tranexamic acid in total hip arthroplasty. A randomized, double-blind study in 40 primary operations. Acta Orthopaedica Scandinavica, 72, 442–448. Bursi, F., Barbieri, A., Politi, L., Di Girolamo, A. & Malagoli, A. (2009) Peri-operative red blood cell transfusion and outcome in stable patients after elective major vascular surgery. European Journal of Vascular and Endovascular Surgery, 37, 311–318. Camarasa, M.A., Ollé, G., Serra-Prat, M., Martín, A. & Sánchez, M. (2006) Efficacy of aminocaproic, tranexamic acids in the control of bleeding during total knee replacement: a randomized clinical trial. British Journal of Anaesthesia, 96, 576–582. Charoencholvanich, K. & Siriwattanasakul, P. (2011) Tranexamic acid reduces blood loss and blood transfusion after TKA: a prospective randomized controlled trial. Clinical Orthopaedics and Related Research, 469, 2874–2880. Claeys, M.A., Vermeersch, N. & Haentjens, P. (2007) Reduction of blood loss with Tranexamic acid in primary total Hip replacement surgery. Acta Chirurgica Belgica, 107, 397–401. Clave, A., Fazilleau, F., Dumser, D. & Lacroix, J. (2012) Efficacy of tranexamic acid on blood loss after primary cementless total hip replacement with rivaroxaban thromboprophylaxis: a case-control study in 70 patients.
© 2015 British Blood Transfusion Society
and statistical analysis: M. l.. Data acquisition, data analysis, manuscript preparation, manuscript editing and manuscript review: Z. W.
CONFLICT OF INTEREST
Guarantor of integrity of the entire study, study concepts, study design, definition of intellectual content, literature research
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The authors have no competing interests.
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