Is combined use of intravenous and intraarticular tranexamic acid superior to intravenous or intraarticular tranexamic acid alone in total knee arthroplasty? A meta-analysis of randomized controlled trials
© The Author(s). 2017
Received: 6 December 2016
Accepted: 30 March 2017
Published: 18 April 2017
Tranexamic acid (TXA) has been proven to be effective in reducing blood loss and transfusion rate after total knee arthroplasty (TKA) without increasing the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE). Recently, an increasing number of studies have been interested in applying combined intravenous (IV) with intraarticular (IA) tranexamic acid in total knee arthroplasty. The purpose of this meta-analysis was to compare the blood loss and complications of combined TXA with IV TXA or IA TXA on TKA.
Systematic search of literatures were conducted to identify related articles that were published in PubMed, MEDLINE, Embase, the Cochrane Library, SpringerLink, ClinicalTrials.gov, and Ovid from their inception to September 2016. All studies that compare blood loss and complications of combined TXA and IV TXA or IA TXA on TKA were included. Main outcomes were collected and analyzed by the Review Manager 5.3.
Five studies were included in the present meta-analysis. There was significant difference in total blood loss and blood volume of drainage when compared combined TXA group with IV TXA group or IA TXA group (P < 0.05). There was no difference in transfusion rate and thromboembolic complications when comparing combined TXA with IV TXA or IA TXA alone (P > 0.05).
Compared with administration of IA TXA or IV TXA alone on TKA, combined use of TXA has advantages in reducing total blood loss and blood volume of drainage without increasing the incidence of thromboembolic complications. We recommend combined TXA as the preferred option for patients undergoing TKA.
KeywordsTranexamic acid Combined Intravenous Intraarticular Total knee arthroplasty
As the number of patients who were afflicted with osteoarthritis (OA) is steadily increasing, the surgical volume of primary total knee arthroplasty (TKA) is increasing as well . However, primary TKA is closely associated with the increase of total blood loss and transfusion rate. Some studies reported that the total blood loss can reach to 1500 mL and 60% of patients need allogeneic blood transfusion [2, 3]. Massive blood transfusion requirements in TKA increased the risks of allergic reaction, immune response, cost, and infection [4, 5]. Various blood-conserving techniques have been used to reduce blood transfusion, including controlled hypertension, tourniquet, and tranexamic acid (TXA) [6–8].
It has been widely accepted that patients undergoing TKA have an increased risk of perioperative bleeding . TXA is an antifibrinolytic drug that inhibits the activation of plasminogen so as to decrease the amount of blood loss . TXA can be applied by the intravenous (IV) or the intraarticular (IA) route. However, to achieve the maximum plasma concentration, TXA takes about 5–15 min for IV administration and 30 min for IA administration. Thus, IV administration is a rapid route for patients to increase the therapeutic concentration of TXA. Then, an increasing number of studies began to pay close attention on the effect of IV TXA on TKA [11, 12]. It was reported that IV TXA decreased perioperative bleeding and caused a reduction in total blood loss by up to 32%. Compared with IV TXA, the IA TXA has some advantages, such as easy administration, providing a maximum concentration of TXA at the bleeding site and inhibiting local activation of fibrinolysis . Recent studies have confirmed that the administration of TXA, which is used directly into the surgical wound, reduced postoperative bleeding from 20 to 25% .
Recently, more and more studies tended to use combined TXA instead of using IV or IA TXA alone [14, 15]. It was shown that this method (combined TXA) can effectively reduce the amount of bleeding after TKA. Nevertheless, these studies reported inconsistent results of comparing combined TXA with IV or IA TXA alone on TKA [15–17]. Therefore, this meta-analysis was designed to compare the effectiveness and safety of combined TXA with IV TXA or IA TXA for patients undergoing primary TKA through evaluating the total blood loss, blood volume of drainage, transfusion rate, and thromboembolic complications.
Articles were searched in the following databases from their inception to September 2016: PubMed, MEDLINE, Embase, the Cochrane Library, SpringerLink, ClinicalTrials.gov, and Ovid. The following search terms were used: tranexamic acid or TXA or topical tranexamic acid or topical TXA or intraarticular tranexamic acid or IA TXA or intravenous tranexamic acid or IV TXA or total knee arthroplasty or TKA or total knee replacement or TKR.
To evaluate eligibility for inclusion, two investigators screened the title and abstracts of the articles independently. Any disagreements were resolved by discussion among the authors. A third researcher was the adjudicator when there were debates between two investigators. Articles should meet the following criteria: (1) the studies should be designed as RCTs, (2) the participants should be at least 18 years old, (3) the articles should be comparing the combined TXA with IV or IA TXA, and (4) the articles were restricted to English language.
Two authors independently extracted the following data from each eligible study: study design, type of study population, age, number of participants, and interventions. Discrepancies were resolved by a third investigator.
Quality and risk of bias assessments
The modified Jadad scale was used to assess the methodological quality of each study. A score of ≥4 indicates high quality. The Cochrane Handbook for Reviews of Interventions (RevMan Version 5.3) was used to assess the risk of bias. Two authors subjectively reviewed all articles and assigned a value of “high,” “low,” or “unclear” based on the following: selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias. Any disagreements were resolved by discussion and consensus. In order to improve accuracy, a third investigator was consulted when any disagreement emerged.
RevMan software was used to analyze the data from included studies. For binary data, risk ratio (RR) and 95% confidence interval (CI) were assessed (\( \alpha \) = 0.05 for the inspection standards). For continuous data, means and standard deviations were pooled to a weighted mean difference (WMD) and 95% confidence internal (CI) in the meta-analysis. Heterogeneity was tested using the I 2 statistic. Studies with an I 2 statistic of 25 to 50% were considered to have low heterogeneity. Those with an I 2 statistic of 50 to 75% were considered to have moderate heterogeneity. Those with an I 2 statistic >75% were considered to have high heterogeneity. When the I 2 statistic was >50%, sensitivity analyses were performed to identify the potential sources of heterogeneity . Statistical significance was indicated by a P value <0.05.
Description of studies and demographic characteristics
The characteristics of included studies
65.4 ± 8.7
64.7 ± 9.5
68.2 ± 8.66
70.0 ± 6.56
70.7 ± 8.2
71.0 ± 7.2
65.5 ± 7.8
63.2 ± 8.6
70.8 ± 6.8
69.8 ± 6.8
69.2 ± 6.4
Characteristics of the five trials selected showing general intervention information
DVT screening method
1.5 g TXA 50 mL NS after implantation of the components
1.5 g TXA before inflation of the tourniquet
3 g TXA before inflation of the tourniquet
7.0 g/dL < HB < 10 g/dL + symptomatic anemia HB < 7.0 g/dL
2 g TXA 30 mL NS 5 min before closure of arthrotomy
15 mg/kg TXA
30 min before skin incision 10 mg/kg TXA 3 and 6 h after surgery
15 mg/kg TXA 30 min before skin incision
10 mg/kg TXA 3 and 6 h after surgery
7.0 g/dL < HB < 8.0 g/dL + symptoms HB < 7.0 g/dL
Ultrasonographic + clinical symptom
1 g TXA after joint capsule closure
1 g TXA 15 min before skin incision
1 g TXA 20 mL NS after joint capsule closure
HB < 8.0 g/dL
HB < 9.0 g/dL +symptoms
3 g TXA 100 mL NS after closure of the capsule
1 g TXA preoperative
1 g of TXA
HB < 7.5 g/dL
HB < 10 g/dL +symptoms
postoperative Hb level was reduced >25% + symptoms
1.5 g TXA 50 mL NS after wound close
10 mg/kg 20 min before tourniquet application
10 mg/kg 3 h after the second dose
1.5 g TXA 50 mL NS after wound closure
10 mg/kg 20 min before tourniquet application
10 mg/kg 15 min before deflation of the tourniquet
10 mg/kg 3 h after the second dose
HB < 8 g/dL
Clinical symptom + Doppler ultrasonography and CT angiography
Risk of bias in included studies
Sensitivity and heterogeneity analysis
There was significant heterogeneity for the impact of IV TXA application on total blood loss. The leave-one-out analysis showed that the key contributor to this high heterogeneity was one study conducted by Jain et al. . After excluding it, heterogeneity was reduced to I 2 = 73% for total blood loss. But significance of the pooled changes was not altered, which demonstrated that the results were robust.
Total blood loss
Blood volume of drainage
TXA is an antifibrinolytic agent which has been widely used today. Several studies have reported that IV administration of TXA can effectively reduce total blood on TKA . Compared with IV TXA, the IA administration of TXA has the advantage of reaching to a maximum concentration of TXA at the bleeding site, and it is associated with low systemic absorption . Considering the advantages of both IV TXA and IA TXA, it is logical to suggest that combined use of IV TXA and IA TXA is a more efficient method of reducing total blood loss. Karaaslan et al.  reported that combined use of TXA in patients undergoing TKA can reduce blood loss with negligible side effects. Other studies [15, 16] that compared combined TXA with IV or IA TXA also reported that combined TXA was more effective than IV or IA TXA alone for patients undergoing TKA. In this meta-analysis, when compared with the IV group, we found that the combined group had reduced total blood loss by a mean of −148.64 mL (CI −194.28 to −103.01), and when compared with the IA group, it reduced total blood loss by a mean of −82.29 mL (CI −150.91 to −13.68). These results confirmed that combined TXA was more efficient for patients undergoing TKA in terms of reducing total blood loss.
Previous studies and several meta-analysis of IV TXA showed that administration of TXA intravenously reduced blood volume of drainage by up to 50% [12, 24]. Since IA administration of TXA can inhibit local activation of fibrinolysis and reduce time to vascular occlusion , it also has the advantage of limiting local blood loss . Then, combined use of TXA has the advantages of both IV TXA and IA TXA in terms of reducing blood volume of drainage. Our meta-analysis also suggested that TXA administration that used the combination method resulted in a lower blood volume of drainage than TXA administration that used IV or IA alone (−38.19 and −42.34 mL, respectively, P < 0.05). Interestingly, there was a slightly higher transfusion rate in the combined group when compared with the IV or the IA group (0.46, 0.33, respectively), even though there was no significant difference (P > 0.05). These results may be attributed to the fact that the transfusion criteria were inconsistent among these studies. In addition, a limited number of RCTs and patients may also lead to these results.
It is well known that patients undergoing TKA will take risks of DVT or PE [27, 28]. TXA has been widely used in TKA, while the risk of thromboembolic events are increasingly concerned . Our meta-analysis had shown that there was no significant difference in thromboembolic complications when comparing the combined group with the IV or the IA group. This result was consistent with those studies that recommend the use of combined TXA on TXA [15, 19]. One highly observable time of DVT or PE was the postoperative of TKA within 30 days , and chemoprophylaxis [31, 32] has been recommended to those patients. All of our studies observed the DVT or PE at least 30 days, and chemical prophylaxis was given to all patients or to those high-risk patients. Only one case of DVT was detected in the IV group 3 days after operation . It should be noted that pneumatic tourniquet application could increase the risk of DVT or PE . All patients reported by Huang et al.  used pneumatic tourniquet, and one case of DVT was detected in the IV group. In addition, Song  reported that three patients from the IV group, two from the combined group, and one patient from the IA group had clinical suspicion of DVT based on calf swelling and tenderness. Then, which one was the main reason for increased DVT or PE, TXA, or pneumatic tourniquet? The reason should be further confirmed. In addition, some included studies [19, 20] had evaluated symptomatic patients only, which may have caused a lower incidence of thromboembolic complications and missed the real patients who have DVT or PE. Considering the above factors, the results need to be further confirmed.
There was significant heterogeneity in the administration of IV TXA on total blood loss. The leave-one-out analysis showed that the key contributor to this high heterogeneity was one study conducted by Jain et al. . After excluding this study, heterogeneity was reduced to I 2 = 73% for total blood loss. By comparing these four studies that compared the combined group with the IV group, we found that the total blood loss in this study was calculated by hemoglobin balance method, whereas the total blood loss in other studies was calculated by gross formula . Therefore, we infer that the calculation formula of total blood loss might be partly responsible for the heterogeneity.
There are several limitations in this meta-analysis. Firstly, the present meta-analysis focused only on papers published in English; the ones that were reported in other languages may increase heterogeneity and change the present results. Secondly, because four studies included subjects coming from Asia and one from Europe, the results cannot be extended to populations elsewhere. Besides, the dose and the timing of administrate IV TXA or IA TXA in the combined group were inconsistent among those studies. Further rigorously designed RCTs with larger sample sizes are needed to confirm the efficacy of combined TXA in primary TKA.
Present meta-analysis results demonstrated that combined use of TXA in TKA significantly reduce the total blood loss and blood volume of drainage without increasing the adverse effect of DVT or PE. Further studies are needed to investigate an appropriate dose and times of administering IV TXA combined with IA TXA in patients undergoing TKA.
Total knee arthroplasty
Thanks are due to Wu Zhou for assistance with the analysis of the data and Xi Chen for valuable discussion.
No external funding was received for the initiation or completion of this study.
Availability of data and materials
Please contact author for data requests.
BM and HL conceptualized the study. YL and QW helped in the data curation. KZ and HL carried out the formal analysis. JL and QW performed the investigation. BM and YL provided the methodology. BM and JL helped in the project administration. YL and KZ are responsible for the software. KZ supervised the study. HL and QW participated in the validation. GL wrote the original draft. BM and GL wrote, reviewed, and edited the paper. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Visuri T, Makela K, Pulkkinen P, Artama M, Pukkala E. Long-term mortality and causes of death among patients with a total knee prosthesis in primary osteoarthritis. Knee. 2016;23:162–6. doi:10.1016/j.knee.2015.09.002.View ArticlePubMedGoogle Scholar
- Kim DH, Lee GC, Lee SH, Pak CH, Park SH, Jung S. Comparison of blood loss between neutral drainage with tranexamic acid and negative pressure drainage without tranexamic acid following primary total knee arthroplasty. Knee Surg Relat Res. 2016;28:194–200. doi:10.5792/ksrr.2016.28.3.194.View ArticlePubMedPubMed CentralGoogle Scholar
- Seol YJ, Seon JK, Lee SH, et al. Effect of tranexamic acid on blood loss and blood transfusion reduction after total knee arthroplasty. Knee Surg Relat Res. 2016;28:188–93. doi:10.5792/ksrr.2016.28.3.188.View ArticlePubMedPubMed CentralGoogle Scholar
- Liu JJ, Mullane P, Kates M, et al. Infectious complications in transfused patients after radical cystectomy. Can J Urol. 2016;23:8342–7.PubMedGoogle Scholar
- Wang Q, Du T, Lu C. Perioperative blood transfusion and the clinical outcomes of patients undergoing cholangiocarcinoma surgery: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. 2016. doi;10.1097/MEG.0000000000000706.
- Liu D, Dan M, Martinez MS, Beller E. Blood management strategies in total knee arthroplasty. Knee Surg Relat Res. 2016;28:179–87. doi:10.5792/ksrr.2016.28.3.179.View ArticlePubMedPubMed CentralGoogle Scholar
- Samujh C, Falls TD, Wessel R, et al. Decreased blood transfusion following revision total knee arthroplasty using tranexamic acid. J Arthroplasty. 2014;29:182–5. doi:10.1016/j.arth.2014.03.047.
- Shimizu M, Kubota R, Nasu M, et al. [The influence of tourniquet during total knee arthroplasty on perioperative blood loss and postoperative complications]. Masui. 2016;65:131–5.PubMedGoogle Scholar
- Oremus K. Tranexamic acid for the reduction of blood loss in total knee arthroplasty. Ann Transl Med. 2015;3:S40. doi:10.3978/j.issn.2305-5839.2015.03.35.PubMedPubMed CentralGoogle Scholar
- Rozen L, Faraoni D, Sanchez TC, et al. Effective tranexamic acid concentration for 95% inhibition of tissue-type plasminogen activator induced hyperfibrinolysis in children with congenital heart disease: a prospective, controlled, in-vitro study. Eur J Anaesthesiol. 2015;32:844–50. doi:10.1097/EJA.0000000000000316.PubMedGoogle Scholar
- Charoencholvanich K, Siriwattanasakul P. Tranexamic acid reduces blood loss and blood transfusion after TKA: a prospective randomized controlled trial. Clin Orthop Relat Res. 2011;469:2874–80. doi:10.1007/s11999-011-1874-2.View ArticlePubMedPubMed CentralGoogle Scholar
- Tan J, Chen H, Liu Q, Chen C, Huang W. A meta-analysis of the effectiveness and safety of using tranexamic acid in primary unilateral total knee arthroplasty. J Surg Res. 2013;184:880–7. doi:10.1016/j.jss.2013.03.099.View ArticlePubMedGoogle Scholar
- Wong J, Abrishami A, El BH, et al. Topical application of tranexamic acid reduces postoperative blood loss in total knee arthroplasty: a randomized, controlled trial. J Bone Joint Surg Am. 2010;92:2503–13. doi:10.2106/JBJS.I.01518.View ArticlePubMedGoogle Scholar
- Buntting C, Sorial R, Coffey S, et al. Combination intravenous and intra-articular tranexamic acid compared with intravenous only administration and no therapy in total knee arthroplasty: a case series study. Reconstructive Review. 2016;6:13–20. doi:10.15438/rr.6.2.138.
- Huang Z, Ma J, Shen B, Pei F. Combination of intravenous and topical application of tranexamic acid in primary total knee arthroplasty: a prospective randomized controlled trial. J Arthroplasty. 2014;29:2342–6. doi:10.1016/j.arth.2014.05.026.View ArticlePubMedGoogle Scholar
- Lin SY, Chen CH, Fu YC, Huang PJ, Chang JK, Huang HT. The efficacy of combined use of intraarticular and intravenous tranexamic acid on reducing blood loss and transfusion rate in total knee arthroplasty. J Arthroplasty. 2015;30:776–80. doi:10.1016/j.arth.2014.12.001.View ArticlePubMedGoogle Scholar
- Nielsen CS, Jans O, Orsnes T, Foss NB, Troelsen A, Husted H. Combined intra-articular and intravenous tranexamic acid reduces blood loss in total knee arthroplasty: a randomized, double-blind, placebo-controlled trial. J Bone Joint Surg Am. 2016;98:835–41. doi:10.2106/JBJS.15.00810.View ArticlePubMedGoogle Scholar
- Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60. doi:10.1136/bmj.327.7414.557.View ArticlePubMedPubMed CentralGoogle Scholar
- Jain NP, Nisthane PP, Shah NA. Combined administration of systemic and topical tranexamic acid for total knee arthroplasty: can it be a better regimen and yet safe? A randomized controlled trial. J Arthroplasty. 2016;31:542–7. doi:10.1016/j.arth.2015.09.029.View ArticlePubMedGoogle Scholar
- Song EK, Seon JK, Prakash J, et al. Combined administration of iv and topical tranexamic acid is not superior to either individually in primary navigated TKA. J Arthoplasty. 2016. doi:10.1016/j.arth.2016.06.052.
- Akgul T, Buget M, Salduz A, et al. Efficacy of preoperative administration of single high dose intravenous tranexamic acid in reducing blood loss in total knee arthroplasty: a prospective clinical study. Acta Orthop Traumatol Turc. 2016. doi;10.1016/j.aott.2016.06.007.
- Goyal N, Chen DB, Harris IA, Rowden NJ, Kirsh G, MacDessi SJ. Intravenous vs intra-articular tranexamic acid in total knee arthroplasty: a randomized, double-blind trial. J Arthroplasty. 2016. doi;10.1016/j.arth.2016.07.004.
- Karaaslan F, Karaoglu S, Mermerkaya MU, Baktir A. Reducing blood loss in simultaneous bilateral total knee arthroplasty: combined intravenous-intra-articular tranexamic acid administration. A prospective randomized controlled trial. Knee. 2015;22:131–5. doi:10.1016/j.knee.2014.12.002.View ArticlePubMedGoogle Scholar
- Good L, Peterson E, Lisander B. Tranexamic acid decreases external blood loss but not hidden blood loss in total knee replacement. Br J Anaesth. 2003;90:596–9.View ArticlePubMedGoogle Scholar
- Sperzel M, Huetter J. Evaluation of aprotinin and tranexamic acid in different in vitro and in vivo models of fibrinolysis, coagulation and thrombus formation. J Thromb Haemost. 2007;5:2113–8. doi:10.1111/j.1538-7836.2007.02717.x.View ArticlePubMedGoogle Scholar
- Gomez-Barrena E, Ortega-Andreu M, Padilla-Eguiluz NG, Perez-Chrzanowska H, Figueredo-Zalve R. Topical intra-articular compared with intravenous tranexamic acid to reduce blood loss in primary total knee replacement: a double-blind, randomized, controlled, noninferiority clinical trial. J Bone Joint Surg Am. 2014;96:1937–44. doi:10.2106/JBJS.N.00060.View ArticlePubMedGoogle Scholar
- Chotanaphuti T, Ongnamthip P, Silpipat S, Foojareonyos T, Roschan S, Reumthantong A. The prevalence of thrombophilia and venous thromboembolism in total knee arthroplasty. J Med Assoc Thai. 2007;90:1342–7.PubMedGoogle Scholar
- Levy YD, Hardwick ME, Copp SN, Rosen AS, Colwell CJ. Thrombosis incidence in unilateral vs. simultaneous bilateral total knee arthroplasty with compression device prophylaxis. J Arthroplasty. 2013;28:474–8. doi:10.1016/j.arth.2012.08.002.View ArticlePubMedGoogle Scholar
- Izumi M, Migita K, Nakamura M, et al. Risk of venous thromboembolism after total knee arthroplasty in patients with rheumatoid arthritis. J Rheumatol. 2015;42:928–34. doi:10.3899/jrheum.140768.View ArticlePubMedGoogle Scholar
- Mantilla CB, Horlocker TT, Schroeder DR, Berry DJ, Brown DL. Risk factors for clinically relevant pulmonary embolism and deep venous thrombosis in patients undergoing primary hip or knee arthroplasty. Anesthesiology. 2003;99:552–60. 5A.View ArticlePubMedGoogle Scholar
- Odeh K, Doran J, Yu S, Bolz N, Bosco J, Iorio R. Risk-stratified venous thromboembolism prophylaxis after total joint arthroplasty: aspirin and sequential pneumatic compression devices vs aggressive chemoprophylaxis. J Arthroplasty. 2016;31:78–82. doi:10.1016/j.arth.2016.01.065.View ArticlePubMedGoogle Scholar
- Mostafavi TR, Rasouli MR, Maltenfort MG, Parvizi J. Cost-effective prophylaxis against venous thromboembolism after total joint arthroplasty: warfarin versus aspirin. J Arthroplasty. 2015;30:159–64. doi:10.1016/j.arth.2014.08.018.View ArticleGoogle Scholar
- Mori N, Kimura S, Onodera T, Iwasaki N, Nakagawa I, Masuda T. Use of a pneumatic tourniquet in total knee arthroplasty increases the risk of distal deep vein thrombosis: a prospective, randomized study. Knee. 2016;23:887–9. doi:10.1016/j.knee.2016.02.007.View ArticlePubMedGoogle Scholar
- Kvederas G, Porvaneckas N, Andrijauskas A, et al. A randomized double-blind clinical trial of tourniquet application strategies for total knee arthroplasty. Knee Surg Sports Traumatol Arthrosc. 2013;21:2790–9. doi:10.1007/s00167-012-2221-1.View ArticlePubMedGoogle Scholar