Background
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 [
1]. 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 [
9]. TXA is an antifibrinolytic drug that inhibits the activation of plasminogen so as to decrease the amount of blood loss [
10]. 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 [
13]. Recent studies have confirmed that the administration of TXA, which is used directly into the surgical wound, reduced postoperative bleeding from 20 to 25% [
13].
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.
Methods
Search strategy
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.
Data selection
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.
Statistical analysis
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 [
18]. Statistical significance was indicated by a
P value <0.05.
Discussion
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 [
21]. 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 [
22]. 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. [
23] 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 [
25], it also has the advantage of limiting local blood loss [
26]. 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 [
29]. 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 [
30], 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 [
15]. It should be noted that pneumatic tourniquet application could increase the risk of DVT or PE [
33]. All patients reported by Huang et al. [
15] used pneumatic tourniquet, and one case of DVT was detected in the IV group. In addition, Song [
20] 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. [
19]. 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 [
34]. 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.
Acknowledgements
Thanks are due to Wu Zhou for assistance with the analysis of the data and Xi Chen for valuable discussion.