Inclusion and Exclusion Criteria
Randomized controlled trials that investigated the effectiveness and safety of tranexamic acid for the reduction of blood loss in total knee arthroplasty were retrieved by searching PubMed, MEDLINE, and Embase for English-language studies, as well as by searching the bibliographies of all relevant retrieved articles that had been published before May 2011.
The inclusion criteria for the meta-analysis were studies that were randomized controlled trials and studies that had treatment with tranexamic acid, an experimental group that used tranexamic acid, a control group that received a placebo, and both groups that used a pneumatic tourniquet intraoperatively. Neither the group who received tranexamic acid nor the control group who received a placebo used anticoagulant drugs, and both groups reported one of the following: amount of blood loss, the number of blood transfusion units per patient, prothrombin time, postoperative activated partial thromboplastin time, the number of patients with deep-vein thrombosis or pulmonary embolism, and the number of patients needing transfusion after total knee arthroplasty.
The exclusion criteria were studies that were nonrandomized controlled clinical trials or low-quality randomized controlled trials, studies that had a lack of the interventions described above, and studies that did not contain any of the above outcomes.
The quality of the randomized controlled trial design was assessed according to the method described by Jadad et al.7. The maximum quality score given to a study by this instrument is 5 points (up to 2 points for random assignment, up to 2 points for blinding investigators and patients, and 1 point if all enrolled patients are accounted for at the conclusion of the study, with reasons given for all dropouts and withdrawals). Studies with a score of ≥3 points were considered to represent high-quality research and were included in the meta-analysis.
Two reviewers extracted information independently with use of a pre-designed data extraction form from all eligible randomized controlled trials. Any differences in opinion were resolved by discussion.
Statistical Analysis
Two investigators (Z.-G.Y., W.-P.C.) independently extracted data from the tranexamic acid group and the placebo group, including the amount of blood loss, the number of blood transfusion units per patient, the number of patients who needed transfusion, prothrombin time, activated partial thromboplastin time, and the rates of deep-vein thrombosis and pulmonary embolism. All data were expressed as the mean and the standard deviation. Variables were analyzed with use of the Review Manager (RevMan) version 5.0 (The Cochrane Library) to obtain the 95% confidence interval (CI).
The amount of blood loss, the number of blood transfusion units per patient, prothrombin time, and activated partial thromboplastin time were expressed in terms of the weighted mean difference with a 95% CI evaluation. The rate of patients needing transfusion, the rate of deep-vein thrombosis, and the rate of pulmonary embolism were based on an odds ratio (OR) evaluation with a 95% CI.
Source of Funding
No funding source was involved in the conduction of this study.
According to the inclusion and exclusion criteria, we identified fifteen randomized controlled trials8-22 associated with total knee arthroplasty. The quality of the studies is shown in the Appendix. The number of patients included in these randomized controlled trials ranged from twenty to 102. A total of 837 patients were enrolled in the randomized controlled trials, including 608 women (73%) and 229 men (27%). The mean age ranged from sixty-two to seventy-six years. The details are shown in Table I. Patients stopped taking nonsteroidal anti-inflammatory drugs two weeks before surgery in one study, one week before surgery in six studies, twenty-four hours before surgery in two studies, and twelve hours before surgery in one study; five studies did not show these data. Five studies involved the use of spinal anesthesia, four involved the use of general anesthesia, one involved the use of spinal and general anesthesia, one involved the use of spinal and epidural anesthesia, and one involved the use of epidural anesthesia; three studies did not show these data. Fourteen studies involved the administration of a low dose of tranexamic acid (range, 10 to 50 mg/kg) and one involved the administration of a high dose of tranexamic acid (150 mg/kg). Seven studies had a mean duration of surgery of less than 100 minutes, and four studies had a mean duration of more than 100 minutes. The duration of surgery was not shown in four studies.
Amount of Blood Loss per Patient
This outcome measure was available in fourteen studies. The amount of blood loss at the end of surgery was recorded by means of measuring the volume in the suction apparatus and estimating the blood lost in the sponges. Postoperative blood loss was recorded from the drain reservoirs from one to three days postoperatively. Another method of calculating the amount of blood loss was based on the preoperative and postoperative maximum changes of hemoglobin concentration. The amount of blood loss per patient was significantly less in the tranexamic acid group compared with the placebo group (weighted mean difference, −504.90 mL [95% CI, −620.89 to −388.92 mL]; p < 0.00001) (Fig. 1).
Number of Transfusions per Patient
This outcome measure was available in six studies. The number of blood transfusions per patient was significantly less in the tranexamic acid group compared with the placebo group (weighted mean difference, −1.43 units [95% CI, −1.69 to −1.17 units]; p < 0.00001) (Fig. 2).
Odds Ratio of Transfusion
This outcome measure was available in fourteen studies. The rate of patients who required transfusion was significantly less in the tranexamic acid group compared with the placebo group (OR, 0.16 [95% CI, 0.10 to 0.25]; p < 0.00001) (Fig. 3).
Odds Ratio of Developing Deep-Vein Thrombosis
This outcome measure was available in thirteen studies. The rates of deep-vein thrombosis of the tranexamic acid and placebo groups were ten of 361 patients and thirteen of 361 patients. The rate of deep-vein thrombosis was not affected by the use of tranexamic acid when the tranexamic acid group was compared with the placebo group (OR, 0.75 [95% CI, 0.34 to 1.67]; p = 0.48) (Fig. 4).
Odds Ratio of Developing Pulmonary Embolism
This outcome measure was available in six studies. The rates of pulmonary embolism in the tranexamic acid and placebo groups were two of 174 patients and four of 175 patients, respectively. The rate of pulmonary embolism was not affected by the use of tranexamic acid when the tranexamic acid group was compared with the placebo group (OR, 0.65 [95% CI, 0.18 to 2.33]; p = 0.50) (Fig. 5).
Change in Prothrombin Time
This outcome measure was available in four studies. Prothrombin time was not affected by the use of tranexamic acid when the tranexamic acid group was compared with the placebo group (weighted mean difference, −0.04 second [95% CI, −0.33 to 0.24 second]; p = 0.77) (Fig. 6).
Change in Activated Partial Thromboplastin Time
This outcome measure was available in five studies. Activated partial thromboplastin time was not affected by the use of tranexamic acid when the tranexamic acid group was compared with the placebo group (weighted mean difference, 0.37 second [95% CI, −0.56 to 1.29 seconds]; p = 0.44) (Fig. 7).
Our meta-analysis showed that the use of tranexamic acid for patients undergoing total knee arthroplasty is effective and safe for the reduction of blood loss, the number of blood transfusion units, and the number of patients needing transfusion, and that it does not change prothrombin time, activated partial thromboplastin time, and the prevalence of deep-vein thrombosis or pulmonary embolism. These results are similar to a meta-analysis performed by Cid and Lozano23, although the method and the studies included were different from ours. Our meta-analysis included all of the high-quality randomized controlled trials (Jadad score, ≥3 points) published before May 2011.
Our meta-analysis showed that the use of tranexamic acid in total knee arthroplasty significantly reduced the amount of blood loss. The reason for this is that tranexamic acid inhibits the activation of plasminogen molecules, which prevents plasmin from binding with fibrinogen and fibrin structures after clot formation. These results are similar to those observed in other clinical trials24,25.
Our meta-analysis also showed that the use of tranexamic acid significantly reduced the number of blood transfusions per patient and the rate of patients requiring transfusion when the tranexamic acid group was compared with the placebo group. With use of tranexamic acid for patients undergoing total knee arthroplasty, fewer patients are at risk for transfusion and related complications, because risk is calculated per unit of transfusion. Accordingly, the use of tranexamic acid for patients undergoing total knee arthroplasty reduced the rate of patients requiring blood transfusion and reduced the number of transfusion units needed.
Tranexamic acid is known to affect the fibrinolytic system, and its potential to increase the risk of venous thrombosis after total knee arthroplasty cannot be ignored. However, our meta-analysis showed no significant difference in the prevalence of deep-vein thrombosis or pulmonary embolism when the tranexamic acid group was compared with the placebo group. These results are similar to those in other studies2,11,26,27. Accordingly, compared with patients who received a placebo, patients who received tranexamic acid did not have a higher risk of deep-vein thrombosis and pulmonary embolism. The rates of deep-vein thrombosis in the tranexamic acid and placebo groups were ten of 361 patients and thirteen of 361 patients, respectively, and the rates of pulmonary embolism in the tranexamic acid and placebo groups were two of 174 patients and four of 175 patients, respectively. The numbers of patients in both groups were small, and larger numbers of patients in samples of randomized controlled trials are needed to support the results of our meta-analysis.
The effect of tranexamic acid on the fibrinolytic system also means that it may affect prothrombin time and activated partial thromboplastin time. Our meta-analysis showed no significant difference, based on the numbers available, in prothrombin time or activated partial thromboplastin time when the tranexamic acid group was compared with the placebo.
Our meta-analysis and other studies23,28 have demonstrated that the most consistent way to reduce transfusion was associated with use of tranexamic acid in total knee arthroplasty.
In summary, based on our meta-analysis, the use of tranexamic acid in patients undergoing total knee arthroplasty appears to be effective and safe in reducing the need for transfusions associated with the use of a tourniquet in knee surgery. The use of tranexamic acid reduces the volume of blood transfusion and the transfusion rate. At the same time, the application of tranexamic acid does not increase the prevalence of deep-vein thrombosis or pulmonary embolism and does not affect prothrombin time or activated partial thromboplastin time. The intravenous administration of 10 to 20 mg/kg of tranexamic acid thirty minutes before deflation of the tourniquet, followed by 10 to 15 mg/kg every three to eight hours for twenty-four hours or once a day for three days, appears to be a safe and effective method. Another feasible method is the intra-articular injection of 50 mg/kg once postoperatively. More high-quality randomized controlled trials are needed to strengthen our conclusion that the use of tranexamic acid in total knee arthroplasty does not increase the rate of complications.