Orthopedics

Feature Article 

Safety, Efficacy, and Cost-effectiveness of Tranexamic Acid in Orthopedic Surgery

Zilan X. Lin, MD; Shane K. Woolf, MD

Abstract

Perioperative bleeding and postsurgical hemorrhage are common in invasive surgical procedures, including orthopedic surgery. Tranexamic acid (TXA) is a pharmacologic agent that acts through an antifibrinolytic mechanism to stabilize formed clots and reduce active bleeding. It has been used successfully in orthopedics to reduce perioperative blood loss, particularly in total hip and knee arthroplasty and spine surgery. Numerous research studies have reported favorable safety and efficacy in orthopedic cases, although there is no universal standard on its administration and its use has not yet become the standard of practice. Reported administration methods often depend on the surgeon's preference, with both topical and intravenous routes showing efficacy. The type and anatomic site of the surgery seem to influence the decision making but also result in conflicting opinions. Reported complication rates with TXA use are low. The incidence of both arterial and venous thromboembolic events, particularly deep venous thrombosis and pulmonary embolism, has not been found to be significantly different with TXA use for healthy patients. The route of administration and dosage do not appear to affect complication rates either. However, data on patients with higher-risk conditions are deficient. In addition, TXA has shown potential to reduce blood loss, transfusion rates and volumes, perioperative hemoglobin change, and hospital-related costs at various degrees among the published studies. Conservation of blood products, reduced laboratory costs, and shorter hospital stays are likely the major factors driving the cost savings associated with TXA use. This article reviews current data supporting the safety, efficacy, and cost-effectiveness of TXA in orthopedic surgery. [Orthopedics. 2016; 39(2):119–130.]


Abstract

Perioperative bleeding and postsurgical hemorrhage are common in invasive surgical procedures, including orthopedic surgery. Tranexamic acid (TXA) is a pharmacologic agent that acts through an antifibrinolytic mechanism to stabilize formed clots and reduce active bleeding. It has been used successfully in orthopedics to reduce perioperative blood loss, particularly in total hip and knee arthroplasty and spine surgery. Numerous research studies have reported favorable safety and efficacy in orthopedic cases, although there is no universal standard on its administration and its use has not yet become the standard of practice. Reported administration methods often depend on the surgeon's preference, with both topical and intravenous routes showing efficacy. The type and anatomic site of the surgery seem to influence the decision making but also result in conflicting opinions. Reported complication rates with TXA use are low. The incidence of both arterial and venous thromboembolic events, particularly deep venous thrombosis and pulmonary embolism, has not been found to be significantly different with TXA use for healthy patients. The route of administration and dosage do not appear to affect complication rates either. However, data on patients with higher-risk conditions are deficient. In addition, TXA has shown potential to reduce blood loss, transfusion rates and volumes, perioperative hemoglobin change, and hospital-related costs at various degrees among the published studies. Conservation of blood products, reduced laboratory costs, and shorter hospital stays are likely the major factors driving the cost savings associated with TXA use. This article reviews current data supporting the safety, efficacy, and cost-effectiveness of TXA in orthopedic surgery. [Orthopedics. 2016; 39(2):119–130.]


Numerous studies have been conducted on the development and use of pharmaceutical agents and other methods to reduce perioperative surgical bleeding. Among the most common complications, severe perioperative bleeding and postsurgical hemorrhage can lead to significant consequences, including hematoma, acute anemia, need for transfusion, and prolonged hospital stay with greater costs. With a growing geriatric population, increased activity levels, and the development of more advanced surgical techniques, the volume of orthopedic surgeries and procedures—ranging from simple fracture and soft tissue repair to prosthetic replacement and revision reconstructive surgery—has been rising.1,2 Thus, minimizing peri- and postoperative complications, especially bleeding, is imperative to contain health care costs.

In orthopedic cases, controlled hypotensive anesthesia and tourniquets with pressure-controlled pumps have been used along with other methods to control intraoperative bleeding. However, these extrinsic methods do not eliminate blood loss completely and are not without issues. For example, in total knee arthroplasty (TKA), tourniquet-related ischemia can inadvertently cause a rebound effect when the tourniquet is released at the end of the procedure. This can lead to increased fibrinolytic activity, resulting in up to 2 L of ongoing blood loss even after wound closure, sometimes necessitating transfusion.1–7 Furthermore, transfusions can cause complications, including anaphylactic and allergic reactions to blood products, infections, and even death.2,8,9 Current medical standard of care advocates a conservative and limited use of blood products,1,10 which further emphasizes the need for better control of bleeding. For this purpose, antifibrinolytic drugs such as epsilon-aminocaproic acid and since-discontinued aprotinin have been investigated.5,11 Tranexamic acid (TXA) is another such agent shown to be safe and effective in orthopedic surgery.

Tranexamic acid has shown efficacy in reducing bleeding and possibly other surgical complications. It was initially introduced more than 40 years ago in cardiothoracic surgery and has shown application in controlling gynecologic hemorrhage and providing life-saving hemostasis in acute trauma. In addition to cardiothoracic12; trauma13; gynecological and obstetric14,15; gastrointestinal16; hepatic12; urologic17; and ear, nose, and throat surgeries,12,18 TXA has also been studied and used for diseases such as von Willebrand–factor deficiencies,19 hemophilia,20 and thrombocytopenia.1,5,21 However, use in orthopedic surgery is not universal and remains subject to research. The current article reviews details of TXA in orthopedic surgery, including possible benefits beyond reduced blood loss and transfusion requirements, such as treatment cost savings and decreased length of hospital stay.

Mechanism of Action and Pharmacology

Tranexamic acid is a synthetic derivative of the amino acid lysine and carries out its effects through an antifibrinolytic action. It stabilizes formed clots and prevents the degradation of fibrin by reversibly inhibiting the lysine binding site on plasminogen. This impairs plasminogen's linkage with fibrin to become plasmin, which normally creates a fibrinolytic effect and dissolves clots.1,12,18 The capacity of TXA to bind to plasminogen appears to be 6 to 10 times more potent than epsilon-aminocaproic acid.5,12 Its half-life is approximately 2 hours,1,5,18 and it is eliminated via the kidneys.

Safety and Complications

Contraindications of TXA use are controversial. It is generally well tolerated but can cause uncommon dose-dependent side effects, including nausea, vomiting, diarrhea, headache, orthostatic reactions, blurred vision, and vertigo.12,18,22 Of particular concern is the drug's antifibrinolytic action, which could theoretically lead to a hypercoagulable state and induce thrombosis. However, multiple primary studies and reviews have suggested no significant differences between TXA and placebo in the incidence of both arterial and venous thromboembolic events, particularly deep venous thrombosis and pulmonary embolism.2,5,9,12,23–34 Reported complications with TXA use in orthopedic surgery from published meta-analyses are shown in Table 1. No reported data have shown a correlation between TXA and any significant major complication, thromboembolic or nonthromboembolic, including numerous recent studies of topical and intravenous (IV) administration not included in previously published meta-analyses.25,26,32,34–52 According to Tuttle et al,35 readmissions within 30 days with topical TXA use was not statistically significant after total hip arthroplasty (THA) and TKA. A meta-analysis by Yang et al27 concluded that the addition of TXA did not affect prothrombin time and activated partial thromboplastin time after TKA. Two randomized, controlled trials (RCTs) on scoliosis surgery showed no statistically significant difference in prothrombin time, international normalization ratio, partial thromboplastin time, fibrinogen, or d-dimer with TXA use,53,54 whereas Mutsuzaki and Ikeda36 reported that d-dimer was lower on postoperative day 7 after cementless TKA in their cohort study. Thus, in terms of thrombotic complications, TXA has been shown to be a relatively safe agent for control of perioperative bleeding in orthopedic surgery.


Mean Blood Loss, Transfusion Rates, and Reported Complications Noted in Published Meta-Analyses
Mean Blood Loss, Transfusion Rates, and Reported Complications Noted in Published Meta-Analyses

Table 1:

Mean Blood Loss, Transfusion Rates, and Reported Complications Noted in Published Meta-Analyses

Although most studies do not suggest that TXA lowers thromboembolic and other complication rates, some have reported intriguing results. A retrospective cohort study by Lozano et al37 suggests a tendency toward fewer thromboembolic events with TXA use. Poeran et al34 reported that the rate of admission to the intensive care unit was decreased significantly from 7.5% to 3.1% with TXA use in their cohort study. According to Wong et al,30 the percent of patients who required discharge to rehabilitation facilities was shown to be lower with 3 g of topical TXA, compared with 1.5 g or placebo. To clarify whether TXA has the potential to reduce complication rates or facilitate recovery, larger controlled studies are necessary.

Different routes of administration and dosages do not appear to cause a significant rise in adverse outcomes. No study has shown a significant correlation between TXA use, regardless of route of administration, and complications. By comparing the effects of TXA administered topically and intravenously, Hegde et al38 concluded that both routes are equally safe in simultaneous bilateral computer-assisted TKA. Hourlier and Fennema26 found in an RCT that administration of TXA by a single shot or a loading dose and followed 2 hours later by a continuous infusion was equally safe in THA. In general, TXA appears to be a safe agent for use in healthy patients undergoing orthopedic surgery.

However, most studies excluded patients with significant risk factors, such as a history of cardiovascular disease, thromboembolic events, and renal failure.2,7,23,29 Thus, most of the available data would likely support TXA's safety in healthy patients rather than those with higher risk. Furthermore, there are proposed contraindications for TXA use, including arterial and venous thrombosis, cerebral thrombosis, myocardial infarct, and acute renal failure.5,28 For example, a case report by Bruce-Brand et al55 revealed that a 65-year-old man with a previously undiagnosed patent foramen ovale suffered pulmonary emboli and cerebrovascular infarction after synchronous bilateral TKA, during which TXA was administered intravenously. With current evidence, the safety of TXA in patients with higher-risk conditions is still uncertain. Prudence would suggest withholding TXA in higher-risk individuals, including those with a history of venous thromboembolic disease, cardiac disease, cerebrovascular disease, or significant risk factors for blood clots.

Administration in Orthopedic Surgery

In orthopedics, numerous studies and reviews have focused on TXA use in TKA.2,5–7,9,23,25,27–31,34,36,37,39–41,56–62 This relates to seeking alternatives to the use of tourniquets and the potential volume of blood loss due to location. Total hip arthroplasty9,26,32–34,39,40,42,59,62–64 and spine surgery9,22,43,53,54,65 have also been areas of research focus.

The administration of TXA in orthopedic surgery has been studied in various dosing regimens, including fixed32,40,64 or weighted9,24,26,28,44 IV doses, a single IV dose9,26,28,40,44 or multiple IV doses,9,28,37 continuous IV infusion,22,26,43,53,54,58,65 and topical (ie, intra-articular) application by direct wash or injection, with or without drain clamping.6,7,23,25,29–31,33,36,41,42,57,61 Although agreement has not been reached on the standards for TXA administration, suggestions have been made depending on the type and site of the surgery.

First, route of administration has been an area of specific research interest. Often TXA is administered intravenously,5,26 and by doing so, TXA is directly loaded into the vascular system and could reach the body systemically. Intravenous administration seems to be the most effective because TXA can penetrate into large joints relatively quickly.1,57 In their comparison of topical TXA vs placebo, Alshryda et al57 reviewed previous studies of topical and IV TXA. Their meta-analysis of this group showed that topical administration was significantly less effective than intravenous TXA in TKA, with a transfusion risk difference of 30%.57 However, when Wang et al66 compared topical and intravenous TXA use in TKA, they concluded that there was no statistically significant difference in blood loss and transfusion rates. The argument for local administration of TXA is that only a small portion of intravenously administered TXA will reach the target surgical site, whereas local application of the drug can supply a higher concentration. One meta-analysis indicated that topical TXA provides a greater benefit in reducing postoperative blood loss and transfusion rates than IV TXA in arthroplasty.67 Moreover, in TKA, intravenous TXA may decrease external blood loss only, meaning blood loss that could be observed or measured intraoperatively or in the drain but not potentiate ongoing postoperative blood loss, which likely contributes to hematoma formation.23,33,41,57,60

It may be useful to apply TXA locally at the conclusion of surgery. Sarzaeem et al45 reported that injection through the drain was more effective at decreasing postoperative drainage after TKA, although IV TXA injection seemed to reduce the number of transfused units and magnitude of the drop in hemoglobin more effectively. Two studies also examined oral TXA use and suggested efficacy.68,69 Therefore, it may be the surgeon's preference as to what route of administration to use, and consideration of expected postoperative ongoing blood losses should be made.

Second, surgical location seems to make a difference in terms of route of administration. Table 1 illustrates the choice of topical or IV TXA in various orthopedic specialties. Consistency is noted in spine surgery but not THA and TKA. The reason for popularity of IV administration in spine cases may be due to multiple spinal levels involved and large exposure, resulting in the practical need for systematic distribution. However, it seems to matter less in THA and TKA. This is most likely associated with the previously mentioned benefits of local and IV TXA use and depends on the surgeon's preference. Of note, a feature specific to TKA is the common use of a tourniquet. The tourniquet would help reduce local bleeding before TXA administration and likely impair TXA delivery to the surgical site intraoperatively.

Third, the dosage of TXA administered has not been standardized. Often TXA is administered intravenously with a loading dose of 10 or 15 mg/kg, followed by an infusion or repeated bolus.5,26 According to a meta-analysis of 6 RCTs by Zhao-Yu et al,23 topical injections can range from 0.5 g TXA/100 mL normal saline to 3 g/100 mL in TKA. Some studies have suggested a dose-response effect with TXA use.26,31,70,71 Wong et al30 reported that 3 g TXA/100 mL normal saline was more effective in reducing total blood loss than 1.5 g in TKA, although similar efficacy was found in transfusion rates. Panteli et al31 reported in their meta-analysis that a higher dose (>2 g) of topical TXA in TKA significantly reduced blood transfusion requirements compared with a lower dose (≤2 g). Alshryda et al72 also concluded in their meta-analysis that higher doses (>4 mg) of TXA may provide a larger, homogenous treatment effect in TKA, whereas lower doses may provide a smaller, heterogeneous effect. Poeran et al34 reported that 2 g of IV TXA seemed to have the best effectiveness and safety profile in arthroplasty compared with ≤1 or ≥3 g of IV TXA. All of these data illustrate that the dosage of TXA matters within a certain range. However, a meta-analysis by Sukeik et al73 found that a higher dose of IV TXA did not necessarily reduce intraoperative and total blood loss or transfusion rates but did reduce postoperative blood loss in THA. Overall, it seems that a higher dose of TXA may increase the drug's efficacy until the dosage reaches a certain upper limit.

Finally, the timing of TXA administration is worthy of attention, although the current available data demonstrate inconsistency. Tranexamic acid can be administered before skin incision, during surgery, around tourniquet deflation, and postoperatively, whereas continuous infusion is only possible with IV usage. The timing can also depend on the location of interest. Hourlier and Fennema26 suggested that a single bolus dose in THA was less cumbersome than continuous infusion but with equivalent safety, whereas Lin et al46 reported that 1 IV TXA injection was as effective as 2 injections for blood conservation after minimally invasive TKA. When a tourniquet was used in TKA, a single dose of 10, 15, or 20 mg/kg of TXA would be administered before tourniquet deflation with or without another dosage postoperatively.28,44 The argument for this is that TXA is most effective at the active bleeding site rather than inside the blood vessels.41 When there is no tourniquet involved, such as in THA or spine surgery, others favor administering TXA early during the surgery and argue that it would work most effectively in the early phase of the fibrinolytic cascade.64,71 Likely due to the same reason, continuous IV infusion appears to be somewhat more popular in spine surgery. The majority of recently published spine studies chose to use continuous IV infusion.43,47,48,65 Furthermore, in Table 1, 3 meta-analyses addressed TXA in spine surgery and included a total of 10 studies.9,24,74 Half of them chose continuous IV infusion,53,54,75–77 3 bolus,22,78,79 and 2 unknown.80,81 However, there is also counterevidence. According to a cohort study by George et al,40 no significant difference in total blood loss was noticed with TXA administration within or after 30 minutes of the anesthetic induction. Furthermore, topical TXA could be administered after fascia closure to prevent leakage6,29 or before closure to ensure adequate contact time.7,41

In short, the optimal dose and route of administration of TXA is still unclear. Although studies with different doses and routes of administration have shown statistical significance for using TXA, few have actually compared and concluded a correlation between efficacy and administration method or between efficacy and dosage. Further data are needed to define the optimal practices for dosing and administration.

Potential Advantages of Tranexamic Acid in Clinical Pathways

Many researchers agree that TXA decreases peri- and postoperative blood loss volume and transfusion rates and minimizes hemoglobin change. Studies and reviews in TKA,2,6,7,9,23,25,27–31,34,36,37,39–41,51,56–58,60–62 THA,9,26,32–34,39,40,42,62–64 and spine surgery9,22,43,53,54,65 have supported TXA's ability to lower blood loss and transfusion requirements.1,5 Data were also obtained with similar results in revision,44,56 bilateral,38 and computer-assisted TKA3,29 and cementless THA.32 A meta-analysis by Huang et al9 included 46 RCTs of 2925 patients in major orthopedic surgery and concluded that, on average, TXA use reduced the number of blood transfusions per patient by 0.78 units; the volume of blood transfusion per patient by 205 mL; and total, intraoperative, and postoperative blood loss by 408, 125, and 214 mL, respectively.9 Similar trends were demonstrated by a meta-analysis of 22 RCTs exclusively in TKA28 and a meta-analysis of 6 RCTs in spine surgery.24Table 1 summarizes details of blood loss and transfusion rate differences in published reports. Both transfusion rates and transfusion volume are decreased by TXA. In 2 level I studies, the transfusion rates were significantly decreased from 47.5% to 25% in TKA and from 22.4% to 5.7% in THA after TXA administration.52,82 In addition, TXA further reduced blood transfusions in TKA when a blood conservation program was applied.58 Other evidence shows significant decreases in drain output,49,61 hemoglobin loss,25,35,37,44,49 and hematocrit reduction42,49,61,64 with TXA use, although the control group with placebo had a higher rate of transfusion.

The efficacy of TXA may vary with timing. In a nonrandomized, controlled trial of cementless THA, Yamasaki et al32 noted the greatest reduction in blood loss during the first 4 hours. Mutsuzaki and Ikeda36 reported that the hemoglobin level was higher with TXA use on postoperative day 7 but not on days 1 and 14. Overall, there is ample agreement on TXA's efficacy in reducing surgical blood loss and transfusion requirements in orthopedic surgery.

The efficacy of TXA seems to vary by location. Zufferey et al70 suggested that the efficacy of TXA is higher in TKA than THA, whereas Vigna-Taglianti et al62 reported that the reduction in blood transfusions was greater in THA than in TKA. The efficacy of TXA in spine surgery seems to be somewhat less potent and more inconsistent. For example, in pediatric scoliosis surgery, Sethna et al54 concluded that TXA significantly reduced blood loss but not transfusion requirements, whereas Neilipovitz et al53 reported no significant difference in blood loss, although perioperative blood transfusion was reduced. An RCT by Elwatidy et al22 showed significant reduction in both blood loss and transfusion need. Although TXA does not seem to always affect multiple hematologic metrics in spine surgery, as seen more commonly in TKA and THA, most studies still show significant effects of TXA in 1 or more ways. Therefore, most researchers still argue that the effect of TXA on hemostasis would support routine administration in orthopedic spine surgery.

Other than decreasing blood loss and transfusion requirements, TXA use may have other benefits as well. Swelling after surgery is inversely linked to postoperative recovery. An RCT by Ishida et al6 suggested that topical injection of TXA could reduce knee joint swelling after TKA because it was most evident in suprapatellar girth at 1 week postoperatively and in calf girth at 2 weeks. This observation suggests that TXA may have an effect on hidden blood loss related to hematoma or hemarthrosis formation. Zhou et al83 reported in their meta-analysis that topical TXA in TKA could reduce hidden blood loss by a mean of 152.70 mL, whereas another study showed that IV TXA was able to decrease external but not hidden blood loss in TKA.60 In addition, other studies report that no difference in postoperative joint function exists with TXA use according to hip or knee scores, generic quality of life scores, visual analog scale pain scores, active range of motion, or osteoarthritis index.7,29,30,33,57 Controlled, prospective studies are still needed to examine TXA's correlation with patient functional outcomes.

Shorter hospital stays are a significant economic benefit of using TXA. Among the studies listed in Table 2 reporting hospital stay or economic data, 11 of 24 illustrate shorter stays. Three of these show statistical significance.25,44,57 Smit et al44 demonstrated that the TXA group was associated with a hospital stay shortened by approximately 2 days after revision TKA. Interestingly, all 3 studies involved TKA or revision TKA, whereas no THA studies show any significant difference in length of hospital stay. The other significant finding in Table 2 is that there was no change in the median length of hospital stay in one study; however, the interquartile range for length of stay was lower with TXA use.34 The shorter hospital stay could be attributed to reduced bleeding and transfusion requirements, which can lead to quicker recovery time.


Length of Hospital Stay and Hospital Costs Associated With TXA Use in Orthopedic Surgery
Length of Hospital Stay and Hospital Costs Associated With TXA Use in Orthopedic Surgery
Length of Hospital Stay and Hospital Costs Associated With TXA Use in Orthopedic Surgery

Table 2:

Length of Hospital Stay and Hospital Costs Associated With TXA Use in Orthopedic Surgery

The effect of TXA on operative time seems to be minimal but not fully clear. Some studies have shown a decrease22,29,30,41,47,61 and others an increase,6,39,42–44,53,54,64 although few have shown any statistical significance.36 A possible factor for this difference may be that some of these data were collected from TKA surgeries where TXA was administered at the end of the procedure and thus did not affect operative time.

The advantages of using TXA can lead to better economic outcomes. Tranexamic acid is relatively inexpensive and widely available. Currently, hospital cost is roughly $100 per 2000-mg infusion. Although adding TXA will increase pharmacy costs, evidence shows that operating room, blood bank and laboratory, room and board, and total direct hospital costs could be reduced.25,33,39,59,62,64Table 2 shows the percentages saved on total hospital cost per patient stay with TXA use in 5 studies that report these data, ranging from 1% to 23%. Considering pharmacy and transfusion costs alone, the combined expense is typically reduced with TXA use as well. According to a cohort study by Gillette et al,59 pharmacy expenses were the only increased component, from an average of $781 to $921 (an increase equivalent to $140), in TKA and THA, whereas the savings in blood bank and laboratory, operating room, room and board, and hospital total costs were $139, $222, $457, and $870 per patient, respectively. Smit et al44 calculated a potential annual savings of $22,300 in revision TKA with TXA. Chimento et al25 computed an average savings of $1500 per patient after TKA. Interestingly, Slover and Bosco84 suggested that the cost-effectiveness of TXA in arthroplasty was correlated with transfusion rates and was more noticeable when baseline blood transfusion rates at an institution were above 25% and the reduction in transfusion rates with TXA use was at least 12%. Although many factors, such as calculation method for costs, market fluctuation, and regional or national variation in health care expenses, can lead to discrepancies, the majority of studies reporting costs offer strong evidence that TXA use is cost-effective.

Conclusion

Tranexamic acid has shown safety and efficacy in orthopedic surgery, especially TKA, THA, and spine surgery, for controlling peri- and postoperative bleeding. Although universal agreement has not been reached on its administration, it is capable of reducing blood loss and transfusion requirements. By lowering various hospital-related costs, including blood bank, operating room, and room and board, TXA is cost-effective in certain orthopedic procedures. Further study is needed to learn more about TXA's cost-saving potential and to examine the drug's safety and complication rates in high-risk patients; the correlation of TXA's efficacy with different administration methods, dosages, and timing; and the correlation of TXA use with postoperative joint functional outcomes.

References

  1. Aguilera-Roig X, Jordan-Sales M, Natera-Cisneros L, Monllau-Garcia JC, Martinez-Zapata MJ. Tranexamic acid in orthopedic surgery [in Spanish]. Rev Esp Cir Ortop Traumatol. 2014; 58(1):52–56.
  2. Zhang H, Chen J, Chen F, Que W. The effect of tranexamic acid on blood loss and use of blood products in total knee arthroplasty: a meta-analysis. Knee Surg Sports Traumatol Arthrosc. 2012; 20(9):1742–1752. doi:10.1007/s00167-011-1754-z [CrossRef]
  3. Kalairajah Y, Simpson D, Cossey AJ, Verrall GM, Spriggins AJ. Blood loss after total knee replacement: effects of computer-assisted surgery. J Bone Joint Surg Br. 2005; 87(11):1480–1482. doi:10.1302/0301-620X.87B11.16474 [CrossRef]
  4. Petaja J, Myllynen P, Myllyla G, Vahtera E. Fibrinolysis after application of a pneumatic tourniquet. Acta Chir Scand. 1987; 153(11–12):647–651.
  5. Eubanks JD. Antifibrinolytics in major orthopaedic surgery. J Am Acad Orthop Surg. 2010; 18(3):132–138. doi:10.5435/00124635-201003000-00002 [CrossRef]
  6. Ishida K, Tsumura N, Kitagawa A, et al. Intra-articular injection of tranexamic acid reduces not only blood loss but also knee joint swelling after total knee arthroplasty. Int Orthop. 2011; 35(11):1639–1645. doi:10.1007/s00264-010-1205-3 [CrossRef]
  7. Georgiadis AG, Muh SJ, Silverton CD, Weir RM, Laker MW. A prospective double-blind placebo controlled trial of topical tranexamic acid in total knee arthroplasty. J Arthroplasty. 2013; 28(suppl 8):78–82. doi:10.1016/j.arth.2013.03.038 [CrossRef]
  8. Nielsen HJ. Detrimental effects of perioperative blood transfusion. Br J Surg. 1995; 82(5):582–587. doi:10.1002/bjs.1800820505 [CrossRef]
  9. Huang F, Wu D, Ma G, Yin Z, Wang Q. The use of tranexamic acid to reduce blood loss and transfusion in major orthopedic surgery: a meta-analysis. J Surg Res. 2014; 186(1):318–327. doi:10.1016/j.jss.2013.08.020 [CrossRef]
  10. Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev. 2012; 4:CD002042.
  11. Henry DA, Carless PA, Moxey AJ, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2011; (3):CD001886.
  12. Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgery and other indications. Drugs. 1999; 57(6):1005–1032. doi:10.2165/00003495-199957060-00017 [CrossRef]
  13. Pusateri AE, Weiskopf RB, Bebarta V, et al. Tranexamic acid and trauma: current status and knowledge gaps with recommended research priorities. Shock. 2013; 39(2):121–126. doi:10.1097/SHK.0b013e318280409a [CrossRef]
  14. Peitsidis P, Kadir RA. Antifibrinolytic therapy with tranexamic acid in pregnancy and postpartum. Expert Opin Pharmacother. 2011; 12(4):503–516. doi:10.1517/14656566.2011.545818 [CrossRef]
  15. Naoulou B, Tsai MC. Efficacy of tranexamic acid in the treatment of idiopathic and nonfunctional heavy menstrual bleeding: a systematic review. Acta Obstet Gynecol Scand. 2012; 91(5):529–537. doi:10.1111/j.1600-0412.2012.01361.x [CrossRef]
  16. Gluud LL, Klingenberg SL, Langholz SE. Systematic review: tranexamic acid for upper gastrointestinal bleeding. Aliment Pharmacol Ther. 2008; 27(9):752–758. doi:10.1111/j.1365-2036.2008.03638.x [CrossRef]
  17. Rannikko A, Petas A, Taari K. Tranexamic acid in control of primary hemorrhage during transurethral prostatectomy. Urology. 2004; 64(5):955–958. doi:10.1016/j.urology.2004.07.008 [CrossRef]
  18. Abbasi H, Behdad S, Ayatollahi V, Nazemian N, Mirshamsi P. Comparison of two doses of tranexamic acid on bleeding and surgery site quality during sinus endoscopy surgery. Adv Clin Exp Med. 2012; 21(6):773–780.
  19. Mohri H. High dose of tranexamic acid for treatment of severe menorrhagia in patients with von Willebrand disease. J Thromb Thrombolysis. 2002; 14(3):255–257. doi:10.1023/A:1025013213192 [CrossRef]
  20. Nuvvula S, Gaddam KR, Kamatham R. Efficacy of tranexamic acid mouthwash as an alternative for factor replacement in gingival bleeding during dental scaling in cases of hemophilia: a randomized clinical trial. Contemp Clin Dent. 2014; 5(1):49–53. doi:10.4103/0976-237X.128663 [CrossRef]
  21. Fricke W, Alling D, Kimball J, Griffith P, Klein H. Lack of efficacy of tranexamic acid in thrombocytopenic bleeding. Transfusion. 1991; 31(4):345–348. doi:10.1046/j.1537-2995.1991.31491213301.x [CrossRef]
  22. Elwatidy S, Jamjoom Z, Elgamal E, Zakaria A, Turkistani A, El-Dawlatly A. Efficacy and safety of prophylactic large dose of tranexamic acid in spine surgery: a prospective, randomized, double-blind, placebo- controlled study. Spine (Phila Pa 1976). 2008; 33(24):2577–2580. doi:10.1097/BRS.0b013e318188b9c5 [CrossRef]
  23. Zhao-Yu C, Yan G, Wei C, Yuejv L, Ying-Ze Z. Reduced blood loss after intra-articular tranexamic acid injection during total knee arthroplasty: a meta-analysis of the literature. Knee Surg Sports Traumatol Arthrosc. 2014; 22(12):3181–3190. doi:10.1007/s00167-013-2814-3 [CrossRef]
  24. Li ZJ, Fu X, Xing D, Zhang HF, Zang JC, Ma XL. Is tranexamic acid effective and safe in spinal surgery? A meta-analysis of randomized controlled trials. Eur Spine J. 2013; 22(9):1950–1957. doi:10.1007/s00586-013-2774-9 [CrossRef]
  25. Chimento GF, Huff T, Ochsner JL Jr, Meyer M, Brandner L, Babin S. An evaluation of the use of topical tranexamic acid in total knee arthroplasty. J Arthroplasty. 2013; 28(suppl 8):74–77. doi:10.1016/j.arth.2013.06.037 [CrossRef]
  26. Hourlier H, Fennema P. Single tranexamic acid dose to reduce perioperative morbidity in primary total hip replacement: a randomised clinical trial. Hip Int. 2014; 24(1):63–68. doi:10.5301/hipint.5000090 [CrossRef]
  27. Yang ZG, Chen WP, Wu LD. Effectiveness and safety of tranexamic acid in reducing blood loss in total knee arthroplasty: a meta-analysis. J Bone Joint Surg Am. 2012; 94(13):1153–1159. doi:10.2106/JBJS.K.00873 [CrossRef]
  28. Fu DJ, Chen C, Guo L, Yang L. Use of intravenous tranexamic acid in total knee arthroplasty: a meta-analysis of randomized controlled trials. Chin J Traumatol. 2013; 16(2):67–76.
  29. Sa-Ngasoongsong P, Channoom T, Kawinwonggowit V, et al. Postoperative blood loss reduction in computer-assisted surgery total knee replacement by low dose intra-articular tranexamic acid injection together with 2-hour clamp drain: a prospective triple-blinded randomized controlled trial. Orthop Rev (Pavia). 2011; 3(2):e12. doi:10.4081/or.2011.e12 [CrossRef]
  30. Wong J, Abrishami A, El Beheiry H, 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(15):2503–2513. doi:10.2106/JBJS.I.01518 [CrossRef]
  31. Panteli M, Papakostidis C, Dahabreh Z, Giannoudis PV. Topical tranexamic acid in total knee replacement: a systematic review and meta-analysis. Knee. 2013; 20(5):300–309. doi:10.1016/j.knee.2013.05.014 [CrossRef]
  32. Yamasaki S, Masuhara K, Fuji T. Tranexamic acid reduces postoperative blood loss in cementless total hip arthroplasty. J Bone Joint Surg Am. 2005; 87(4):766–770. doi:10.2106/JBJS.D.02046 [CrossRef]
  33. Alshryda S, Mason J, Sarda P, et al. Topical (intra-articular) tranexamic acid reduces blood loss and transfusion rates following total hip replacement: a randomized controlled trial (TRANX-H). J Bone Joint Surg Am. 2013; 95(21):1969–1974. doi:10.2106/JBJS.L.00908 [CrossRef]
  34. Poeran J, Rasul R, Suzuki S, et al. Tranexamic acid use and postoperative outcomes in patients undergoing total hip or knee arthroplasty in the United States: retrospective analysis of effectiveness and safety. BMJ. 2014; 349:4829. doi:10.1136/bmj.g4829 [CrossRef]
  35. Tuttle JR, Ritterman SA, Cassidy DB, Anazonwu WA, Froehlich JA, Rubin LE. Cost benefit analysis of topical tranexamic acid in primary total hip and knee arthroplasty. J Arthroplasty. 2014; 29(8):1512–1515. doi:10.1016/j.arth.2014.01.031 [CrossRef]
  36. Mutsuzaki H, Ikeda K. Intra-articular injection of tranexamic acid via a drain plus drain- clamping to reduce blood loss in cementless total knee arthroplasty. J Orthop Surg Res. 2012; 7:32. doi:10.1186/1749-799X-7-32 [CrossRef]
  37. Lozano M, Basora M, Peidro L, et al. Effectiveness and safety of tranexamic acid administration during total knee arthroplasty. Vox Sang. 2008; 95(1):39–44. doi:10.1111/j.1423-0410.2008.01045.x [CrossRef]
  38. Hegde C, Wasnik S, Kulkarni S, Pradhan S, Shetty V. Simultaneous bilateral computer assisted total knee arthroplasty: the effect of intravenous or intraarticular tranexamic acid. J Arthroplasty. 2013; 28(10):1888–1891. doi:10.1016/j.arth.2013.03.018 [CrossRef]
  39. Irisson E, Hemon Y, Pauly V, Parratte S, Argenson JN, Kerbaul F. Tranexamic acid reduces blood loss and financial cost in primary total hip and knee replacement surgery. Orthop Traumatol Surg Res. 2012; 98(5):477–483. doi:10.1016/j.otsr.2012.05.002 [CrossRef]
  40. George DA, Sarraf KM, Nwaboku H. Single perioperative dose of tranexamic acid in primary hip and knee arthroplasty. Eur J Orthop Surg Traumatol. 2015; 25(1):12–133. doi:10.1007/s00590-014-1457-5 [CrossRef]
  41. Chen JY, Rikhraj IS, Zhou Z, et al. Can tranexamic acid and hydrogen peroxide reduce blood loss in cemented total knee arthroplasty?Arch Orthop Trauma Surg. 2014; 134(7):997–1002. doi:10.1007/s00402-014-1958-z [CrossRef]
  42. Chang CH, Chang Y, Chen DW, Ueng SW, Lee MS. Topical tranexamic acid reduces blood loss and transfusion rates associated with primary total hip arthroplasty. Clin Orthop Relat Res. 2014; 472(5):1552–1557. doi:10.1007/s11999-013-3446-0 [CrossRef]
  43. Shapiro F, Zurakowski D, Sethna NF. Tranexamic acid diminishes intraoperative blood loss and transfusion in spinal fusions for duchenne muscular dystrophy scoliosis. Spine (Phila Pa 1976). 2007; 32(20):2278–2283. doi:10.1097/BRS.0b013e31814cf139 [CrossRef]
  44. Smit KM, Naudie DD, Ralley FE, Berta DM, Howard JL. One dose of tranexamic acid is safe and effective in revision knee arthroplasty. J Arthroplasty. 2013; 28(suppl 8):112–115. doi:10.1016/j.arth.2013.05.036 [CrossRef]
  45. Sarzaeem MM, Razi M, Kazemian G, Moghaddam ME, Rasi AM, Karimi M. Comparing efficacy of three methods of tranexamic acid administration in reducing hemoglobin drop following total knee arthroplasty. J Arthroplasty. 2014; 29(8):1521–1524. doi:10.1016/j.arth.2014.02.031 [CrossRef]
  46. Lin PC, Hsu CH, Huang CC, Chen WS, Wang JW. The blood-saving effect of tranexamic acid in minimally invasive total knee replacement: is an additional pre-operative injection effective?J Bone Joint Surg Br. 2012; 94(7):932–936. doi:10.1302/0301-620X.94B7.28386 [CrossRef]
  47. Wang Q, Liu J, Fan R, et al. Tranexamic acid reduces postoperative blood loss of degenerative lumbar instability with stenosis in posterior approach lumbar surgery: a randomized controlled trial. Eur Spine J. 2013; 22(9):2035–2038. doi:10.1007/s00586-013-2836-z [CrossRef]
  48. Yagi M, Hasegawa J, Nagoshi N, et al. Does the intraoperative tranexamic acid decrease operative blood loss during posterior spinal fusion for treatment of adolescent idiopathic scoliosis?Spine (Phila Pa 1976). 2012; 37(21):E1336–E1342. doi:10.1097/BRS.0b013e318266b6e5 [CrossRef]
  49. Bidolegui F, Arce G, Lugones A, Pereira S, Vindver G. Tranexamic acid reduces blood loss and transfusion in patients undergoing total knee arthroplasty without tourniquet: a prospective randomized controlled trial. Open Orthop J. 2014; 8:250–254. doi:10.2174/1874325001408010250 [CrossRef]
  50. Gomez-Barrena E, Ortega-Andreu M, Padilla-Eguiluz NG, Perez-Chrzanowska H, Figuere-do-Zalve R. Topical intra-articular compared with intravenous tranexamic acid to reduce blood loss in primary total knee replacement: a double-blind, randomized, controlled, non-inferiority clinical trial. J Bone Joint Surg Am. 2014; 96(23):1937–1944. doi:10.2106/JBJS.N.00060 [CrossRef]
  51. Soni A, Saini R, Gulati A, Paul R, Bhatty S, Rajoli SR. Comparison between intravenous and intra-articular regimens of tranexamic acid in reducing blood loss during total knee arthroplasty. J Arthroplasty. 2014; 29(8):1525–1527. doi:10.1016/j.arth.2014.03.039 [CrossRef]
  52. Yang Y, Lv YM, Ding PJ, Li J, Ying-Ze Z. The reduction in blood loss with intra-articular injection of tranexamic acid in unilateral total knee arthroplasty without operative drains: a randomized controlled trial. Eur J Orthop Surg Traumatol. 2015; 25(1):135–139. doi:10.1007/s00590-014-1461-9 [CrossRef]
  53. Neilipovitz DT, Murto K, Hall L, Barrowman NJ, Splinter WM. A randomized trial of tranexamic acid to reduce blood transfusion for scoliosis surgery. Anesth Analg. 2001; 93(1):82–87. doi:10.1097/00000539-200107000-00018 [CrossRef]
  54. Sethna NF, Zurakowski D, Brustowicz RM, Bacsik J, Sullivan LJ, Shapiro F. Tranexamic acid reduces intraoperative blood loss in pediatric patients undergoing scoliosis surgery. Anesthesiology. 2005; 102(4):727–732. doi:10.1097/00000542-200504000-00006 [CrossRef]
  55. Bruce-Brand R, Dragomir R, Baker J, Harty J. Cerebrovascular infarction following bilateral total knee arthroplasty and tranexamic acid administration. Acta Orthop Belg. 2013; 79(3):351–354.
  56. Aguilera X, Videla S, Almenara M, Fernandez JA, Gich I, Celaya F. Effectiveness of tranexamic acid in revision total knee arthroplasty. Acta Orthop Belg. 2012; 78(1):68–74.
  57. Alshryda S, Mason J, Vaghela M, et al. Topical (intra-articular) tranexamic acid reduces blood loss and transfusion rates following total knee replacement: a randomized controlled trial (TRANX-K). J Bone Joint Surg Am. 2013; 95(21):1961–1968. doi:10.2106/JBJS.L.00907 [CrossRef]
  58. Alvarez JC, Santiveri FX, Ramos I, Vela E, Puig L, Escolano F. Tranexamic acid reduces blood transfusion in total knee arthroplasty even when a blood conservation program is applied. Transfusion. 2008; 48(3):519–525. doi:10.1111/j.1537-2995.2007.01564.x [CrossRef]
  59. Gillette BP, Maradit Kremers H, Duncan CM, et al. Economic impact of tranexamic acid in healthy patients undergoing primary total hip and knee arthroplasty. J Arthroplasty. 2013; 28(suppl 8):137–139. doi:10.1016/j.arth.2013.04.054 [CrossRef]
  60. 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(5):596–599. doi:10.1093/bja/aeg111 [CrossRef]
  61. Roy SP, Tanki UF, Dutta A, Jain SK, Nagi ON. Efficacy of intra-articular tranexamic acid in blood loss reduction following primary unilateral total knee arthroplasty. Knee Surg Sports Traumatol Arthrosc. 2012; 20(12):2494–2501. doi:10.1007/s00167-012-1942-5 [CrossRef]
  62. Vigna-Taglianti F, Basso L, Rolfo P, et al. Tranexamic acid for reducing blood transfusions in arthroplasty interventions: a cost-effective practice. Eur J Orthop Surg Traumatol. 2014; 24(4):545–551. doi:10.1007/s00590-013-1225-y [CrossRef]
  63. Benoni G, Fredin H, Knebel R, Nilsson P. Blood conservation with tranexamic acid in total hip arthroplasty: a randomized, double-blind study in 40 primary operations. Acta Orthop Scand. 2001; 72(5):442–448. doi:10.1080/000164701753532754 [CrossRef]
  64. Rajesparan K, Biant LC, Ahmad M, Field RE. The effect of an intravenous bolus of tranexamic acid on blood loss in total hip replacement. J Bone Joint Surg Br. 2009; 91(6):776–783. doi:10.1302/0301-620X.91B6.22393 [CrossRef]
  65. Lykissas MG, Crawford AH, Chan G, Aronson LA, Al-Sayyad MJ. The effect of tranexamic acid in blood loss and transfusion volume in adolescent idiopathic scoliosis surgery: a single-surgeon experience. J Child Orthop. 2013; 7(3):245–249. doi:10.1007/s11832-013-0486-7 [CrossRef]
  66. Wang H, Shen B, Zeng Y. Comparison of topical versus intravenous tranexamic acid in primary total knee arthroplasty: a meta-analysis of randomized controlled and prospective cohort trials. Knee. 2014; 21(6):987–993. doi:10.1016/j.knee.2014.09.010 [CrossRef]
  67. Alshryda S, Sukeik M, Sarda P, Blenkinsopp J, Haddad FS, Mason JM. A systematic review and meta-analysis of the topical administration of tranexamic acid in total hip and knee replacement. Bone Joint J. 2014; 96(8):1005–1015. doi:10.1302/0301-620X.96B8.33745 [CrossRef]
  68. Alipour M, Tabari M, Keramati M, Zarmehri AM, Makhmalbaf H. Effectiveness of oral tranexamic acid administration on blood loss after knee arthroplasty: a randomized clinical trial. Transfus Apher Sci. 2013; 49(3):574–577. doi:10.1016/j.transci.2013.09.005 [CrossRef]
  69. Irwin A, Khan SK, Jameson SS, Tate RC, Copeland C, Reed MR. Oral versus intravenous tranexamic acid in enhanced-recovery primary total hip and knee replacement: results of 3000 procedures. Bone Joint J. 2013; 95-B(11):1556–1561. doi:10.1302/0301-620X.95B11.31055 [CrossRef]
  70. Zufferey P, Merquiol F, Laporte S, et al. Do antifibrinolytics reduce allogeneic blood transfusion in orthopedic surgery?Anesthesiology. 2006; 105(5):1034–1046. doi:10.1097/00000542-200611000-00026 [CrossRef]
  71. Benoni G, Lethagen S, Nilsson P, Fredin H. Tranexamic acid, given at the end of the operation, does not reduce postoperative blood loss in hip arthroplasty. Acta Orthop Scand. 2000; 71(3):250–254. doi:10.1080/000164700317411834 [CrossRef]
  72. Alshryda S, Sarda P, Sukeik M, Nargol A, Blenkinsopp J, Mason JM. Tranexamic acid in total knee replacement: a systematic review and meta-analysis. J Bone Joint Surg Br. 2011; 93(12):1577–1585. doi:10.1302/0301-620X.93B12.26989 [CrossRef]
  73. Sukeik M, Alshryda S, Haddad FS, Mason JM. Systematic review and meta-analysis of the use of tranexamic acid in total hip replacement. J Bone Joint Surg Br. 2011; 93(1):39–46. doi:10.1302/0301-620X.93B1.24984 [CrossRef]
  74. Yang B, Li H, Wang D, He X, Zhang C, Yang P. Systematic review and meta- analysis of perioperative intravenous tranexamic acid use in spinal surgery. PLoS One. 2013; 8(2):e55436. doi:10.1371/journal.pone.0055436 [CrossRef]
  75. Wong J, El Beheiry H, Rampersaud YR, et al. Tranexamic acid reduces perioperative blood loss in adult patients having spinal fusion surgery. Anesth Analg. 2008; 107(5):1479–1486. doi:10.1213/ane.0b013e3181831e44 [CrossRef]
  76. Jalaeian Taghaddomi R, Mashhadinezhad H, Sharifian Attar AR, Peivandi A. The effect of intravenous tranexamic acid on blood loss in lumbar hernial disc resection under inhalation and total intravenous anesthesia. Iran Red Crescent Med J. 2009; 11(3):265–270.
  77. Xu C, Wu A, Yue Y. Which is more effective in adolescent idiopathic scoliosis surgery: batroxobin, tranexamic acid or a combination?Arch Orthop Trauma Surg. 2012; 132(1):25–31. doi:10.1007/s00402-011-1390-6 [CrossRef]
  78. Farrokhi MR, Kazemi AP, Eftekharian HR, Akbari K. Efficacy of prophylactic low dose of tranexamic acid in spinal fixation surgery: a randomized clinical trial. J Neurosurg Anesthesiol. 2011; 23(4):290–296. doi:10.1097/ANA.0b013e31822914a1 [CrossRef]
  79. Tsutsumimoto T, Shimogata M, Ohta H, Yui M, Yoda I, Misawa H. Tranexamic acid reduces perioperative blood loss in cervical laminoplasty: a prospective randomized study. Spine (Phila Pa 1976). 2011; 36(23):1913–1918. doi:10.1097/BRS.0b013e3181fb3a42 [CrossRef]
  80. Kim MO, Bae SW. Tranexamic acid versus placebo in decreasing blood loss in patients undergoing spine surgery. Korean J Anesthesiol. 2000; 39:645–650. doi:10.4097/kjae.2000.39.5.645 [CrossRef]
  81. Huang C, Yang ML. The effect of tranexamic acid in perioperative blood loss control and its safety assessment in old patients with multiple lumbar spinal stenosis. Chin J Postgrad Med. 2011; 10(34):17–20.
  82. Yue C, Kang P, Yang P, Xie J, Pei F. Topical application of tranexamic acid in primary total hip arthroplasty: a randomized double-blind controlled trial. J Arthroplasty. 2014; 29(12):2452–2456. doi:10.1016/j.arth.2014.03.032 [CrossRef]
  83. Zhou XD, Tao LJ, Li J, Wu LD. Do we really need tranexamic acid in total hip arthroplasty? A meta-analysis of nineteen randomized controlled trials. Arch Orthop Trauma Surg. 2013; 133(7):1017–1027. doi:10.1007/s00402-013-1761-2 [CrossRef]
  84. Slover J, Bosco J. Cost analysis of use of tranexamic acid to prevent major bleeding complications in hip and knee arthroplasty surgery. Am J Orthop (Belle Mead NJ). 2014; 43(10):E217–E220.
  85. 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(2):880–887. doi:10.1016/j.jss.2013.03.099 [CrossRef]
  86. Johansson T, Pettersson LG, Lisander B. Tranexamic acid in total hip arthroplasty saves blood and money: a randomized, double-blind study in 100 patients. Acta Orthop. 2005; 76(3):314–319.
  87. Kazemi SM, Mosaffa F, Eajazi A, et al. The effect of tranexamic acid on reducing blood loss in cementless total hip arthroplasty under epidural anesthesia. Orthopedics. 2010; 33(1):17. doi:10.3928/01477447-20091124-30 [CrossRef]
  88. Harris RN, Moskal JT, Capps SG. Does tranexamic acid reduce blood transfusion cost for primary total hip arthroplasty? A case-control study. J Arthroplasty. 2015; 30(2):192–195. doi:10.1016/j.arth.2014.08.020 [CrossRef]
  89. Moskal JT, Harris RN, Capps SG. Transfusion cost savings with tranexamic acid in primary total knee arthroplasty from 2009 to 2012. J Arthroplasty. 2015; 30(3):365–368. doi:10.1016/j.arth.2014.10.008 [CrossRef]
  90. Singh J, Ballal MS, Mitchell P, Denn PG. Effects of tranexamic acid on blood loss during total hip arthroplasty. J Orthop Surg (Hong Kong). 2010; 18(3):282–286.

Mean Blood Loss, Transfusion Rates, and Reported Complications Noted in Published Meta-Analyses

StudySurgeryAdministration RouteIncluded Studies (No. of Patients)Mean TBL Reduction With TXA, mLMean IBL Reduction With TXA, mLMean PBL Reduction With TXA, mLBlood Transfusion Relative Risk of TXANo. of Reported VTE Complications: Non-TXA/TXANo. of Other Reported Complications: Non-TXA/TXAOther Values
Alshryda et al72TKAIV, topical, oral19 RCTs591 (P<.001)n/a245 (P<.001)0.39 (P<.001)DVT: NS; PE: 4/1 (P=.5)n/aDVT risk difference: 0.00 (P=.98)
Alshryda et al67THA, TKATopical14 RCTs: 11 TKA/2 THA/2 bothTKA: 461.8 (P<.001); THA: 364 (P=.02)n/aTKA: 314.5 (P<.001)TKA: 0.22 (P<.001); THA: 0.39 (P=.004)DVT: NS; PE: 4/2n/aDVT risk difference: −0.01 (P=.24)
Fu et al28TKAIV22 RCTs (1361)435.41 (P<.01)10.28 (P=.62)406.69 (P<.01)n/aDVT: 27/47 (P=.77); PE: 3/0 (P=.44)Infections: 1/5; hematoma: 6/9; wound secretions: 2/3; MI: 0/1; death: 1/1Mean reduction in blood transfusion units: 0.95 unit (P<.01); transfusion rate risk difference: −0.30 (P<.01)
Huang et al9Orthopedic surgeryn/a46 RCTs (2925)408.33 (P<.00001)125.65 (P<.0001)214.58 (P<.00001)0.51 (P<.00001)DVT: 26/30 (P=.66)n/aMean reduction in blood transfusion rate: 49% (P<.00001); mean reduction in blood transfusion units per patient: 0.78 unit (P<.0002); mean reduction in blood transfusion volume per patient: 205.33 mL (P<.0001); DVT relative risk: 1.11 (P=.66)
Li et al24Spine surgeryIV6 RCTs (411)285.35 (P=.01)n/an/a0.71 (P=.01)DVT: 1/0n/aMean reduction in blood transfusion volume per patient: 198.12 mL (P=.08)
Panteli et al31TKATopical7 studies220.08 (P<.00001)n/a268.36 (P=.02)0.47 (P=.01)DVT: 1/3 (P=0.66); PE: 1/1 (P=.67)n/aMean reduction in maximum postoperative Hb drop: 0.94 g/dL (P<.00001)
Sukeik et al73THAIV11 RCTs289 (P<.0002)104 (P=.0006)172 (P=.0002)n/aDVT: NS; PE: 1/2 (P=.76)Infections: 2/2 (P=.97)Transfusion rate risk difference: −0.20 (P<.00001)
Tan et al85TKAIV19 RCTs (1114)570 (P<.00001)n/a290 (P<.00001)0.39 (P<.00001)NSHematoma: 13/11; superficial infections: 2/3; deep infections: 0/1; cardiac events: 0/1; pulmonary infection: 1/1; respiratory insufficiency: 0/1Mean reduction in blood transfusion units per patient: 0.96 unit (P<.00001); mean reduction in blood transfusion volume per patient: 440 mL (P<.00001)
Yang et al74Spine surgeryIV9 studies (581)389.21 (P=.0003)128.28 (P=.008)98.49 (P<.00001)0.65 (P<.0001)DVT: 1/0n/aMean reduction in blood transfusion volume: 134.55 mL (P=.0001); DVT relative risk: 0.34 (P=.50)
Yang et al27TKAn/a15 RCTs (837)504.9 (P<.00001)n/an/an/aNSn/aMean reduction in blood transfusion units: 1.43 units (P<.00001); transfusion odds ratio: 0.16 (P=.00001); odds ratio on DVT: 0.75 (P=.48); odds ratio on PE: 0.65 (P=.50); no significant changes on PT, aPTT
Zhang et al2TKAn/a15 RCTs (842)486.7 (P<.00001)126.75 (P=.18)245.0 (P=.004)n/aDVT: 12/12 (NS); PE: 3/2 (NS)Hematoma: 4/7; drain secretions: 2/3; death: 1/1; MI: 1/0; infections: 2/6Mean reduction in blood transfusion units per patient: 1.3 units (P<.00001); transfusion rate risk difference: −0.4 (P<.00001); DVT risk difference: 0.00 (P=.85)
Zhao-Yu et al23TKATopical6 RCTs (647)320.44 (P<.01)n/a206.09 (P<.01)0.28 (P<.01)PE: 2/1n/aMean reduction in Hb drop: 0.63 g/dL (P=.02); DVT relative risk: 1.75 (P=.82)
Zhou et al83THAIV19 RCTs (1030)305.27 (P<.001)86.33 (P=.01)176.79 (P<.001)n/aDVT: 19/15 (NS); PE: 1/3 (NS)n/aTransfusion odds ratio: 0.28 (P<.001); mean reduction in Hb drop: 0.603 g/dL (P<.001); mean reduction in Hct drop: 2.29% (P<.001)

Length of Hospital Stay and Hospital Costs Associated With TXA Use in Orthopedic Surgery

StudyLevel of EvidenceSurgeryTXA DoseAdministration RouteTotal No. of Cases (Non-TXA/TXA)Average Hospital Stay, d: Non-TXA/TXAMean Reduction in Combined Pharmacy and Transfusion Costs per Patient With TXAMean Cost of Hospital Stay per Patient: Non-TXA/TXA/% Savings
Alshryda et al33ITHAn/aTopical161 (81/80)6.2/5.2 (P=.109)n/a£1526/£1221 (P=.05)/19.99%
Alshryda et al57ITKA1 g TXA/50 mL normal saline sprayed into wound at end of surgery before closureTopical157 (78/79)6.1/4.8 (P=.041)n/a£1450/£1117 (P=.028)/22.97%
Bidolegui et al49ITKA15 mg/kg (diluted in 100 mL of normal saline) 10-min IV infusion twice, first dose during induction of anesthesia and second 3 h laterIV50 (25/25)3.8/4.1 (P=.271)n/an/a
Elwatidy et al22ISpine surgeryLoading dose of 2 g (adults) or 30 mg/kg (children) followed by continuous infusion of 100 mg/h (adults) or 1 mg/kg/h (children) intraoperatively and 5 h postoperativelyIV64 (32/32)10.69/8.45 (P=.21)n/an/a
Georgiadis et al7ITKA2 g TXA/75 mL normal saline applied to wound for 5 min under tourniquet before suctioningTopical101 (51/50)2.8/2.7 (P=.495)n/an/a
Gomez-Barrena et al50ITKA2 IV doses (15 mg/kg in 100 mL of physiological saline solution, 1 dose before tourniquet release and another 3 h postoperatively), or 3 g/100 mL physiological saline solution intra-articularlyIV or topical78 (39 IV/39 topical)a3.9/3.5 (P=.316)an/an/a
Johansson et al86ITHABolus infusion of 15 mg/kg mixed in 100 mL normal saline immediately preoperativelyIV100 (53/47)n/a47 eurosn/a
Kazemi et al87ICementless THA15 mg/kg administered 5 min preoperativelyIV64 (32/32)15.5/13 (P=.34)n/an/a
Lin et al46IMinimally invasive TKA(1) Non-TXA; (2) 1 dose of 10 mg/kg at 5 min before tourniquet deflation; (3) 2 doses of 10 mg/kg at 5 min before incision and 5 min before tourniquet deflationIV151 (50 group 1/52 group 2/49 group 3)5.5/5.3 (P=.175)b/5.7 (P=.596)bn/an/a
Wong et al30ITKA1.5 g TXA/100 mL normal saline or 3.0 g TXA/100 mL normal saline applied into joint for 5 min at end of surgeryTopical99 (35 non-TXA, 31 given 1.5 g dose, 33 given 3 g dose)4.3/4.7/4.5n/an/a
Chen et al41IICemented TKA1500 mg TXA/100 mL normal saline as a wash with 5-min contact time after cementing and before closure of retinaculumTopical100 (50/50)5/5 (NS)n/an/a
Vigna-Talianti et al62IIArthroplasty10 mg/kg in 30 min immediately preoperatively and 2 additional doses on postoperative d 1 and 2 in 6-h infusion periodIV198 (100/98)n/aTHA alone: 138 euros; both THA & TKA: 135c eurosn/a
Chang et al42IIITHA10 mL 5% TXA in topical cocktail solution with 1/3 injected intra-muscularly and intra-capsularly and 2/3 intra-articularly after fasciae closureTopical388 (234/154)5.2/5.7n/an/a
Chimento et al25IIITKA3 g TXA/100 mL normal saline used to irrigate wound following cementingTopical683 (373/310)5.3/4.7 (P<.001)$187.63$13,854.02/$12,333.72 (P<.001)/10.97%
George et al40IIITHA & TKA1 g bolusIVHip: 50 (20/30); knee: 60 (30/30)Hip: 6/6.43 (P=.70); knee: 5.23/5.62 (P=.68)n/an/a
Gillette et al59IIITHA & TKA1 g at incision and 1 g at closuren/a1018 (438/580)n/an/a$15,978/$15,099 (P<.0002)/5.50%
Harris et al88IIITHA1 g IV infusion within 1 h of incision and again as wound closure began; topical TXA placed in wound before closure and hemovac drain clamped for 30 min postoperativelyIV or topical1595 (1047 non-TXA/478 IV/70 topical)n/aIV: $163.52/topical: $154.49n/a
Lozano et al37IIITKA10 mg/kg infused over 10 min immediately before tourniquet inflation and immediately after releaseIV414 (215/199)n/a115.07 eurosn/a
Moskal et al89IIITKA1 g IV infusion within 1 h of incision and again as wound closure began; topical TXA placed in wound before closure and hemovac drain clamped for 30 min postoperativelyIV or topical2299 (1839 non-TXA/330 IV/130 topical)n/aIV: $2.31/topical: $45.76n/a
Poeran et al34IIITHA & TKANone, ≤1000 mg, 2000 mg, ≥3000 mgIV872,416 (852,365/20,051 [≤1000 mg: 7041; 2000 mg: 8992; ≥3000 mg: 4018])3 (3–4)/3 (2–4)d,e (P<.001)n/a$15,110/$14,980 (P<.001)/0.86%d
Singh et al90IIITHASingle dose of 10 mg/kg administered 10 min prior to incisionIV42 (21/21)6.4/5.9 (P=.34)n/an/a
Smit et al44IIIRevision TKA20 mg/kg given prior to tourniquet releasen/a424 (178/246)8.6/6.7 (P=.005)n/an/a
Tuttle et al35IIITHA & TKAIn THA, 1 g TXA/10 mL normal saline injected in pericapsular and deep tissue spaces or intra-articularly following iliotibial band or tensor fascia closure; in TKA, 1 g TXA/10 mL normal saline injected intra-articularly after capsular closureTopical591 (280/311)3.16/3.15 (P=.84)$83.73n/a
Irisson et al39IVTHA & TKA1 g (15 mg/kg) at incision and wound closure then at 6-h intervals for 24 hIV451 (241/210)n/a41 eurosn/a
Authors

The authors are from the Department of Orthopaedics, Medical University of South Carolina, Charleston, South Carolina.

The authors have no relevant financial relationships to disclose.

Correspondence should be addressed to: Shane K. Woolf, MD, Department of Orthopaedics, Medical University of South Carolina, 171 Ashley Ave, CSB 708, Charleston, SC 29425 ( woolfsk@musc.edu).

Received: May 01, 2015
Accepted: August 20, 2015

10.3928/01477447-20160301-05

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