The Efficacy of Tranexamic Acid in Anterior Cruciate Ligament Reconstruction: A Systematic Review and Meta-Analysis.

New and Off-Label Uses of Tranexamic Acid.

Effects of tranexamic acid on vascular occlusive events and perioperative resuscitation in patients with atrial fibrillation undergoing total joint arthroplasty.

This issue of TRANSFUSION features two clinical trials on the use of tranexamic acid (TXA) in joint replacement surgery. The first study examines the use of TXA for reducing autologous blood transfusion in total knee or hip replacement surgery.1 The second study reports the effect of TXA on allogeneic blood transfusion for two-staged bilateral total knee replacement surgery.2 The first study is a double-blinded randomized placebo controlled trial in which Oremus and colleagues1 compared TXA with placebo to evaluate the efficacy of TXA to reduce autologous transfusion of shed blood in unilateral primary total knee or hip replacement. Ninety-eight primary hip or primary knee replacement patients were randomly allocated to receive an intraoperative intravenous (IV) dose of 1 g of TXA or placebo 15 minutes before skin incision for total hip replacement or 15 minutes before tourniquet release for total knee replacement. After 3 hours, a second dose of 1 g of TXA or an equivalent volume of placebo (saline) was administered IV. The minimum volume of retransfusion was set at 250 mL and a transfusion trigger of hemoglobin (Hb) level of less than 8 or 8 to 10 g/dL with symptoms of anemia. Only 10.2% in the TXA group versus 85.7% in the placebo group received autologous transfusion. The TXA group had a 75% lower requirement for autologous transfusion than the placebo group. The median total external blood loss during the first 24 hours was 320 mL (80-930 mL) in the TXA group versus 970 mL (100-2600 mL) in the placebo group. This study also examined the safety profile of TXA by measuring hemodynamic changes during administration of TXA and performed postoperative screening for deep vein thrombosis (DVT). Clinical assessment for DVT was performed three times a day and ultrasonography, fibrinogen, and D-dimer measurements were performed in suspected cases. The authors did not find any difference in hemodynamic changes or DVT between both groups. In addition, there was no difference in blood loss between the total knee replacement and total hip replacement surgery. This study provides evidence that using TXA with a restrictive transfusion trigger policy can potentially replace the use of an autologous drain system. This protocol can avoid the autologous blood transfusion related complications such as febrile reactions and possible retrograde infection. The use of closed suction drainage for joint replacement surgery is controversial and there is practice variation in whether surgical drains are used. Although the use of a drain is based on individual or institutional practice, evidence has shown that the use of a closed system suction drainage increases the total blood loss after joint replacement surgery.3 At the same time, a recent meta-analysis has confirmed that autologous shed blood transfusion is an effective method to reduce allogeneic blood transfusion.4 Other techniques used to reduce the blood loss are clamping the drain, retrograde injection of TXA through the drain, and closure without a drain.5 The current study by Oremus and coworkers suggests that TXA could potentially eliminate the need for surgical drains and autologous shed blood transfusion. The cost-effectiveness of using TXA rather than autologous transfusion of shed blood was not analyzed in this study, although the cost of TXA may be lower. Overall this well-designed randomized controlled trial shows the efficacy of TXA on reducing autologous shed blood transfusion. The second study is a retrospective study in which Kelley and coworkers2 determined the effect of TXA on blood transfusion in patients undergoing bilateral total knee replacement staged 3 days apart. Transfusion rates were compared between patients who did not receive TXA (before the routine use of TXA) and after the institution of TXA for bilateral total knee replacement. The TXA group received 1 g of TXA IV 15 minutes before incision and 1 g IV before tourniquet release. The main findings were the TXA group had lower mean blood loss than the non-TXA group (373.8 ± 264.6 mL vs. 871.6 ± 457.7 mL, respectively). The blood transfusion rate was lower (43.1% vs. 71.4%) in the TXA group and the amount of allogeneic blood transfusion was lower (0.64 ± 0.84 units vs. 1.53 ± 1.30 units) in the TXA group. In addition, the TXA group had significantly higher Hb level on Day 1 and Day 2 with each stage of total knee replacement. Otherwise there was no difference in postoperative complications including infection, venous thromboembolism, reoperation, hematoma, or pre- and postoperative Knee Society score and range of movement. Since this study was retrospective, routine screening for venous embolism was not done. The transfusion trigger was 9 g/L for the first surgery and 8 g/L for the second surgery. These two studies add to the growing literature supporting the efficacy of TXA for reducing blood loss6, 7 and blood transfusion in joint replacement surgery. Surgical trauma and the use of a tourniquet have been shown to activate fibrinolysis. TXA is a lysine analog that helps to prevent fibrinolysis in conditions that promote fibrinolysis. TXA is relatively inexpensive, easy to administer, and more cost-effective than transfusion and other blood conservation techniques. Existing studies in the orthopedic surgical literature have not shown an increase in adverse events such as thromboembolic complications with the use of TXA for joint replacement surgery. Although the study designs differ, both current studies used the same total dose of TXA and used closed suction drain systems. The total dose of TXA used in both studies was 2 g, but the timing of administration was different. The timing of administration and dosage of TXA have varied in previous studies. A recent study found a preoperative and intraoperative IV dose of TXA was more effective than a single dose of TXA given intraoperatively or an intraoperative dose followed by a postoperative dose.8 These authors also concluded that a single dose with local application was more effective than a single dose administered IV.8 The optimal dose, timing of administration, mode of administration, and duration of treatment have not been determined. A recent systematic review and meta-analysis concluded that the effect of TXA on blood loss varied with the timing of administration of TXA, but the extent of this variation was small, and the authors questioned the clinical importance of this variation.9 The authors also found a lack of a dose–response relationship of TXA, with a total dose of about 14 mg/kg (approx. 1 g) appearing to be sufficient. However, these authors did not specifically examine joint replacement surgery, but included different types of surgery. Most of the blood loss in total knee replacements occurs during the first few hours after surgery.10 A recent pharmacokinetic study showed that peak fibrinolytic activity occurred at 6 hours from the incision time for both total hip and total knee replacement, and the fibrinolysis activity persisted for 18 hours.11 This finding supports a multiple dose regime or a postoperative infusion as the most effective way to reduce blood loss with use of TXA in joint replacement surgery. However, this protocol must be balanced with the high risk for DVT in this patient population. These studies support the use of TXA to reduce blood loss and transfusion in joint replacement surgery. The optimal timing, dose, duration of treatment, and route of administration of TXA, however, remain uncertain. There is a need for more pharmacokinetics studies to optimize the use of TXA to reduce blood loss and blood transfusion, while minimizing any potential adverse effects in joint replacement surgery. These studies should be encouraged by the transfusion medicine community since TXA appears to be a useful pharmacologic alternative to transfusion in orthopedic surgery. None.

Objectives: Previous studies in shoulder and knee arthroscopy have reported that tranexamic acid (TXA) may improve early functional recovery, prevent postoperative intra-articular bleeding, reduce subjective pain, and improve intra-operative visual field clarity. However, there is a paucity of literature describing the use of TXA in hip arthroscopy. Previous studies have reported statistically significant improvements in VAS pain and Modified Hip Harris scores. However, they used a limited subset of Patient Reported Outcome Measures (PROMs) and did not characterize the effects of TXA on visibility during arthroscopy. The primary objective of this study is to determine the role of TXA in hip arthroscopy based on assessment of postoperative pain and function. A second objective of this study is to determine whether TXA influences intra-operative visual clarity and pump pressures. Methods: This double blinded randomized controlled trial is enrolling 70 patients undergoing primary hip arthroscopy. Subjects are randomized to receive TXA (n=35) or not receive TXA (n=35). The TXA group receives 1g of TXA intravenously at the time of incision and another 1g of TXA during closure. For the duration of the surgery, arthroscopic visual field clarity is rated by the surgeon every 15 minutes as poor, fair, or good and assigned a score of 1, 2, and 3, respectively. Each time the visual clarity is rated, pump pressure is also recorded. Range of motion, VAS Pain, iHOT-12, HOS Sport and activities of daily living, PROMIS Physical Function (PF), and PROMIS Pain Interference (PI) scores are collected preoperatively and postoperatively at days 14 and 42. Additionally, VAS pain is assessed at postoperative day 1. At the completion of all study activities, patient charts are reviewed to determine whether they have requested any additional analgesic medication during the study. Results: The preliminary data for this study includes completed data from 16 (9 female, 7male) patients with a mean age of 44 years. The TXA and control groups had 9 and 7 patients, respectively. No significant difference in VAS pain scores were observed preoperatively, at 1 day postoperatively, or at 42 days postoperatively. There was a significant difference (p=0.01) in VAS pain scores between the two groups at 14 days postoperatively, with the TXA and control groups having mean scores of 2.22 ± 1.48 and 4.33 ± 1.21, respectively. Both groups have shown improvements in PROMs between preoperative scores and postoperative day 42, with larger improvements being seen in the TXA group (although failing to meet statistical significance). Complete preliminary data for PROMs can be seen in Table 1. The average visual score in the TXA group (2.85 ± 0.25) was better than that of the control group (2.67 ± 0.2) but failed to meet statistical significance (p=0.132). The frequency that each rating was assigned was calculated for each group and can be seen in Table 2. A chi-squared test of independence was conducted to examine the relationship between the distribution of grades (Good, Fair, Poor) and the treatment groups (TXA and Control). The test indicated no association between the two variables (Pearson’s χ² = 5.6, df = 2, p = 0.06). Although the p-value did not reach significance level (α<0.05), the preliminary data favored the TXA group in terms of visibility. Pump pressures did not show any significant difference between the TXA group and the control group at any of the time points. No patients have requested additional pain medications during their involvement in this study at this time. Conclusions: The use of TXA in hip arthroscopy descriptively demonstrated improvements in post-operative pain and function, but not intraoperative visual clarity. The trends in the preliminary data, particularly for visual clarity and the measures of pain such as VAS Pain (Figure 1) and PROMIS-PI (Figure 2), suggest a clinical benefit to intraoperative TXA use. Larger sample sizes are needed to establish the significance of these findings and further explore the relationship between TXA and postoperative outcomes, visual clarity, and pump pressures in hip arthroscopy.

Tranexamic Acid Administration in Arthroscopic Surgery Is a Safe Adjunct to Decrease Postoperative Pain and Swelling: A Systematic Review and Meta-analysis

Bleeding and the need for allogeneic transfusions are still problems after off-pump coronary artery bypass grafting (OPCAB) surgery. We therefore evaluated the effects of an antifibrinolytic, tranexamic acid, on postoperative bleeding and transfusion requirements in patients undergoing OPCAB surgery. Two hundred thirty-one consecutive patients scheduled for elective OPCAB were enrolled in the study. Using a double-blind method, the patients were randomly assigned to receive either tranexamic acid (bolus 1 g before surgical incision followed by an infusion of 400 mg/h during surgery; n = 116) or a placebo (infusion equivalent volume of saline solution; n = 115). The primary outcome was 24-hour postoperative chest tube drainage. Allogeneic transfusion, mortality, major morbidities, and resource utilization were also recorded. In comparison with the placebo group, the patients receiving tranexamic acid had a significant reduction in chest tube drainage at 6 hours (270 ± 118 mL vs 416 ± 179 mL, P < 0.001) and 24 hours (654 ± 224 mL vs 891 ± 295 mL, P < 0.001). There was also a significant reduction in allogeneic red blood cell transfusions (47 vs 31.9%, P = 0.019) and fresh frozen plasma (29.6% vs 17.2%, P = 0.027) transfusions. There were no differences in mortality, morbidity, and resource utilization between the 2 groups. Tranexamic acid reduces postoperative chest tube drainage and the requirement for allogeneic transfusion in off-pump coronary surgery.

Background: Hemarthrosis after anterior cruciate ligament (ACL) reconstruction procedures can delay rehabilitation and have toxic effects on the cartilage and synovium. Tranexamic acid is widely used in adult reconstruction procedures; however, its use in ACL reconstruction is a novel topic of study. Purpose: To analyze the available literature on hemarthrosis, pain, functional outcomes, and complications after administration of tranexamic acid in ACL reconstruction procedures. Study Design: Meta-analysis. Methods: A literature search was performed to retrieve randomized controlled trials examining the use of tranexamic acid at the time of ACL reconstruction procedures. The studied outcomes included postoperative joint drain output, hemarthrosis grade, visual analog scale scores for pain, range of motion, Lysholm score, postoperative rates of deep venous thrombosis, and pulmonary embolism. Outcomes were pooled to perform a meta-analysis. Results: Five prospective randomized controlled trials met inclusion criteria for analysis. Four studies administered intravenous tranexamic acid in bolus or infusion form before ACL reconstruction, while 2 studies administered tranexamic acid via intra-articular injection. Specifically, tranexamic acid was administered intravenously (preoperative 15-mg/kg bolus 10 minutes before tourniquet inflation with or without 10 mg/kg/h for 3 hours postoperatively) or intra-articularly (10 mL [100 mg/mL] intraoperatively), and 1 study consisted of tranexamic acid administration in combined intravenous and intra-articular forms (15-mg/kg bolus 10 minutes before tourniquet inflation and intra-articular 3 g 10 minutes before tourniquet deflation). Tranexamic acid use in ACL reconstruction cases resulted in a mean reduction of 61.5 mL in postoperative drain output at 24 hours (95% CI, –95.51 to −27.46; P = .0004), lower hemarthrosis grade (P < .00001), improved Lysholm scores, and reduction in visual analog scale scores for pain (−1.96 points; 95% CI, −2.19 to −1.73; P < .00001) extending to postoperative week 6. Range of motion was improved in the immediate postoperative period, and the need for joint aspiration within 2 weeks was reduced (P < .001). There was no difference in venous thromboembolic event rate between the experimental and control groups. Conclusion: The use of intravenous tranexamic acid in ACL reconstruction surgery results in reduced joint drain output and hemarthrosis and improved pain scores and range of motion in the initial postoperative period without increased complications or thromboembolic events.

What's New in Sports Medicine.

Randomized prospective evaluation of the use of tranexamic acid and effects on blood loss for proximal humeral fracture surgery

Background:Pediatric patients are at risk for bleeding after cardiac surgery. Administration of antifibrinolytic agents reduces postoperative blood loss.Objective:Evaluation of the efficacy of combined administration of tranexamic acid (TXA) and ethamsylate in the reduction of postoperative blood loss in pediatric cardiac surgery.Methods:This prospective randomized study included 126 children submitted for cardiac surgery, and they were allocated into three groups: control group (n = 42); TXA group (n = 42):- received only TXA; and combined ethamsylate TXA group (n = 42):- received a combination of TXA and ethamsylate. The main collected data included sternal closure time, the needs for intraoperative transfusion of blood and its products, the total amount of blood loss, and the amount of the whole blood and its products transfused to the patients in the first 24 postoperative hours.Results:Blood loss volume in the first 24 postoperative hours was significantly smaller in combined group than the TXA and control groups and was significantly smaller in the TXA group than the control group. The sternal closure time was significantly shorter in the combined group than the other 2 groups and significantly shorter in TXA than the control group. The amount of whole blood transfused to patients in the combined group during surgery and in the first postoperative 24 h was significantly smaller than the other 2 groups and smaller in TXA group than the control group during surgery.Conclusion:Combined administration of ethamsylate and TXA in pediatric cardiac surgery was more effective in reducing postoperative blood loss and whole blood transfusion requirements than the administration of TXA alone.

Chronic subdural hematoma (CSDH) is a common neurosurgical disease and generally treated with burr-hole surgery alone. Tranexamic acid (TXA) is an antifibrinolytic agent that potentially reduces recurrence rates and the residual hematoma volume. However, the role of postoperative TXA medication remains unclear to date. This study aimed to verify the effectiveness of adjunctive TXA in the view of early hematoma resolution. Between January 2018 and September 2021, patients with CSDH who underwent burr-hole trephination in a single tertiary institute were reviewed. The study population was divided into three groups, TXA, non-TXA, and antithrombotics (AT) groups, according to the medical history of cardio-cerebrovascular disease and TXA administration. The primary endpoint was CSDH recurrence, defined as re-appearance or re-accumulation of CSDH requiring neurosurgical interventions. The secondary outcome was CSDH resolution, defined as complete or near-complete resorption of the CSDH. The CSDH resolution time and serial changes of hematoma thickness were also investigated. A total of 240 patients was included in the analysis consisting of 185 male and 55 female, with a median age of 74 years. During the median imaging follow-up period of 75 days, 222 patients were reached to the primary or secondary endpoint. TXA was administered as an adjunctive therapy in 41 patients (TXA group, 16.9%) while 114 patients were included in the non-TXA group (47.9%) and 85 were in the AT group. The recurrence rate was the lowest in the TXA group (2.4%), followed by non-TXA (7.0%) and AT (8.2%) groups. However, there was no statistical significance due to the small number of patients with recurrence. CSDH resolution was achieved in 206 patients, and the median estimated time to resolution was significantly faster in the TXA group (p<0.001). Adjunctive TXA administration was a significant positive factor for achieving CSDH resolution (p<0.001). The hematoma thickness was comparable among the three groups at the initial time and after surgery. However, CSDH thickness in the TXA group decreased abruptly in a month and showed a significant difference from that in the other groups (p<0.001). There was no TXA-related adverse event. The adjunctive use of TXA after CSDH surgery significantly facilitated the resorption of residual CSDH and resulted in the early CSDH resolution. Adjunctive TXA may be an effective treatment option to reduce recurrence by enhancing CSDH resolution in the selective patients.

Visual clarity during shoulder arthroscopy can ensure an efficient and effective performance of the procedure, and it is highly related to bleeding without a tourniquet. Tranexamic acid (TXA) is widely used in adult reconstruction procedures; however, its use in shoulder arthroscopic operations is a relatively novel topic. To analyze the available literature on visual clarity, blood loss, pain control, functional outcomes, and complications after the administration of tranexamic acid in shoulder arthroscopic surgery. A literature search was performed to retrieve randomized controlled trials examining the use of tranexamic acid at the time of shoulder arthroscopic surgery. The literature search included the MEDLINE, Embase, Web of Science, and Cochrane Library databases. The primary outcomes included visual clarity, blood loss, and visual analog scale scores for pain. Secondary outcomes were operative time, irrigation amount used, postoperative shoulder swelling, the need for pressure increase, mean arterial pressure (MAP), functional outcomes, postoperative adverse effects such as deep venous thrombosis, and pulmonary embolism. The outcomes were pooled to perform a meta-analysis. Seven prospective randomized controlled trials met the inclusion criteria for analysis. All of the included studies performed arthroscopic rotator cuff repair. No significant difference in visual clarity was observed (SMD (standardized mean difference), 0.45 [95% CI(confidence interval), -0.68, 1.59]; p = 0.44) nor in pain score (MD (mean difference), -0.46 [95% CI, -0.97, 0.05]; p = 0.08) between the TXA group and the control group. Two studies found no significant difference in blood loss between the TXA group and the control group. The meta-analysis from five studies demonstrated no significant difference between the TXA and control groups in operative time (MD, -3.51 [95% CI, -15.82, 8.80]; p = 0.58) or irrigation amount used (MD, -2.53 [95% CI, -5.93, 0.87]; p = 0.14). Two trials reported different statistical results in postoperative shoulder swelling. No significant differences regarding the need for pressure increase and MAP were reported between groups. No wound complications or infections or cardiac, thrombotic, or thromboembolic complications were recorded in either group. The use of intravenous or local TXA in shoulder arthroscopic surgery did not increase complications or thromboembolic events, but TXA had no obviously effect of reducing bleeding to obtain a clear visual field or pain release in patients undergoing shoulder arthroscopic surgery.

IntroductionHemorrhage is one of the leading causes of death in trauma victims. Historically, paramedics have not had access to medications that specifically target the reversal of trauma-induced coagulopathies. The California Prehospital Antifibrinolytic Therapy (Cal-PAT) study seeks to evaluate the safety and efficacy of tranexamic acid (TXA) use in the civilian prehospital setting in cases of traumatic hemorrhagic shock.MethodsThe Cal-PAT study is a multi-centered, prospective, observational cohort study with a retrospective comparison. From March 2015 to July 2017, patients ≥ 18 years-old who sustained blunt or penetrating trauma with signs of hemorrhagic shock identified by first responders in the prehospital setting were considered for TXA treatment. A control group was formed of patients seen in the five years prior to data collection cessation (June 2012 to July 2017) at each receiving center who were not administered TXA. Control group patients were selected through propensity score matching based on gender, age, Injury Severity Scores, and mechanism of injury. The primary outcome assessed was mortality recorded at 24 hours, 48 hours, and 28 days. Additional variables assessed included total blood products transfused, the hospital and intensive care unit length of stay, systolic blood pressure taken prior to TXA administration, Glasgow Coma Score observed prior to TXA administration, and the incidence of known adverse events associated with TXA administration.ResultsWe included 724 patients in the final analysis, with 362 patients in the TXA group and 362 in the control group. Reduced mortality was noted at 28 days in the TXA group in comparison to the control group (3.6% vs. 8.3% for TXA and control, respectively, odds ratio [OR]=0.41 with 95% confidence interval [CI] [0.21 to 0.8]). This mortality difference was greatest in severely injured patients with ISS >15 (6% vs 14.5% for TXA and control, respectively, OR=0.37 with 95% CI [0.17 to 0.8]). Furthermore, a significant reduction in total blood product transfused was observed after TXA administration in the total cohort as well as in severely injured patients. No significant increase in known adverse events following TXA administration were observed.ConclusionFindings from the Cal-PAT study suggest that TXA use in the civilian prehospital setting may safely improve survival outcomes in patients who have sustained traumatic injury with signs of hemorrhagic shock.

Background: A significant proportion of surgeons use intra-articular drains after arthroscopic anterior cruciate ligament (ACL) reconstruction. Hemarthrosis and pain adversely affect the functional outcomes of ACL reconstruction in the early postoperative period. Purpose: To evaluate the effects of administering tranexamic acid (TXA) to minimize knee joint hemarthrosis and associated pain. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: A total of 105 patients who underwent arthroscopic ACL reconstruction were enrolled in this prospective, randomized, double-blind study. The patients who were randomized to the TXA group (n = 53) received intravenous TXA; the control group (n = 52) did not receive TXA. The anesthetist, surgeon, observer, and patients were blinded to the study groups (double-blinded). TXA was administered as a bolus dose of 15 mg/kg 10 minutes before the inflation of the tourniquet, and an intravenous infusion of 10 mg/kg/h was continued for 3 hours after completion of the operation. In the control group, an equal volume of placebo was administered at the same rate and by the same route. The volume of drained blood was measured 24 hours postoperatively. Pain was evaluated using a visual analog scale (VAS) at a consistent time in the evening of postoperative day 3 and postoperative weeks 2 and 3. The Lysholm knee scoring scale was used to record patient satisfaction and knee function during postoperative weeks 2 and 4. Results: Significant differences were observed between the volume of fluid drained (60 mL [TXA group] vs 150 mL [control group]; P < .001) (between-group difference [95% CI], −90 [−114.15 to −65.85]) and hemarthrosis grade in postoperative weeks 1 and 2. In addition, the pain outcome improved in the TXA group after day 3 (VAS score, 1.4) compared with that in the control group (VAS score, 2.9) (P < .001) (95% CI, −1.51 to −0.49). The VAS scores of the TXA group at the end of weeks 2 and 3 were also significantly lower than those in the control group (P < .001) (95% CI, −2.00 to −1.00). The median Lysholm score at the end of week 2 was 70 (range, 40-85) in the control group and 75 (range, 50-90) in the TXA group; at the end of week 4, the score was 75 (range, 50-85) in the control group and 80 (range, 70-85) in the TXA group. A significant difference in the Lysholm score was observed between the 2 groups (P < .001) (95% CIs, 0.08-9.92 and 4.00-10.00 for weeks 2 and 4, respectively). Although range of motion was similar between the groups at the end of week 4, the mean was 107.36° ± 8.36° in the TXA group and 103.65° ± 7.68° in the control group on postoperative day 2 (P = .020) (95% CI, 0.60-6.81). The mean hemarthrosis values at the end of weeks 1 and 2 were significantly lower in the TXA group than in the control group (P < .001), and the need for aspiration in the TXA group during the early postoperative period was significantly lower than in the control group (P < .001). There were no infections in either group, and no patient developed deep venous thrombosis by postoperative day 3. Conclusion: The results of this prospective, randomized study show that TXA reduced the amount of postoperative hemarthrosis and decreased the need for aspiration of the knee after arthroscopic ACL reconstruction. Consequently, TXA reduced pain and improved range of motion of the knee in the early postoperative period without side effects.

Preliminary investigation of high-dose tranexamic acid for controlling intraoperative blood loss in patients undergoing spine correction surgery