Tranexamic acid: more evidence for its use in joint replacement surgery

Abstract

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.