Reply to the Letter to the Editor: Combined Intravenous and Intraarticular Tranexamic Acid Does Not Offer Additional Benefit Compared with Intraarticular Use Alone in Bilateral TKA: A Randomized Controlled Trial.

To the Editor, We thank Wu and colleagues for their thoughtful letter to the editor about our study [19], which focused on tranexamic acid (TXA) administration regimen for patients undergoing bilateral TKA. The authors of the letter were concerned that our sample size was not large enough to detect subtle differences in blood loss between combined two groups: Intravenous (IV) plus intraarticular TXA, compared with intraarticular use alone. However, we believe that our sample-size calculation on a plausible minimum clinically meaningful difference in total blood loss and frequency of allogenic blood transfusion between comparison groups was both a scientifically sound and clinically relevant approach [13, 16]. While we understand their concern regarding hidden blood loss and decreased blood hemoglobin levels up to 5 days after TKA, we do not agree that it is likely to have made a clinically meaningful difference in the results of our study. We calculated the hemoglobin drop by subtracting the hemoglobin level on postoperative Day 5 from the preoperative hemoglobin level, unless patients were given an allogenic transfusion [19]. If patients underwent a transfusion, the lowest hemoglobin level before the transfusion was used for the calculation. About 90% of the blood loss occurs within the first 24 hours after lower limb arthroplasty [18], with the majority of the blood loss occurring within 6 hours after TKA [3, 4]. As such, it was imperative to administer a TXA regimen at least 6 hours after surgery. In our study, we considered the half-life of TXA to be 3 hours. The second IV dose of TXA was administered 3 hours after the first IV dose in the combined IV and intraarticular group to extend the effect to the first 6 hours of surgery [19]. We agree with Wu and colleagues that TXA’s safety has been welladdressed in previous meta-analyses [5, 26] and clinical guidelines [8]. We believe that the benefits of using TXA in TKA (as we used it) certainly outweigh its potential risks, including venous thromboembolic events (VTEs), even in patients with comorbidities [7, 22]. However, there are examples of VTEs after administering TXA for patients undergoing orthopaedic procedures. One study reported on a patient with a pulmonary embolism (PE) who received a single dose of systemic TXA during unilateral TKA [21] resulting in cardiac arrest and death. Furthermore, TXA administration is an independent risk factor for VTEs in patients undergoing surgery for traumatic injuries [12, 20]. We have also seen reports of PE associated with TXA administration outside of our specialty [1, 9, 14, 25]. Therefore, topical TXA is our preferred approach (RE:Meshram P, Palanisamy JV, Seo JY, Lee JG, Kim TK. Combined intravenous and intraarticular tranexamic acid does not offer additional benefit compared with intraarticular use alone in bilateral TKA: A randomized controlled trial. Clin Orthop Relat Res. 2020;478:45-54). The authors certify that neither they, nor any members of their immediate families have any commercial associations that might pose conflict of interest in connection with the submitted article. The opinions expressed are those of the writer, and do not reflect the opinion or policy of CORR or The Association of Bone and Joint Surgeons.