Tranexamic Acid: safe to use in every orthopaedic patient
E.S. Veltman1 W.H. Mallee1 J.E. Teodorczyk2 M. Vogel2 R.W. Poolman1,3 1Department of Orthopaedic and Trauma Surgery, Joint Research, OLVG, Amsterdam, The Netherlands 2Department of Anaesthesiology, OLVG, Amsterdam, The Netherlands 3Department of Orthopaedic Surgery, Leiden University Medical Center, Leiden, The Netherlands
Corresponding author: E.S. Veltman, e.veltman@erasmusmc.nl
Background and aim: tranexamic acid (TXA) can be used to prevent perioperative blood loss and therewith helps to facilitate early postoperative mobilisation. Uncertainty about contra-indications for TXA frequently leads to the decision not to administer TXA to supposed high-risk patients. We reviewed the literature to evaluate efficacy and safety of TXA, and we propose a protocol for the use of TXA.
Methods: we constructed a search term and reviewed the three common scientific databases. Studies evaluating efficacy or safety of TXA were included.
Results: 26 studies were included. Nineteen studies showed that TXA is efficient compared to placebo for reducing perioperative blood loss. Seven studies evaluated the safety of TXA, all these studies report no increased risk of complications with the use of TXA, even in patients who are at high-risk of thromboembolic events.
Conclusion: TXA is safe to use in any orthopaedic patient, even in patients with supposed high-risk of thromboembolic events. Administration of TXA reduces the percentage of patients suffering PJI. We recommend that every orthopaedic patient undergoing surgery with an expected blood loss of minimal 200ml should be receiving 2000mg of intravenous TXA prior to the first incision, irrespective of ASA classification and comorbidity.
Introduction In recent years the attention has progressively shifted towards fast-track recovery and early postoperative mobilization and discharge of orthopaedic patients. Perioperative blood loss and postoperative anaemia can cause dizziness and nausea and can withhold the patient from mobilising and therefore postpone hospital discharge. In more serious cases of anaemia a blood transfusion is indicated. Worldwide around 10% of blood transfusions are administered to orthopaedic patients. Perioperative blood loss can contribute to prolonged wound leakage and possibly increase the risk of prosthetic joint infection (PJI).1
The limitation of perioperative blood loss and subsequent anaemia is an important contributor to early postoperative mobilisation. In recent years many studies have focused on options to reduce blood loss, both surgically and with medication. Tranexamic acid (TXA) in particular has been extensively studied for its characteristic of reducing perioperative blood loss. Even though the beneficial effect of TXA is widely recognised, a recent study in the USA showed that its use remains limited.2 Although the safety of TXA has been well established in healthy patients, it remains less clear for patients with pre-existing cardiovascular comorbidities or a history of venous thromboembolic events (VTEs). The aim of this study is to provide an overview of the available literature concerning the efficacy and safety of TXA for orthopaedic surgery patients. We hypothesize that the administration of TXA leads to decreased perioperative blood loss, while there is no increased risk for any type of complication around the use of TXA. With the evidence at hand, we propose a renewed protocol for the perioperative use of TXA in the orthopaedic patient. Methods We constructed a search term with Boolean operators ‘((tranexamic acid[Title]) AND orthop*)’ and searched Pubmed, Embase and the Cochrane Library on May 8th, 2020. All results were screened on title, and the full text articles were evaluated if deemed useful. All studies from 2010 to date including adult patients receiving TXA peri-operatively in orthopaedic procedures were included. For the evaluation of the efficacy of TXA, only prospective randomized controlled trails were included. For the evaluation of the safety of the use of TXA we also included large-scale retrospective studies. Data on number of participants, dosage of TXA, (estimated) blood loss, perioperative antithrombotic prophylaxis and the number of complications were extracted, and the results are given in tables.
Results After removal of doubles, our search resulted in 706 individual studies of interest, of which 25 are included (table 1-2).
Table 1 shows the results of studies performed to evaluate the efficacy of TXA in various doses, single or prolonged administration and types of administration.3-21 Figure 1 shows a flow diagram of the included meta-analyses and systematic reviews and their respective research questions. The patients receiving TXA have significantly less perioperative blood loss compared to placebo or no TXA. Prospective studies that compared two different doses, a different number of doses or different administration route of TXA show comparable reduction of blood loss independent of the intervention or control.5, 6, 10, 11, 13 There seems to be a small non-significant advantage in favour of intravenous administration of TXA.8 All studies report no difference in the occurrence of any type of complication, but recognise their sample size to be too small for a definite answer on safety of TXA.
Table 2 shows the results of large-scale retrospective studies performed to evaluate the safety of TXA.22-27 Groups of patients that underwent orthopaedic surgery with and without the use of TXA are compared. All studies report comparable risk of thromboembolic complications in patient groups with and without TXA. There is no increased risk for any type of complication with the administration of TXA, even in a supposed high-risk population with for example multiple comorbidities and/or prior Venous Thromboembolism (VTE).25-27 There is no higher risk of deep VTE, pulmonary embolism, myocardial infarction, cerebrovascular accidents, renal disfunction, seizures, and perioperative mortality in the TXA group compared to patients not receiving TXA.
Discussion Especially in recent years, the use of TXA has been studied abundantly. The efficacy of TXA to limit perioperative blood loss and subsequent postoperative blood transfusions has extensively been proven in randomised controlled trials.15 We found that TXA significantly reduces perioperative blood loss, without increasing the risk of any type of complication including VTE, even in patients with multiple comorbidities or previous VTE. The aforementioned prospective studies showed no indication of any difference in risk of complications for TXA in any dosage. In addition to prospective studies, several large-scale retrospective cohort studies have been published in recent years, all of which found no differences in risk of complications with the administration of TXA, even in patients with supposed high-risk of thromboembolic complications. Administration of TXA reduces the percentage of patients suffering PJI.18, 22 Therefore, we consider our hypothesis to be true.
This study provides an overview of the currently available literature on the efficacy and safety of the administration of TXA to orthopaedic surgery patients. There is no randomised controlled trial specifically studying the occurrence of VTE after administration of TXA to the orthopaedic patient, which is a limitation of this study.6 However, due to the low absolute number of VTE, the number of patients that should be included in such a study to achieve adequate power, would be immense. All prospective studies evaluating the efficacy of TXA showed no increase in complication risk. In the absence of prospective data, the current combined dataset of prospective efficacy trials and retrospective safety studies supplies a solid basis on the safety for using TXA in orthopaedic patients. Most studies for evaluation of efficacy or safety of TXA have been performed in patients receiving THA or TKA, therefore one should be aware that extrapolation of these results to different patient categories may not be correct. However, also in patients undergoing major non-cardiac surgery, trauma surgery, shoulder arthroplasty, and spine surgery, no rise in complications related to TXA use was reported. Side-effects of TXA are rare, and include allergic rash, VTE, dizziness, temporary (colour)blindness and convulsions. Except for VTE and convulsion, these have not been reported in the included studies.
The dosage of TXA administration has extensively been studied in good quality RCTs.4, 5, 6, 10, 11, 13 Three of these studies evaluated use of TXA compared to placebo and found significantly less blood loss for the TXA-group.4, 5, 10 The studies comparing different dosages of TXA to each other, found no difference in effect.4, 5, 6, 10, 11, 13
Two studies reported that the risk of PJI is decreased with the perioperative administration of TXA.18, 22 Especially the study by Yazdi and colleagues shows a significant decrease in the number of PJI in the group that received TXA compared to the group that didn’t receive TXA.18 The exact mechanism how TXA prevents PJI remains uncertain. It is likely to be caused by a reduction in blood loss, a lower need for allogeneic blood transfusion, issues related to immunomodulation associated with blood transfusion or a lower risk of postoperative wound effusion which is a known risk factor for PJI.1, 18
Another topic of interest has been the route of administration of TXA. Due to the supposed systemic side effects of intravenous administration of TXA, some studies have compared intravenous administration to intraarticular administration of TXA.11, 13, 16 Jules-Elysee and colleagues found significantly less blood loss for iv administration compared to intraarticular administration, while Meshram and colleagues found no difference between their combined iv and intraarticular administration versus intraarticular administration alone.11, 13 Even though the exact mechanism for the beneficial effect is unclear, intraarticular and systemic administration of TXA achieve similar blood loss, drainage volume and transfusion requirement. There was no increase in incidence of VTE, wound complications and other adverse events with intravenous administration of TXA. Intravenous administration of TXA was associated with significantly smaller maximum haemoglobin drop for both hip and knee arthroplasty.16
The following contraindications for the use of TXA have been described in the Dutch pharmacotherapy guide (Farmacotherapeutisch Kompas, www.farmacotherapeutischkompas.nl): (1) active thrombo-embolic condition such as VTE, PE or cerebral thrombosis; (2) subarachnoid bleeding; (3) severe renal insufficiency due to the risk of accumulation; (4) history of convulsions. Unfortunately, it is unclear where, in which setting and in which patient population these contraindications have been established. Additionally, the Netherlands pharmacovigilance centre (Lareb) has signalled a possible risk of VTE in women simultaneously using oral TXA and oral hormonal contraception drugs. They reported 4 VTE cases in about 96003 patients using TXA between 2014 and 2018.30 The results reported in Table 2 show no evidence of a higher risk for any of these supposed contra-indications with the administration of TXA to a total of 950.070 orthopaedic patients. The same has been reported in a meta-analysis for patients undergoing surgery in other specialties.28 Possibly the absence of increased risk of complications with the administration of TXA is caused by the early start of postoperative mobilisation and thrombosis prophylaxis that is standard of care in orthopaedic surgery. Another explanation may be that surgery will not often be performed in a short window after an active thrombo-embolic event or subarachnoid bleeding.
We recommend that every orthopaedic patient undergoing surgery with an expected blood loss of a minimal of 200ml should be receiving 2000mg of intravenous TXA prior to the first incision, irrespective of ASA classification and comorbidity, which is in concordance with the clinical practice guideline in the USA.31 The preoperative intravenous administration of TXA should be recommended in the national guidelines for joint arthroplasty, spine surgery, trauma surgery, perioperative medication, and antithrombotic management. For patients with a medical history of convulsions the only data on safety of TXA is described for a dose of 1000mg TXA, therefore a lower dose can be considered in these patients.29 According to the aforementioned studies there appear to be no contra-indications for the use of TXA, except for a registered allergy for TXA.24, 25, 28 For surgeries with a duration longer than three hours a repeat dose of TXA can be considered. In case systemic administration of TXA is somehow undesirable, direct intra-articular administration can be considered as this still significantly reduces blood loss compared to placebo. At a cost of € 3,27 per 500mg, TXA is an inexpensive option to reduce blood loss and risk of PJI, and to facilitate early postoperative rehabilitation.
Disclosure statement The authors have no conflict of interest to mention regarding this manuscript.
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