Tranexamic acid versus aminocapro ́ ic acid in multiple doses via the oral route for the reduction of postoperative bleeding in total primary hip arthroplasty: a prospective, randomized, double-blind, controlled study
To compare the effects of oral e-aminocaproic acid (EACA) as a hemostatic agent versus the use of oral tranexamic acid (TXA) administered in multiple doses pre and postsurgery in patients undergoing elective primary total hip arthroplasty (THA). We enrolled 102 patients that were randomly divided into two groups: received three oral doses of EACA (2000 mg per dose) or three oral doses of TXA (1300 mg per dose). The medication was given according to the following schedule: 2 h before surgery and 6 and 12 h after surgery. The variables analyzed to compare the effectiveness of the hemostatic agents were total blood loss, hidden blood loss, external blood loss, transfusion rate, intraoperative blood loss, decreases in hemoglobin and hematocrit values, surgical drainage output, visual analog scale, and surgical complications. There were no significant differences between any of the study variables for the group receiving oral TXA and the group receiving oral EACA (P > 0.05). Our study showed that the use of oral EACA was similar to its counterpart TXA regarding the evaluated parameters. TXA did not have superior blood conservation effects, safety profile, or differences in functional scales compared with EACA in THA. We consider the use of multiple oral doses of aminocaproic acid at the selected dose to be effective as a standard protocol to achieve less blood loss and a lower rate of transfusion and adverse events related to the medication in patients undergoing a THA. Blood Coagul Fibrinolysis 30:000 – 000 Copyright ß 2021 Wolters Kluwer Health, Inc. All rights reserved.
Introduction
Total hip arthroplasty (THA) is one of the most common used surgeries for the treatment of endstage degenerative hip disease. However, the procedure is associated with substantial perioperative blood loss, often leading to acute anemia and blood transfusion, which can lead to serious morbidity, including, but not limited to hemolytic reactions, acute lung injuries, and transfusion related infections [1].
Therefore, a number of strategies have been applied to reduce blood loss and need for transfusion, particularly the administration of antifibrinolytic agents, such as tranexamic acid (TXA) or eaminocaproic acid (EACA) has been shown to be very effective [2]. Recent studies have shown that the oral administration of these medications is just as effective as their topical or intravenous administration but with less cost, lower side effects rate, and a more comfortable and easy administration for the patient that does not require specific equipment for its administration, increasing the frequency and preference of oral rout administration [3,4].
A previous study determined that oral administration of EACA in patients undergoing total knee arthroplasty (TKA) did not show significant differences in total blood loss (TBL), external blood loss (EBL), hidden loss of blood (HBL), intraoperative blood loss (IBL), hemoglobin (Hb), and hematocrit (Hct) drop, transfusion rate as well as complications compared with oral administration of TXA [5], no studies have determined their use in prosthetic hip surgery until now. By consequence, the hypothesis of this study is that there will be no differences in the measured parameters when comparing these two drugs orally in patients undergoing THA.
The aim of this study was to compare the effects of oral EACA as a hemostatic agent versus the use of oral TXA administered in multiple doses pre and postsurgery in patients undergoing elective primary THA.
Materials and methods
This was a single-center prospective, double-blinded, randomized trial designed to test the equivalence between TXA and EACA administered both orally in the setting of a primary THA. This study was approved by the Institutional Review Board of our center (OR19- 00003) and prospectively registered at ClinicalTrials.gov (NCT04187014). All patients gave their written informed consent for participation in the study before operation and the study was conducted in accordance with the World Medical Association Declaration of Helsinki of 1964, with its revision in 2013 [6], and following established guidelines for the reporting of randomized clinical trials by the Consolidated Standards of Reporting Trials group [7].
All patients were over 18 years undergoing cementless primary unilateral THA for osteoarthritis, osteonecrosis of the femoral head (Ficat III or IV), or developmental dysplasia of hip (Crowe I/II) and were in the anesthetic risk groups American Society of Anesthesiologists I–III, all patients were considered eligible for enrollment from February 2020 to June 2020. Excluding criteria involved patients with anemia (<120 g/l for female, <130 g/l for male), patients with bilateral arthroplasty, planned revision surgery, developmental dysplasia of the hip (Crowe III/IV), prosthetic surgery for a fracture of the femoral head or neck or acetabulum, infected patients, pregnancy, lactating patients, use of oral contraceptives, a BMI more than 35 kg/m2, history of an arterial thrombotic event such as stroke or myocardial infarction in the last year, placement of an arterial stent within the last year, history of deep vein thrombosis (DVT) or pulmonary embolism, history of congenital or acquired clotting dis- order, family history of thrombotic conditions, medication history of anticoagulant or antiplatelet prophylaxis in the perioperative period, complicated primary THAs with osteotomy, an existing implant removal or bone grafting, kidney failure, kidney transplant, and anaphylaxis to either EACA or TXA. We also excluded patients if they declined to participate, declined to consent receiving blood products or if they were unable to ingest or receive the medication orally. All patients included did not present clinical symptoms consistent with symptoms caused by COVID-19 and all had a negative preoperative PCR test for COVID-19.
Enrolled patients were randomly allocated into two study groups, oral TXA group or oral EACA. Randomization was done blind and with help of closed envelopes at a ratio of 1:1 that were eventually opened before the surgical procedure. To get a stratified randomized-schedule we used a computer to develop random number tables. Each patient received three doses of the drug corresponding to the group (one preoperative and two postoperative). The oral TXA group received 1.3g of TXA (two tablets of 650mg) (Lysteda, Pierre Fabre, Mexico City, Mexico) approximately 2 h before the incision, and the same dose was repeated 6 and 12 h postoperatively. The oral EACA group received 2g of EACA (two tablets of 1000mg) (Amikar, Wyeth, Quebec, Canada) at the same times previously described. The dose administered was based on the results of a previous similar study conducted in patients undergoing TKA [5].
Patients who presented any medical, anesthetic or intraoperative surgical complication were excluded. If the treatment was either not given or suspended, the patient was also excluded. In case any complication was identified after the administration, the patient was then excluded from the outcome measurements required but remained checked for any complications.
For the development of this study, researchers and patients who worked and gathered the clinical data and information were blinded to patient allocation until the data was analyzed. We prepared the medication used in the study in generic equal bottles and gave them numbered in a randomized schedule for each patient. Nurses were in charge to manage and give the medication and were not involved in this trail.
A prophylactic dose of antibiotics was given to the involved patients: vancomycin 1 g intravenous (Vanaurus; PISA, Mexico City, Mexico) dissolved in 250 ml of physiological solution for 2 h administered 120 min prior to the procedure. Anesthetists decided the anesthesia method. Intraoperative fluids were administered to maintain the heart rate and mean arterial blood pressure within 20% of baseline values and urine output of at least 2ml/kg/h. Patient axillary temperature was recorded at specific time points during the perioperative period, including preoperatively in the anesthetic bay, postoperatively prior to leaving the operating theatre, prior to exiting the recovery room and then at six hourly intervals for the first 24 h postoperatively. Active skin (forced-air) and fluid warming were used to maintain normothermia during the surgery (intraoperative monitoring was performed through the anesthesia machine sensor placed on the patient’s forehead).
All the surgical procedures were performed by one of the two senior subspecialists in joint hip replacement surgery from the same orthopedic clinic (T.R.-M. and F.V.-C.). A direct lateral hip approach (modified Hardinge) was used. The prosthesis was a single brand cementless acetabular cup (Pinnacle, DePuy Synthes; J&J, Warsaw, Indiana, USA) and a cementless femoral stem (Summit, DePuy Synthes; J&J). In all cases, a postsurgical drain was placed (Drenovac, Alser Medica, Mexico).
Postoperative care
All patients were given physical prophylaxis and chemo- prophylaxis to avoid venous thromboembolism. Once the patients were recovered from the anesthetic, ankle pump, and knee extension exercises were started. Subcutaneous Heparin (5000 IU) (Inhepar; PISA) was given 8 h after the procedure was performed, and then every 12h until discharge. Nurses in the hospitalization area were in charge to quantify the output drainage of the Drenovac every 24 and 48 postoperative hours. For the following 3 days, a complete blood count was established every 24 h at 6:00 a.m. Blood transfusion was performed in case a patient had either an Hb level less than 7 g/dl or evolved with any anemia-related organ dysfunction (palpitation, shortness of breath or bad mental status not due to other causes) with the Hb level between 7 and 10 g/dl.
24h after the surgical procedure, wound healing was performed for the first time. Active and passive movements were started as far as the patient could tolerate them, and 48h after the procedure wandering was allowed in an assisted manner. A screening was carried out for symptoms or signs compatible with DVT and pulmonary embolism daily. If there were no complications, the patients were discharged 72 postoperative hours. After discharge, all patients routinely received enteric-coated acetylsalicylic acid 100 mg for 30 days to prevent thrombosis if there was no bleeding as well as analgesia and antibiotics by oral administration with a strict appointment to the Outpatient Clinic a week and a month later for wound assessment, analysis of the laboratory results and application of functional scales. Doppler ultrasound examination was used routinely to detect DVT at any time if there was a clinically suspected DVT. Computed tomography scans were used to diagnose any pulmonary embolism. The patients were evaluated for complications for up to 3 months after the procedure.
Outcome measurements
Demographic characteristics, medical history, drugs, physical exam, anthropometric data, duration of surgery, and preoperative laboratory results of the patients were gathered prior to surgery. The primary results were TBL, HBL, EBL, and transfusion rate. The secondary results were transfusion rate, IBL, Hb, and Hct drop, the drain output, readmission, mortality, the pain indicated by the patients using the visual analog scale (VAS) (0, no pain, and 100, worst pain imaginable) and functionality using the Harris hip score (HHS) in the preoperative and postoperative days (PODs) 3, 7, and 30, in addition to the range of motion (these last three as indirect indicators of functional deficit and pain secondary to the presence of intraarticular bleeding), adverse effects and complica- tions. TBL was estimated from Hct levels using Gross’s formula: TBL 1⁄4 patient’s blood volume X (Hct reduc- tion/mean Hct), where the Hct reduction is the difference between the initial preoperative Hct level and the Hct on the morning of the third POD [8], with total blood volume estimated using the formula described by Nadler et al. [9]. If either reinfusion or allogenic transfusion was performed, the TBL was equal to the loss calculated from the change in Hct and the volume transfused [10]. The IBL was estimated using the difference between the weights of the used gauze and pads and the original dry weights of unused pads (30 g) and gauze (3 g), added to the blood volume accumulated in suction bottles subtracting the volume of saline solution during the procedure. EBL was measured by adding the intraoperative bleeding and the blood in the drain collectors upon removal after 48h. HBL was established as TBL minus EBL.
Statistical analysis
For the statistical analysis of this study we carried out sample size calculations using PASS 2011 (LLC, Salt Lake City, Utah, USA). A power analysis based on previous data, with 90% power (alpha 0.05) [11], would require at least 46 patients in each group. Consequently, 51 were included in the trial, expecting a 10% loss to be followed-up. Mean and SD was calculated for quantitative data in the possible cases. To analyze the normally distributed numerical variable, the Student’s t test was performed. For categorical variables we used percentages and frequencies. In case any numerical variable was nonnormally distributed or had unequal variance, Wilcoxon Mann–Whitney U test was used to compare means. For analyzing categorical variables, we used the Pearson’s Chi-square test or Fisher’s exact test. P values less than 0.05 were considered significant. The SPSS version 22.0 software (SPSS, Chicago, Illinois, USA) statistical package for Mac was used for the statistical analysis.
Results
Throughout the recruitment period, a total count of 114 patients were recruited and scheduled in our hospital to receive a primary unilateral THA. Nevertheless, 10 patients were not qualified, and two patients declined to participate. A total of 102 patients were prospectively randomized to receive oral TXA (Group A, n 1⁄4 51) or EACA (Group B, n 1⁄4 51), and were observed and studied. There was neither loss nor exclusion of patients during follow-up (Fig. 1). Clinical and demographic characteristics between both groups are shown in Table 1. There were no statistically significant differences for any of the mentioned variables analyzed.
Blood loss
All the measured blood loss comparisons were positive for TXA, but no significant difference between both groups was found (P > 0.05) (Table 2). The mean TBL was 785 ml 221 in oral TXA group versus 825 ml 246 in the oral EACA group. Similarly, the HBL, EBL, IBL, and drainage blood loss were not significantly different in the two groups (P > 0.05). The Hb and Hct drop on POD1, POD2, POD3, and POD7 showed no significant difference as well (P > 0.05). Similar results were observed for the transfusion rate and the number of units of packed red blood cells transfused (Table 2). In the EACA group, three of 51 patients received transfusions, as compared with one of 51 in the TXA group (P>0.05). A total of 4 unit were transfused in the EACA group and 2 unit in the TXA group.
Consolidated Standards of Reporting Trials flow diagram of the inclusion and exclusion of the patient’s progression through trial phases.
Pain and functionality
Regarding the VAS, Harris Hip Score and ranges of motion, significant differences were obtained by comparing preoperative versus postoperative results in both groups after the third POD (P<0.001). There is no evidence for a significant difference by comparing the average results of both groups regarding the same variables (P > 0.05) (Table 2).
Adverse effects and complications
All patients remained checked for 3 months. No thrombotic events, such as DVT and pulmonary embolism, occurred in any of the patients. No superficial or deep infection, cardiac infarction or renal failure was observed in any group during the 90-day follow-up period. No mortality nor readmission events appeared throughout the follow-up time. The incidence of adverse events and complications were similar among the groups. All adverse events were successfully resolved without sequelae or death (Table 3).
Discution
As far as our concern, this study is the first one to evaluate the blood-sparing effect between oral EACA and oral TXA in THA. The two treatments tested showed no statistical difference regarding blood loss, functional scales, and complications in patients who underwent THA, which makes this finding the most significant of this study. Most studies that have examined the use of antifibrinolytics in orthopedic surgery mostly evaluate the use of TXA, and less frequently EACA, even though they have the same mechanism of action [2].
Drug allergy with anaphylactic shock was reported with intravenous TXA. However, EACA carries no risk of anaphylaxis [12]. As cost-effectiveness is becoming an important factor in providing high-quality medical care, EACA administration leads to further research. A previous study found that there are no significant differences between the two oral drugs administered in patients undergoing TKA [5]. Since THA is known to increase bleeding in comparison with TKA, higher bleeding values than expected were found. Nevertheless, the outcomes did not find any differences regarding both drugs for any of the variables analyzed. A previous study found that there are no significant differences when comparing both drugs intravenously in patients undergoing THA [2]. However, TXA is well known for its use in most clinical centers, due to its apparent better clinical effects and the experience doctors have using it.
The use of EACA proposed as a first-line treatment in some studies is because its low cost and similar clinical results compared with TXA; even in one study, it was a significantly lower frequency of adverse effects when administering orally compared with TXA, considering it an effective and safe drug [5].
Previous studies published to date that used oral TXA, and had similar results to those reported in our study for both groups [1,3,4,13–19]. In all the studies, no significant differences were demonstrated regarding the topical, intravenous and oral TXA routes of administration. Coming to the conclusion that oral TXA has similar effects and efficiency when compared with the rest, with the advantage of lower costs and less adverse effects. Systematic reviews that analyzed these clinical trials came to the same conclusions [20 – 25]. Therefore, it is logical to wonder if the oral form of EACA is comparable with its homologue TXA. Until now, no scientific evidence is known concerning the oral route of administration.
Luo et al. [13] compared the efficacy of TXA by oral, topical, and intravenous routes, having as a primary outcome the measurement of postoperative Hb, conclud- ing that the blood-sparing efficacy of oral TXA is comparable with that of the intravenous and topical forms and recommend the use of TXA orally because of its cost benefit superiority and ease of administration. Wu et al. [1] compared the use of intravenous versus oral TXA, with three doses in total in both groups, finding similar results in terms of TBL and the decrease in postoperative Hb. Cao et al. [19] and Zhao et al. [15] studied total hip arthroplasty by posterolateral and anterior approaches, respectively, with the primary outcome of TBL, decreased Hb concentration, Hct and need for transfusion, finding both that the intravenous and oral benefits are similar.
Regarding the number of doses used, Cao et al. [14] performed total hip replacements by posterolateral approach, comparing the use of a single oral administration of TXA, against two and three doses, finding that multiple boluses of oral TXA could further reduce blood loss, Hb and Hct drop, and restrain postoperative fibrinolysis in primary THA, without increasing the risk of complications, which include calf muscle vein thrombosis and peroneal vein thrombosis. Wang et al. [4,17] demonstrated that the greater the number of doses, the TXA is more effective in reducing bleeding and avoiding the decrease in postoperative Hb, using up to five doses (preoperative, and at 3, 7, 11, and 15 h postoperatively). In our study, three doses of TXA or aminocaproic acid are used, which is a similar number of doses to that used in these studies, finding similar benefits and similar complication rates.
Regarding oral administration, two clinical trials compared the use of oral TXA versus intravenous and topical in patients who had undergone THA [3,16], reaching the conclusion that if efficiency, safety, and cost are considered the main crucial parameters during the evaluation of TXA administration methods, oral TXA stands as an efficacious, safe, and low-cost method to reduce blood loss after THA compared with the intravenous and topical forms. In addition, considering the ease of drug administration in the tablet form, oral TXA appears to represent a superior mode of administration than intra- venous and topical TXA.
Strengths and limitations
The strengths of this study involve its prospective, per- muted block randomized methodology, rigorous control of variables and community-based setting, the use of VAS and HHS, as well as a complete follow-up without any loss of patients. Even when this study was meticulously designed to decrease the risk of bias, some restrictions were not possible to avoid. A bigger number of patients are needed to prove significant differences in terms of transfusion rate and complications. Other restrictions include the use of direct lateral approach, known for higher amounts of bleeding when compared with the rest of the approaches (posterior, posterolateral, or anterior), in the same way, no measurement was performed to determine that fibrinolysis was equally inhibited in both groups. Furthermore, patients in the EACA group might have been undergone a lower amount of medication in comparison with the TXA group. Another limitation is the use of heparin and acetylsalicylic acid as prophylaxis of thrombotic events in the postoperative period, which do not represent the standard management in most centers.
Conclution
According to the evaluated parameters in this study, we prove that the oral use of EACA is similar to its counterpart TXA. Even when the patients in the TXA group accomplished 70 ml less blood loss than the comparative EACA group of patients, no clinical findings between both groups demonstrated to be significant and almost no transfusion rates and postsurgical complications were found.
As a result, in this study we state that TXA appeared not to have superior blood conservation effects, safety profile, or differences in functional scales when compared with EACA. To decrease blood loss, transfusion rate, as well as complications in patients in which a total primary hip replacement will be performed, we propose as an optional treatment several doses of oral aminocaproic due to its effectiveness and positive results demonstrated in this study.
Acknowledgements
There is no funding source.
Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Each author certifies that his or her institution approved the human protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research (OR19-00003, Institutional Review Board of the School of Medicine, UANL, Monterrey, Mexico).
Consent to participate: Informed consent was obtained from all individual participants included in the study.
Consent for publication: Patients signed informed con- sent regarding publishing their data and photographs.
Conflicts of interest
Each author certifies that neither he or she, or any member of his or her immediate family has funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article.
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