Intravenous Tranexamic Acid Bolus plus Infusion Is Not More Effective than a Single Bolus in Primary Hip Arthroplasty: A Randomized Controlled Trial

TRANEXAMIC acid has been shown to be effective in reducing blood loss and transfusion in surgical patients.¹  The basis for tranexamic acid efficacy is thought to be inhibition of tissue fibrinolysis and consequent clot stabilization.²  In total hip arthroplasty, fibrinolytic activation in the operated limb begins just after the start of surgery and is maintained postoperatively up to 18 h.^3,4  To maximize efficacy in hip arthroplasty, tranexamic acid should be initiated preoperatively.⁵  Yet the optimal duration of intravenous tranexamic acid administration in hip arthroplasty is unknown. A single preoperative bolus may not be the best choice given that about the same amount of bleeding occurs after surgery as during surgery⁶  and given the duration of increased postoperative fibrinolytic activity and the 2-h half-life of tranexamic acid.⁷  Furthermore, results concerning the impact of tranexamic acid use on erythrocyte transfusion in major orthopedic surgery seem to favor administration of more than just a single bolus limited to the intraoperative period.⁸ 

We therefore performed a double-blind, randomized, controlled trial in patients undergoing hip arthroplasty to evaluate the effect of a supplementary 8-h perioperative infusion of tranexamic acid on blood loss in patients having received a preoperative loading dose of tranexamic acid.

The PeriOpeRative Tranexamic acid in hip arthrOplasty (PORTO) study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki, Good Clinical Practice, and relevant French regulations regarding ethics and data protection. The protocol and amendments were approved by the central independent ethics committee (Committee for the Protection of Personal Data South-Est I, Saint-Etienne, France; reference 2013-20). Written informed consent was obtained from all patients before randomization in this prospective, double-blind, parallel-arm, randomized, superiority clinical trial. The PORTO trial was a single-site study conducted at the university hospital of Saint-Etienne, France. This study is registered at EudraCT (2013-000791-15, principle investigator P.J.Z., registered August 8, 2013) and at www.ClinicalTrials.gov (NCT02252497, principle investigator P.J.Z., registered September 26, 2014).

Consecutive patients aged 18 yr or older undergoing primary unilateral total hip arthroplasty through a posterior approach were eligible for inclusion between April 2014 and December 2015. Exclusion criteria were pregnancy or breastfeeding, hip fracture less than 3 months previously, contraindication for venous thromboprophylaxis with apixaban, chronic anticoagulation therapy, absence of French social security health insurance coverage, and contraindication for tranexamic acid treatment (previous or acute arterial or venous thrombosis, creatinine clearance less than 15 ml/min, or previous seizure). Exclusion criteria for patients with arterial or venous thrombosis were amended in June 2014 (2 months after study initiation, by which time six patients had been enrolled) to exclude only those with acute thrombosis, after modification of the French national agency for medicines and health products summary of product characteristics for tranexamic acid. Potential study participants were identified at the preoperative anesthesia consultation and were approached by study staff during their preadmission clinic visit before the day of surgery.

Patients were randomized in a 1:1 ratio to one of the two study groups by means of a central telephone system ensuring concealed allocation. Randomization was performed using a computer-generated randomization sequence with randomly permuted blocks of 4 or 6. After initiation of anesthesia, patients in both study groups received an unblinded intravenous bolus of 1 g of tranexamic acid (Exacyl 0.1 g/ml; Sanofi-Aventis, France). They were then allocated to receive immediately either an intravenous infusion of 1 g of tranexamic acid for 8 h (bolus-plus-infusion group) or a matching placebo (0.9% saline; bolus group). The intravenous solutions were prepared outside the orthopedic department by a nurse and directly sent to the anesthetist in charge in the operating room. Masking was ensured by the use of apparently identical 50-ml syringes. Patient caregivers and investigators collecting the data remained unaware of study-group assignments.

Patient blood management included various individualized strategies. In accordance with the French guidelines for erythrocyte transfusion, a restrictive transfusion trigger strategy was used. The transfusion trigger was a hemoglobin level of 7 g/dl, increased to 8 to 9 g/dl in patients with a history of cardiovascular disease and to 10 g/dl in patients with severe symptoms (e.g., persistent hypotension despite adequate volume replacement, syncope, transient ischemic attack, stroke, acute respiratory failure, or acute coronary syndrome). During surgery, blood losses were replaced by Ringer’s lactate solution in a 3:1 ratio. Each patient received 1 l of rehydration fluid (sodium 40 mM, potassium 20 mM, glucose 250 mM) for the first 12 h after surgery. Perioperative hemoglobin was measured before starting surgery (day 1), in the postanesthetic care unit, on days 2 and 5, and after each postoperative transfusion. Patients received an oral iron supplement of 200 mg/day during the postoperative period. Venous thromboprophylaxis included 2.5 mg of apixaban two times daily, initiated 24 h after the end of surgery and continued for 5 weeks. Use of desmopressin, recombinant factor VIIa, topical tranexamic acid, or a cell-salvage device was not allowed. Preoperative anemia was assessed 3 to 4 weeks before surgery without further investigation of the cause. The use of preoperative iron supplementation, the administration of erythropoiesis-stimulating agents, and the perioperative management of antiplatelet therapy were left to the discretion of the anesthetist. No preoperative autologous blood donation was implemented.

The choice of anesthesia and postoperative analgesia was left to the discretion of the anesthetists. All patients received cefazolin (2 g) before surgery and were operated in a lateral position through a posterior approach. The implants chosen combined a cementless femoral stem with a cementless dual-mobility cup. A single intraarticular low-vacuum drain was used for postoperative wound drainage, remaining in place for at least 24 h.

The primary efficacy outcome was calculated: perioperative blood loss based on hemoglobin balance (using preoperative and day 5 hemoglobin values), on the assumption that blood volume on day 5 was the same as before surgery (see formula used to calculate blood loss in the Supplemental Digital Content, https://links.lww.com/ALN/B521). Secondary efficacy outcomes included measured blood loss via the drain during the first 24 h and the percentage of patients requiring transfusion of at least 1 unit of allogeneic erythrocytes from surgery up to week 6. The safety outcome was the incidence of vascular events and death up to 6 weeks. Vascular events were defined as the composite of any confirmed symptomatic deep venous thrombosis, pulmonary embolism, stroke, myocardial infarction, and limb ischemia. Blood samples were collected to perform a pharmacokinetic study of tranexamic acid, which is not reported here.

Sample size calculation was based on data from previous studies assessing a single preoperative tranexamic acid injection with or without additional perioperative tranexamic acid administration (see assumptions for sample size calculation in the Supplemental Digital Content, https://links.lww.com/ALN/B521). Assuming a difference in perioperative blood loss of 250 ml with a SD of 500 ml, we calculated that a sample size of 84 patients per group would be required to achieve a power of 90% with a two-sided α risk of 0.05.

All analyses were performed on a modified intention-to-treat population, defined as all randomized patients except those who withdrew their consent and refused participation (French legislation precludes any reporting of data from these patients). Categorical data were described as frequencies and proportions and were analyzed using Fisher’s exact test. The Shapiro–Wilk test was used to examine the normality of distribution of continuous outcomes, including the primary outcome, calculated perioperative blood loss. Normally distributed continuous variables were described as the mean ± SD and were analyzed using Student’s t test. Continuous data that were not normally distributed were presented as median, first, and third quartiles. They were analyzed using the Mann-Whitney U test. No stratification variables were used in the analyses. No subgroup analyses were planned in the protocol, and none were performed. The analyses were performed using SAS software, version 9.4 (SAS Institute, USA).

A meta-analysis of randomized trials was performed to assess the external validity of our study. A report of the methods used for this meta-analysis, following the PRISMA guidelines, is presented in the Supplemental Digital Content (https://links.lww.com/ALN/B521). Briefly, the studies included had to compare a single preoperative tranexamic acid bolus with preoperative administration of tranexamic acid followed by perioperative tranexamic acid administration as a bolus or a continuous infusion. Studies had to be performed in primary hip arthroplasty and tranexamic acid had to be administered intravenously. Relevant trials were identified by a computerized search up to June 2016 in Medline and the Cochrane Central Registry of Controlled Trials. The Cochrane Collaboration risk-of-bias tool for randomized controlled trials was used for quality assessment. In this meta-analysis, the experimental group corresponded to both pre- and perioperative tranexamic acid administration, and the control group corresponded to single preoperative tranexamic acid bolus administration alone. The ratio of mean perioperative blood loss values between the experimental and control groups was calculated for each study.

Data concerning the continuous outcome, perioperative blood loss, were pooled using the ratio of the means method.⁹  Data concerning the binary outcome, transfusion of at least 1 unit of allogeneic erythrocytes, were pooled using the Mantel–Haenszel odds ratio method without corrections.¹⁰  Both fixed-effect and random-effects models were implemented. The risk of publication bias was checked using the funnel plot technique. The meta-analysis was performed using R software (meta package, version 2.15.1; downloaded from https://CRAN.R-project.org/package=meta; accessed September 12, 2013).

Between April 2014 and December 2015, 279 patients were screened for participation in the study, of whom 168 were included and randomized. One patient withdrew his consent after randomization but before administration of the study drug. A total of 84 patients were analyzed in the bolus-plus-infusion group, and 83 were analyzed in the bolus group (fig. 1). Both patient characteristics and surgical characteristics were similar in the two groups (table 1).

The mean perioperative blood loss was 919 ± 338 ml in the bolus-plus-infusion group and 888 ± 366 in the bolus group (table 2). The difference in mean perioperative blood loss between the groups, namely 30 ml (95% CI: −77 to 137 ml), was not statistically significant (P = 0.58). The hemoglobin values used to calculate perioperative blood loss are presented in table 2. Median blood loss via the drain during the first 24 h was similar in the two groups (fig. 2).

Three patients (3.6%) in each group required transfusion of at least 1 unit of erythrocytes up to day 45 (P > 0.99) (table 2). Two patients experienced symptomatic bilateral distal venous thrombosis up to day 45, both in the bolus group. No other venous or arterial vascular event occurred, and no patient died.

Literature search identified five studies in addition to the current trial, yielding a total of 611 patients (see flow chart of the study selection process in the Supplemental Digital Content, https://links.lww.com/ALN/B521).^5,11–14  The characteristics of the trials included are summarized in table 3. On the basis of the Cochrane Collaboration tool, one study was classified as having a high risk of bias (fig. 3).⁵  In each study the total amount of tranexamic acid administered was greater in the perioperative group than in the preoperative group. In the perioperative groups, tranexamic acid administration was pursued postoperatively either as a bolus (3 or 6 h after the preoperative bolus) or as a continuous infusion (more than 8 or 18 h). For each study, the numerical group-specific summary data on perioperative blood loss and erythrocyte transfusion are presented in the Supplemental Digital Content (https://links.lww.com/ALN/B521). Compared to a single preoperative tranexamic acid bolus alone, additional perioperative administration of tranexamic acid did not reduce bleeding events. The pooled ratio of blood loss was 1.00 (95% CI, 0.94 to 1.06; P = 0.99; fixed-effect model) (fig. 4). There was no evidence of heterogeneity (I² = 1.6%). The treatment effect was not modified when the analysis was limited to studies considered at low risk of bias (two studies, pooled ratio 1.01; 95% CI, 0.93 to 1.10; P = 0.83; fixed-effect model; I² = 7.9%). The odds ratio for transfusion of at least 1 unit of allogeneic erythrocytes was 0.67 (95% CI: 0.26 to 1.75; P = 0.41; fixed-effect model; I² = 0%), see forest plot in the Supplemental Digital Content (https://links.lww.com/ALN/B521). No funnel plot check was performed in view of the small number of studies included.

In this study, an additional perioperative infusion of 1 g of the antifibrinolytic agent tranexamic acid during 8 h did not reduce blood loss in patients having received a preoperative 1 g intravenous loading dose of tranexamic acid for primary hip arthroplasty. To compare our results with previous studies in hip arthroplasty,^5,11–14  we performed a meta-analysis. No difference in blood loss between patients receiving a single preoperative bolus of tranexamic acid and those additionally receiving tranexamic acid perioperatively was seen either in the individual studies included or in the overall analysis. The relatively narrow CI indicates a precise estimate of the absence of any difference between the two regimens.

In orthopedic surgery, the effect of perioperative administration of tranexamic acid in addition to a preoperative bolus has also been studied in patients undergoing knee replacement. Three studies found that additional perioperative administration of tranexamic acid reduced blood loss by 24, 25, and 33%, respectively,^15–17  whereas another study showed no such effect.¹⁸ 

In total hip arthroplasty, fibrinolytic activation begins just after the start of surgery and is maintained postoperatively for up to 18 h.^3,4  Given the 2-h half-life of tranexamic acid,⁷  we designed this study to assess the necessity of maintaining therapeutic plasma concentrations of tranexamic acid with a continuous infusion pump in the intra- and postoperative period. Yet inhibition of fibrinolytic activation, mediated by increased inhibition of tissue plasminogen activator, can also begin during surgery, resulting in a fibrinolytic shutdown that peaks the day after surgery.¹⁹  The timing of transition from hyperfibrinolysis to a hypofibrinolytic state has not yet been defined.³  If this transition occurs soon after hip arthroplasty surgery, postoperative tranexamic acid administration may not be necessary. On the other hand, if the transition occurs later, our perioperative 8-h infusion of tranexamic acid may have been insufficient. This is unlikely, because a study in hip arthroplasty found no additional benefit of an 18-h postoperative tranexamic acid infusion.¹⁸ 

Postoperative fibrinolytic activity may differ according to the surgical procedure. For example, after tourniquet use in knee replacement surgery, postoperative fibrinolytic marker levels are higher than without tourniquet use and are also higher than in hip arthroplasty.^4,20  Although tranexamic acid is effective in many different surgical procedures,¹  the differences in fibrinolytic response according to the type of surgery suggest that the optimal regimen for tranexamic acid administration is probably procedure-specific. Thus, our results concerning primary hip arthroplasty should not be extrapolated to other surgical procedures, in particular knee replacement surgery.

We chose to administer a preoperative loading dose of 1 g of tranexamic acid on the basis of previous randomized trials showing that compared to placebo, a tranexamic acid dose of 10 to 15 mg/kg or 1 g significantly reduced blood loss and transfusion.⁸  One pharmacokinetic study in three healthy volunteers reported that the minimum effective therapeutic plasma concentration of tranexamic acid ranged from 5 to 10 mg/l.⁷  This study showed that a 1-g intravenous dose of tranexamic acid maintained tranexamic acid plasma concentrations above 10 mg/l for 3 h. Our simulation, based on these data and a pharmacokinetic model in cardiac surgery,²¹  suggested that 1 g of tranexamic acid followed by a continuous infusion of 1 g during 8 h would maintain plasma concentrations above 10 mg/l during infusion (unpublished work). The other trials evaluating perioperative administration of tranexamic acid in hip arthroplasty used doses similar to ours.^5,11–14 

The benefit of administering higher perioperative doses is therefore unknown. Two recent trials in hip arthroplasty showed that combined intravenous tranexamic acid and intraoperative topical administration of tranexamic acid reduced blood loss by 13% compared to a single preoperative intravenous tranexamic acid dose.^22,23  Topical administration of tranexamic acid permits delivery of high concentrations of tranexamic acid to the bleeding site. These findings suggest that the effect of higher perioperative tranexamic acid plasma concentrations than those tested in our trial would be worth studying if tranexamic acid is to be administered only intravenously.

Our study is subject to several limitations. The first limitation is the unreliability of the primary outcome measurement. The formulas used to calculate blood loss do not ensure that the values obtained are sufficiently accurate for absolute measurement. Yet a recent study indicates that formulas that take into account both anthropometric and laboratory parameters, as we did, are useful for evaluating the efficacy of interventions aiming to decrease blood loss.²⁴  A second limitation is related to use of a surrogate endpoint as the primary outcome. As a consequence, this study lacked sufficient power to detect any difference concerning infrequent but more clinically relevant outcomes, such as erythrocyte transfusion. The 3.6% rate of allogeneic erythrocyte transfusion up to 6 weeks in this study was similar to those found in other recent trials using tranexamic acid associated with a restrictive transfusion trigger based on hemoglobin level.^{5,11–13,22,23}  Compared with the erythrocyte transfusion rate of 45% reported between 1990 and 2010 in hip replacement surgery,²⁵  these results highlight the decrease in blood transfusion rate achieved through implementation of recently recommended, cost-effective patient blood management measures.²⁶  This study was also underpowered to detect any differences regarding safety endpoints. The 1.2% incidence of death or symptomatic vascular adverse events (two cases of distal deep-vein thrombosis among 167 patients) during 6 weeks postsurgery was in the lower range of those observed in cohort studies in hip arthroplasty.^27,28  We did not search for asymptomatic events, such as cardiac troponin I elevation or asymptomatic deep-vein thrombosis, as a review of 129 trials, including a total of 10,488 surgical patients, did not indicate an increased risk of thromboembolic events with tranexamic acid.¹  A third limitation of this study is the generalizability of the trial findings. Most of our patients underwent general anesthesia with a femoral nerve or fascia iliaca block. As general anesthesia is associated with increased levels of plasminogen activator inhibitor-1,²⁹  an inhibitor of fibrinolysis, it could be suggested that the results of our study might not be applicable to centers using primarily neuraxial anesthesia. Yet our meta-analysis indicates results similar to ours in trials that used exclusively spinal anesthesia or various combinations of neuraxial and general anesthesia. Finally, it should be emphasized that morbidly obese patients, patients undergoing chronic anticoagulation therapy, and those with bleeding disorders were not included in the studies entered in our meta-analysis.

In conclusion, this study indicates that additional perioperative administration of tranexamic acid did not further reduce blood loss in patients having received tranexamic acid before primary hip replacement surgery. A single preoperative bolus of tranexamic acid associated with a restrictive transfusion trigger strategy resulted in low erythrocyte transfusion rates.

The authors are grateful to the following investigators who completed their data for the meta-analysis: Norio Imai, M.D., Department of Orthopedic Surgery, Niigata Prefectural Shibata Hospital, Shibata, Japan, and Borja Barrachina, M.D., Department of Anesthesia and Perioperative Care, Araba University Hospital, Vitoria-Gasteiz, Spain. The authors also thank Paula Harry, Ph.D., MediBridge SA, Vélizy, France, for revision of the English text.

Supported by the University Hospital of Saint-Etienne, France, the study sponsor.

All the authors except Dr. Borisov are employees of the funding source, which had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, and approval of the manuscript; or the decision to submit the manuscript for publication.

Full protocol available at: paul.zufferey@chu-st-etienne.fr. Raw data available at: paul.zufferey@chu-st-etienne.fr.

Group authorship: Paul J. Zufferey, M.D., Ph.D., Julien Lanoiselée, M.B.B.S., Céline Chapelle, M.Sc., Dmitry B. Borisov, M.D., Jean-Yves Bien, M.D., Pierre Lambert, M.D., Rémi Philippot, M.D., Ph.D., Serge Molliex, M.D., Ph.D., Xavier Delavenne, Pharm.D., Ph.D.

Group collaborators: Coordinating and Methods Center, Clinical Research Unit Innovation and Pharmacology, CHU de Saint-Etienne, F-42055, Saint-Etienne, France; Béatrice Deygas, M.Sc., Mathilde Donnat, M.Sc., Juanita Techer, M. Sc., Laurent Tordella, Ph.D., Jean-Noël Fort, M.Sc.

Clinical investigators: Department of Anesthesiology and Intensive Care Medicine, CHU de Saint-Etienne, F-42055, Saint-Etienne, France; Nicolas Barbe, M.D., Julie Gavory, M.D., Sylvie Passot, M.D., Laetitia Burnol, M.D., Stéphanie Seve, M.D.