| Abstract|| |
Background: Tranexamic acid (TA) use in lower-limb arthroplasty has been valued in these surgeries high-risk hemorrhagic due to its antifibrinolytic action. The objective of the present study was to determine the effectiveness of the combined intravenous (IV) and intraarticular (IA) administration of TA in lower-limb arthroplasty. Methods: We conduct a prospective observational study between January 1, 2014, and December 31, 2017, including all programmed lower-limb arthroplasties. Patients were divided into four groups: no TA, 15 mg/kg IV TA, 3 g IA TA, and 15 mg/kg IV and 3 g IA. The effect on calculated total blood loss (milliliter of red blood cell [RBC]), hemoglobin, transfusion, and duration of hospitalization was studied after adjustment on age, American Society of Anesthesiologists, surgery, and postoperative curative anticoagulation. Complications related to TA administration were systematically reported. Results: A total of 1909 patients were included – “no TA,” n = 184; “IV,” n = 1137; “IA,” n = 214; and “IV + IA,” n = 374. In the IV + IA group, a decrease in blood loss was observed compared to the no TA group (+220 ml 95% confidence interval [CI] [184; 255] of RBCP < 0.001) and in the IA group (+65 ml 95% CI [30; 99] of RBCP < 0.001). The length of hospital stay of the IV + IA group was shorter compared to the no TA group (hazard ratio [HR] 0.35, 95% CI [0.29; 0.43],P < 0.001) to the IA group (HR 0.57, 95% CI [0.48; 0.69],P < 0.001) and the IV group (HR 0.45, 95% CI [0.39; 0.50],P < 0.001). One case of deep vein thrombosis occurred in the group without TA. Conclusion: Administration of combined TA appears effective and safe; further studies are needed in order to establish a consensual protocol.
Keywords: Blood loss, combined, intraarticular, intravenous, tranexamic acid
|How to cite this article:|
Vacheron CH, Roy P, Petit PY, Appery J, Fessy M, Piriou V, Viste A, Friggeri A. Effectiveness and safety of the combined use of tranexamic acid: A comparative observational study of 1909 cases. Indian J Orthop 2019;53:708-13
|How to cite this URL:|
Vacheron CH, Roy P, Petit PY, Appery J, Fessy M, Piriou V, Viste A, Friggeri A. Effectiveness and safety of the combined use of tranexamic acid: A comparative observational study of 1909 cases. Indian J Orthop [serial online] 2019 [cited 2019 Dec 14];53:708-13. Available from: http://www.ijoonline.com/text.asp?2019/53/6/708/264549
| Introduction|| |
Elective arthroplasty surgery of the lower limb (total knee arthroplasty [TKA], and total hip arthroplasty) is a surgical procedure widely performed for the treatment of terminal arthrosis. Prevalence is estimated between 2.3% and 4.5% in 2010 among adults aged 50 years or older, and >2 million procedures per year are estimated to be performed by 2020 in the United States. However, it is associated with a higher morbidity and mortality than would be expected for a functional surgery. An increased perioperative blood loss is associated with increased transfusion rate, postoperative infections, poorer physical function and recovery, increased length of hospital stay, and mortality. Furthermore, blood transfusion increases both morbidity and mortality and is a source of cardiovascular, immunological, and viral complications. Therefore, multiple means of reducing blood loss have been studied (for example, use of a tourniquet, autotransfusion, intraoperative blood salvage, and use of iron or erythropoietin) to avoid perioperative blood transfusion.,
The efficacy of intravenous (IV) tranexamic acid (TA) due do its antifibrinolytic action has been confirmed by meta-analyses., Furthermore, its intraarticular (IA) use has been shown to reduce blood loss and the need for transfusion. Since 2014, numerous randomized controlled trials,,,,,,,,, have studied the efficacy of combined IV and IA TA on blood loss as well as transfusion needs. These small studies reported contradictory results as to the efficacy of TA but no increase in the occurrence of adverse events. Three meta-analyses,, have confirmed the benefits of the combined use of TA and its safety. However, none of these studies has formally quantified blood salvation related to the combined IV and IA administration of TA.
In our center, which is a reference in lower-limb arthroplasty, we progressively (from 2014 to 2017) shifted from IV TA use to a combined strategy which allows us herein to quantify the effect of the combined strategy on the perioperative blood loss.
| Materials and Methods|| |
A prospective observational study was conducted at the Lyon Sud Hospital (France) from January 1, 2014, to December 31, 2017. Patients aged 18 years or above who underwent elective primary or secondary arthroplasty of the knee or hip as well as acetabular revision were included; those with prosthesis ablation and unicompartmental knee arthroplasty as well as those who finally did not undergo surgery (contraindications or deceased) were excluded. Patients included successively at the preanesthesia consultation, during which information was given to the patient and his/her oral agreement for inclusion in the study was obtained. According to legislation in place at the time of the study, written informed consent was not required for this study; the database was registered with the national data protection agency (CNIL-HCL number: 18-105).
Demographic data (name, gender, age, height, weight, type of surgery expected, and ASA score) were collected during the preanesthesia consultation. Hemoglobin (Hb) and hematocrit levels the day before the surgery and the postoperative anticoagulant prescribed were collected during the operative time. Hb and hematocrit levels on the 5th day, the length of hospital stay, any blood transfusion, as well as complications (especially thromboembolic or seizures) were collected from the electronic patient medical files. Detection of thrombosis was based on clinical symptoms during hospital stay (daily medical visit) and during the surgical postoperative consultation that was scheduled between the 45th day and the 90th day.
TA (Exacyl®, Sanofi-Aventis® Gentilly, France) was administered during the perioperative period intravenously at a dose of 15 mg/kg, diluted in 100 mL of NaCl 0.9% as a bolus 20 min before incision, and intraarticularly as an injection of 3 g diluted in 100 ml of NaCl 0.9% at the end of the intervention. The route of administration depended on patient characteristics and surgical possibilities.
THA was performed using a posterior approach and TKA by a parapatellar approach; surgeries were conducted without tourniquet. Homologous blood transfusions were administered following national guidelines: Hb threshold of 7.0 g/l, 8.0 g/l in case of cardiovascular history, and 10.0 g/l in case of chronic heart failure. Postoperative analgesia was provided by multimodal analgesia associating regional anesthesia (iliofascial block, femoral block, or a femoral catheter), a combination of step 1 and 2 painkillers (paracetamol, tramadol, nefopam, ketoprofen, and ketamine) and patient-controlled analgesia (morphine). Early mobilization was performed on postoperative day 0 with a protocoled fast-track pathway. A specialized team of physiotherapists was dedicated to the orthopedic department. Thromboprophylaxis was systematically introduced within the first 24 h for a duration of 35 days, either by rivaroxaban, dabigatran, apixaban, enoxaparin, fondaparinux, and unfractionated heparin depending on the patient's medical history. In case of anticoagulant use prior to surgery, it was reintroduced in the first 48 h. The thromboprophylaxis using an antithrombotic drug was associated with an early mobilization protocol.
Patients were separated into four groups depending on the administration of TA: IV + IA, IV, IA, or no TA.
The outcomes considered were blood loss, Hb level on the 5th day, postoperative transfusion, the length of hospital stay, and the occurrence of complications (thromboembolic or seizure). Hb and hematocrit levels were measured on the 5th day, which allowed the evaluation of the postoperative bleeding and the hidden loses while overcoming bias due to the blood regeneration. In the case of blood transfusion, pretransfusion parameters were taken into account. Blood loss was calculated by summing the compensated blood losses (blood recovered during surgery and blood transfusion) with the noncompensated blood loss estimated by the Mercuriali formula. Blood loss was expressed in milliliter of red blood count (ml of red blood cell [RBC]). TA tolerance was evaluated by the occurrence of complications (thromboembolic or seizure) identified clinically during the duration of the hospital stay and during the postoperative consultation that was scheduled between the 45th day and the 90th day.
This article was drafted according to the STROBE statement.
Quantitative variables were presented using mean with standard deviation for descriptive variables and mean with associated 95% confidence interval [95% CI] for outcomes. Qualitative variables were presented using numbers and proportions. In univariate analyses, distributions of variables were compared between the four treatment groups (IV + IA, IV, IA, or no TA) using ANOVA (linear model) and qualitative models using Pearson's Chi-square tests.
For each clinical outcome of interest (perioperative blood loss, postoperative Hb, blood transfusion, and length of hospital stay), multivariate regression models were fitted to analyze the effect of TA on clinical outcome, systematically adjusted on age, ASA score, curative postoperative anticoagulant treatment, and surgical technique (complete model). Linear regression models were fitted to analyze total blood loss and postoperative Hb. A nonconditional logistic regression model was fitted to analyze the necessity of blood transfusion and a Cox proportional hazards model to analyze variables associated with the length of hospital stay. Nested models were compared to the complete model using likelihood ratio tests, and Wald tests were performed for categorical variables. In all statistical tests (two-tailed), P < 0.05 was considered as statistically significant. The P values were not corrected according to the number of tests performed. Statistical analyses were performed using SPSS® statistics 25 (IBM, Armonk, NY, USA).
| Results|| |
A total of 1909 patients who underwent a lower-limb arthroplasty were included. Among them, 374 received a combined IV and IA administration (IV + IA group), 1137 received an IV bolus of TA (IV group), 214 received IA TA (IA group), and 184 patients did not receive any TA (no TA group). Patients underwent primary hip (n = 1170) or knee arthroplasty (n = 508), revision of hip (n = 149) or knee arthroplasty (n = 37), or for an acetabular revision (n = 45). There was no significant difference in Hb (P = 0.15) and hematocrit (P = 0.40) between the groups [Table 1]. There were 84 patients who were receiving curative anticoagulant treatment.
|Table 1: Demographic characteristics and preoperative blood parameters according to tranexamic acid status|
Click here to view
The mean blood loss was 299 ml of RBC (95% CI [280; 317]) in the IV + IA group, 313 ml of RBC (95% CI [302; 324]) in the IV group, 361 ml of RBC (95% CI [328; 393]) in the IA group, and 506 ml of RBC (95% CI [465; 547]) in the no TA group. The mean length of hospital stay was 4.8 days (95% CI [4.7; 5.0]) for the IV + IA group, 6.6 days (95% CI [6.5; 6.8]) for the IV group, 6.5 days (95% CI [6.2; 6.8]) for the IA group, and 7.9 days (95% CI [7.5; 8.3]) for the no TA group [Table 2].
|Table 2: Description of the outcome variables among the four study groups|
Click here to view
After adjustment (covariates of the multivariate model are presented in [Supplementary Data]), the blood loss in the IV group was a mean 23 ml of RBC (95% CI [−0.1; 46]) greater than that found in the IV + IA group; this difference was not significant (P = 0.052). The blood loss in the IA and no TA groups were, respectively, a mean 65 ml of RBC (95% CI [30; 99], P < 0.001) and 220 ml of RBC (95% CI [185; 256], P < 0.001) significantly greater than that found in the IV + IA group. The postoperative Hb in the IV, IA, and no TA groups was significantly lower than that found in the IV + IA group (all P < 0.001). The transfusion rate for the no TA group was significantly greater than in the IV + IA group (OR 7.88, 95% CI [2.71; 22.93], P < 0.001). The hazard of the hospital discharge in the IV, IA, and no TA groups was significantly lower than that found in the IV + IA group (all P < 0.001) [Table 3]; the survival curves for these groups are presented in [Figure 1].
|Figure 1: Survival curve of hospital stay of the four tranexamic acid groups|
Click here to view
No seizure occurred, and there was one case of deep vein thrombosis (no TA group) reported.
| Discussion|| |
The present study found an association between the use of the IV + IA strategy of TA and the reduction of perioperative blood loss, the rise of the postoperative Hb level, and the reduction of postoperative length of hospital stay.
To the best of our knowledge, the study reported herein is the first to have included a large number of patients and to have quantified the amount of blood loss avoided by the combined strategy. It is of note that only a trend toward greater amount of blood loss avoided by the combined strategy with respect to the IV strategy. RCTs have generally found a reduction of total blood loss,,,,,,,,,, but only a minority have found this to be significant; however, meta-analyses concord as to the better efficacy of the combined strategy compared to the use of IV-only strategy.,, The results are expressed as milliliters of RBC because the Mercuriali formula to evaluate blood loss was used, which differs from the Gross formula. The latter is subject to bias related to postoperative hemoconcentration and hemodilution, and therefore, the Mercuriali formula is the most suitable formula for studies regarding blood loss in surgery. A general consideration when interpreting the results concerns the doses of TA used. There is currently no consensus, but in the literature, IV doses vary from 10 to 15 mg/kg, and IA doses fluctuate from 1 to 3 g. In our center, we use highest reported doses of both IV and IA TA. This was chosen because the antifibrinolytic efficacy increases in function of dose; a TA concentration of 10 μg/ml is necessary to block 80% of fibrinolysis, and a concentration of 100 μg/ml is needed for a total nullification of fibrinolysis. Such doses are unlikely to be particularly toxic as TA has a wide therapeutic index, which is illustrated by the doses used in cardiac surgery that can be up to 150 mg/kg intravenously.
Preoperative and postoperative Hb levels were higher compared to the majority of studies on lower-limb arthroplasty. This is likely to be, at least in part, due to the preoperative patient pathway that we introduced in our center, where the patient receives an anesthetic consultation more than 30 days before surgery, and Hb/hematocrit is prescribed during the surgical consultation. This individualizes the protocol in order to reach a sufficient preoperative Hb level and thus avoid blood transfusion. This explains why the transfusion rates (from 1.3% to 12.5% herein) were much lower than that reported in elsewhere, ranging from 18% to 68%. This may also explain why the OR for transfusion was not significant owing to the low number of events.
The duration of hospital stay was significantly reduced in the TA IV + IA group compared to the four other groups. Although postoperative anemia is associated with increased length of hospital stay, this does not seem to be the only factor explaining such a difference in length of stay. For instance, the IA administration of TA leads to a higher IA concentration of TA than IV administration, reducing the postoperative IA bleeding and therefore allowing a faster rehabilitation. Another explanation could be related to the antiinflammatory effect attributed to TA which could reduce the postoperative swelling due to the local inflammation allowing early rehabilitation and a faster discharge compared to placebo. For instance, Huang et al. also have reported reduced postoperative pain and swelling at the climax of inflammation (day 2–day 3) compared to its use intravenously. Krauss et al. studied the influence of IA use of TA on early rehabilitation and proved the efficacy for a shorter mobilization, the 1st and 2nd days. The pathophysiology of the antiinflammatory effect of the TA has been well documented and reviewed by Levy et al. in 2018. TA administered intraarticularly has certainly an effect on postoperative rehabilitation and early discharge, but published studies are small number and the results need confirmation in a larger population.
The only thromboembolic event occurred into the No TA group. Despite its antifibrinolytic activity, TA is probably not associated with an increase of thromboembolic events. Indeed, since the CRASH-2 study has shown a reduction of thromboembolic and cardiovascular events in the group treated by TA, a number of studies including a Cochrane meta-analysis have not shown an association between TA administration and thromboembolic events (arterial or venous).
Our work is a prospective observational study, leading to the absence of randomization. In order to minimize bias, we adjusted the results on the main confounding factors (age, intervention, ASA, and curative anticoagulation). The absence of blind administration of TA could lead to a bias; however, the main outcome measures were objective with very little possibility of interpretation bias. However, our study is still subjected to an important temporal bias: Indeed, in 2014, a large majority of patients received IV therapy, whereas in 2017, the combined administration was predominant. In 4 years, surgeons have gained in experience and have probably decreased their perioperative blood losses. As regards the length of hospital stay, the progress of postoperative rehabilitation and economic considerations is leading to shorter hospitalization, which may explain the significant reduction of hospital stay.
| Conclusion|| |
The administration of combined TA appears effective and safe. Further studies are needed in order to investigate the optimal doses so as to establish a consensual protocol.
We report the interest of the combined use of tranexamic acid (intravenous and intraarticular) during knee and hip arthroplasty on a large cohort of patients for blood salvage and postoperative length of hospital stay.
We would like to thanks Mr. Robinson for his work on this article.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Maradit Kremers H, Larson DR, Crowson CS, Kremers WK, Washington RE, Steiner CA, et al.
Prevalence of total hip and knee replacement in the United States. J Bone Joint Surg Am 2015;97:1386-97.
Kurtz S, Ong K, Lau E, Mowat F, Halpern M. Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Joint Surg Am 2007;89:780-5.
Pulido L, Parvizi J, Macgibeny M, Sharkey PF, Purtill JJ, Rothman RH, et al.
In hospital complications after total joint arthroplasty. J Arthroplasty 2008;23:139-45.
Spahn DR. Anemia and patient blood management in hip and knee surgery: A systematic review of the literature. Anesthesiology 2010;113:482-95.
Hart A, Khalil JA, Carli A, Huk O, Zukor D, Antoniou J. Blood transfusion in primary total hip and knee arthroplasty. Incidence, risk factors, and thirty-day complication rates. J Bone Joint Surg Am 2014;96:1945-51.
Maxwell MJ, Wilson MJ. Complications of blood transfusion. Contin Educ Anaesth Crit Care Pain 2006;6:2259.
Mannucci PM, Levi M. Prevention and treatment of major blood loss. N
Engl J Med 2007;356:2301-11.
Khan N, Troelsen A, Husted H. Prevention of post-operative anaemia in hip and knee arthroplasty – A systematic review. Dan Med J 2015;62:A5170.
Kagoma YK, Crowther MA, Douketis J, Bhandari M, Eikelboom J, Lim W. Use of antifibrinolytic therapy to reduce transfusion in patients undergoing orthopedic surgery: A systematic review of randomized trials. Thromb Res 2009;123:687-96.
Zufferey P, Merquiol F, Laporte S, Decousus H, Mismetti P, Auboyer C, et al.
Do antifibrinolytics reduce allogeneic blood transfusion in orthopedic surgery? Anesthesiology 2006;105:1034-46.
Alshryda S, Sukeik M, Sarda P, Blenkinsopp J, Haddad FS, Mason JM. A systematic review and meta-analysis of the topical administration of tranexamic acid in total hip and knee replacement. Bone Joint J 2014;96-B:1005-15.
Jain NP, Nisthane PP, Shah NA. Combined administration of systemic and topical tranexamic acid for total knee arthroplasty: Can it be a better regimen and yet safe? A randomized controlled trial. J Arthroplasty 2016;31:542-7.
Song EK, Seon JK, Prakash J, Seol YJ, Park YJ, Jin C. Combined administration of IV and topical tranexamic acid is not superior to either individually in primary navigated TKA. J Arthroplasty 2017;32:37-42.
Wu YG, Zeng Y, Yang TM, Si HB, Cao F, Shen B. The efficacy and safety of combination of intravenous and topical tranexamic acid in revision hip arthroplasty: A randomized, controlled trial. J Arthroplasty 2016;31:2548-53.
Yi Z, Bin S, Jing Y, Zongke Z, Pengde K, Fuxing P. Tranexamic acid administration in primary total hip arthroplasty: A randomized controlled trial of intravenous combined with topical versus single-dose intravenous administration. J Bone Joint Surg Am 2016;98:983-91.
Nielsen CS, Jans Ø, Ørsnes T, Foss NB, Troelsen A, Husted H. Combined intra-articular and intravenous tranexamic acid reduces blood loss in total knee arthroplasty: A randomized, double-blind, placebo-controlled trial. J Bone Joint Surg Am 2016;98:835-41.
Karaaslan F, Karaoǧlu S, Mermerkaya MU, Baktir A. Reducing blood loss in simultaneous bilateral total knee arthroplasty: Combined intravenous-intra-articular tranexamic acid administration. A prospective randomized controlled trial. Knee 2015;22:131-5.
Lin SY, Chen CH, Fu YC, Huang PJ, Chang JK, Huang HT. The efficacy of combined use of intraarticular and intravenous tranexamic acid on reducing blood loss and transfusion rate in total knee arthroplasty. J Arthroplasty 2015;30:776-80.
Huang Z, Ma J, Shen B, Pei F. Combination of intravenous and topical application of tranexamic acid in primary total knee arthroplasty: A prospective randomized controlled trial. J Arthroplasty 2014;29:2342-6.
Prakash J, Seon JK, Song EK, Lee DH, Yang HY, Jin C. Is combined administration of tranexamic acid better than both intravenous and topical regimes for total loss, hidden loss and post-operative swelling? A Randomized control trial. Indian J Orthop 2018;52:117-23.
] [Full text]
Adravanti P, Di Salvo E, Calafiore G, Vasta S, Ampollini A, Rosa MA. A prospective, randomized, comparative study of intravenous alone and combined intravenous and intraarticular administration of tranexamic acid in primary total knee replacement. Arthroplast Today 2018;4:85-8.
Yang L, Du S, Sun Y. Is combined topical and intravenous tranexamic acid superior to single use of tranexamic acid in total joint arthroplasty?: A meta-analysis from randomized controlled trials. Medicine (Baltimore) 2017;96:e7609.
Li JF, Li H, Zhao H, Wang J, Liu S, Song Y, et al.
Combined use of intravenous and topical versus intravenous tranexamic acid in primary total knee and hip arthroplasty: A meta-analysis of randomised controlled trials. J Orthop Surg Res 2017;12:22.
Sun Y, Jiang C, Li Q. A systematic review and meta-analysis comparing combined intravenous and topical tranexamic acid with intravenous administration alone in THA. PLoS One 2017;12:e0186174.
Mercuriali F, Inghilleri G. Proposal of an algorithm to help the choice of the best transfusion strategy. Curr Med Res Opin 1996;13:465-78.
Gibon E, Courpied JP, Hamadouche M. Total joint replacement and blood loss: What is the best equation? Int Orthop 2013;37:735-9.
Andersson L, Nilsoon IM, Colleen S, Granstrand B, Melander B. Role of urokinase and tissue activator in sustaining bleeding and the management thereof with EACA and AMCA. Ann N
Y Acad Sci 1968;146:642-58.
Karski JM, Dowd NP, Joiner R, Carroll J, Peniston C, Bailey K, et al.
The effect of three different doses of tranexamic acid on blood loss after cardiac surgery with mild systemic hypothermia (32°C). J Cardiothorac Vasc Anesth 1998;12:642-6.
Wong J, Abrishami A, El Beheiry H, Mahomed NN, Roderick Davey J, Gandhi R, et al.
Topical application of tranexamic acid reduces postoperative blood loss in total knee arthroplasty: A randomized, controlled trial. J Bone Joint Surg Am 2010;92:2503-13.
Krauss ES, Cronin M, Suratwala SJ, Enker P, Rosen L, Segal A. Use of intravenous tranexamic acid improves early ambulation after total knee arthroplasty and anterior and posterior total hip arthroplasty. Am J Orthop (Belle Mead NJ) 2017;46:E314-E319.
Levy JH, Koster A, Quinones QJ, Milling TJ, Key NS. Antifibrinolytic therapy and perioperative considerations. Anesthesiology 2018;128:657-70.
CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, et al.
Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): A randomised, placebo-controlled trial. Lancet 2010;376:23-32.
Henry DA, Carless PA, Moxey AJ, O'Connell D, Stokes BJ, Fergusson DA, et al.
Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2011;(1):CD001886.
Dr. Charles-Herve Vacheron
Departement D‘fanesthesie Reanimation, Hospices Civils De Lyon, Centre Hospitalier Lyon Sud, 165 Chemin Du Grand Revoyet, 69310 Pierre Benite
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3]