Evaluating the Use of Tranexamic Acid in Total Joint Replacement
The authors of this population-based study say their results provide incremental evidence of the potential safety and effectiveness of tranexamic acid to reduce blood loss and the need for blood transfusions in patients undergoing elective total hip and total knee arthroplasty.
Jashvant Poeran, MD, PhD; Rehana Rasul, MPH, MA; Suzuko Suzuki, MD; Thomas Danninger, MD; Madhu Mazumdar, MD; Mathias Opperer, MD; Friedrich Boettner, MD; and Stavros G. Memtsoudis, MD, PhD, FCCP
The authors have no disclosures relevant to this article.
Reducing blood loss and the need for blood transfusions in the perioperative period remains a major concern in total joint replacement. Many interventions have been developed over the past decades, including controlled hypotensive anesthesia  and various blood salvage techniques.
Pharmacologic approaches have also become more popular in recent years, especially the use of tranexamic acid, [2-6] with a recent study showing that administration of tranexamic acid may render the use of blood salvage equipment unnecessary. 
Despite promising results, valid data on safety of tranexamic acid are lacking, as large sample sizes are needed to determine this outcome. Thus, concerns about the routine use of tranexamic acid remain, [5,8,9]
Perioperative outcomes, especially those related to thromboembolic events and renal complications, have traditionally been of concern with the use antifibrinolytic use; however, data on these complications are rare.
Further, no population-based data are available detailing outcomes in a large cohort outside of randomized controlled trials, which often only include patients who meet stringent inclusion criteria. These data are not reflective of real world practice and are burdened by low external validity. 
Utilizing a large national database, we compared the characteristics and outcomes of total joint replacement patients who did and who did not receive tranexamic acid and analyzed whether the use of tranexamic acid is independently associated with altered odds for blood transfusions and perioperative complications, particularly thromboembolic events and acute renal failure.
We hypothesized that the characteristics associated with treated and untreated patients differe, and that tranexamic acid decreases the odds for blood transfusions while not increasing the risk of perioperative complications.
Data Source and Study Design
For this retrospective cohort study we used the Premier Perspective database (Premier, Charlotte, NC) containing information on surgical hospital discharges from January 2006 to October 2012. 
This database provides complete billing information on a patient’s hospital stay as well as information on international classification of diseases-9th revision clinical modification codes (ICD-9 CM) and current procedural terminology codes. Billed items are standardized by the database vendor after the hospital both reviews and consents to the items.
We included cases if they had an indication of elective total hip or knee arthroplasty by the presence of ICD-9 CM codes 81.51 and 81.54, respectively.
Cases were excluded if information on sex was unavailable (n=10), discharge status was unknown, patients were still listed as in-patients at the end of the data collection period (n=291), or patients had both a total hip and a total knee arthroplasty during the same hospital stay (n=193).
The main intervention variable was the use of intravenous tranexamic acid on the day of surgery (further referred to as perioperative tranexamic acid use), which we categorized into 4 groups based on billing information retrieved dosing:
- ≤1000 mg
- 2000 mg
- ≥3000 mg
Patient characteristics included:
- Race (white, black, Hispanic, other)
Healthcare related variables included:
- Type of insurance (commercial, Medicaid, Medicare, uninsured, other)
- Hospital location (rural, urban)
- Hospital bed size (<300, 300-499, ≥500)
- Hospital teaching status
- Mean annual number of total hip and knee arthroplasties per hospital
Procedure related variables included:
- Type of procedure (total hip or knee arthroplasty, unilateral or bilateral for both)
- Type of anesthesia (general, neuraxial, general and neuraxial combined, other, unknown)
- Use of peripheral nerve block
- Use of anticoagulants
- Year of procedure
Analogous to a previous report by our study group,  we used billed items to define type of anesthesia. The same applied to the definition of the use of anticoagulants, for which we also took into account simultaneous use of multiple medications.
We used the Deyo adaptation of the Charlson comorbidity index to measure overall comorbidity burden.  Individual Elixhauser comorbidities,  and the presence of sleep apnea (not included in either index) were evaluated.
Primary outcome variables included:
- Transfusion (allogeneic or both allogeneic and autologous)
- Thromboembolic complications (pulmonary embolism, deep venous thrombosis)
- Acute renal failure
In addition, we considered a combined complication variable, which included thromboembolic complications and acute renal failure as well as in-hospital mortality, cerebrovascular events, and acute myocardial infarction.
Secondary outcome variables included:
- Mechanical ventilation
- Admission to an intensive care unit
- Length of hospital stay in days
- Cost of hospital stay in US dollars
The study sample consisted of 872,416 cases of elective total hip or knee arthroplasty from 510 hospitals.
Except for average age (65.9 years for the tranexamic acid groups vs. 65.8 years for the no tranexamic acid group), all differences between the group of patients receiving tranexamic acid versus the group not receiving tranexamic acid were significant.
Most notably, tranexamic acid was given more often to white patients (82.7% vs. 75.7%), in medium sized (300-499 beds) hospitals (57.7% vs. 37.4%), and in hospitals with a higher mean annual number of total hip or knee arthroplasties (776.6 vs. 731.2).
Moreover, perioperative tranexamic acid use increased dramatically, from almost 0% in 2006 to 11.2% in 2012.
The mean Deyo-Charlson comorbidity index differed only slightly between the groups (0.72 for patients in the tranexamic acid group vs. 0.74 for patients in the no tranexamic acid group, P=0.0267).
The incidence of individual comorbidities was similar in both groups for most comorbidities.
Primary and Secondary Outcome Variables
Compared with patients who did not receive tranexamic acid, patients receiving tranexamic acid had lower rates of all binary outcomes:
- Allogeneic or autologous transfusion (7.7% vs. 20.1%, P<0.001)
- Thromboembolic complications (0.6% vs. 0.8%, P=0.0057)
- Combined complications (1.9% vs. 2.6%, P<0.001)
- Need for mechanical ventilation (0.1% vs. 0.2%, P=0.0003)
- Admission to an intensive care unit (3.1% vs. 7.5%, P<0.001)
Median length of hospital stay was 3 days for both groups; median cost of hospital stay was $14 890 for the tranexamic acid group compared with $15 110 for the group not receiving tranexamic acid (P<0.001).
Multilevel Logistic Regression Analysis
When controlling for covariates, the use of tranexamic acid was significantly associated with a decreased need for allogeneic or autologous blood transfusions (odds ratio varying from 0.31 to 0.38 by dose category), and allogeneic blood transfusions (odds ratio 0.29 to 0.37), with no significantly increased risk for complications:
- Thromboembolic complications (0.85 to 1.02)
- Acute renal failure (0.70 to 1.11)
- Combined complications (0.75 to 0.98)
- Admission to an intensive care unit (0.73 to 1.01)
For the dosage categories, 2000 mg of tranexamic acid seemed to have the best effectiveness and safety profile. For all models, the C statistics were high (range 0.83 to 0.90).
Propensity Score Matching
Out of the 20,051 patients who received tranexamic acid (cases), 5486 were successfully matched to patients who did not receive tranexamic acid (controls). The matched sample was well balanced (standardized differences <10%) for almost all variables.
Similar to the multilevel models, the propensity score analyses showed decreased odds for allogeneic or autologous transfusion (odds ratio 0.50, 95% confidence interval 0.45 to 0.55) and allogeneic transfusion (0.47, 0.42 to 0.53) in patients given tranexamic acid.
In this model too, we found no increased risk for complications:
- Thromboembolic complications (0.86, 0.59 to 1.25)
- Acute renal failure (0.74, 0.57 to 0.96)
- Combined complications (0.75, 0.61 to 0.92)
- Admission to an intensive care unit (0.85, 0.74 to 0.99)
In this population-based study of 872,416 total hip and knee arthroplasty procedures, the use of tranexamic acid was significantly associated with an up to 69% reduction in the need for allogeneic or autologous blood transfusions.
Further, irrespective of the use of anticoagulants, tranexamic acid use was not associated with an increased risk for perioperative complications, including thromboembolic events and acute renal failure.
In a univariable context, we also found the use of tranexamic acid to be associated with reduced healthcare utilization: lower rates of advanced care need, lower length of hospital stay, and lower costs of hospital stay.
Strengths and Limitations of This Study
The main strengths of our study are
- Large sample size
- Use of data from actual, everyday practice (establishing generalizability)
- Multivariable multilevel analysis controlling not only for individual level factors but also for hospital clusters
In particular, the ability to control for the use of anticoagulants and type of anesthesia—both important determinants of transfusion risk—is unique for population-based databases.
Further, the large sample size allows for the study of safety concerns regarding the incidence of rare complications such as pulmonary embolism or deep venous thrombosis. Meta-analyses are limited in their utility to assess generalizable safety concerns about perioperative tranexamic acid use, as patients with, for example, a history of cardiovascular disease or those taking warfarin or low molecular weight heparin, are often excluded from these trials. 
Our study has several limitations:
- First, our analysis utilized data from an administrative database, and detailed clinical information was missing, including hemoglobin levels or other transfusion triggers. We expect the multilevel model to account in part for this limitation as it adjusts for practice variations among hospitals (of which transfusion practices are a part).
- In addition, our outcome is the actual transfusion being administered regardless of the existence of triggers. As in all other guidelines, transfusion triggers are not static and, especially in the perioperative period, may be dynamic and only partially dependent on hemoglobin levels, as rapidly changing variables such as patients’ symptoms and expected trajectory may also play important roles. Thus, lack of detailed clinical data will remain a problem for studies that use retrospective data.
- Furthermore, having detailed clinical information still would not guarantee perfect validity of data as there will always be unmeasured factors influencing decisions and outcomes. This problem is dealt with in a randomized clinical trial setting, but then again at the cost of loss of generalizability to more general populations.
- Another important facet of the lack of detailed clinical data refers to the selective use of tranexamic acid in patients with arterial stents or a history of thromboembolic events, both considered relative contraindications for tranexamic acid use by some practitioners. However, the pseudorandomized approach of the propensity score analysis showed the same results as the multilevel analysis. Moreover, although the Elixhauser comorbidities (but also other patient characteristics) do not specifically capture these contraindications, they might act as a partial proxy, thus reducing the effect of this limitation.
- Another limitation refers to residual confounding. Although we included many important covariates in our analytic models while also accounting for correlation of patients within hospitals, residual confounding might remain. However, the multilevel models showed high C statistics (up to 0.90), indicating good model discrimination between subjects for each level of the outcome.
- The use of ICD-9 codes and billing data may also be associated with registration bias. However, this bias should be equally distributed between our treatment groups, thus reducing its impact. Although we did have information on the dose of tranexamic acid using billing data, we do not know with complete certainty how much of the billed medication was actually administered to the patients as this is a topic of major controversy. We therefore have limited our statements to the categorical (“yes or no”) use of tranexamic acid.
- Finally, with respect to the safety of tranexamic acid, we were only able to study complications that occurred during the patients’ hospital stay, which is an inherent limitation of our data source. This may cause an underestimation of the actual incidence of complications. However, 1 study showed that more than 90% of complications in unilateral arthroplasties occur within 4 days after surgery, suggesting that most complications should be encompassed within our dataset. 
Comparison with Existing Literature
The use of tranexamic acid has been shown to be effective in reducing blood transfusions in small, randomized controlled trials and in meta-analytic publications. [2-7,9] Our study validates these findings by providing data on effectiveness from information gathered in a wide range of settings representing actual, “real world” practice.
This is important, as the information gathered from randomized controlled trials conducted in single institutional—often academic—settings frequently lacks external validity, as participants tend to be highly selected.
The effect size, as measured by the reduction in the odds for the need of allogeneic or autologous blood transfusions by up to 69% was large even by conservative standards. This finding has significant implications for 2 reasons:
- Firstly, total hip and knee arthroplasty are common procedures, with over 1 million interventions annually in the United States alone,  and the utilization is expected to increase dramatically in the future. 
- Secondly, joint arthroplasty is associated with significant blood loss with relatively high transfusion rates compared with other elective surgeries.  In this context, the use of tranexamic acid in patients undergoing total joint arthroplasty may have a profound clinical and economic impact if used in appropriate candidates—that is, those at high risk for requiring blood transfusions. [23,24]
When analyzing the impact of tranexamic acid use on complications, we found no increased risk for adverse outcomes in general, and for thromboembolic events and acute renal failure in particular. In fact, the multilevel model showed significantly decreased risks for some complications.
These complications have been put forward by several clinicians as major reasons for a conservative use of tranexamic acid given previously published concerns with agents of this category.  As tranexamic acid inhibits fibrinolysis, safety concerns are based on the fact that interference with the coagulation cascade may promote a procoagulable state and thus increase the risk for complications such as pulmonary embolism, deep venous thrombosis, myocardial infarctions, and cerebrovascular events. 
This is of particular concern in total joint arthroplasty, as these patients have been identified as an especially vulnerable group for clotting-based complications as the source of major morbidity and mortality.  Further, previous publications have identified the use of certain antifibrinolytics to be associated with increased mortality in surgical patients, leading to the withdrawal of aprotinin from the US market.  Renal failure was identified as a major contributor to this outcome and has since been the focus of many outcome studies related to antifibrinolytics. 
Although comparative evaluations between aprotinin and other agents such as tranexamic acid have shown improved safety profiles with tranexamic acid, such studies are scarce for the population of patients requiring orthopedic procedures.  Even though a meta-analysis showed efficacy of either agent in patients requiring orthopedic surgery, the authors concluded that safety data are needed before recommending the use of these agents in this patient population. 
Despite encouraging results derived from our analysis regarding the safety of tranexamic acid, we cannot provide support for the ubiquitous use of tranexamic acid in all patients requiring total joint arthroplasty as the differential impact on complications among patient subpopulations remains to be studied.
In this context, studies with aprotinin have suggested that the use of this antifibrinolytic agent among low- to intermediate-risk patients requiring cardiac surgery may increase mortality risk, while not having the same effect in high-risk patients.  Thus, a conservative approach taking into account appropriate stratification strategies for bleeding risk seems prudent when deciding to use any antifibrinolytic perioperatively.
Future studies might focus on this subgroup specific effectiveness and safety of tranexamic acid.
Conclusions and Implications
Utilizing population-based data, we found that tranexamic acid was effective in reducing the need for blood transfusions in total joint arthroplasty patients while not increasing the risk of complications, including thromboembolic events and renal failure.
Although our data provide incremental evidence of the potential effectiveness and safety of tranexamic acid in these patients, this study has limitations inherent to observational analyses. Moreover, outcome data in subpopulations of patients remain to be studied.
Therefore, the prudent identification of patients most likely to benefit from tranexamic acid—that is, those at increased risk of bleeding—is warranted. Additional studies focusing not only on subgroup specific effectiveness and safety but also on optimal dosing schemes are needed.
What Is Already Known on This Topic
- Tranexamic acid has been shown to reduce perioperative blood loss and blood transfusions in orthopedic surgery
- Safety concerns remain, however, as small and highly selective populations were studied
- Large scale effectiveness studies are lacking
What This Study Adds
- Tranexamic acid is associated with a decreased risk for blood transfusions, while not increasing the risk of complications, including thromboembolic events and renal failure
- Our data provide incremental evidence of the potential effectiveness and safety of tranexamic acid in patients requiring orthopedic surgery
Jashvant Poeran, MD, PhD; Rehana Rasul, MPH, MA; Madhu Mazumdar and , MD, are from the Institute of Healthcare Delivery Science, Mount Sinai Hospital System/Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York, New York. Suzuko Suzuki, MD; Thomas Danninger, MD; Mathias Opperer and , MD, are from the Department of Anesthesiology, Hospital for Special Surgery, New York, New York. Friedrich Boettner, MD, is from the Department of Orthopedic Surgery, Hospital for Special Surgery, New York, New York. Stavros G. Memtsoudis, MD, PhD, FCCP, is from the Department of Anesthesiology, Hospital for Special Surgery, New York, New York, and the Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, New York.
Poeran J, Rasul R, Suzuki S, Danninger T, Mazumdar M, Opperer M, Boettner F, Memtsoudis SG. Tranexamic acid use and postoperative outcomes in patients undergoing total hip or knee arthroplasty in the United States: retrospective analysis of effectiveness and safety. BMJ. 2014 Aug 12;349:g4829. doi: 10.1136/bmj.g4829. © Poeran et al 2014. This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.
- Sharrock NE, Mineo R, Urquhart B, Salvati EA. The effect of two levels of hypotension on intraoperative blood loss during total hip arthroplasty performed under lumbar epidural anesthesia. Anesth Analg 1993;76:580-4.
- Irisson E, Hemon Y, Pauly V, Parratte S, Argenson JN, Kerbaul F. Tranexamic acid reduces blood loss and financial cost in primary total hip and knee replacement surgery. Orthop Traumatol Surg RES 2012;98:477-83.
- Zhang H, Chen J, Chen F, Que W. The effect of tranexamic acid on blood loss and use of blood products in total knee arthroplasty: a meta-analysis. Knee Surg Sports Traumatol Arthrosc 2012;20:1742-52.
- Huang F, Wu D, Ma G, Yin Z, Wang Q. The use of tranexamic acid to reduce blood loss and transfusion in major orthopedic surgery: a meta-analysis. J Surg Res 2014;186:318-27.
- Zhou XD, Tao LJ, Li J, Wu LD. Do we really need tranexamic acid in total hip arthroplasty? A meta-analysis of nineteen randomized controlled trials. Arch Orthop Trauma Surg 2013;133:1017-27.
- George DA, Sarraf KM, Nwaboku H. Single perioperative dose of tranexamic acid in primary hip and knee arthroplasty. Eur J Orthop Surg Traumatol (forthcoming).
- Oremus K, Sostaric S, Trkulja V, Haspl M. Influence of tranexamic acid on postoperative autologous blood retransfusion in primary total hip and knee arthroplasty: a randomized controlled trial. Transfusion 2014;54:31-41.
- Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ 2012;344:e3054.
- Yang ZG, Chen WP, Wu LD. Effectiveness and safety of tranexamic acid in reducing blood loss in total knee arthroplasty: a meta-analysis. J Bone Joint Surg Am 2012;94:1153-9.
- Premier. Premier Perspective Database. 2014. (www.premierinc.com/wps/portal/premierinc/public/transforminghealthcare/improvingperformance/servicesprograms/researchservices).
- Memtsoudis SG, Danninger T, Rasul R, Poeran J, Gerner P, Stundner O, et al. Inpatient falls after total knee arthroplasty: the role of anesthesia type and peripheral nerve blocks. Anesthesiology 2014;120:551-63.
- Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 1992;45:613-9.
- Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use with administrative data. Med Care 1998;36:8-27.
- Moineddin R, Matheson FI, Glazier RH. A simulation study of sample size for multilevel logistic regression models. BMC Med Res Methodol 2007;7:34.
- Hosmer DW, Lemeshow S. Applied logistic regression. 2nd ed. Wiley, 2000.
- Ury HK. Efficiency of case-control studies with multiple controls per case: continuous or dichotomous data. Biometrics 1975;31:643-9.
- Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 2011;46:399-424.
- Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med 2009;28:3083-107.
- Parvizi J, Mui A, Purtill JJ, Sharkey PF, Hozack WJ, Rothman RH. Total joint arthroplasty: when do fatal or near-fatal complications occur? J Bone Joint Surg Am 2007;89:27-32.
- Kirksey M, Chiu YL, Ma Y, Della Valle AG, Poultsides L, Gerner P, et al. Trends in in-hospital major morbidity and mortality after total joint arthroplasty: United States 1998-2008. Anesth Analg 2012;115:321-7.
- 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.
- Memtsoudis SG, Sun X, Chiu YL, Nurok M, Stundner O, Pastores SM, et al. Utilization of critical care services among patients undergoing total hip and knee arthroplasty: epidemiology and risk factors. Anesthesiology 2012;117:107-16.
- Browne JA, Adib F, Brown TE, Novicoff WM. Transfusion rates are increasing following total hip arthroplasty: risk factors and outcomes. J Arthroplasty 2013;28(8 Suppl):34-7.
- Ahmed I, Chan JK, Jenkins P, Brenkel I, Walmsley P. Estimating the transfusion risk following total knee arthroplasty. Orthopedics 2012;35:e1465-71.
- Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006;354:353-65.
- Memtsoudis SG, Della Valle AG, Besculides MC, Esposito M, Koulouvaris P, Salvati EA. Risk factors for perioperative mortality after lower extremity arthroplasty: a population-based study of 6,901,324 patient discharges. J Arthroplasty 2010;25:19-26.
- Murkin JM. Lessons learned in antifibrinolytic therapy: the BART trial. Sem Cardiothoracic Vasc Anesth 2009;13:127-31.
- Hutton B, Joseph L, Fergusson D, Mazer CD, Shapiro S, Tinmouth A. Risks of harms using antifibrinolytics in cardiac surgery: systematic review and network meta-analysis of randomised and observational studies. BMJ 2012;345:e5798.
- 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.
- Meybohm P, Herrmann E, Nierhoff J, Zacharowski K. Aprotinin may increase mortality in low and intermediate risk but not in high risk cardiac surgical patients compared to tranexamic acid and epsilon-aminocaproic acid—a meta-analysis of randomised and observational trials of over 30.000 patients. PloS One 2013;8:e58009.