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. Author manuscript; available in PMC: 2022 Jun 1.
Published in final edited form as: J Am Acad Orthop Surg. 2021 Jun 1;29(11):e555–e562. doi: 10.5435/JAAOS-D-20-00658

One Dose Versus Two Doses of Intravenous Tranexamic Acid in Total Joint Arthroplasty

Andrew G Golz 1, Heather K Yee 2, Benjamin J Davis 3, William H Adams 4, Nicholas M Brown 5
PMCID: PMC8166358  NIHMSID: NIHMS1688689  PMID: 32826662

Abstract

Introduction:

Despite its widespread use, a single formulation or dosing regimen of tranexamic acid (TXA) has not been universally agreed on for total joint arthroplasty. The purpose of this study is to compare previously uninvestigated single-dose and two-dose regimens in postoperative hemoglobin level and secondary outcomes within 30 days of surgery.

Methods:

A retrospective search of our institution’s database of patients who underwent primary total knee arthroplasty and primary total hip arthroplasty between January 1, 2017, and July 1, 2019, was performed. Patients were divided into two groups: one group received a 1-g bolus of intravenous TXA just before incision and another intravenous 1-g bolus during wound closure, and the second group received a single 1-g intravenous bolus of TXA just before incision. Two doses of TXA were administered in 873 procedures, and a single dose was administered in 647 procedures.

Results:

A single intravenous TXA dose just before incision was comparable with using two doses of intravenous TXA on patients’ postoperative hemoglobin value, length of stay, rate of transfusion, and 30-day postoperative complication rate, although those receiving two doses of TXA trended toward being less likely to require a transfusion (odds ratio = 0.561; 95% confidence interval: 0.296 to 1.062; P = 0.08). A sensitivity analysis was unable to identify a preoperative hemoglobin value that would identify whether patients would benefit from two versus one dose of TXA.

Discussion:

The use of a single intravenous TXA dose was as efficacious as two doses, without an increase in postoperative complications. Further studies may identify patient subgroups that would benefit from a second dose.

Level of Evidence:

Level III, retrospective cohort study

Total knee arthroplasty (TKA) and total hip arthroplasty (THA) are commonly performed procedures for the treatment of end-stage degenerative joint disease. Substantial perioperative blood loss often accompanies total joint arthroplasty (TJA), which historically results in a third of patients requiring transfusion.1 Tranexamic acid (TXA) is commonly used during TJA to reduce perioperative blood loss and lower the incidence of postoperative transfusion. As a synthetic derivative of lysine that competitively inhibits the conversion of plasminogen to plasmin, it alters the termination of the clotting cascade, leading to clot stabilization and decreased surgical blood loss.2 Of note, TXA is not currently FDA approved for use in TJA.

Many studies have demonstrated the ability of TXA to decrease perioperative blood loss and transfusion in primary TJA,1,3 revision TJA,4,5 and simultaneous bilateral TKA.6 Despite the widespread use of TXA, a single formulation or dosing regimen is not universally accepted in the orthopaedic literature.2 Although multiple formulations and varying dose amounts have demonstrated superiority over placebo—including intravenous, topical, and oral—none by themselves or in various combinations have demonstrated superior efficacy or safety.1,3,7,8

Previous research capitalizing on a control group that did not receive TXA suggests that a single-dose regimen has some efficacy in preventing perioperative blood loss.9–14 However, other studies comparing a single dose with two or more doses have shown variable results.15–24 A recent large, retrospective study demonstrated noninferiority of the single-dose regimen compared with two doses.25 However, they used a different protocol than the one followed at this institution.

Our current regimen of administering TXA consists of a single 1 g intravenous dose before inflation of the tourniquet (ie, if the surgeon uses a tourniquet) and incision. This protocol was instituted in September 2018. Before this, a 1 g intravenous dose was administered before inflation of the tourniquet and incision and another intravenous 1 g dose was administered at the time of wound closure after tourniquet deflation. The purpose of this study was to compare previously uninvestigated single-dose and two-dose regimens in postoperative hemoglobin level and secondary outcomes of transfusion requirement, hospital length of stay, and postoperative complications occurring within 30 days of the procedure. We hypothesized that there would be no differences between groups for any of these variables. In addition, we hypothesized that there would be a threshold preoperative hemoglobin level below which two doses of TXA would be more efficacious, as manifested by a lower rate of transfusion.

Methods

Study Cohort

Approval for this study was obtained from the Institutional Review Board. A search of our institution’s database of patients who underwent primary TKA and primary THA between January 2017 and July 2019 was performed. Patients were excluded if they underwent a revision, conversion, or simultaneous bilateral arthroplasty or if they did not receive perioperative TXA.

All included patients were divided into two groups: patients seen between September 2018 and July 2019 received two doses of TXA consisting of a 1 g intravenous bolus just before the inflation of the tourniquet and incision and another 1 g intravenous bolus after deflation of the tourniquet and during wound closure; the control group comprised all patients between January 2017 and August 2018 who received a single 1 g intravenous bolus of TXA just before inflation of the tourniquet and incision. The use of a tourniquet was dependent on surgeon preference. In addition, tourniquet use fully correlated with the surgeon, and given that the later variable was controlled for in our analysis, variability in tourniquet use should not have affected the primary outcome of postoperative hemoglobin level.

After surgery, all patients received mechanical deep vein thrombosis (DVT) prophylaxis in the form of sequential compression devices while in the hospital. They also received a total of 30 days of pharmacologic prophylaxis, where the specific medication was dependent on surgeon preference. Although the pharmacologic prophylaxis regimen was not completely uniform, aspirin was administered in nearly all cases (1,468/1,520, 96%). Thus, all medications other than aspirin were grouped together and named “nonaspirin anticoagulation.”

In this study, transfusion was indicated for a hemoglobin level less than 7.0 g/dL or at higher hemoglobin levels if the patient exhibited symptoms of anemia, including (but not limited to) lightheadedness, dizziness, or shortness of breath. Patients were excluded from the change in hemoglobin analysis if they received allogeneic or autologous blood transfusion in the operating room or the postanesthesia care unit. It is a standard practice at our institution to measure hemoglobin on postoperative days one through three and to continue measurements thereafter if a patient receives a blood transfusion or if transfusion is being considered. Finally, we defined a postoperative complication as a cerebrovascular accident (CVA), myocardial infarction (MI), DVT, pulmonary embolism (PE), or wound complication related to hematoma during the hospitalization and up to 30 days after surgery.

Statistical Analysis

In this study, patients could contribute multiple procedures to the analysis, and all analyses were at the procedure level. Procedure characteristics are displayed as valid counts and proportions by TXA status for all nominal covariates including sex, anesthesia type, procedure type, type of anticoagulation (aspirin versus nonaspirin), coronary artery disease, chronic obstructive pulmonary disease (COPD), hypertension (HTN), diabetes, stroke (CVA), MI, DVT, PE, hematoma, and transfusion. Mean with standard deviation was used to describe all quantitative characteristics by TXA status including preoperative hemoglobin value, body mass index (BMI), age, and length of stay.

Univariable generalized estimating equations models were used to compare the distributions of these characteristics between patients who received one dose versus two doses of TXA. In these comparisons, a normal distribution with identity link was specified for quantitative responses, whereas a binomial distribution with logit link was specified for binary responses. Because patients could contribute multiple procedures to the analysis, an exchangeable working correlation matrix was used to account for patients’ within-subject correlation.

Subsequently, a multivariable linear mixed-effects model was used to compare repeated (daily) postoperative hemoglobin values between the two dosing groups while controlling for their preoperative hemoglobin level, BMI, age, type of anesthesia, procedure type, sex, HTN status, and surgeon. These covariates were selected using a backward selection procedure that minimized Akaike information criterion as the measure of improvement in model parsimony and fit. Furthermore, the model allowed an interaction term to compare the two TXA doses at each postoperative day while using a Sidak correction to control the type 1 error rate for multiple pairwise comparisons between the two dosing groups; the same correction was used to adjust for multiple pairwise comparisons among anesthesia types. As before, patients could contribute multiple procedures to the analysis and, for this reason, random intercepts were allowed for each patient to account for their within-subject correlation using a completely general (unstructured) covariance structure.

Regarding transfusion, we used a multivariable generalized estimating equation model to compare the odds of receiving a transfusion between the two dosing groups while controlling for patients’ preoperative hemoglobin level, type of anesthesia, procedure type, and type of anticoagulation. Owing to the sparse event rate, only four explanatory variables were selected for the analysis. These were the covariates that minimized the quasi-likelihood under the independence model criterion—a measure of model parsimony and fit.26–28 In this model, a binomial distribution with logit link was specified for the transfusion event and an exchangeable working correlation matrix was used to account for patients’ repeated procedures (within-subject correlation); a Sidak correction was used to adjust confidence limits and significance values for multiple pairwise comparisons among the three anesthesia types. A similar approach was used to compare the odds of 30-day postoperative complication and length of stay between the two dosing groups, although a negative binomial distribution with log link was specified for the length of stay response. All analyses were completed using SAS version 9.4.

Results

Twenty-four procedures were excluded from the analysis because TXA was not administered because of surgeon or anesthesiology preference given a patient history of previous MI (17 procedures), CVA (3 procedures), or venous thromboembolism (4 procedures). Five procedures were excluded because they did not have either preoperative or postoperative hemoglobin levels available for review. Four procedures were excluded from the primary outcome analysis of postoperative hemoglobin level because blood was transfused during surgery or in the postanesthesia care unit. This left 1,336 patients who underwent 1,520 TJAs for the analysis. For the overall cohort, 873 procedures received two 1 g doses of TXA, whereas 647 procedures received a single 1 g dose.

Patients receiving two doses of TXA were nominally younger than those receiving one dose of TXA (μdiff = −0.94, 95% confidence interval [CI]: −1.63 to −0.25; P = 0.01), and compared with patients receiving combined general and regional anesthesia, those receiving only general anesthesia were 3.65 (95% CI: 2.15 to 6.20) times more likely to receive two doses of TXA (P < 0.001), whereas those receiving regional anesthesia were 3.19 (95% CI: 2.01 to 5.06) times more likely to receive two doses of TXA (P < 0.001). Compared with patients receiving one dose of TXA, those receiving two doses were less likely to have coronary artery disease (19.7% versus 25.5%; P = 0.01), less likely to have HTN (71.5% versus 76.2%; P = 0.04), and less likely to have diabetes (24.9% versus 28.3%; P = 0.046) (Supplemental Table 1, Supplemental Digital Content 1, http://links.lww.com/JAAOS/A530).

Postoperative Hemoglobin Level

Controlling for baseline hemoglobin level, BMI, age, anesthesia type, procedure type, sex, HTN status, and surgeon, the average difference in postoperative hemoglobin level between the two dosing groups was furthest apart on postoperative day 2, although the overall association between the number of TXA doses and postoperative hemoglobin level did not necessarily depend on elapsed time in the hospital (overall P = 0.13). In fact, removing the interaction term and simply controlling for elapsed time and all other variables in the model revealed that no significant difference existed in postoperative hemoglobin values between patients receiving two versus one dose of TXA (μdiff = 0.06 g/dL, 95% CI: −0.03 to 0.15 g/dL; P = 0.17) (Figure 1, Supplemental Table 2, Supplemental Digital Content 1, http://links.lww.com/JAAOS/A530).

Figure 1.

Figure 1

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Graph showing the mean hemoglobin on postoperative days 1 through 5 for patients receiving one and two doses of tranexamic acid.

Still, all remaining covariates were associated with patients’ postoperative hemoglobin value. Controlling for all other variables in the model, every 1 g/dL increase in patients’ preoperative hemoglobin value was associated with a 0.60 g/dL (95% CI: 0.57 to 0.63 g/dL) increase in their postoperative hemoglobin value (P < 0.001). Conclusions were similar for BMI, age, and sex, that is, controlling for all other variables in the model, a 10 kg/m2 increase in patients’ BMI was associated with a 0.18 g/dL (95% CI: 0.11 to 0.25 g/dL) increase in patients’ postoperative hemoglobin value (P < 0.001), and every 10-year increase in age was associated with a 0.09 g/dL (95% CI: 0.04 to 0.14 g/dL) increase in the postoperative hemoglobin value (P = 0.001). Men tended to have higher postoperative hemoglobin values than women (μdiff = 0.33, 95% CI: 0.23 to 0.44; P < 0.001).

In this model, some covariates were associated with a decline in postoperative hemoglobin. Patients receiving general anesthesia had lower postoperative hemoglobin values than those receiving regional anesthesia (μdiff = −0.20 g/dL, 95% CI: −0.32 to −0.07 g/dL; P = 0.001), patients who underwent THA had lower postoperative hemoglobin values than those who had TKA (μdiff = −0.36, 95% CI: −0.45 to −0.27; P < 0.001), and patients with HTN tended to have lower postoperative hemoglobin values (μdiff = −0.16, 95% CI: −0.27 to −0.05; P = 0.004).

Transfusion

Controlling for the preoperative hemoglobin level, type of anesthesia, procedure type, and type of anticoagulation, those receiving two doses of TXA trended toward being less likely to require a transfusion (odds ratio [OR] = 0.561; 95% CI: 0.296 to 1.062; P = 0.08). However, no statistically significant difference existed in the odds of transfusion (Table 1). In addition, no preoperative hemoglobin threshold was observed below which patients would benefit from two versus one dose of TXA (Figure 2). However, preoperative hemoglobin level, procedure type, and type of anticoagulation were associated with receiving a transfusion. The odds of receiving a transfusion decreased by approximately 51% for every 1 g/dL increase in patients’ preoperative hemoglobin value (OR = 0.49; 95% CI: 0.34 to 0.70; P < 0.001). Conversely, patients who underwent THA were 2.02 (95% CI: 1.04 to 3.92) times more likely than those who had TKA to require a transfusion (P = 0.04), and patients using nonaspirin anticoagulation were 2.53 (95% CI: 1.24 to 5.13) times more likely than those taking aspirin to require a transfusion (P = 0.01).

Table 1.

Odds of Transfusion as a Function of TXA While Controlling for Preoperative Hemoglobin Level, Anesthesia Type, and Procedure Type

Covariate OR 95% CI
 P Value
Lower Upper
Preoperative Hgb (per 1 g/dL increase) 0.491 0.344 0.701  <0.001
Anesthesia type  0.07a
 Combination versus general 0.328 0.058 1.853 0.33
 Combination versus regional 0.811 0.158 4.167 0.99
 General versus regional 2.476 1.074 5.707 0.03
Procedure: THA versus TKA 2.022 1.043 3.921 0.04
Nonaspirin anticoagulation: yes versus no 2.526 1.244 5.131 0.01
TXA: two versus one dose 0.561 0.296 1.062 0.08
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CI = confidence interval, Hgb = hemoglobin value (g/dL), OR = odds ratio, THA = total hip arthroplasty, TKA = total knee arthroplasty, TXA = tranexamic acid

a

Overall type-3 score test.

Valid N = 1,336 patients contributing 1,516 procedures to the analysis. Among these procedures, there were 45 (3.0%) transfusion events. Confidence limits and significance values for type of anesthesia are adjusted for multiple pairwise comparisons using a Sidak correction.

Figure 2.

Figure 2

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Graph showing the probability of transfusion as a function of preoperative hemoglobin level for patients receiving one and two doses of TXA. TXA = tranexamic acid

30-Day Postoperative Complications

Controlling for the type of anticoagulation, COPD status, and HTN status, no significant difference was observed in the odds of a complication between dosing groups (OR = 0.95; 95% CI: 0.57 to 1.60; P = 0.86) (Table 2). Patients who were administered nonaspirin anticoagulation (OR = 4.69; 95% CI: 2.61 to 8.42; P < 0.001), COPD (OR = 2.39; 95% CI: 1.17 to 4.89; P = 0.02), and with HTN (OR = 3.43; 95% CI: 1.36 to 8.66; P = 0.01) were more likely to experience a complication within 30 days of surgery.

Table 2.

Odds of a Complication as a Function of TXA While Controlling for Patient Comorbidities

Covariate OR 95% CI
 P Value
Lower Upper
Nonaspirin anticoagulation: yes versus no 4.688 2.609 8.422 <0.001
COPD: yes versus no 2.388 1.166 4.890 0.02
HTN: yes versus no 3.431 1.360 8.656 0.01
TXA: two versus one dose 0.953 0.567 1.602 0.86
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CI = confidence interval, COPD = chronic obstructive pulmonary disease, HTN = hypertension, OR = odds ratio, TXA = tranexamic acid Valid N = 1,336 patients contributing 1,520 procedures to the analysis. Among these procedures, there were 60 (3.9%) complication events.

Length of Stay

Finally, after controlling for preoperative hemoglobin value, BMI, age, type of anesthesia, type of anticoagulation, procedure type, and COPD status, no significant difference existed in the length of stay between patients receiving two versus one dose of TXA (rate ratio [RR] = 1.02; 95% CI: 0.98 to 1.07 ; P = 0.38) (Supplemental Table 3, Supplemental Digital Content 1, http://links.lww.com/JAAOS/A530). However, controlling for all other variables in the model, a longer duration of stay was associated with increasing BMI, age, specific anesthesia types, use of nonaspirin anticoagulation, and COPD status.

For every 10-year increase in age, the number of inpatient days increased by approximately 4% (RR = 1.04; 95% CI: 1.01 to 1.07; P = 0.01), and for every 10 kg/m2 increase in BMI, the number of inpatient days increased by approximately 9% (RR = 1.09; 95% CI: 1.04 to 1.13; P < 0.001). Furthermore, the length of stay was also approximately 8% higher for those who received general versus regional anesthesia (RR = 1.08; 95% CI: 1.02 to 1.14; P = 0.01), and the number of inpatient days was approximately 12% higher for patients with COPD (RR = 1.12; 95% CI: 1.03 to 1.21; P = 0.01). Conversely, increasing preoperative hemoglobin level (RR = 0.97; 95% CI: 0.95 to 0.98; P < 0.001) and undergoing a THA instead of TKA (RR = 0.95; 95% CI: 0.91 to 0.99; P = 0.02) were associated with a reduction in length of stay.

Discussion

Antifibrinolytic treatment with TXA has fundamentally changed blood management in TJA by limiting perioperative blood loss and reducing the need for postoperative blood transfusions without increasing perioperative thromboembolic complications.7 The efficacy of TXA in various routes of administration compared with the placebo has been well demonstrated in the arthroplasty literature.1,3,7,29 Similarly, variable dose strength does not seem to affect outcomes. Levine et al2 demonstrated equivalent blood loss and transfusion requirements for patients receiving a single, 1 g dose of TXA compared with a weighted (20 mg/kg) dose. However, a preferred, standardized regimen has not yet been identified, and there is conflicting evidence on whether single-dose TXA is equivalent to multidose regimens.15–24 This study was conducted to compare previously uninvestigated 1-dose and 2-dose TXA regimens in postoperative hemoglobin level, transfusion requirement, length of stay, and 30-day postoperative complications. The first portion of our hypothesis was supported; all these variables were similar between groups.

It has been suggested that multiple doses of TXA may be necessary to maintain a therapeutic level of TXA in the plasma, and previous studies suggest that multidose regimens may be superior to a single dose.20–24 Iwai et al20 compared single-dose and two-dose regimens and found a lower estimated blood loss in the two-dose regimen. However, their study was limited by a low sample size. Sun et al21 compared the same total dose of TXA in single, two-dose, and three-dose regimens and found lower blood loss in the multidose regimens. Of note, no notable difference was observed between the two-dose and three-dose groups.

Conversely, an alternative theory states that the efficacy of a second dose is dampened by the body’s natural antifibrinolytic process after surgery.19 In accordance with this theory and in contrast to these previous studies, our study demonstrated no difference in postoperative hemoglobin level between one- and two-dose regimens. Our results are in agreement with Wilde et al,25 who demonstrated that one dose of TXA was as effective as two doses for decreasing blood loss and transfusion rate after both THA and TKA without a change in venous thromboembolic complications. Their TXA regimen was dependent on whether the patient had TKA or THA. For their two-dose regimen, TKA patients received a 1 g bolus just after tourniquet release and a 1 g bolus 6 hours later, and THA patients received a 1 g bolus just before incision and a second 1 g bolus 6 hours later. They transitioned to a 1 g bolus regimen in which THA patients received a bolus just before incision and TKA patients just after tourniquet release. In our study, the two-dose regimen consisted of a bolus just before incision or inflation of the tourniquet (if used) and the second bolus during wound closure, and the one-dose regimen consisted of a single bolus just before incision. These consistent findings despite differing regimens further suggest that a single 1 g dose is as efficacious as two doses for decreasing perioperative blood loss.

This study identified some interesting findings in postoperative transfusion. Although not generalizable to the cohort, there is some evidence in our data that patients receiving two rather than one TXA dose were less likely to require a transfusion. Nonetheless, this trend did not reach statistical significance. In addition, an attempt was made to identify a preoperative hemoglobin level threshold below which two doses of TXA would be more efficacious, as manifested by a lower rate of transfusion. Although the probability of requiring a transfusion trended lower for patients receiving one dose of TXA compared with two below a preoperative hemoglobin level of 10 g/dL, no statistical difference existed. Therefore, the second portion of our hypothesis was not supported; it was not possible to identify a specific hemoglobin threshold predictive of transfusion for both one and two doses of TXA.

Although efficacious, TXA’s mechanism of action as a clot stabilizer has led to concern over its cardiovascular safety. A recent meta-analysis demonstrated no increased risk of venous or arterial thromboembolism in low-risk patients undergoing TJA with the administration of TXA,29 and the limited sample of randomized clinical trials in high-risk patients (ie, history of MI, CVA, transient ischemic attack, vascular stenting, or venous thromboembolism/PE) suggests similar results.7,30 In agreement with these previous studies, our results showed no difference between the two dosing groups in the incidence of perioperative thromboembolic events within 30 days of surgery, including DVT/PE, CVA, and MI. In addition, our overall rate of thromboembolic events was low at 3.4%.

Using a single-dose regimen reduces costs. If price estimations of $39.14 by Moskal et al31 for a single, 1 g intravenous TXA dose and $78.28 for two doses were used for the projected 1,563,421 primary TKAs and THAs that will be performed in 202032; approximately $61.2 million could be saved over the course of this year if all patients receive a single dose as opposed to two doses. However, generalizing cost analysis to the state or nationwide level is difficult because there is currently no estimation of what proportion of TJAs are performed with a specific TXA dose or route of administration.

This study has several limitations. First, it is limited by its retrospective nature. Second, although all surgeries were performed within a single institution by the same five fellowship-trained joint arthroplasty surgeons, some aspects of the perioperative protocol were not uniform. For example, the decision to apply a tourniquet was at the surgeon’s discretion. Nonetheless, tourniquet use fully correlated with the surgeon and because the later variable was controlled for, it should have not markedly affected our analysis on the primary outcome. In addition, postoperative DVT/PE prophylaxis was not identical for all patient encounters. A small number of patients received warfarin, rivaroxaban, heparin, or enoxaparin after surgery. However, this is unlikely to affect our results, given that aspirin was administered in nearly all cases (1,468/1,520, 96%). Third, this study investigated a specific, intravenous regimen, so these results may not be generalizable to other dosing regimens or routes of administration. Fourth, the study cohort was too small to fully elucidate if there may be certain subgroups of patients that would benefit from a second dose.

In conclusion, the use of a single intravenous TXA dose just before incision resulted in similar postoperative hemoglobin, length of stay, rate of transfusion, and 30-day postoperative complications compared with using two doses of intravenous TXA. Although a patient-specific optimal dosing regimen of TXA has not been elucidated, this study demonstrated that one dose of TXA just before incision was a safe and effective protocol.

Supplementary Material

supp tables

Footnotes

None of the following authors or any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Golz, Ms. Yee, Dr. Davis, Dr. Adams, and Dr. Brown.

Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.jaaos.org).

Contributor Information

Andrew G. Golz, Department of Orthopaedic Surgery and Rehabilitation, Loyola University Medical Center Stritch School of Medicine, Maywood, IL.

Heather K. Yee, Department of Orthopaedic Surgery and Rehabilitation, Loyola University Medical Center Stritch School of Medicine, Maywood, IL.

Benjamin J. Davis, Department of Orthopaedic Surgery and Rehabilitation, Loyola University Medical Center Stritch School of Medicine, Maywood, IL.

William H. Adams, Department of Public Health Sciences, Loyola University Medical Center, Parkinson School of Health Sciences and Public Health, Maywood, IL.

Nicholas M. Brown, Department of Orthopaedic Surgery and Rehabilitation, Loyola University Medical Center Stritch School of Medicine, Maywood, IL.

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References printed in bold type are those published within the past 5 years.

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