The Michigan Experience with Safety and Effectiveness of Tranexamic Acid Use in Hip and Knee Arthroplasty

Hallstrom, Brian MD; Singal, Bonita MD, MS, PhD; Cowen, Mark E. MD; Roberts, Karl C. MD; Hughes, Richard E. PhD

Journal of Bone & Joint Surgery - American Volume:
doi: 10.2106/JBJS.15.01010
Scientific Articles
Abstract

Background: The efficacy of tranexamic acid (TXA) in reducing blood loss and transfusion requirements in total hip and knee arthroplasty has been well established in small controlled clinical trials and meta-analyses. The purpose of the current study was to determine the risks and benefits of TXA use in routine orthopaedic surgical practice on the basis of data from a large, statewide arthroplasty registry.

Methods: From April 18, 2013, to September 30, 2014, there were 23,236 primary total knee arthroplasty cases and 11,489 primary total hip arthroplasty cases completed and registered in the Michigan Arthroplasty Registry Collaborative Quality Initiative (MARCQI). We evaluated the association between TXA use and hemoglobin drop, transfusion, length of stay (LOS), venous thromboembolism (VTE), readmission, and cardiovascular events by fitting mixed-effects generalized linear and mixed-effects Cox models. We used inverse probability of treatment weighting to enhance causal inference.

Results: For total hip arthroplasty, TXA use was associated with a smaller drop in hemoglobin (mean difference = −0.65 g/dL; 95% confidence interval [CI] = −0.60 to −0.71 g/dL), decreased odds of blood transfusion (odds ratio [OR] = 0.72; 95% CI = 0.60 to 0.86), and decreased readmissions (OR = 0.77; 95% CI = 0.64 to 0.93) compared with no TXA use. There was no effect on VTE (hazard ratio [HR] = 0.91; 95% CI = 0.62 to 1.33), LOS (incident rate ratio [IRR] = 1.00; 95% CI = 0.97 to 1.03), or cardiovascular events (OR = 0.85; 95% CI = 0.47 to 1.52). For total knee arthroplasty, TXA was associated with a smaller drop in hemoglobin (mean difference = −0.68 g/dL; 95% CI = −0.64 to −0.71 g/dL) and one-fourth the odds of blood transfusion (OR = 0.26; 95% CI = 0.21 to 0.31). There was an association with decreased risk of VTE within 90 days after surgery (HR = 0.56; 95% CI = 0.42 to 0.73), slightly decreased LOS (IRR = 0.93; 95% CI = 0.92 to 0.95), and no association with readmissions (OR = 0.90; 95% CI = 0.79 to 1.04) or cardiovascular events (OR = 1.12; 95% CI = 0.74 to 1.71).

Conclusions: In routine orthopaedic surgery practice, TXA use was associated with decreased blood loss and transfusion risk for both total knee and total hip arthroplasty, without evidence of increased risk of complications. TXA use was also associated with reduced risk of readmission among total hip arthroplasty patients and reduced risk of VTE among total knee arthroplasty patients, and did not have an adverse effect on cardiovascular complications in either group.

Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Author Information

1Department of Orthopaedic Surgery, University of Michigan Medical Center, Ann Arbor, Michigan

2Department of Orthopaedic Surgery, MARCQI Coordinating Center, University of Michigan, Ann Arbor, Michigan

3Quality Institute, St. Joseph Mercy Hospital, Ann Arbor, Michigan

4West Michigan Orthopaedics, GRMEP-MSU Orthopaedic Surgery Residency Program, Spectrum Health Hospitals, Grand Rapids, Michigan

E-mail address B. Hallstrom: hallstro@med.umich.edu

E-mail address for B. Singal: bsingal@umich.edu

E-mail address for M.E. Cowen: Mark.Cowen@stjoeshealth.org

E-mail address for K.C. Roberts: KRoberts@WMOrtho.net

E-mail address for R.E. Hughes: rehughes@umich.edu

Article Outline

Blood transfusion can be accompanied by rare, life-threatening complications, including acute and delayed hemolytic reactions, acute lung injury, and disease transmission1. Several observational studies have raised concerns over the association of blood transfusion with poorer outcomes after surgery, including longer length of stay (LOS), higher hospital costs, and increased infections and mortality2-10. In a meta-analysis of randomized trials comparing liberal and conservative transfusion strategies, the conservative strategy (fewer transfusions) was associated with a decreased risk of serious infections (risk ratio [RR] = 0.83; 95% confidence interval [CI] = 0.69 to 0.99), including within the subgroup of patients undergoing orthopaedic surgery (RR = 0.72; 95% CI = 0.53 to 0.97)11. Blood transfusion is also expensive. Estimates for the cost of obtaining, storing, testing, and administering 1 unit of blood range from $700 to $1,130 (U.S.)12,13. Despite clinical trials showing the safety and effectiveness of restrictive transfusion practices, a reduction of unnecessary transfusions in elective joint arthroplasty has not yet been demonstrated. An analysis of data from the Nationwide Inpatient Sample showed an increase in the percentage of patients receiving allogeneic blood transfusions from 2000 to 2009 (total hip arthroplasty: 11% to 19%, p < 0.001; and total knee arthroplasty: 8% to 12%, p < 0.001)14.

Tranexamic acid (TXA) is an antithrombolytic agent that inhibits the activation of plasminogen to plasmin. Recent meta-analyses of high-quality randomized controlled trials and several reviews of large cohorts have shown that TXA is effective in reducing blood loss and transfusion rates in total hip arthroplasty and total knee arthroplasty, with no evidence of increased risk of thrombogenic events15-25. However, a few reports have raised concerns about the risk of vascular complications, including venous thromboembolism (VTE), myocardial infarction, and stroke26-28. Because these complications are relatively rare in modern elective total joint replacement, they are difficult to study in clinical trials that may not be adequately powered to detect small but clinically important increased risk. In addition, the results of clinical trials and meta-analyses may not be completely generalizable to routine clinical practice.

We sought to determine the real-world effectiveness and safety of TXA across a broad spectrum of hospitals and providers through the use of a common total joint registry. To assess effectiveness, we asked whether the use of TXA is associated with a smaller drop in hemoglobin and a lower risk of transfusion of at least 1 unit of blood compared with cases in which TXA was not used. To evaluate safety, we compared the risk of VTE and readmission within 90 days of surgery; myocardial infarction, stroke, or transient ischemic attack within 7 days of surgery; and hospital LOS between patients receiving TXA and those not receiving it.

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Materials and Methods

Study Design and Data Source

This was a retrospective cohort study of cases enrolled in the Michigan Arthroplasty Registry Collaborative Quality Initiative (MARCQI), a statewide collaborative begun in 2011 to improve the quality of care for patients undergoing elective hip and knee arthroplasty. By the date of this study, MARCQI had 43 participating hospitals and 296 surgeons. At each participating institution, clinical, administrative, and medical-device data are collected on 100% of total hip and total knee arthroplasty cases. A probability sample of the data is audited annually. Additional administrative data are captured by linking MARCQI cases to a statewide database of hospital admissions, the Michigan Inpatient Database (MIDB). Further details regarding the collaborative data collection and management were previously reported29.

We studied all registry cases of primary elective total hip and knee arthroplasty performed from April 18, 2013, when TXA use was added as a data element, to September 30, 2014. We also required that registry cases be matched to the MIDB so that subsequent hospitalizations could be identified. We excluded cases from 4 hospitals in which no TXA was used and cases for which no information regarding TXA use was recorded (Fig. 1).

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Statistical Methods
Study Variables

The treatment variable of interest was perioperative use of TXA, including topical or intravenous routes. The outcome variables of interest were the drop in hemoglobin (measured as the difference between the preoperative hemoglobin level and the postoperative hemoglobin nadir), transfusion, LOS, readmission and VTE within 90 days of surgery, and the composite cardiovascular outcome of myocardial infarction, stroke, or transient ischemic attack within 7 days of surgery. The identification of at least 1 cardiovascular-complication diagnosis from the index encounter or a present-on-admission diagnosis from the matched readmission encounter was used to create the composite cardiovascular disease outcome using primary and secondary International Classification of Diseases, Ninth Revision (ICD-9) diagnostic codes from the MIDB. All other outcomes were routinely collected by MARCQI.

We controlled for numerous patient, surgical, and hospital-level variables that might have confounded the relationship between TXA and the outcomes of interest. Chart abstraction was used to obtain patient age, sex, race, and body mass index (BMI); preoperative values of hemoglobin, platelets, and creatinine; smoking history; preoperative treatment with antiplatelet agents and anticoagulants; American Society of Anesthesiologists (ASA) status; marital status; type of insurance; surgical approach; anesthesia type (general or other); bilateral cases; and type of VTE prophylaxis (aspirin or other chemoprophylaxis). VTE chemoprophylaxis was defined as treatment with an anticoagulant such as a low-molecular-weight heparin, vitamin K antagonist, factor Xa inhibitor, or direct thrombin inhibitor. Aspirin therapy was recorded separately (Tables I and II). Elixhauser comorbidity diagnoses30 were obtained from the MIDB registry. We also controlled for the hospital’s frequency of screening for VTE, calculated as the total number of venous ultrasound examinations performed postoperatively divided by the number of cases performed at the hospital31.

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Inverse Probability of Treatment Weighting (IPTW) Analysis

There is the potential for serious bias by indication in observational studies of therapeutic interventions. In our case, the relationship between the motivation for TXA use and subsequent bleeding-related outcomes might have confounded any relationship between the actual effect of the drug and the outcomes of interest. In order to minimize the effect of differences between patients who did and did not receive TXA and to enhance causal inference, we created a series of IPT weights. IPTW has been shown to effectively balance identifiable risk factors between treatment groups32. The IPT weight was the inverse of the propensity score for patients receiving TXA, and the inverse of 1 minus the propensity score for patients not receiving TXA. The propensity score was the probability of receiving TXA treatment based on patient and hospital-related variables. Stabilized weights were used33. The adequacy of this approach for addressing confounding was checked by comparing standardized differences between patients receiving versus not receiving TXA in the weighted and unweighted samples34.

Because of the hierarchical nature of the data, we addressed hospital-level clustering (covariance) in the propensity score model and surgeon-level clustering in the outcome model35. The propensity model predicting TXA use was fitted with a mixed-effects logistic regression model with a random effect for hospital. A different propensity model was fitted to derive weights for the VTE outcome analysis, because this analysis excluded patients using anticoagulants before admission. Also, a hospital-level variable reflecting the frequency of VTE screening was added.

All outcome models were mixed-effects models with a random effect for surgeon, weighted using IPTW, and included the following surgical-level variables as covariates: general anesthesia, surgical approach, bilateral surgery, and type of VTE prophylaxis used. A linear model was fitted for the drop in hemoglobin. Logistic models were used for transfusion, readmission, and cardiovascular events. A negative binomial model was fitted for LOS. For VTE, a Cox proportional hazard model, with treatment with aspirin and/or anticoagulant agent included as a time-dependent covariate, was used. In the transfusion analysis, we included a covariate for the calendar time period (6-month intervals) in which the surgery was performed to account for quality-improvement initiatives during the study period that might have affected transfusion practices. The effect estimate in the LOS analysis was expressed as an incident rate ratio (IRR), comparing LOS in the TXA group with LOS in the no-TXA group. SAS software (version 9.4; SAS Institute) was used for all data analyses.

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Power Analysis

A power analysis was performed using PASS 13 software (NCSS). TXA was used in approximately 51% of the hip cases and 48% of the knee cases. Cardiovascular events within 7 days of surgery occurred in approximately 0.8% of the hip cases and 0.6% of the knee cases in which TXA was not administered. With 11,489 hip cases and 23,236 knee cases, and an r2 of approximately 0.03 for the association of the other surgical-level variables and the use of TXA, this study had 80% power to show a significant adverse cardiovascular effect of TXA if the true odds ratios (ORs) were at least 1.69 and 1.55 for total hip arthroplasty and total knee arthroplasty, respectively. Using the same logic, and given that the incidence of VTE within 90 days among patients not given TXA in this registry is approximately 0.8% in hip arthroplasty and 1.8% in knee arthroplasty, this study would have a power of 80% to show a significant adverse VTE effect if the true ORs were at least 1.58 and 1.30, respectively.

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Results

The frequencies of baseline patient and surgical-level variables for hip and knee arthroplasty are shown in Tables I and II, respectively. Standardized differences before and after sample weighting with IPTW are shown in Table III. The closer the standardized differences are to 0, the less impact the risk factors have on the outcomes, making the calculated TXA effect less confounded. It has been suggested that a difference of <0.1 provides acceptable risk adjustment between groups36. Similarly, good risk adjustment or balance was achieved for the VTE data set.

The results of the adjusted outcome analyses are summarized in Figure 2. In primary elective hip arthroplasty, the use of TXA was associated with a smaller drop in hemoglobin (mean difference = −0.65 g/dL; 95% CI = −0.60 to −0.71 g/dL; p < 0.0001) and decreased odds of transfusion (OR = 0.72; 95% CI = 0.60 to 0.86; p = 0.0004). At the same time, there was no evidence of increased relative LOS (IRR = 1.00; 95% CI = 0.97 to 1.03; p = 0.9825), risk of VTE within 90 days of surgery (hazard ratio [HR] = 0.91; 95% CI = 0.62 to 1.33; p = 0.5586), or risk of composite cardiovascular outcomes by 7 days after surgery (OR = 0.85; 95% CI = 0.47 to 1.52; p = 0.5761). Use of TXA was associated with decreased odds of readmission (OR = 0.77; 95% CI = 0.64 to 0.93; p = 0.0080).

In primary elective knee arthroplasty, perioperative TXA use was associated with a smaller drop in hemoglobin (mean difference = −0.68 g/dL; 95% CI = −0.64 to −0.71 g/dL; p < 0.0001) and decreased odds of transfusion (OR = 0.26; 95% CI = 0.21 to 0.31; p < 0.0001). This beneficial outcome associated with TXA was accompanied by a slightly decreased relative LOS (IRR = 0.93; 95% CI = 0.92 to 0.95; p < 0.0001) and decreased risk of VTE within 90 days after surgery (HR = 0.56; 95% CI = 0.42 to 0.73; p < 0.0001). We found no evidence of increased odds of readmission (OR = 0.90; 95% CI = 0.79 to 1.04; p = 0.1511) or cardiovascular outcomes (OR = 1.12; 95% CI = 0.74 to 1.71; p = 0.5715).

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Discussion

We found a significant reduction in the risk of transfusion with the use of TXA in primary total hip and total knee replacement surgery in the clinical practice setting. Hip and knee patients were three-fourths and one-fourth as likely, respectively, to receive transfusions if TXA was administered. Additionally, TXA was associated with a reduction in the drop in hemoglobin by an average of 0.6 g/dL per case. These findings are consistent with those of several randomized controlled clinical trials and meta-analyses of the use of TXA in arthroplasty patients16,19-25.

However, clinical trials have inclusion and exclusion criteria that may not represent all contemporary patients undergoing total joint replacement in the United States. Rare thrombogenic events such as myocardial infarction, transient ischemic attack, or stroke are hard to detect in clinical trials because of the relatively small number of cases. For example, Sukeik et al. performed a meta-analysis of 11 randomized controlled trials investigating the use of TXA in total hip arthroplasty23; 10 of the studies had <50 cases and the other had 100, for a total of 505 cases. They reported that there was no significant difference in deep-vein thrombosis (DVT) or pulmonary embolism (PE) between TXA and no-TXA groups, but they did not report on the absolute numbers of DVTs, and there were only 3 cases with PE. Aguilera et al. randomized 150 patients to intravenous or topical administration of TXA or to placebo15. Exclusion criteria were an allergy to TXA, a history of coagulopathy or VTE events, previous bypass surgery, use of anticoagulant or contraceptive treatment, and a cardiovascular prosthesis. They did not attempt to identify thromboembolic complications because they excluded cases “with possible TXA related complications.” Our study was designed specifically to have sufficient statistical power to test the relationship of TXA and these untoward events. A study such as ours provides reassurance that the results of randomized controlled trials are relevant and generalizable to the broader, unselected population.

We showed a significantly decreased risk of VTE within 90 days of total knee arthroplasty associated with TXA, and we did not find an increase in VTE events in total hip arthroplasty. This is consistent with the findings of 1 study involving a large administrative database and 2 meta-analyses in which no increased risks of DVT or PE were identified37-39. Our finding of the association of TXA with a significantly decreased risk of VTE in total knee arthroplasty is preliminary and may be due to residual confounding not accounted for in the propensity model. As demonstrated in Table II, patients with more comorbidities may not be treated with TXA as often and may be at higher risk for VTE at baseline, biasing the results. Alternately, a possible physiologic explanation for this observation might be that decreased bleeding in and around the knee leads to decreased swelling and less venous obstruction. The key clinical point is that TXA was not associated with an increased risk.

We found no association between TXA and an increased risk of myocardial infarction, stroke, or transient ischemic attack in either hip or knee arthroplasty. In a meta-analysis of surgery trials, Ker et al. also found no difference in myocardial infarction or stroke events associated with the use of TXA38. In our study, 58 (0.5%) of the hip cases and 108 (0.5%) of the knee cases experienced cardiovascular events within 7 days of surgery. Because the outcomes are rare, the CIs around our estimates are wide enough to allow for a 50% to 70% increase in cardiovascular outcomes associated with treatment. We also found a decreased risk of readmission among the hip patients treated with TXA, along with strong evidence of no increase in LOS. Those outcomes were not investigated in other large studies, to our knowledge.

The current study had several limitations. We did not assess the effect of intravenous versus topical administration or TXA dosage on outcomes. We focused on the potential impact of TXA use on thrombogenic events and readmissions but did not explore relationships with all adverse events associated with total joint replacement. Patients were not randomly assigned to treatment, and bias by indication is a possibility. We also found that surgeons changed practice over time: the percentage of surgeons using TXA in <10% of their cases went from 76% in the first 3 months to 30% in the last 3 months of this study, while the percentage of surgeons using it in >90% of their cases went from 12% to 41% (Fig. 3). The change in TXA utilization at the surgeon level creates the potential for patient selection bias, resulting in an exaggerated benefit attributable to TXA. Our strategies to delineate the TXA effect more clearly given this potential selection bias were to balance patient-level variables using IPTW based on the patients’ propensity to receive TXA given their characteristics and to account for the potential correlation of outcomes among patients cared for in the same hospital or by the same surgeon. We were reassured because we were able to achieve excellent balance on covariates, indicating that we were able to adequately control for identified confounders.

Even with these efforts, there could still be other unidentified confounders responsible for the apparent lack of thrombogenic events with TXA use. For example, a surgeon may choose to withhold TXA from patients with cardiovascular risk factors that we did not measure, which in turn could obscure a true underlying increased risk of myocardial infarction or stroke. Although some level of uncertainty remains, techniques exist to estimate how strong the impact of such unmeasured confounders would need to be to overturn our conclusions40. Given reasonable assumptions about the differential prevalence of the unmeasured confounder, this seems unlikely. For example, a confounder would have to have an RR of close to 6 to reverse our conclusions about cardiovascular outcomes.

In summary, our registry-based study adds to the evidence that the use of TXA in primary total hip and knee arthroplasty patients is a safe and effective adjunct to reduce blood loss and the need for transfusion. Additionally, TXA was associated with reduced readmissions among total hip arthroplasty patients and reduced risk of VTE among total knee arthroplasty patients.

NOTE: The authors thank Steven Coon, MPH, for his assistance with data analysis and preparation of this manuscript. Support for the quality improvement work of MARCQI is provided by Blue Cross Blue Shield of Michigan and Blue Care Network as part of the BCBSM Value Partnerships program. No funding is provided for research related to MARCQI. Although BCBSM and MARCQI work collaboratively, the opinions, beliefs, and viewpoints expressed by the authors do not necessarily reflect those of BCBSM or any of its employees. To learn more about Value Partnerships, see http://http://www.valuepartnerships.com.

Investigation performed at the MARCQI Coordinating Center, University of Michigan, Ann Arbor, Michigan

A commentary by Richard Joel Friedman, MD, FRCSC, is linked to the online version of this article at jbjs.org.

Disclosure: Two of the authors (B.H. and R.E.H.) receive partial salary support as the Co-Directors of MARCQI, and one of the authors (M.E.C.) reports a contract for data management with the University of Michigan through funding for MARCQI by Blue Cross Blue Shield of Michigan. No funding was provided for the preparation of this article. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article.

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