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Anticoagulation in patients with atrial fibrillation undergoing inpatient total knee arthroplasty: A matched analysis
, Mariah Balmaceno-Criss, Jonathan Liu, Manjot Singh, Michael J. Kuharski, Alan H. Daniels, Eric M. Cohen
⁎Corresponding author: Eric M. Cohen. eric_cohen@brown.edu
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Received: ,
Accepted: ,
This article was originally published by Reed Elsevier India Pvt. Ltd. and was migrated to Scientific Scholar after the change of Publisher.
Abstract
Abstract
Patients with atrial fibrillation (AF) often require lifetime anticoagulation using drugs such as Warfarin and Direct-acting Oral Anticoagulants (DOAC). It is important to assess the impact that prior anticoagulant use has on the post-operative complications in patients with AF undergoing TKA.
This is a retrospective analysis of the PearlDiver database querying all patients who underwent an inpatient TKA. Patients who had AF and filled a prescription for at least 30 days of either Warfarin or a DOAC were matched to control cohorts. Medical and surgical complications 30 and 90 days post-operatively were compared between the two groups.
4396 patients made up the group with AF on warfarin, while 5383 patients made up the cohort with AF on DOAC and their corresponding controls. Patients on anticoagulation had more AKI (OR 2.70, OR: 2.37), pneumonia (OR: 2.89, OR: 2.46), MI (OR: 2.70, OR: 3.14), transfusion (OR: 6.94, OR: 3.16), sepsis (OR: 2.47, OR: 1.96), and aseptic loosening at 90 days (OR: 17.06, OR:7.01). However, PE (OR: 3.32) and hematoma (OR: 1.71) were only higher in the warfarin cohort. TKA instability was higher in the DOAC cohort (OR: 6.00). Conversely, patients in the control group exhibited more wound dehiscence compared to the warfarin group (OR: 0.28), and higher rates of revision surgery compared to both the DOAC (OR:0.27) and Warfarin (OR:0.31) groups at 90 days.
Patients on DOAC and Warfarin for AF, and undergoing TKA are exposed to a higher risk of post-operative complications.
Keywords
Total knee arthroplasty
Direct-acting oral anticoagulants
Warfarin
Atrial fibrillation
1 Introduction
Between 1990 and 2019, the prevalence of osteoarthritis (OA) grew by 113.25 % worldwide, with the knee joint being identified as the most impacted region.1–3 When conservative methods fail to provide symptomatic relief for advanced and end-stage OA of the knee joint, total knee arthroplasty (TKA) is recommended as an effective treatment option to address pain and functional limitations.4 With 4.7 million Americans living with TKA in 2010, the annual rate of TKA is steadily rising both globally and in the US.5,6 In fact, TKA was the second-fastest growing surgery in the US between 2003 and 2012, going from 421,700 to 700,100 procedures annually.7
The frequency of atrial fibrillation (AF), a relatively common arrhythmia, rises noticeably with age.8,9 It is anticipated that there would be over 8 million AF patients in the US by the year 2050.8,9 In fact, the majority of people with AF require lifetime anticoagulation medication in order to reduce their risk of thrombotic events such as direct-acting oral anticoagulants (DOAC) and warfarin.10,11 However, such patients continue to have higher risks of thrombotic events such as cerebrovascular accidents and blood loss peri-operatively compared to the general population..9,10,12 Patients with persistent AF undergoing total joint arthroplasty have unique challenges and considerations due to these concerns. Although these patients need sufficient anticoagulant therapy to avoid thrombotic events, improper use of these drugs can increase their risk of bleeding.13
In fact, studies have previously shown that patients with AF undergoing knee surgery had an increased length of stay (LOS), increased transfusion requirements, an increased risk of periprosthetic joint infection and unplanned hospital readmission, and higher rates of thromboembolic events and death.12,14,15 However, no previous study has assessed the impact of prior and long-term DOAC and Warfarin use for AF in patients undergoing TKA. Thus, this study will compare the medical and surgical complications between AF patients on DOAC and Warfarin undergoing TKA, and a matched group of controls.
2 Methods
2.1 Data source
A retrospective analysis of the PearlDiver (PearlDiver Technologies, Colorado Springs, CO) database was performed by querying all patients who underwent an in-patient total knee arthroplasty between January 1, 2010 and April 31, 2020. This dataset uses International Classifications of Diseases, ninth (ICD-9) and tenth revision (ICD-10), and Current Procedural Terminology (CPT) billing codes tied to insurance claims to longitudinally track patients’ data. These data were used to calculate rates of postoperative surgical and medical complications in patients with atrial fibrillation who filled at least a 30-day prescription for either warfarin or a direct-acting oral anticoagulant (DOAC, i.e. apixaban, dabigatran, rivaroxaban) within the immediate preoperative period prior to undergoing a TKA. No protected health information (PHI) was gathered during this study and thus this study was exempt from Institutional Review Board (IRB) review.
2.2 Creating the experimental cohorts
All patients who underwent an inpatient TKA between January of 2010 and April of 2022 were identified. Patients were excluded if they had TKA after April 31, 2020 or were not active within the dataset for at least 2 years after their TKA to allow for a minimum of 2 years of follow-up data for each patient. Patients who were diagnosed with a traumatic fracture within the 7 days before and after their TKA were also excluded. Patients who had a history of metastatic cancer or comorbid autoimmune conditions were excluded. Following these exclusions, 1,247,982 patients comprised the initial base sample. This sample was then filtered to create two cohorts of patients who had atrial fibrillation and filled a prescription for at least 30 days of either warfarin or a direct-acting oral anticoagulant. These cohorts of patients with atrial fibrillation on anti-coagulants was then matched to control cohorts with no warfarin or a direct-acting oral anticoagulant use using 1-to-1 direct matching on age, sex, alcohol use, chronic kidney disease, drug use, chronic pulmonary disease, coagulopathy, congestive heart failure, coronary artery disease, diabetes, hypertension, obesity, liver disease, renal disease, deficiency anemia, or tobacco use. Following the one-to-one matching, 4396 comprised the atrial fibrillation on warfarin cohort and its respective control and 5383 patients comprised the atrial fibrillation on DOAC cohort and its respective control.
2.3 Determining and comparing rates of postoperative complications
Rates of postoperative medical and surgical complications were calculated at different postoperative timepoints using ICD-9, ICD-10, and CPT billing codes. All postoperative medical complications in the first 30 days, and surgical complications in the first 30 and 90 days following the procedure were identified and odds ratios for the complications compared to control were calculated. Student's t-test and chi-square analyses were used to compare the demographics and comorbidities between the experimental and control cohorts. A p-value of <0.05 was determined to represent statistical significance a priori. All statistical analyses were performed using the R Statistical Package (v4.2.1; R Core Team 2022, Vienna, Austria) embedded within PearlDiver.
3 Results
3.1 Demographics
3.1.1 Warfarin
There were no significant differences observed in the mean age (mean age 70.58 years) or gender distribution (female n = 2104) of patients with atrial fibrillation on warfarin undergoing in-patient TKA compared to controls (p = 1.000). However, the warfarin group displayed a lower mean Charlson Comorbidity Index (CCI) score compared with the control group (warfarin: 1.69 versus control: 1.84, p < 0.001). Despite this, there were no significant differences found in the prevalence of matched comorbidities, p = 1.000 (Table 1).
| Warfarin N = 4396 | Control N = 4396 | p-value | |
| Age | 70.58 (5.65) | 70.58 (5.65) | 1.000 |
| Female (n) | 2104 | 2104 | 1.000 |
| CCI | 1.69 (2.02) | 1.84 (2.05) | <0.001 |
| Alcohol Abuse | 39 | 39 | 1.000 |
| Chronic Kidney Disease | 1413 | 1413 | 1.000 |
| Drug Abuse | 52 | 52 | 1.000 |
| Chronic Pulmonary Disease | 1939 | 1939 | 1.000 |
| Coagulopathy | 730 | 730 | 1.000 |
| Congestive Heart Failure | 965 | 965 | 1.000 |
| Coronary Artery Disease | 2983 | 2983 | 1.000 |
| Diabetes | 2473 | 2473 | 1.000 |
| Hypertension | 4352 | 4352 | 1.000 |
| Obesity | 2548 | 2548 | 1.000 |
| Liver Disease | 346 | 346 | 1.000 |
| Renal Disease | 1414 | 1414 | 1.000 |
| Deficiency Anemia | 722 | 722 | 1.000 |
| Tobacco Use | 1770 | 1770 | 1.000 |
3.1.2 DOAC
The DOAC group did not significantly differ from its control group in terms of age (mean age 70.25 years), gender distribution (female n = 2647), or matched comorbidities but had a significantly higher mean CCI (DOAC: 1.65 versus control: 1.58, p < 0.001) (Table 2).
| DOACN = 5383 | ControlN = 5383 | p-value | |
| Age | 70.25 (6.58) | 70.25 (6.58) | 1.000 |
| Female (n) | 2647 | 2647 | 1.000 |
| CCI | 1.65 (1.96) | 1.58 (1.89) | <0.001 |
| Alcohol Abuse | 67 | 67 | 1.000 |
| Chronic Kidney Disease | 1306 | 1306 | 1.000 |
| Drug Abuse | 57 | 57 | 1.000 |
| Chronic Pulmonary Disease | 1998 | 1998 | 1.000 |
| Coagulopathy | 470 | 470 | 1.000 |
| Congestive Heart Failure | 601 | 601 | 1.000 |
| Coronary Artery Disease | 3102 | 3102 | 1.000 |
| Diabetes | 2694 | 2694 | 1.000 |
| Hypertension | 5299 | 5299 | 1.000 |
| Obesity | 3385 | 3385 | 1.000 |
| Liver Disease | 496 | 496 | 1.000 |
| Renal Disease | 1307 | 1307 | 1.000 |
| Deficiency Anemia | 807 | 807 | 1.000 |
| Tobacco Use | 2192 | 2192 | 1.000 |
3.2 Complications
3.2.1 Warfarin
Patients in the warfarin group had a significantly higher incidence of acute kidney injury (AKI) (OR 2.70), pneumonia (OR: 2.89), pulmonary embolism (OR: 3.32), myocardial infarction (MI) (OR: 2.70), transfusion (OR: 6.94), sepsis (OR: 2.47), and hematoma (OR: 1.71) compared to the control group. Conversely, patients in the control group exhibited a higher rate of wound dehiscence compared to the warfarin group (OR: 0.28). The incidences of joint infection, periprosthetic fracture, aseptic loosening, periprosthetic dislocation, TKA instability, and TKA revision, did not show significant differences between the two groups at 30 days post-operatively (Table 3). At 90 days post-operatively, patients in the Warfarin group had a higher rate of aseptic loosening (OR: 17.06), and a lower rate of revision (OR:0.31) (Table 3).
| 30-day Complication | ||||
| Warfarin N = 4396 | Control N = 4396 | Odd's Ratio | 95 % CI | |
| AKI∗ | 161 | 61 | 2.70 | 2.01–3.64 |
| Pneumonia∗ | 108 | 38 | 2.89 | 1.99–4.19 |
| DVT | 20 | 11 | 1.82 | 0.87–3.81 |
| Pulmonary Embolism∗ | 69 | 21 | 3.32 | 2.03–5.42 |
| Myocardial Infarction∗ | 153 | 58 | 2.7 | 1.99–3.66 |
| Transfusion∗ | 102 | 15 | 6.94 | 4.03–11.95 |
| Sepsis∗ | 32 | 13 | 2.47 | 1.30–4.72 |
| Wound Dehiscence∗ | <10 | 21 | 0.28 | 0.11–0.71 |
| Hematoma | 29 | 17 | 1.71 | 0.94–3.12 |
| Manipulation under anesthesia | 0 | 0 | – | – |
| Joint Infection | 24 | 26 | 0.92 | 0.53–1.61 |
| Periprosthetic Fracture | <10 | <10 | 0.33 | 0.05–5.52 |
| Aseptic Loosening | 14 | 0 | – | – |
| Periprosthetic Dislocation | 0 | <10 | – | – |
| TKA Instability | <10 | <10 | 1.00 | 0.06–15.99 |
| TKA Revision | <10 | <10 | 0.33 | 0.09–1.23 |
| 90-day Surgical Complications | ||||
| Warfarin N = 4396 | Control N = 4396 | Odd's Ratio | 95 % CI | |
| Manipulation under anesthesia | 0 | 0 | – | – |
| Joint Infection | 53 | 47 | 1.13 | 0.76–1.67 |
| Periprosthetic Fracture | <10 | <10 | 0.50 | 0.09–2.73 |
| Aseptic Loosening∗ | 17 | <10 | 17.06 | 2.27–128.27 |
| Periprosthetic Dislocation | 0 | <10 | – | – |
| TKA Instability | <10 | <10 | 1.00 | 0.06–15.99 |
| TKA Revision∗ | <10 | 19 | 0.31 | 0.13–0.79 |
3.2.2 DOAC
Patients in the DOAC group exhibited a significantly higher incidence of AKI (OR 2.37), pneumonia (OR: 2.46), MI (OR: 3.14), transfusion (OR: 3.16), sepsis (OR: 1.96), and aseptic loosening (OR: 5.51) compared to the control group with no difference in the remaining outcomes at 30 days (Table 4). At 90 days post-operatively, patients in the DOAC group had a higher rate of aseptic loosening (OR: 7.01), a higher rate of TKA instability (OR: 6.00), and a lower rate of revision (OR:0.27) (Table 4).
| 30-day Complication | ||||
| DOAC N = 5383 | Control N = 5383 | Odd's Ratio | 95 % CI | |
| AKI∗ | 161 | 69 | 2.37 | 1.79–3.16 |
| Pneumonia∗ | 102 | 42 | 2.46 | 1.71–3.53 |
| DVT | 29 | 19 | 1.53 | 0.86–2.73 |
| Pulmonary Embolism | 20 | 23 | 0.87 | 0.48–1.58 |
| Myocardial Infarction∗ | 181 | 59 | 3.14 | 2.33–4.22 |
| Transfusion∗ | 69 | 22 | 3.16 | 1.96–5.12 |
| Sepsis∗ | 45 | 23 | 1.96 | 1.19–3.25 |
| Wound Dehiscence | 11 | 21 | 0.52 | 0.25–1.09 |
| Hematoma | 23 | 12 | 1.92 | 0.95–3.86 |
| Manipulation under anesthesia | 0 | 0 | – | – |
| Joint Infection | 21 | 24 | 0.87 | 0.49–1.57 |
| Periprosthetic Fracture | <10 | <10 | 1.33 | 0.30–5.96 |
| Aseptic Loosening∗ | 11 | <10 | 5.51 | 1.22–24.87 |
| Periprosthetic Dislocation | <10 | 0 | – | – |
| TKA Instability | <10 | 0 | – | – |
| TKA Revision | 0 | 10 | – | – |
| 90-day Surgical Complications | ||||
| DOAC N = 5383 | Control N = 5383 | Odd's Ratio | 95 % CI | |
| Manipulation under anesthesia | 0 | 0 | – | – |
| Joint Infection | 46 | 51 | 0.90 | 0.60–1.34 |
| Periprosthetic Fracture | <10 | <10 | 0.89 | 0.34–2.30 |
| Aseptic Loosening∗ | 14 | <10 | 7.01 | 1.59–30.88 |
| Periprosthetic Dislocation | <10 | 0 | – | – |
| TKA Instability∗ | 12 | <10 | 6.00 | 1.34–26.87 |
| TKA Revision∗ | <10 | 18 | 0.27 | 0.10–0.74 |
4 Discussion
In an aging population with improved accessibility to healthcare, the rate of TKA in patients with concurrent AF continues to increase. As AF is primarily managed by anticoagulants such as DOAC and warfarin, it is important to study how these medications affect medical and surgical complications in patients undergoing TKA. In our study, patients taking warfarin were shown to have a higher rate of AKI, pneumonia, pulmonary embolism, MI, transfusion, sepsis, and hematoma, though a lower rate of wound dehiscence compared to the control group at 30 days. Similarly, patients in the DOAC group had a higher rate of AKI, pneumonia, MI, transfusion, sepsis, and aseptic loosening compared to the control group. At 90 days, both groups on anticoagulation exhibited higher rates of aseptic loosening, and only the DOAC group had a higher rate of TKA instability. However, they both had a lower rate of revision surgery.
AKI, and transfusions were both higher in patients on DOAC and Warfarin compared to their controls. However, hematoma formations and PE were only higher in patients on warfarin. Patients on anticoagulants are more prone to bleeding intra-operatively12,14,15 which may explain the higher rates of transfusions. Furthermore, more intra-operative bleeding may predispose the patients to post-operative AKI resultant from intra-operative hypotension and kidney hypoperfusion.16–18 On the other hand, hematoma formation was trending towards significance in DOAC patients compared to their controls, however, it was significantly higher in Warfarin patients when compared to their controls (OR: 1.71). Similarly, PE rates were only higher in the Warfarin group (OR: 3.32). These discrepancies could be explained by the fact that Warfarin, a vitamin K antagonist requires strict monitoring and titration for optimal therapeautic effect. In fact, it takes around four days for the antithrombotic effect of warfarin to recede.12,19,20 In addition, three days are also usually required to reestablish therapeutic anticoagulation after resuming Warfarin, an issue not faced with DOAC.12,19,20
A lower rate of wound dehiscence was experienced in patients on warfarin while a higher rate of non-surgical site infections (pneumonia and sepsis) was seen in patients on DOAC and Warfarin. In fact, patients with AF are shown to have longer LOS when compared to controls in both TKA and cardiac surgeries.12,21,22 The longer LOS could predispose patients to nosocomial infections and the higher rate of transfusions could be contributing to the higher rates of pneumonia and sepsis seen in patients on DOAC and warfarin. In addition, the longer LOS could contribute as well to the lower rate of wound dehiscence as these patients might be receiving better monitoring and wound care during their hospital stay as opposed to their discharged controls. The higher rate of TKA instability might as well be caused by the longer LOS since risk factors for prosthetic dislocation include implant malpositioning, mismatch of the flexion–extension gap, and incompetence of the extensor mechanism which could be the result of longer immobilization.23 Another factor that might be contributing to both aseptic loosening and TKA instability could be the higher intra-operative blood loss resulting in a longer, and more technically challenging procedure contributing to malpositioning. Additionally, medical comorbidities and complications in this patient subset may contribute to delayed biologic healing and surgical complications. As for the increased rate of MI in patients on DOAC (OR: 3.14) and Warfarin (OR: 2.70), this could be attributed to the AF itself since the latter was shown to be a predictor of MI independent of age, sex, and comorbidities.14
Interestingly, while medical and surgical complications were significantly higher in patients on chronic anticoagulation, revisions were lower. This could be explained by the high burden that a surgery such as revision TKA might pose for this subset of patients. By having this comorbidity and the medical complications resulting from TKA, the threshold for revision TKA might be higher for them compared to the control population. Thus, patients undergoing TKA in the setting of prior AC use should be counseled carefully and medically optimized pre- and post-operatively. Additionally, further studies should investigate patient reported outcomes in such patients to help guide decision making and counseling. Understanding additional risk factors and relevant co-morbidities will also help guide patient selection and optimize outcomes.
4.1 Limitations
This study is not without limitations. First of all, it is a retrospective study, making it prone to several biases inherent to its design. Second of all, being a Pearldiver study, the results rely on accurate coding using ICD and CPT codes. Finally, due to the lack of similar studies in the literature, it was not possible to directly compare our results with other studies of patients with preexisting atrial fibrillation and taking DOAC or warfarin while undergoing TKA.
5 Conclusion
Patients undergoing TKA on DOAC and Warfarin for AF, were shown to have higher rates of post-operative infections (pneumonia, sepsis), bleeding-related complications such as AKI and the requirement of more transfusions, and MI. More specifically, patients taking Warfarin were shown to have a higher rate of hematoma formation as well as PE, findings not seen in patients on DOAC. In addition, higher rates of aseptic loosening and TKA instability, and lower rates of revision surgery were seen in patients on anticoagulation. Nevertheless, to confirm such findings, more high-quality studies are needed since this study is based on a large private dataset, and it cannot establish causation but only associations.
CRediT authorship contribution statement
Mohammad Daher: Writing and Data collection. Mariah Balmaceno-Criss: Writing and Data collection. Jonathan Liu: Writing and Data collection. Manjot Singh: Writing and Data collection. Michael J. Kuharski: Writing and Data collection. Alan H. Daniels: Review, and, Supervision. Eric M. Cohen: Review, and, Supervision.
Guardian/patient's consent
Not required due to the nature of the study.
Ethical statement
The format in which the deidentified patient record data are received complies with HIPAA regulations and IRB is not needed.
Funding statement
None
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