Multifactorial Risk Assessment and Anticoagulation Strategy Optimization for Deep Vein Thrombosis After Major Joint Surgery: A Retrospective Study

Summary

This multicenter retrospective cohort study compares rivaroxaban and low molecular weight heparin for deep vein thrombosis (DVT) prevention after total hip arthroplasty and total knee arthroplasty. Rivaroxaban reduced DVT risk but increased bleeding, underscoring the importance of individualized prophylaxis and patient-specific decision-making.

Abstract

Deep vein thrombosis (DVT) is a major concern following total hip arthroplasty (THA) and total knee arthroplasty (TKA), with prophylactic anticoagulation being the cornerstone of postoperative care. This multicenter retrospective cohort study evaluated the relative effectiveness and safety of rivaroxaban and low molecular weight heparin (LMWH) in DVT prevention after joint replacement surgery. It also aimed to identify patient-related risk factors for thrombotic and hemorrhagic events. It was hypothesized that rivaroxaban would reduce DVT incidence compared with LMWH but may increase bleeding risk, and that patient-specific factors would influence these outcomes. The study included 32,512 patients undergoing elective TKA or THA. Categorization of patients was based on the postoperative anticoagulation strategy, and propensity scores were used to match them using nearest-neighbor propensity score matching based on baseline covariates, including age, sex, body mass index, smoking status, comorbidities (e.g., diabetes, prior venous thromboembolism [VTE]), American Society of Anesthesiologists (ASA) class, and type of surgery (THA/TKA). All patients underwent standardized duplex ultrasonography to detect DVT. Results showed that rivaroxaban was less likely to be associated with DVT at 30 days than LMWH (2.3% vs. 3.6%) with an adjusted odds ratio of 0.62 (p < 0.001). These values represent the cumulative incidence of DVT within 30 days postoperatively. However, rivaroxaban use was associated with a higher incidence of major bleeding (1.48% vs. 1.08%) and a postoperative hemoglobin drop. No significant differences were observed in 30-day pulmonary embolism (PE), readmissions, or mortality between the two groups. Subgroup analysis demonstrated benefit across key patient groups, including obese, elderly, diabetic, and TKA patients. Multivariable modeling established that pre-existing VTE, obesity, and age above 75 years were predictors of DVT, whereas baseline anemia and rivaroxaban use were independent predictors of major bleeding. These findings highlight the need for individualized prophylaxis strategies that balance thrombotic and hemorrhagic risks in patients undergoing major joint arthroplasty.

Introduction

Deep vein thrombosis (DVT) remains one of the most important postoperative complications following total hip arthroplasty (THA) and total knee arthroplasty (TKA). Together with pulmonary embolism (PE), it contributes significantly to postoperative morbidity, mortality, and healthcare utilization. Patients undergoing lower‑limb joint arthroplasty are particularly vulnerable to venous thromboembolism (VTE) due to venous stasis, endothelial injury, and postoperative hypercoagulability. Despite modern prophylaxis, symptomatic VTE occurs in approximately 0.6–1.5% of patients within 30 days postoperatively¹. Given the high procedural volume, with over one million THA and TKA performed annually in the United States, this represents a substantial clinical burden². Historically, DVT rates exceeded 40%–50%, largely due to asymptomatic thrombosis detected by screening imaging³. These results indicate the thrombogenic nature of major joint surgery and the significance of effective prophylaxis.

VTE following major joint surgery is associated with prolonged hospitalization, delayed recovery, readmissions, and increased healthcare costs. Although VTE mortality is relatively low in elective arthroplasty, PE is a potentially lethal complication, especially in the elderly and patients with multiple comorbid conditions. Over the past decade, advances in perioperative care, including early mobilization, mechanical compression devices, and routine anticoagulant prophylaxis, have led to a reduction in symptomatic VTE events following THA and TKA. Contemporary studies report VTE rates of approximately 1% or less when guideline-recommended prophylaxis is used⁴. However, the optimal choice of pharmacologic agent remains a subject of ongoing debate.

Low molecular weight heparin (LMWH) is a well-known standard prophylactic agent with proven efficacy and safety. More recently, direct oral anticoagulants (DOACs), such as rivaroxaban, have emerged as alternatives. DOACs such as rivaroxaban have become viable options. Rivaroxaban is a direct factor Xa inhibitor, with the practical advantage of oral administration, and has demonstrated comparable or superior efficacy to LMWH in multiple randomized trials and meta-analyses^5,6. However, there is still concern regarding bleeding risk, wound complications, and adherence in real-world settings, and there is no single agent that has shown unequivocal superiority in all patient groups. Furthermore, aspirin has been increasingly considered as a possible low-cost substitute for VTE prophylaxis in selected low-risk arthroplasty patients. Recent studies and guideline updates indicate similar efficacy of aspirin versus anticoagulants in carefully selected patient groups and have added to the understanding that risk-stratified prophylaxis should be favored over uniform treatment approaches^7,8. As a result, recent approaches to VTE prevention are increasingly considering patient-specific and procedural factors by balancing thrombotic risk with bleeding risk.

A growing body of evidence indicates that VTE risk after THA and TKA is heterogeneous. Advanced age, obesity, smoking, diabetes mellitus, prior history of VTE, hypercoagulable states, bilateral procedures, and prolonged operative time have all been implicated as contributors to increased postoperative thrombosis risk^9,10,11. However, comparative data on rivaroxaban and LMWH in diverse patient populations remain limited in real-world settings.

Despite widespread use of rivaroxaban and LMWH, their comparative effectiveness and safety in routine clinical practice remain uncertain, particularly in large-scale real-world settings where patient heterogeneity and risk stratification are insufficiently addressed. Randomized controlled trials have strict patient selection criteria and may not entirely represent the real-world variation in comorbidities, adherence, and perioperative care. Furthermore, the growing interest in early discharge and outpatient arthroplasty has also increased the value of pragmatic factors like route of administration and patient compliance. Importantly, the interaction between patient-specific risk factors and prophylactic strategies remains insufficiently defined. This study addresses these gaps by integrating large-scale multicenter real-world data with comprehensive multifactorial risk modeling, enabling more precise, clinically actionable personalized thromboprophylaxis strategies. Addressing these gaps is essential for refining clinical decision-making and optimizing VTE prevention in modern arthroplasty practice. Importantly, unlike prior randomized trials and meta-analyses, this study integrates large-scale real-world data with patient-level multifactorial risk assessment, enabling clinically applicable risk stratification rather than uniform treatment comparisons.

The primary objective of this study was to evaluate the comparative efficacy and safety of rivaroxaban versus low molecular weight heparin as postoperative thromboprophylaxis in patients undergoing total hip and knee arthroplasty, with a particular focus on the incidence of postoperative DVT and major bleeding complications. Secondary objectives included identifying and quantifying key demographic, lifestyle, comorbid, and surgical risk factors associated with postoperative DVT; examining how these factors modify the effectiveness of different prophylactic regimens; assessing real-world adherence and practical considerations associated with oral versus injectable anticoagulation; and developing a risk stratification framework to support individualized, evidence-based VTE prophylaxis following major joint arthroplasty.

Protocol

This study was conducted using de-identified, routinely collected clinical data. In accordance with institutional policies and national regulations, formal ethical approval and informed consent were waived as no identifiable patient information was used and no intervention was performed. The study adhered to the principles of the Declaration of Helsinki.

Study design

This multicenter retrospective cohort study was conducted using data from institutional joint replacement registries and electronic health records across several high-volume orthopedic centers. The study utilized prospectively collected registry data complemented by retrospective chart review. The study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for observational cohort studies¹². Data quality was ensured through internal validation checks and selective audits. A schematic overview of the study design, including patient selection, grouping, and outcome assessment, is provided in Figure 1.

Figure 1: Study flow diagram and schematic overview of study design. Please click here to view a larger version of this figure.

Study population

Adults (≥18 years) undergoing elective primary THA or TKA for osteoarthritis were included. Exclusion criteria included preoperative anticoagulation therapy, known coagulopathy, revision surgery, or trauma-related arthroplasty. In cases of bilateral arthroplasty, only the first procedure was analyzed to avoid duplication. Patients were identified from multiple tertiary orthopedic centers to enhance generalizability.

Data collection

Data were extracted from electronic medical records and institutional databases using a standardized data collection form. Variables included demographics (age, sex, body mass index [BMI]), lifestyle factors (smoking status and alcohol use), comorbidities (history of VTE, diabetes mellitus, hypertension, dyslipidemia, chronic kidney disease, active cancer, and thrombophilia), and surgical variables (procedure type, operative duration, and tranexamic acid administration). The American Society of Anesthesiologists (ASA) classification and Charlson Comorbidity Index were calculated. Perioperative care variables included pharmacologic and mechanical prophylaxis, early mobilization (postoperative day 0–1), and hospital length of stay.

Thromboprophylaxis groups

Patients were categorized according to postoperative anticoagulation strategy. The rivaroxaban group received rivaroxaban 10 mg orally once daily, starting 6–10 h postoperatively and continued for 14 days (TKA) or 35 days (THA), in line with clinical guidelines¹³. The LMWH group received low molecular weight heparin (e.g., enoxaparin 40 mg once daily or 30 mg twice daily per institutional protocol), initiated 12–24 h postoperatively and continued for the same duration. Adherence was assessed using prescription records and patient self-reports. Rivaroxaban’s oral route was noted to potentially improve adherence in comparison to parenteral LMWH¹⁴.

Imaging and DVT/PE diagnostic protocols

All patients underwent standardized bilateral lower-extremity duplex ultrasonography for DVT screening between postoperative days 7 and 10 or at the time of hospital discharge, irrespective of symptom status. DVT diagnosis included both symptomatic and asymptomatic cases, identified through routine bilateral lower-extremity duplex ultrasonography performed according to the study protocol. Duplex studies were performed by certified vascular technologists using compression and Doppler flow criteria. Symptomatic DVT was defined based on clinical presentation with confirmatory imaging, whereas asymptomatic DVT was detected through scheduled screening ultrasonography. Symptomatic pulmonary embolism was diagnosed based on clinical suspicion and confirmed using computed tomography pulmonary angiography. Imaging protocols were harmonized across participating centers to ensure consistency in diagnostic criteria and timing.

Adherence and exposure assessment

Exposure to thromboprophylaxis was verified using a triangulated approach including electronic prescription records, pharmacy refill documentation, and structured patient self-report in the course of the postoperative follow-up visits. Adherence was defined as the patient having 80% or more of the prescription doses verified during the prophylaxis period. A per-protocol sensitivity analysis excluded patients with early discontinuation, non-adherence, or crossover between anticoagulant regimens.

Outcome measures

The primary endpoint was the 30-day incidence of postoperative DVT, confirmed by duplex ultrasonography. All patients underwent standardized ultrasound screening around postoperative day 7–10 or at discharge, regardless of symptoms. Secondary outcomes included pulmonary embolism, major bleeding, minor bleeding, laboratory parameters, wound complications, readmissions, and mortality.

Major bleeding was defined according to the International Society on Thrombosis and Haemostasis (ISTH) criteria¹⁵, including bleeding leading to reoperation, transfusion ≥ 2 units, a hemoglobin decrease of ≥2 g/dL within the first 5 postoperative days, or critical organ involvement. Minor bleeding included wound oozing, hematomas, and prolonged drainage. Laboratory parameters, including D-dimer, hemoglobin (Hb), and glucose levels, were recorded preoperatively and on postoperative days 1, 3, and 5. Elevated D-dimer has been associated with postoperative DVT, although its specificity is limited. Wound complications included prolonged drainage, superficial infection, or dehiscence.

Risk factor assessment

A comprehensive set of known or suspected DVT risk factors was recorded, including age, obesity, smoking, diabetes, prior VTE, and surgery-specific variables. Advanced age, obesity, and history of VTE are established risk factors¹⁶. Diabetes mellitus was examined because it has been found to be associated with enhanced DVT risk in joint replacement arthroplasty¹⁷. The influence of bilateral procedures, extended operating time¹⁶, and TXA use¹⁸ on thrombotic and bleeding outcomes was also compared.

Center-level variation handling

Random-effects modeling was used to test the heterogeneity, which might occur among the participating institutions, by including the treatment center as a clustering variable. Multilevel mixed-effects logistic regression models were applied to remove center-level variations in surgical volume, perioperative practice, and imaging practice. Sensitivity analyses incorporating center-specific random intercepts were performed to ensure robustness of the primary and secondary outcome estimates.

Statistical analysis

Baseline characteristics were compared using Student’s t-test or Mann–Whitney U test for continuous variables and chi-square or Fisher’s exact test for categorical variables. Multivariable logistic regression identified independent predictors of DVT and bleeding. Variables significant in univariate analysis (p < 0.10) or strongly supported by literature were included, including pre-existing venous thromboembolism (VTE), defined as any documented history of deep vein thrombosis or pulmonary embolism prior to the index surgery, and baseline anemia, defined according to World Health Organization (WHO) criteria as a preoperative hemoglobin level < 13 g/dL in males and <12 g/dL in females. Preoperative hemoglobin values were obtained from routine laboratory testing performed within 48 h prior to surgery.

The effect of prophylactic agents on DVT incidence was assessed through multivariate adjustment, where adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were reported; propensity score matching (nearest-neighbor matching with caliper restriction), where patients were matched on key baseline covariates including age, sex, body mass index (BMI), smoking status, comorbidities (e.g., diabetes, prior VTE), ASA class, and type of surgery (THA/TKA) to minimize confounding, followed by paired statistical tests. Balance between groups was assessed using standardized mean differences, with values <0.1 indicating adequate covariate balance.

Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards models to assess DVT-free survival within 30 days. Sensitivity analyses included exclusion of asymptomatic DVT cases, per-protocol analysis (excluding patients with early discontinuation or crossover), and random-effects modeling to account for center-level clustering. Statistical significance was set at two-sided p < 0.05, and analyses were conducted using an appropriate statistical software.

Results

Patient cohort and baseline characteristics

A total of 38,745 patients were screened across participating centers. Of these, 6,233 patients were excluded due to preoperative anticoagulation, known coagulopathy, trauma-related arthroplasty, revision surgery, or incomplete data. This resulted in a final cohort of 32,512 patients included in the comparative propensity score–adjusted analysis. The patient selection process is illustrated in Figure 2.<...

Discussion

This cohort study evaluated the comparative effectiveness and safety of rivaroxaban versus LMWH for VTE prophylaxis following total hip and knee arthroplasty, providing clinically relevant real-world evidence that complements and extends findings from controlled trials by incorporating patient-level heterogeneity and risk stratification. This study’s findings demonstrate a significantly lower 30-day incidence of DVT with rivaroxaban compared with LMWH, consistent with prior randomized and observational studies. It ...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Automated Hematology Analyzer	Sysmex Corporation	XN-Series	Hemoglobin and hematocrit monitoring pre- and postoperatively (POD 1, 3, 5).
CT Pulmonary Angiography Systems	Siemens Healthineers AG	SOMATOM Force	Confirmatory imaging for symptomatic PE events.
D-Dimer ELISA Kit	BioMedica Diagnostics Inc.	BI-20752	Plasma D-dimer measured on POD 1, 3, 5; used for trend analysis and thrombotic risk assessment.
Duplex Ultrasonography Machines	GE HealthCare Technologies Inc.	LOGIQ E9	Used for standardized DVT screening between POD 7–10, regardless of symptoms.
Electronic Medical Record System	Epic Systems Corporation	N/A	Data extracted retrospectively using standard templates from EMRs and joint registries.
Enoxaparin (LMWH)	Sanofi S.A.	Institutional Protocols	Subcutaneous injection; 30 mg BID or 40 mg OD depending on site protocol.
Rivaroxaban (10 mg tablets)	Bayer Aktiengesellschaft (Bayer AG)	NDC 50419-576-01	Oral factor Xa inhibitor; administered once daily postoperatively (14 days for TKA, 35 days for THA).
SPSS Statistical Software	International Business Machines Corporation (IBM)	Version 27	Used for all statistical analyses including logistic regression, PSM, and survival curves.
Tranexamic Acid (TXA)	Pfizer Inc.	NDC 0143-9684-01	Used intraoperatively via IV or topical route to reduce bleeding.