Venous Thromboembolism (VTE) is a major cause of postoperative morbidity in orthopedic surgery, particularly after Total Hip Arthroplasty (THA), Total Knee Arthroplasty (TKA), and surgery for femoral neck fractures. Pharmacologic prophylaxis aims to reduce VTE risk while minimizing bleeding. Recent years have seen increased use of Direct Oral Anticoagulants (DOACs) alongside traditional agents such as Low Molecular Weight Heparins (LMWH) and warfarin. Given patient variability and differing safety-efficacy profiles, updated evidence synthesis is needed.

To evaluate the efficacy of novel prophylactic strategies in preventing venous thromboembolism (VTE) in patients undergoing major orthopedic surgeries.

A systematic search was conducted in PubMed using the following descriptors and Boolean operators: (“Venous Thromboembolism”[MeSH] OR VTE OR Thromboembolism) AND (“Thromboprophylaxis”[MeSH] OR Prophylactic Strategies OR VTE prophylaxis) AND (“Orthopedic Procedures”[MeSH] OR Hip Replacement OR Knee Replacement OR Major Orthopedic Surgery) AND (“Anticoagulants”[MeSH] OR DOACs OR NOACs OR Factor Xa inhibitors) AND (Safety OR Adverse Effects OR Bleeding risk) AND (Efficacy OR “Treatment Outcome”[MeSH]). Filters were applied for articles published between 2015 and 2025. After title, abstract, and full-text screening based on predefined inclusion and exclusion criteria, 42 studies were selected for qualitative synthesis focusing on efficacy and safety outcomes.

Building on the overall analysis, the evidence indicates that Direct Oral Anticoagulants (DOACs/NOACs) consistently demonstrate high efficacy in VTE prophylaxis. Edoxaban has proven effective following major orthopedic surgeries, while apixaban shows comparable outcomes to enoxaparin in total knee arthroplasty. Rivaroxaban’s efficacy appears influenced by patient exposure and is similar to aspirin in primary total hip arthroplasty. Overall, DOACs remain effective for VTE prevention in elderly patients undergoing elective post-arthroplasty, with network meta- analyses reinforcing their role across diverse populations. Similarly, aspirin demonstrates comparable efficacy to more potent anticoagulants, including enoxaparin and DOACs, in total hip and knee arthroplasty. Its use is supported after revision arthroplasty, hip arthroplasty for femoral neck fractures, and in high-risk total joint arthroplasty patients, without an increased VTE risk. Enoxaparin, a low molecular weight heparin, continues to serve as a widely used and effective standard for VTE prophylaxis, frequently acting as the reference in clinical trials. Comparisons with fondaparinux sodium have been made in specific populations, such as Chinese patients. Warfarin also shows efficacy, with aspirin yielding comparable results in certain subgroups, while low- intensity regimens have been explored to prevent VTE or death. In summary, pharmacologic strategies including DOACs, aspirin, enoxaparin, and warfarin demonstrate strong effectiveness in reducing VTE events after major orthopedic surgery. Novel strategies, especially DOACs, have expanded VTE prevention options in major orthopedic surgeries. Aspirin, LMWH, and warfarin remain relevant in specific contexts. Current evidence supports individualized prophylaxis to maximize efficacy while minimizing bleeding. Further research should refine protocols to optimize outcomes across patient populations.