Background: Increasing evidence for the use of the aspirin in patients undergoing an orthopaedic surgery for venous thromboembolism prophylaxis has led to a change in the national guidelines substituting anticoagulants with aspirin. Little is known about the impact of such substitution on real-world outcomes from clinical practice. Objective: The study was designed to examine clinical outcomes associated with the use of aspirin and apixaban. Setting: Two large-scale general hospitals in West Yorkshire region of England. Method: A 1-year observational study among adults who underwent elective knee replacements and received venous thromboembolism prophylaxis within the first 14 days post replacements. Main outcome measure The incidence of postoperative venous thromboembolism, leaking wounds during the hospital stay, and 30-day any readmission for the two drugs. Results: A total of 420 patients were included. There was a significant drop in apixaban prescribing (from 80.37 to 10.51%) and increase in aspirin use (from 19.02 to 81.71%) after the implementation of the revised guidelines. There were 52 (12.38%) cases of leaking wound, 16 (3.81%) cases of postoperative venous thromboembolism, 45 (10.71%) cases of 30-day readmission and no case of 30-day major bleeding. The leaking wounds and 30-day readmissions were almost twice more frequent in obese compared to non-obese patients. Multivariate logistic regression found an increased risk of leaking wound with apixaban and postoperative venous thromboembolism and 30-day readmission with aspirin use but the differences were not statistically significant. Conclusion: The results suggest aspirin to be as effective as apixaban in preventing venous thromboembolism and readmission. Apixaban usage decreased with a corresponding increase in Aspirin use. The impact of obesity and length of hospital stay need further investigations.