41 – Are there differences between various factor Xa inhibitors for management of VTE with regard to efficacy and safety profile?

Charles Marc Samama, Jared Warren.

Response/Recommendation: There is insufficient data to recommend one factor Xa inhibitor over another for venous thromboembolism (VTE) prophylaxis in major orthopaedic surgery.

Strength of Recommendation: Limited.

Rationale: With the advent of factor Xa inhibitors, also known as direct oral anticoagulants (DOAC), multiple investigations comparing DOAC to more traditional VTE chemoprophylactic agents in orthopaedic surgery have been undertaken1–5. However, while there is ample research on DOACs for VTE prophylaxis, controversy exists regarding the superiority of one specific DOAC over other members of this drug class.

No randomized control trials (RCT) directly comparing various DOAC exists, although several indirect comparisons are currently available4,6,7. A meta-analysis evaluating DOAC and dabigatran for VTE prophylaxis in 20 orthopaedic trials found that rivaroxaban 20 mg/day and apixaban 5 mg/day were comparable in terms of clinical efficacy, but these two regimens more effective than dabigatran 110 or 150 mg/twice daily6. A second meta-analysis conducted by Cohen et.4, consisting of 40 RCT found a similar efficacy between rivaroxaban 10 mg/daily and apixaban 2.5 mg/ twice daily in the prevention of VTE and all-cause mortality following total hip arthroplasty (THA) (odds ratio [OR] 0.686; 95% confidence interval [CI] 0.375-1.253) and total knee arthroplasty (TKA) (OR 0.827; 95% CI 0.573-1.192). Similarly, there was no difference in major VTE rates for both TKA (OR 0.757; 95% CI 0.272-2.105) and THA (OR 0.301; 95% CI 0.081-1.135) after excluding the RECORD 2 trial. Hur et al.7, performed a meta-analysis of 19 studies of THA and TKA patients and found no difference in VTE rates between the cohorts receiving rivaroxaban 10 mg/day and apixaban 2.5 mg/ twice daily (OR 0.75; 95% CI 0.52-1.07). Additionally, there was no significant difference when comparing edoxaban 30 mg/day, apixaban 2.5 mg/ twice daily (OR 0.75; 95% CI 0.36-1.55) and rivaroxaban 10 mg/day (OR 1.08; 95% CI 0.53-2.21).

Multiple studies have used enoxaparin as a base reference for comparing the effectiveness DOAC. Yoshida et al.8, performed a meta-analysis of 15 studies comparing multiples DOAC to enoxaparin in major orthopaedic surgery. They found that rivaroxaban (relative risk [RR] 0.50; 95% CI 0.34-0.73) was superior to mixed-dose enoxaparin for any deep venous thrombosis (DVT), nonfatal pulmonary embolism (PE), and all-cause mortality, whereas no difference was observed with apixaban (RR 0.63, 95% CI 0.65-1.01). A similar meta-analysis of 10 RCT in THA and TKA patients by Nieto et al., found identical results9. A network meta-analysis of 42 RCT ranked rivaroxaban as the most effective at preventing DVT (RR 0.06; 95% CI 0.01-0.29), while apixaban ranked lower (RR 0.16; 95% CI 0.03-0.76) compared to no chemoprophylaxis or mechanical prophylaxis10. The same group reported similar results in a network meta-analysis of 25 RCT11. Conversely, a meta-analysis of 9 RCT in elderly TKA and THA patients found that VTE or VTE-related death (OR 0.10; 95% CI 0.01-0.81) was reduced with apixaban compared to enoxaparin, although the rates were similar for rivaroxaban compared to enoxaparin (OR 0.75; 95% CI 0.35-1.59)12.

Cohen et al.4, found no difference in major bleeding when comparing rivaroxaban 10 mg/daily and apixaban 2.5 mg/ twice daily for TKA (OR 1.859; 95% CI 0.473-7.304) and THA (OR 2.475; 95% CI 0.444-13.81) after excluding the RECORD 2 trial. Similar findings were observed for any bleeding and clinically relevant non-major bleeding. Conversely, Hur et al.7, found an increased risk of major and clinically relevant non-major bleeding when comparing rivaroxaban 10 mg/day and apixaban 2.5 mg/ twice daily (OR 1.53; 95% CI 1.16-2.01). However, there was no difference between edoxaban 30 mg/day and apixaban 2.5 mg/twice daily (OR 1.54; 95% CI 0.86-2.77), and rivaroxaban 10 mg/day (OR 0.99; 95% CI 0.55-1.80).  Nieto et al.9, found that there was the highest risk of major bleeding with rivaroxaban compared to enoxaparin (RR 1.88; 95% CI 0.92-3.82), while apixaban (RR 0.76; 95% CI 0.43-1.33) trended toward less events compared to enoxaparin. Pathak et al.12, found that apixaban (OR 0.71; 95% CI 0.47-1.08) and rivaroxaban (OR 0.78; 95% CI 0.48-1.27) had similar risk of major or clinically relevant bleeding compared to enoxaparin. Lewis et al.10, reported similar risk of major bleeding for apixaban (RR 3.16; 95% CI 0.47-21.15) and rivaroxaban (RR 2.74; 95% CI 0.42-16.16). The same group went on to report similar results in a smaller network meta-analysis11.


1.         Torrejon Torres R, Saunders R, Ho KM. A comparative cost-effectiveness analysis of mechanical and pharmacological VTE prophylaxis after lower limb arthroplasty in Australia. J Orthop Surg Res. 2019;14(1):93. doi:10.1186/s13018-019-1124-y

2.         Rostagno C. New Oral Anticoagulants in Prophylaxis of Venous Thromboembolic Disease in Major Orthopedic Surgery. Cardiovasc Hematol Disord Drug Targets. 2016;15(3):204-209. doi:10.2174/1871529×16666160101122632

3.         Matharu GS, Kunutsor SK, Judge A, Blom AW, Whitehouse MR. Clinical Effectiveness and Safety of Aspirin for Venous Thromboembolism Prophylaxis After Total Hip and Knee Replacement: A Systematic Review and Meta-analysis of Randomized Clinical Trials. JAMA Intern Med. 2020;180(3):376-384. doi:10.1001/jamainternmed.2019.6108

4.         Cohen A, Drost P, Marchant N, et al. The efficacy and safety of pharmacological prophylaxis of venous thromboembolism following elective knee or hip replacement:  systematic review and network meta-analysis. Clin Appl Thromb Hemost. 2012;18(6):611-627. doi:10.1177/1076029612437579

5.         Fuji T, Wang C-J, Fujita S, Kawai Y, Kimura T, Tachibana S. Safety and efficacy of edoxaban, an oral factor xa inhibitor, for thromboprophylaxis after total hip arthroplasty in Japan and Taiwan. J Arthroplasty. 2014;29(12):2439-2446. doi:10.1016/j.arth.2014.05.029

6.         Messori A, Fadda V, Maratea D, Trippoli S, Marinai C. Testing the therapeutic equivalence of novel oral anticoagulants for thromboprophylaxis in orthopedic surgery and for prevention of stroke in atrial fibrillation. Int J Clin Pharmacol Ther. 2015;53(3):211-219. doi:10.5414/CP202183

7.         Hur M, Park S-K, Koo C-H, et al. Comparative efficacy and safety of anticoagulants for prevention of venous thromboembolism after hip and knee arthroplasty. Acta Orthop. 2017;88(6):634-641. doi:10.1080/17453674.2017.1361131

8.         Yoshida R de A, Yoshida WB, Maffei FH de A, El Dib R, Nunes R, Rollo HA. Systematic review of randomized controlled trials of new anticoagulants for venous thromboembolism prophylaxis in major orthopedic surgeries, compared with enoxaparin. Ann Vasc Surg. 2013;27(3):355-369. doi:10.1016/j.avsg.2012.06.010

9.         Nieto JA, Espada NG, Merino RG, González TC. Dabigatran, rivaroxaban and apixaban versus enoxaparin for thomboprophylaxis after total knee or hip arthroplasty: pool-analysis of phase III randomized clinical trials. Thromb Res. 2012;130(2):183-191. doi:10.1016/j.thromres.2012.02.011

10.       Lewis S, Glen J, Dawoud D, et al. Venous Thromboembolism Prophylaxis Strategies for People Undergoing Elective Total Hip Replacement: A Systematic Review and Network Meta-Analysis. Value Health. 2019;22(8):953-969. doi:10.1016/j.jval.2019.02.013

11.       Lewis S, Glen J, Dawoud D, et al. Venous thromboembolism prophylaxis strategies for people undergoing elective total knee replacement: a systematic review and network meta-analysis. Lancet Haematol. 2019;6(10):e530-e539. doi:10.1016/S2352-3026(19)30155-3

12.       Pathak R, Giri S, Karmacharya P, et al. Meta-analysis on efficacy and safety of new oral anticoagulants for venous thromboembolism prophylaxis in elderly elective postarthroplasty patients. Blood Coagul Fibrinolysis. 2015;26(8):934-939. doi:10.1097/MBC.0000000000000369