Efficacy and safety of DOAC on preventing venous thromboembolism after major orthopedic surgery: a systematic review_Chinese Journal of Evidence-Based Medicine

Authors：

ZHAO Zinan , SUN Xuelin ,  HU Xin

Department of Pharmacy, National Center of Gerontology, Clinical Trial Center, Beijing Hospital, Beijing, 100730, P.R.China;

Corresponding author：

HU Xin, Email: huxinbjyy@126.com

Keywords：

Direct oral anticoagulant; Venous thromboembolism; Major orthopedic surgery; Meta-analysis; Systematic review; Randomized controlled trial

DOI：

10.7507/1672-2531.201905056

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Objectives To systematically review the efficacy and safety of direct oral anticoagulants (DOAC) on preventing venous thromboembolism (VTE) after major orthopedic surgery (MOS).Methods The Cochrane Library, PubMed, EMbase, CNKI, WanFang Data and CBM databases were electronically searched for randomized controlled trials (RCTs) on the efficacy and safety of DOAC on preventing VTE after MOS from inception to March 2019. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies, then, meta-analysis was performed by using RevMan 5.3 software.Results A total of 22 RCTs involving 41 244 patients were included. The results of meta-analysis showed that: the rate of symptomatic deep vein thrombosis (DVT) after MOS in rivaroxaban (Peto OR=0.54, 95%CI 0.35 to 0.82, P=0.004) and apixaban (Peto OR=0.49, 95%CI 0.26 to 0.92, P=0.03) were lower than enoxaparin. Additionally, the rate of symptomatic pulmonary embolism (PE) after MOS in rivaroxaban was lower than enoxaparin (Peto OR=0.53, 95%CI 0.29 to 0.96, P=0.04), however, in major bleeding after MOS rivaroxaban was significant higher than enoxaparin (Peto OR=1.98, 95%CI 1.30 to 3.01, P=0.001).Conclusions Current evidence shows that rivaroxaban and apixaban is superior to enoxaparin on preventing symptomatic DVT after MOS. Rivaroxaban is superior to enoxaparin on preventing symptomatic PE, however, the risk of major bleeding is higher than enoxaparin. Due to limited quality and quantity of the included studies, more high quality studies are required to verify the above conclusions.

Citation： ZHAO Zinan, SUN Xuelin, HU Xin. Efficacy and safety of DOAC on preventing venous thromboembolism after major orthopedic surgery: a systematic review. Chinese Journal of Evidence-Based Medicine, 2019, 19(10): 1217-1225. doi: 10.7507/1672-2531.201905056 Copy

1.	Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 2012, 141(2 Suppl): e278S-325S.
2.	Mont MA, Jacobs JJ. AAOS clinical practice guideline: preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Am Acad Orthop Surg, 2011, 19(12): 777-778.
3.	Cohen AT, Asia-Pacific Thrombosis Advisory Board. Asia-Pacific Thrombosis Advisory Board consensus paper on prevention of venous thromboembolism after major orthopaedic surgery. Thromb Haemost, 2010, 104(5): 919-930.
4.	中华医学会骨科学分会. 中国骨科大手术静脉血栓栓塞症预防指南. 中华骨科杂志, 2016, 36(2): 65-71.
5.	徐娟, 张久星, 刘娟, 等. 骨科大手术后 VTE 预防国内外指南及质量评价和 NOAC 的应用. 药品评价, 2018, 15(18): 9-12, 17.
6.	Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions (version 5.1.0). The Cochrane Collaboration, 2011. Available at: http://www.cochrane-handbook.org.
7.	Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet, 2007, 370(9591): 949-956.
8.	Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost, 2007, 5(11): 2178-2185.
9.	RE-MOBILIZE Writing Committee, Ginsberg JS, Davidson BL, et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty, 2009, 24(1): 1-9.
10.	Eriksson BI, Dahl OE, Huo MH, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II^*). A randomised, double-blind, non-inferiority trial. Thromb Haemost, 2011, 105(4): 721-729.
11.	Mirdamadi A, Dashtkar S, Kaji M, et al. Dabigatran versus Enoxaparin in the prevention of venous thromboembolism after total knee arthroplasty: a randomized clinical trial. ARYA Atheroscler, 2014, 10(6): 292-297.
12.	Turpie AG, Fisher WD, Bauer KA, et al. BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study. J Thromb Haemost, 2005, 3(11): 2479-2486.
13.	Eriksson BI, Borris LC, Dahl OE, et al. A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation, 2006, 114(22): 2374-2381.
14.	Eriksson BI, Borris L, Dahl OE, et al. Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost, 2006, 4(1): 121-128.
15.	Eriksson BI, Borris LC, Dahl OE, et al. Dose-escalation study of rivaroxaban (BAY 59-7939)-an oral, direct Factor Xa inhibitor--for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Res, 2007, 120(5): 685-693.
16.	Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med, 2008, 358(26): 2765-2775.
17.	Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet, 2008, 372(9632): 31-39.
18.	Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med, 2008, 358(26): 2776-2786.
19.	Turpie AG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet, 2009, 373(9676): 1673-1680.
20.	Lassen MR, Davidson BL, Gallus A, et al. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost, 2007, 5(12): 2368-2375.
21.	Lassen MR, Raskob GE, Gallus A, et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med, 2009, 361(6): 594-604.
22.	Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet, 2010, 375(9717): 807-815.
23.	Lassen MR, Gallus A, Raskob GE, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med, 2010, 363(26): 2487-2498.
24.	Raskob G, Cohen AT, Eriksson BI, et al. Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement. A randomised double-blind dose-response study. Thromb Haemost, 2010, 104(3): 642-649.
25.	Fuji T, Wang CJ, Fujita S, et al. 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.
26.	Fuji T, Wang CJ, Fujita S, et al. Safety and efficacy of edoxaban, an oral factor Xa inhibitor, versus enoxaparin for thromboprophylaxis after total knee arthroplasty: the STARS E-3 trial. Thromb Res, 2014, 134(6): 1198-1204.
27.	Fuji T, Fujita S, Kawai Y, et al. Safety and efficacy of edoxaban in patients undergoing hip fracture surgery. Thromb Res, 2014, 133(6): 1016-1022.
28.	Fuji T, Fujita S, Kawai Y, et al. Efficacy and safety of edoxaban versus enoxaparin for the prevention of venous thromboembolism following total hip arthroplasty: STARS J-V. Thromb J, 2015, 13: 27.
29.	UK National Institute for Health and Clinical Excellence. Dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults. Available at: http://nice.org.uk/guidance/ta157.
30.	Friedman RJ, Dahl OE, Rosencher N, et al. Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials. Thromb Res, 2010, 126(3): 175-182.
31.	Thomas TF, Ganetsky V, Spinler SA. Rivaroxaban: an oral factor Xa inhibitor. Clin Ther, 2013, 35(1): 4-27.
32.	UK National Institute for Health and Clinical Excellence. Rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults. Available at: http://nice.org.uk/guidance/ta170.
33.	Turpie AG, Lassen MR, Eriksson BI, et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost, 2011, 105(3): 444-453.
34.	UK National Institute for Health and Clinical Excellence. Apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults. Available at: http//nice.org.uk/guidance/ta245.

1. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 2012, 141(2 Suppl): e278S-325S.
2. Mont MA, Jacobs JJ. AAOS clinical practice guideline: preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Am Acad Orthop Surg, 2011, 19(12): 777-778.
3. Cohen AT, Asia-Pacific Thrombosis Advisory Board. Asia-Pacific Thrombosis Advisory Board consensus paper on prevention of venous thromboembolism after major orthopaedic surgery. Thromb Haemost, 2010, 104(5): 919-930.
4. 中华医学会骨科学分会. 中国骨科大手术静脉血栓栓塞症预防指南. 中华骨科杂志, 2016, 36(2): 65-71.
5. 徐娟, 张久星, 刘娟, 等. 骨科大手术后 VTE 预防国内外指南及质量评价和 NOAC 的应用. 药品评价, 2018, 15(18): 9-12, 17.
6. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions (version 5.1.0). The Cochrane Collaboration, 2011. Available at: http://www.cochrane-handbook.org.
7. Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet, 2007, 370(9591): 949-956.
8. Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost, 2007, 5(11): 2178-2185.
9. RE-MOBILIZE Writing Committee, Ginsberg JS, Davidson BL, et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty, 2009, 24(1): 1-9.
10. Eriksson BI, Dahl OE, Huo MH, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II^*). A randomised, double-blind, non-inferiority trial. Thromb Haemost, 2011, 105(4): 721-729.
11. Mirdamadi A, Dashtkar S, Kaji M, et al. Dabigatran versus Enoxaparin in the prevention of venous thromboembolism after total knee arthroplasty: a randomized clinical trial. ARYA Atheroscler, 2014, 10(6): 292-297.
12. Turpie AG, Fisher WD, Bauer KA, et al. BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study. J Thromb Haemost, 2005, 3(11): 2479-2486.
13. Eriksson BI, Borris LC, Dahl OE, et al. A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation, 2006, 114(22): 2374-2381.
14. Eriksson BI, Borris L, Dahl OE, et al. Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost, 2006, 4(1): 121-128.
15. Eriksson BI, Borris LC, Dahl OE, et al. Dose-escalation study of rivaroxaban (BAY 59-7939)-an oral, direct Factor Xa inhibitor--for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Res, 2007, 120(5): 685-693.
16. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med, 2008, 358(26): 2765-2775.
17. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet, 2008, 372(9632): 31-39.
18. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med, 2008, 358(26): 2776-2786.
19. Turpie AG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet, 2009, 373(9676): 1673-1680.
20. Lassen MR, Davidson BL, Gallus A, et al. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost, 2007, 5(12): 2368-2375.
21. Lassen MR, Raskob GE, Gallus A, et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med, 2009, 361(6): 594-604.
22. Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet, 2010, 375(9717): 807-815.
23. Lassen MR, Gallus A, Raskob GE, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med, 2010, 363(26): 2487-2498.
24. Raskob G, Cohen AT, Eriksson BI, et al. Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement. A randomised double-blind dose-response study. Thromb Haemost, 2010, 104(3): 642-649.
25. Fuji T, Wang CJ, Fujita S, et al. 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.
26. Fuji T, Wang CJ, Fujita S, et al. Safety and efficacy of edoxaban, an oral factor Xa inhibitor, versus enoxaparin for thromboprophylaxis after total knee arthroplasty: the STARS E-3 trial. Thromb Res, 2014, 134(6): 1198-1204.
27. Fuji T, Fujita S, Kawai Y, et al. Safety and efficacy of edoxaban in patients undergoing hip fracture surgery. Thromb Res, 2014, 133(6): 1016-1022.
28. Fuji T, Fujita S, Kawai Y, et al. Efficacy and safety of edoxaban versus enoxaparin for the prevention of venous thromboembolism following total hip arthroplasty: STARS J-V. Thromb J, 2015, 13: 27.
29. UK National Institute for Health and Clinical Excellence. Dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults. Available at: http://nice.org.uk/guidance/ta157.
30. Friedman RJ, Dahl OE, Rosencher N, et al. Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials. Thromb Res, 2010, 126(3): 175-182.
31. Thomas TF, Ganetsky V, Spinler SA. Rivaroxaban: an oral factor Xa inhibitor. Clin Ther, 2013, 35(1): 4-27.
32. UK National Institute for Health and Clinical Excellence. Rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults. Available at: http://nice.org.uk/guidance/ta170.
33. Turpie AG, Lassen MR, Eriksson BI, et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost, 2011, 105(3): 444-453.
34. UK National Institute for Health and Clinical Excellence. Apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults. Available at: http//nice.org.uk/guidance/ta245.

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Efficacy and safety of DOAC on preventing venous thromboembolism after major orthopedic surgery: a systematic review

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