Comparison of the Therapeutic Effects of Rivaroxaban Versus Warfarin in Antiphospholipid Syndrome: A Systematic Review

Objectives: This study aims to review the studies evaluating the therapeutic effects of rivaroxaban versus those of warfarin in patients with antiphospholipid syndrome (APS). Materials and methods: The study included randomized clinical trials, comparative studies, cross-sectional investigations, and case series that focused on the effects of warfarin and rivaroxaban and compared the effects of these anticoagulants in patients with APS. The relevant articles published until 2018 were searched in several databases, including PubMed, Scopus, ScienceDirect, Google Scholar, Embase, and Web of Science. Results: The findings of the reviewed studies showed that rivaroxaban can be used as an effective and safe alternative to warfarin in APS patients. However, the effectiveness of rivaroxaban in the prevention of thrombosis in high-risk APS patients is suspected. Conclusion: Given the high risk of using rivaroxaban in thrombotic APS patients with labile international normalized ratio (INR) or poor adherence to INR monitoring, it is not suggested to use this agent for these patients.


1. Cohen H, Hunt BJ, Efthymiou M, Arachchillage DR, Mackie IJ, Clawson S, et al. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol 2016;3:e426-36.

2. Ahluwalia J, Sreedharanunni S, Kumar N, Masih J, Bose SK, Varma N, et al. Thrombotic Primary Antiphospholipid Syndrome: the profile of antibody positivity in patients from North India. Int J Rheum Dis 2016;19:903-12.

3. de Groot PG, de Laat B, Rand J, Vlachoyiannopoulos PG, El-Assaad F, Krilis SA, et al. Natural Proteins Involved in Antiphospholipid Syndrome. In: Erkan D, Lockshin MD, editors. Antiphospholipid syndrome. Cham: Springer; 2017. p. 15-27.

4. Pengo V, Denas G. Diagnostics and treatment of thrombotic antiphospholipid syndrome (APS): A personal perspective. Thromb Res 2018;169:35-40.

5. Andreoli L, Chighizola CB, Banzato A, Pons-Estel GJ, Ramire de Jesus G, Erkan D. Estimated frequency of antiphospholipid antibodies in patients with pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis: a critical review of the literature. Arthritis Care Res (Hoboken) 2013;65:1869-73.

6. Ruiz-Irastorza G, Egurbide MV, Ugalde J, Aguirre C. High impact of antiphospholipid syndrome on irreversible organ damage and survival of patients with systemic lupus erythematosus. Arch Intern Med 2004;164:77-82.

7. Pierangeli SS, de Groot PG, Dlott J, Favaloro E, Harris EN, Lakos G, et al. ‘Criteria’ aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, Texas, April 2010. Lupus 2011;20:182-90.

8. Keswani SC, Chauhan N. Antiphospholipid syndrome. J R Soc Med 2002;95:336-42.

9. Forastiero R. Multiple antiphospholipid antibodies positivity and antiphospholipid syndrome criteria re-evaluation. Lupus 2014;23:1252-4.

10. Pengo V, Ruffatti A, Legnani C, Gresele P, Barcellona D, Erba N, et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost 2010;8:237-42.

11. Keeling D, Baglin T, Tait C, Watson H, Perry D, Baglin C, et al. Guidelines on oral anticoagulation with warfarin - fourth edition. Br J Haematol 2011;154:311-24.

12. Pengo V, Ruffatti A, Tonello M, Cuffaro S, Banzato A, Bison E, et al. Antiphospholipid syndrome: antibodies to Domain 1 of b2-glycoprotein 1 correctly classify patients at risk. J Thromb Haemost 2015;13:782-7.

13. Bungard TJ, Semchuk W. The management of venous thromboembolism: A practical tool for the front-line clinician. Can Pharm J (Ott) 2017;150:81-9.

14. Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 2003;349:1133-8.

15. Zirlik A, Bode C. Vitamin K antagonists: relative strengths and weaknesses vs. direct oral anticoagulants for stroke prevention in patients with atrial fibrillation. J Thromb Thrombolysis 2017;43:365-79.

16. Cohen H, Doré CJ, Clawson S, Hunt BJ, Isenberg D, Khamashta M, et al. Rivaroxaban in antiphospholipid syndrome (RAPS) protocol: a prospective, randomized controlled phase II/ III clinical trial of rivaroxaban versus warfarin in patients with thrombotic antiphospholipid syndrome, with or without SLE. Lupus 2015;24:1087-94.

17. Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2009;7:1737-40.

18. Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-510.

19. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366:9-19.

20. Green S, Higgins J. Cochrane handbook for systematic reviews of interventions. Version; 2005. Available at: Cochrane-Hand-booktext.pdf

21. Higgins J. Cochrane handbook for systematic reviews of interventions. Version 5.1.0. The Cochrane Collaboration. Available at: http://handbook-5-1. [Updated: March 2011].

22. Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, et al. Rivaroxaban vs warfarin in highrisk patients with antiphospholipid syndrome. Blood 2018;132:1365-71.

23. Arachchillage DR, Mackie IJ, Efthymiou M, Chitolie A, Hunt BJ, Isenberg DA, et al. Rivaroxaban limits complement activation compared with warfarin in antiphospholipid syndrome patients with venous thromboembolism. J Thromb Haemost 2016;14:2177-86.

24. Arachchillage DR, Efthymiou M, Mackie IJ, Lawrie AS, Machin SJ, Cohen H. Rivaroxaban and warfarin achieve effective anticoagulation, as assessed by inhibition of TG and in-vivo markers of coagulation activation, in patients with venous thromboembolism. Thromb Res 2015;135:388-93.

25. Arachchillage DR, Mackie IJ, Efthymiou M, Isenberg DA, Machin SJ, Cohen H. Interactions between rivaroxaban and antiphospholipid antibodies in thrombotic antiphospholipid syndrome. J Thromb Haemost 2015;13:1264-73.

26. Kunk P, Macik B, Rice M. Non-warfarin oral anticoagulants in anti-phospholipid syndrome. Blood 2015;126:1133.

27. Malec K, Góralczyk T, Undas A. The use of direct oral anticoagulants in 56 patients with antiphospholipid syndrome. Thromb Res 2017;152:93-7.

28. Son M, Wypasek E, Celinska-Lowenhoff M, Undas A. The use of rivaroxaban in patients with antiphospholipid syndrome: A series of 12 cases. Thromb Res 2015;135:1035-6.

29. Signorelli F, Nogueira F, Domingues V, Mariz HA, Levy RA. Thrombotic events in patients with antiphospholipid syndrome treated with rivaroxaban: a series of eight cases. Clin Rheumatol 2016;35:801-5.

30. Sciascia S, Breen K, Hunt BJ. Rivaroxaban use in patients with antiphospholipid syndrome and previous venous thromboembolism. Blood Coagul Fibrinolysis 2015;26:476-7.

31. Noel N, Dutasta F, Costedoat-Chalumeau N, Bienvenu B, Mariette X, Geffray L, et al. Safety and efficacy of oral direct inhibitors of thrombin and factor Xa in antiphospholipid syndrome. Autoimmun Rev 2015;14:680-5.

32. Betancur JF, Bonilla-Abadía F, Hormaza AA, Jaramillo FJ, Cañas CA, Tobón GJ. Direct oral anticoagulants in antiphospholipid syndrome: a real life case series. Lupus 2016;25:658-62.

33. Haladyj E, Olesinska M. Rivaroxaban - a safe therapeutic option in patients with antiphospholipid syndrome? Our experience in 23 cases. Reumatologia 2016;54:146-9.

34. Dufrost V, Risse J, Wahl D, Zuily S. Direct oral anticoagulants use in antiphospholipid syndrome: are these drugs an effective and safe alternative to warfarin? a systematic review of the literature: response to comment. Curr Rheumatol Rep 2017;19:52.

35. Burns PB, Rohrich RJ, Chung KC. The levels of evidence and their role in evidence-based medicine. Plast Reconstr Surg 2011;128:305-10.

36. Harter K, Levine M, Henderson SO. Anticoagulation drug therapy: a review. West J Emerg Med 2015;16:11-7.

37. Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e152S-e84S.

38. Chighizola CB, Moia M, Meroni PL. New oral anticoagulants in thrombotic antiphospholipid syndrome. Lupus 2014;23:1279-82.

39. Kuruvilla M, Gurk-Turner C. A review of warfarin dosing and monitoring. Proc (Bayl Univ Med Cent) 2001;14:305-6.

40. Cohen H, Efthymiou M, Isenberg DA. Use of direct oral anticoagulants in antiphospholipid syndrome. J Thromb Haemost 2018;16:1028-39.

41. Ruiz-Irastorza G, Hunt BJ, Khamashta MA. A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum. 2007;57:1487-95.

42. Efthymiou M, Lawrie AS, Mackie I, Arachchillage D, Lane PJ, Machin S, et al. Thrombin generation and factor X assays for the assessment of warfarin anticoagulation in thrombotic antiphospholipid syndrome. Thromb Res 2015;135:1191-7.

43. Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005;78:412-21.

44. Gerotziafas GT, Elalamy I, Depasse F, Perzborn E, Samama MM. In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct factor Xa inhibitor rivaroxaban. J Thromb Haemost 2007;5:886-8.

45. Arachchillage DJ, Cohen H. Use of new oral anticoagulants in antiphospholipid syndrome. Curr Rheumatol Rep 2013;15:331.

46. Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I, Brey R, Crowther M, Derksen R, et al. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies. Lupus 2011;20:206-18.

47. Tripodi A, Chantarangkul V, Clerici M, Negri B, Galli M, Mannucci PM. Laboratory control of oral anticoagulant treatment by the INR system in patients with the antiphospholipid syndrome and lupus anticoagulant. Results of a collaborative study involving nine commercial thromboplastins. Br J Haematol 2001;115:672-8.

48. Mueck W, Lensing AW, Agnelli G, Decousus H, Prandoni P, Misselwitz F. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 2011;50:675-86.

49. Cervera R, Serrano R, Pons-Estel GJ, Ceberio-Hualde L, Shoenfeld Y, de Ramón E, et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis 2015;74:1011-8.

50. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.

51. Cohen H, Hunt BJ, Efthymiou M, Mackie IJ, Khamashta M, Isenberg DA. Direct oral anticoagulants use in antiphospholipid syndrome: are these drugs an effective and safe alternative to warfarin? a systematic review of the literature: comment. Curr Rheumatol Rep 2017;19:50.

52. Win K, Rodgers GM. New oral anticoagulants may not be effective to prevent venous thromboembolism in patients with antiphospholipid syndrome. Am J Hematol 2014;89:1017.

53. Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F, Musial J, et al. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost 2005;3:848-53.

54. Schaefer JK, McBane RD, Black DF, Williams LN, Moder KG, Wysokinski WE. Failure of dabigatran and rivaroxaban to prevent thromboembolism in antiphospholipid syndrome: a case series of three patients. Thromb Haemost 2014;112:947-50.

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