Direct Oral Anticoagulants Use in Antiphospholipid Syndrome: Are These Drugs an Effective and Safe Alternative to Warfarin? A Systematic Review of the Literature

  • Virginie Dufrost
  • Jessie Risse
  • Stéphane ZuilyEmail author
  • Denis Wahl
Antiphospholipid Syndrome (S Zuily, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Antiphospholipid Syndrome



The cornerstone of thrombotic antiphospholipid syndrome (APS) patients’ management is to prevent recurrent thrombosis by long-term anticoagulation.

Purpose of review

The purpose of the review is to summarize available literature on direct oral anticoagulants (DOACs) use in APS patients through a systematic review and to determine factors associated with thrombosis recurrence.

Recent findings

The recent RAPS trial demonstrated that APS patients treated with rivaroxaban had a significant twofold-increased thrombin potential, suggesting a higher thrombotic risk, in comparison with warfarin users. Furthermore, several reports of APS patients treated with DOACs have raised safety issues. Our systematic review identified 122 published APS patients treated with DOACs; among them, 19 experienced a recurrent thrombosis while on DOACs. Of note, triple positivity (positivity of all three laboratory criteria for APS) was associated with a 3.5-fold increased risk for recurrent thrombosis.


In conclusion, DOACs should be used with caution in APS patients and randomized control trials with clinical primary endpoints assessing clinical efficacy and safety are awaited to establish whether the prescription of DOACs could be a safe alternative to warfarin.


Antiphospholipid syndrome Direct oral anticoagulants Rivaroxaban Antiphospholipid antibodies Thrombosis recurrence Triple positivity 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost JTH. 2006;4(2):295–306.CrossRefPubMedGoogle Scholar
  2. 2.
    Pengo V, Ruffatti A, Legnani C, Testa S, Fierro T, Marongiu F, et al. Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study. Blood. 2011;118(17):4714–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Erkan D, Aguiar CL, Andrade D, Cohen H, Cuadrado MJ, Danowski A, et al. 14th international congress on antiphospholipid antibodies: task force report on antiphospholipid syndrome treatment trends. Autoimmun Rev. 2014;13(6):685–96.CrossRefPubMedGoogle Scholar
  4. 4.
    Lancaster TR, Singer DE, Sheehan MA, Oertel LB, Maraventano SW, Hughes RA, et al. The impact of long-term warfarin therapy on quality of life. Evidence from a randomized trial. Boston area anticoagulation trial for atrial fibrillation investigators. Arch Intern Med. 1991;151(10):1944–9.CrossRefPubMedGoogle Scholar
  5. 5.
    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(10):1087–94.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    •• Cohen H, Hunt BJ, Efthymiou M, Arachchillage DRJ, 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(9):e426–36. This first randomized controlled trial of rivaroxaban vs. warfarin in APS patients showed that thrombin potential determined by thrombin generation was doubled.Google Scholar
  7. 7.
    Levy RA, Signorelli F. Patient-health care provider relationship: how can it impact on APS (Hughes’ syndrome) adherence to treatment? Lupus. 2014;23(12):1265–8.CrossRefPubMedGoogle Scholar
  8. 8.
    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(3):672–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51.CrossRefPubMedGoogle Scholar
  10. 10.
    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(10):883–91.CrossRefPubMedGoogle Scholar
  11. 11.
    Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–92.CrossRefPubMedGoogle Scholar
  12. 12.
    Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–104.CrossRefPubMedGoogle Scholar
  13. 13.
    Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342–52.CrossRefPubMedGoogle Scholar
  14. 14.
    Investigators EINSTEIN, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499–510.CrossRefGoogle Scholar
  15. 15.
    Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799–808.CrossRefPubMedGoogle Scholar
  16. 16.
    Hokusai-VTE Investigators, Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406–15.CrossRefGoogle Scholar
  17. 17.
    EINSTEIN–PE Investigators, Büller HR, Prins MH, Lensin AWA, Decousus H, Jacobson BF, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287–97.CrossRefGoogle Scholar
  18. 18.
    Van de Werf F, Brueckmann M, Connolly SJ, Friedman J, Granger CB, Härtter S, et al. A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: THE randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement (RE-ALIGN). Am Heart J. 2012;163(6):931–937.e1.CrossRefPubMedGoogle Scholar
  19. 19.
    Hohnloser SH, Oldgren J, Yang S, Wallentin L, Ezekowitz M, Reilly P, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (randomized evaluation of long-term anticoagulation therapy) trial. Circulation. 2012;125(5):669–76.CrossRefPubMedGoogle Scholar
  20. 20.
    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. 2013;65(11):1869–73.CrossRefGoogle Scholar
  21. 21.
    Clark CA, Laskin CA. Unrealistic estimation of population prevalence of antiphospholipid antibody-related pregnancy loss: comment on the article by Andreoli et al. Arthritis Care Res. 2014;66(6):966.CrossRefGoogle Scholar
  22. 22.
    •• Pengo V, Banzato A, Bison E, Zoppellaro G, Padayattil Jose S, Denas G. Efficacy and safety of rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome: rationale and design of the trial on rivaroxaban in antiphospholipid syndrome (TRAPS) trial. Lupus. 2016;25(3):301–6. This paper describes the protocol of an ongoing clinical trial that will compare the efficacy and safety of rivaroxaban vs. warfarin in high-risk APS patients using clinical endpoints (mainly thrombosis and bleeding).Google Scholar
  23. 23.
    •• Woller SC, Stevens SM, Kaplan DA, Branch DW, Aston VT, Wilson EL, et al. Apixaban for the secondary prevention of thrombosis among patients with antiphospholipid syndrome: study rationale and design (ASTRO-APS). Clin Appl Thromb Off J Int Acad Clin Appl Thromb. 2016;22(3):239–47. This paper describes the protocol of an ongoing clinical trial that will compare the efficacy and safety of edoxaban vs. warfarin in high-risk APS patients using clinical endpoints (mainly thrombosis and bleeding).Google Scholar
  24. 24.
    Olah Z, Szarvas M, Bereczky Z, Kerenyi A, Kappelmayer J, Boda Z. Direct thrombin inhibitors and factor xa inhibitors can influence the diluted prothrombin time used as the initial screen for lupus anticoagulant. Arch Pathol Lab Med. 2013;137(7):967–73.CrossRefPubMedGoogle Scholar
  25. 25.
    Arachchillage DRJ, Mackie IJ, Efthymiou M, Isenberg DA, Machin SJ, Cohen H. Interactions between rivaroxaban and antiphospholipid antibodies in thrombotic antiphospholipid syndrome. J Thromb Haemost JTH. 2015;13(7):1264–73.CrossRefPubMedGoogle Scholar
  26. 26.
    van Os GMA, de Laat B, Kamphuisen PW, Meijers JCM, de Groot PG. Detection of lupus anticoagulant in the presence of rivaroxaban using Taipan snake venom time. J Thromb Haemost JTH. 2011;9(8):1657–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Merriman E, Kaplan Z, Butler J, Malan E, Gan E, Tran H. Rivaroxaban and false positive lupus anticoagulant testing. Thromb Haemost. 2011;105(2):385–6.CrossRefPubMedGoogle Scholar
  28. 28.
    Sciascia S, Savino S, Breen K, Hunt BJ. Rivaroxaban use in patients with antiphospholipid syndrome and previous venous thromboembolism. Blood Coagul Fibrinolysis Int J Haemost Thromb. 2015;26(4):476–7.CrossRefGoogle Scholar
  29. 29.
    Murer LM, Pirruccello SJ, Koepsell SA. Rivaroxaban therapy, false-positive lupus anticoagulant screening results, and confirmatory assay results. Lab Med. 2016;47(4):275–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Góralczyk T, Iwaniec T, Wypasek E, Undas A. False-positive lupus anticoagulant in patients receiving rivaroxaban: 24 h since the last dose are needed to exclude antiphospholipid syndrome. Blood Coagul Fibrinolysis Int J Haemost Thromb. 2015;26(4):473–5.CrossRefGoogle Scholar
  31. 31.
    Martinuzzo ME, Barrera LH, D’adamo MA, Otaso JC, Gimenez MI, Oyhamburu J. Frequent false-positive results of lupus anticoagulant tests in plasmas of patients receiving the new oral anticoagulants and enoxaparin. Int J Lab Hematol. 2014;36(2):144–50.CrossRefPubMedGoogle Scholar
  32. 32.
    Joalland F, de Boysson H, Darnige L, Johnson A, Jeanjean C, Cheze S, et al. Seronegative antiphospholipid syndrome, catastrophic syndrome, new anticoagulants: learning from a difficult case report. Rev Médecine Interne Fondée Par Société Natl Francaise Médecine Interne. 2014;35(11):752–6.CrossRefGoogle Scholar
  33. 33.
    Delgado MG, Rodríguez S, García R, Sánchez P, Sáiz A, Calleja S. Antiphospholipid syndrome of late onset: a difficult diagnosis of a recurrent embolic stroke. J Stroke Cerebrovasc Dis Off J Natl Stroke Assoc. 2015;24(8):e209–11.CrossRefGoogle Scholar
  34. 34.
    Bachmeyer C, Elalamy I. Rivaroxaban as an effective treatment for recurrent superficial thrombophlebitis related to primary antiphospholipid syndrome. Clin Exp Dermatol. 2014;39(7):840–1.CrossRefPubMedGoogle Scholar
  35. 35.
    Sugie M, Iizuka N, Shimizu Y, Ichikawa H. Cerebral venous thromboembolism in antiphospholipid syndrome successfully treated with the combined use of an anti-Xa inhibitor and corticosteroid. Intern Med Tokyo Jpn. 2015;54(23):3051–6.CrossRefGoogle Scholar
  36. 36.
    Rokos J, Heger M, Stöllberger C, Finsterer J, Laufer G, Wiedemann D. Bipolar disorder, ischemic stroke, mitral valve vegetation and recurrent venous thrombosis due to antiphospholipid syndrome despite rivaroxaban. Int J Cardiol. 2016;221:383–4.CrossRefPubMedGoogle Scholar
  37. 37.
    Reshetnyak TM, Seredavkina NV, Satybaldyeva MA, Nasonov EL, Reshetnyak VI. Liver transplantation in a patient with primary antiphospholipid syndrome and Budd-Chiari syndrome. World J Hepatol. 2015;7(19):2229–36.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    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(8):680–5.CrossRefPubMedGoogle Scholar
  39. 39.
    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(5):1035–6.CrossRefPubMedGoogle Scholar
  40. 40.
    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(6):658–62.CrossRefPubMedGoogle Scholar
  41. 41.
    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(3):801–5.CrossRefPubMedGoogle Scholar
  42. 42.
    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(10):1017.CrossRefPubMedGoogle Scholar
  43. 43.
    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(5):947–50.CrossRefPubMedGoogle Scholar
  44. 44.
    Haładyj E, Olesińska M. Rivaroxaban—a safe therapeutic option in patients with antiphospholipid syndrome? Our experience in 23 cases. Reumatologia. 2016;54(3):146–9.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Sciascia S, Lopez-Pedrera C, Cecchi I, Pecoraro C, Roccatello D, Cuadrado MJ. Non-vitamin K antagonist oral anticoagulants and antiphospholipid syndrome. Rheumatology (Oxford). 2016;55(10):1726–35.Google Scholar
  46. 46.
    • Arachchillage DRJ, Mackie IJ, Efthymiou M, Chitolie A, Hunt BJ, Isenberg DA, et al. Rivaroxaban limits complement activation compared to warfarin in antiphospholipid syndrome patients with venous thromboembolism. J Thromb Haemost JTH. 2016. doi: 10.1111/jth.13475. An interesting pilot study showing that rivaroxaban may limit complement activation in APS.
  47. 47.
    Arachchillage DJ, Cohen H. Use of new oral anticoagulants in antiphospholipid syndrome. Curr Rheumatol Rep. 2013;15(6):331.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Virginie Dufrost
    • 1
  • Jessie Risse
    • 1
    • 2
  • Stéphane Zuily
    • 1
    • 2
    Email author
  • Denis Wahl
    • 1
    • 2
  1. 1.CHRU de Nancy, Vascular Medicine Division and Regional Competence Center For Rare Vascular And Systemic Autoimmune DiseasesNancyFrance
  2. 2.Inserm UMR_S 1116 at Lorraine UniversityNancyFrance

Personalised recommendations