Direct Oral Anticoagulants Use in Antiphospholipid Syndrome: Are These Drugs an Effective and Safe Alternative to Warfarin? A Systematic Review of the Literature
- 2.5k Downloads
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.
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.
KeywordsAntiphospholipid 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
- 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.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.•• 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
- 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
- 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.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.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
- 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.•• 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
- 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
- 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.• 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.