Antiphospholipid antibody syndrome

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Last updated on 2024-07-23:4 regimens on this page
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=Overview=
*Antiphospholipid syndrome (APS) is an acquired hypercoagulable state causing increased risk of thrombosis or pregnancy-related adverse outcomes.
*Patients who have persistently positive antiphospholipid antibodies plus a thrombotic event meet criteria for thrombotic APS (TAPS) and warrant long-term anticoagulation for secondary thrombosis prevention. 
=Guidelines=
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
*Long-term anticoagulation with vitamin K antagonists remains the mainstay of treatment of APS patients. 
*Studies have shown superiority of vitamin K antagonists such as warfarin versus direct oral anticoagulants (DOACs) for secondary prevention of thrombosis in patients with high risk, triple positive APS. 
*The evidence for the efficacy of DOACs in patients with single and double positive APS remains unclear and societal guidelines differ as to the use of DOACs in patients with TAPS who do not have triple positive disease. 
==British Society for Haemotology (BSH)==
*2020: Arachchillage et al. Addendum to British Society for Haematology Guidelines on Investigation and Management of Antiphospholipid syndrome, 2012 (Br. J. Haematol. 2012; 157: 47–58): use of direct acting oral anticoagulants EuroPMC
*2012: Keeling et al. Guidelines on the investigation and management of antiphospholipid syndrome EuroPMC
==European League Against Rheumatism (EULAR)==
*2019: Tektonidou et al. EULAR recommendations for the management of antiphospholipid syndrome in adults link to PMC article EuroPMC
==International Society on Thrombosis and Haemostasis (ISTH)==
*2020: Zuily et al. Use of direct oral anticoagulants in patients with thrombotic antiphospholipid syndrome: Guidance from the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis EuroPMC
=All lines of therapy=
== Aspirin & Warfarin ==
===Regimen ===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Okuma et al. 2009	2002-10 to 2004-11 	Phase 3 (E-esc)	Aspirin 	Lower cumulative incidence of ischemic stroke (primary endpoint)
Note: Small study of 20 patients. All meeting the 2006 Sydney criteria for APS in setting of an ischemic stroke. 
====Anticoagulation====
* Warfarin (Coumadin) PO with INR goal 2 to 3.0
* Aspirin 100 mg PO once per day
Continued indefinitely
=== References ===
# Okuma H, Kitagawa Y, Yasuda T, Tokuoka K, Takagi S. Comparison between single antiplatelet therapy and combination of antiplatelet and anticoagulation therapy for secondary prevention in ischemic stroke patients with antiphospholipid syndrome. Int J Med Sci. 2009 Dec 5;7(1):15-8. link to original article link to PMC article EuroPMC
== Rituximab monotherapy ==
===Regimen ===
Study 	Dates of enrollment	Evidence	Efficacy
Erkan et al. 2012 (RITAPS)	Not reported 	Phase 2 	Some improvement in non-criteria manifestations of APS
Note: This small phase 2 study (19 patients) did not identify any significant change in the antiphospholipid antibody profiles of the enrolled patients, but it did observe some improvements in the non-criteria manifestations of APS. This included thrombocytopenia, cardiac valve disease, skin ulcer, aPL nephropathy, and cognitive dysfunction. 
====Immunosuppressive therapy====
* Rituximab (Rituxan) 1000 mg IV once on day 1
14-day cycle for 2 cycles
=== References ===
# RITAPS: Erkan D, Vega J, Ramon G, Kozora E, Lockshin MD. A pilot open-label phase II trial of rituximab for non-criteria manifestations of antiphospholipid syndrome. Arthritis Rheum. 2013 Feb;65(2):464-71. Epub 2012 Nov 2. link to original article EuroPMC NCT00537290
== Rivaroxaban monotherapy ==
===Regimen ===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Cohen et al. 2016 (RAPS) 	2013-06-05 to 2014-11-11	Phase 2/3 (E-switch-ooc)	Warfarin 	Inconclusive whether non-inferior percent change in endogenous thrombin potential (primary endpoint)
Pengo et al. 2018 (TRAPS)	2014-11-02 to 2018-01-25	Phase 3 (E-switch-ooc) 	Warfarin 	Higher rate of thromboembolic events, major bleeding, and vascular death (primary endpoint)
Note: TRAPS was closed prematurely due to excess events in the rivaroxaban arm. Although we include here for historical context, this regimen should not be used outside of the context of a clinical trial.
====Anticoagulation====
* Rivaroxaban (Xarelto) PO 20 mg PO once per day
Continued indefinitely
===References===
# RAPS: Cohen H, Hunt BJ, Efthymiou M, Arachchillage DR, Mackie IJ, Clawson S, Sylvestre Y, Machin SJ, Bertolaccini ML, Ruiz-Castellano M, Muirhead N, Doré CJ, Khamashta M, Isenberg DA; RAPS trial investigators. 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 Sep;3(9):e426-36. link to original article link to PMC article EuroPMC ISRCTN68222801
# TRAPS: Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. Epub 2018 Jul 12. link to original article EuroPMC NCT02157272
==Warfarin monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Crowther et al. 2003 	1998-02 to 2001-05 	Phase 3 (C) 	Warfarin; high-intensity (INR 3.1 to 4.0)	Did not meet primary endpoint of recurrent VTE
Finazzi et al. 2005 (WAPS) 	Not reported 	Phase 3 (C) 	Warfarin; high-intensity (INR 3 to 4.5) 	Did not meet primary endpoint of recurrent symptomatic VTE
Ordi-Ros et al. 2019 (SAP-02)	2013-03 to 2014-12 	Phase 2/3 (C)	Rivaroxaban 	Inconclusive whether non-inferior new thrombosis rate (primary outcome)new thrombosis rate: 6.3% vs 11.6%(RR 0.55, 95% CI 0.21-1.41)
Cohen et al. 2016 (RAPS) 	2013-06-05 to 2014-11-11	Phase 2/3 (C)	Rivaroxaban 	Inconclusive whether non-inferior percent change in endogenous thrombin potential
Pengo et al. 2018 (TRAPS) 	2014-11-02 to 2018-01-25	Phase 3 (C) 	Rivaroxaban 	Fewer events
Note: TRAPS was closed prematurely due to excess events in the rivaroxaban arm.
====Anticoagulation====
*Warfarin (Coumadin) PO titrated to goal INR 2 to 3.0
**Note: some trials specify a goal INR 2.5 without a range given
Continued indefinitely
===References===
# Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, Laskin C, Fortin P, Anderson D, Kearon C, Clarke A, Geerts W, Forgie M, Green D, Costantini L, Yacura W, Wilson S, Gent M, Kovacs MJ. 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 Sep 18;349(12):1133-8. Erratum in: N Engl J Med. 2004 Jul 8;351(2):200. N Engl J Med. 2003 Dec 25;349(26):2577. link to original article EuroPMC
# WAPS: Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F, Musial J, Baudo F, Berrettini M, Testa S, D'Angelo A, Tognoni G, Barbui T. 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 May;3(5):848-53. link to original article EuroPMC
# RAPS: Cohen H, Hunt BJ, Efthymiou M, Arachchillage DR, Mackie IJ, Clawson S, Sylvestre Y, Machin SJ, Bertolaccini ML, Ruiz-Castellano M, Muirhead N, Doré CJ, Khamashta M, Isenberg DA; RAPS trial investigators. 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 Sep;3(9):e426-36. link to original article link to PMC article EuroPMC ISRCTN68222801
# TRAPS: Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. Epub 2018 Jul 12. link to original article EuroPMC NCT02157272
# SAP-02: Ordi-Ros J, Sáez-Comet L, Pérez-Conesa M, Vidal X, Riera-Mestre A, Castro-Salomó A, Cuquet-Pedragosa J, Ortiz-Santamaria V, Mauri-Plana M, Solé C, Cortés-Hernández J. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome: a randomized noninferiority trial. Ann Intern Med. 2019 Nov 19;171(10):685-694. Epub 2019 Oct 15. link to original article EuroPMC EudraCT 2010-019764-36
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