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Direct oral anticoagulants versus vitamin K antagonists in antiphospholipid syndrome: A meta-analysis.

  • Pau Cerdà
    Affiliations
    Internal Medicine Department, Hospital Universitari Bellvitge - IDIBELL, Barcelona, Spain
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  • Cecilia Becattini
    Affiliations
    Internal and Cardiovascular Medicine – Stroke Unit, University of Perugia, Perugia, Italy
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  • Adriana Iriarte
    Affiliations
    Internal Medicine Department, Hospital Universitari Bellvitge - IDIBELL, Barcelona, Spain
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  • Josefina Cortés Hernández
    Affiliations
    Internal Medicine Department. Rheumatology Research Group. Vall d´Hebrón University Hospital Research Institute, Barcelona, Spain
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  • Author Footnotes
    1 1 X. Corbella and A. Riera-Mestre are joint last authors.
    Xavier Corbella
    Footnotes
    1 1 X. Corbella and A. Riera-Mestre are joint last authors.
    Affiliations
    Internal Medicine Department, Hospital Universitari Bellvitge - IDIBELL, Barcelona, Spain

    Faculty of Medicine and Health Sciences. Universitat Internacional de Catalunya, Barcelona, Spain
    Search for articles by this author
  • Author Footnotes
    1 1 X. Corbella and A. Riera-Mestre are joint last authors.
    Antoni Riera-Mestre
    Correspondence
    Corresponding author. Internal Medicine Department. Hospital Universitari Bellvitge - IDIBELL. Feixa Llarga s/n. L'Hospitalet de Llobregat (08907), Barcelona, Spain
    Footnotes
    1 1 X. Corbella and A. Riera-Mestre are joint last authors.
    Affiliations
    Internal Medicine Department, Hospital Universitari Bellvitge - IDIBELL, Barcelona, Spain

    Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain
    Search for articles by this author
  • Author Footnotes
    1 1 X. Corbella and A. Riera-Mestre are joint last authors.

      Abstract

      Background

      Anticoagulant treatment is recommended in patients with thrombosis and antiphospholipid syndrome (APS). Conflicting results have been reported on the role of direct oral anticoagulants (DOACs) in these patients. We performed a meta-analysis of randomized controlled trials (RCTs) focused on this issue.

      Methods

      We searched MEDLINE and EMBASE for RCTs comparing DOACs and vitamin K antagonists (VKAs) for secondary thromboprophylaxis in patients with thrombotic APS. The primary objective was to assess the efficacy of DOACs compared to VKAs to prevent recurrence of thromboembolic events. Risk difference (RD) was reported as weighted RD according to Mantel-Haenszel random-effect method.

      Results

      Three RCTs (426 patients) were included, all comparing rivaroxaban with VKAs. The proportion of recurrences (either arterial or venous) was higher among rivaroxaban patients when compared with those receiving VKAs (9.5% vs 2.8%; RD 6%, 95% CI, -0.05 – 0.18, p=0.29), although non-statistically significant. In patients with an arterial index event, thromboembolic recurrences were more frequent in those treated with rivaroxaban compared to those treated with VKAs (25% vs 6.2%; RD 19%, 95% CI, 0.04 – 0.33; p =0.01; I2 49%). In triple aPL positive patients, rivaroxaban showed higher rates of thromboembolic recurrences compared with VKAs (12% vs 3%; RD 9%, 95% CI, 0.02 – 0.15; p= 0.01; I2 13%). Non-statistically significant differences were observed in major bleeding events or mortality.

      Conclusions

      The use of rivaroxaban in APS patients is associated with an increased rate of thromboembolic recurrences compared to VKAs, at least in those with arterial index event or triple aPL positivity.

      Keywords

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      REFERENCES

        • 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. 2006; 4: 295-306
        • Ruiz-irastorza G
        • Crowther M
        • Branch W
        • Khamashta MA
        Antiphospholipid syndrome.
        Lancet. 2010; 376: 1498-1509
        • Schreiber K
        • Sciascia S
        • de Groot PG
        • Devreese K
        • Jacobsen S
        • Ruiz-Irastorza G
        • et al.
        Antiphospholipid syndrome.
        Nat Rev Dis Prim. 2018; 4: 17103
        • 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 (4717–478)
        • 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: 206-218
        • Tektonidou MG
        • Andreoli L
        • Limper M
        • Amoura Z
        • Cervera R
        • Costedoat-Chalumeau N
        • et al.
        EULAR recommendations for the management of antiphospholipid syndrome in adults.
        Ann Rheum Dis. 2019; 78: 1296-1304
        • Ruiz-Irastorza G
        • Khamashta MA.
        The treatment of antiphospholipid syndrome: A harmonic contrast.
        Best Pract Res Clin Rheumatol. 2007; 21: 1079-1092
        • Cervera R
        Antiphospholipid syndrome.
        Thromb Res. 2017; 151: S43-S47
        • Bazzan M
        • Vaccarino A
        • Stella S
        • Sciascia S
        • Montaruli B
        • Bertero MT
        • et al.
        Patients with antiphosholipid syndrome and thrombotic recurrences: A real world observation (the Piedmont cohort study).
        Lupus. 2016; 25: 479-485
        • Schulman S
        • Svenungsson E
        • Granqvist S
        Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy.
        Duration of Anticoagulation Study Group. Am J Med. 1998; 104: 332-338
        • 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: 2342-2352
        • Bauersachs R
        • Berkowitz SD
        • Brenner B
        • Buller HR
        • Decousus H
        • et al.
        • EINSTEIN Investigators
        Oral rivaroxaban for symptomatic venous thromboembolism.
        N Engl J Med. 2010; 363: 2499-2510
        • 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: 799-808
        • Büller HR
        • Décousus H
        • Grosso MA
        • Mercuri M
        • Middeldorp S
        • Prins MH
        • et al.
        Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
        N Engl J Med. 2013; 369: 1406-1415
        • Konstantinides S V
        • Meyer G
        • Becattini C
        • Bueno H
        • Geersing G-J
        • et al.
        ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of.
        Eur Respir J. 2019; 2019: 1-61
        • 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: e426-e436
        • Dufrost V
        • Risse J
        • Zuily S
        • Wahl D
        Direct Oral Anticoagulants Use in Antiphospholipid Syndrome : Are These Drugs an Effective and Safe Alternative to Warfarin ? A Systematic Review of the Literature.
        Curr Rheumatol Rep. 2016;
        • Pengo V
        • Denas G
        • Zoppellaro G
        • Jose SP
        • Hoxha A
        • Ruffatti A
        • et al.
        Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome.
        Blood. 2018; 132: 1365-1371
        • Dufrost V
        • Risse J
        • Reshetnyak T
        • Satybaldyeva M
        • Du Y
        • Yan X-X
        • et al.
        Increased risk of thrombosis in antiphospholipid syndrome patients treated with direct oral anticoagulants.
        Results from an international patient-level data meta-analysis. Autoimmun Rev. 2018; 17: 1011-1021
        • Ordi-Ros J
        • Saez-Comet L
        • Pérez-Conesa M
        Rivaroxaban versus Vitamin K Antagonist in Antiphospholipid Syndrome: A randomized non-inferiority trial.
        Ann Intern Med. 2019;
        • Sterne JAC
        • Savović J
        • Page MJ
        • Elbers RG
        • Blencowe NS
        • Boutron I
        • et al.
        RoB 2: a revised tool for assessing risk of bias in randomised trials.
        BMJ. 2019; 366: l4898
        • Higgins JPT
        • Altman DG
        • Gøtzsche PC
        • Jüni P
        • Moher D
        • Oxman AD
        • et al.
        The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
        BMJ. 2011; 343: d5928
        • Egger M
        • Davey-Smith G
        • Altman D
        Systematic reviews in Health Care: Meta-analysis in context.
        2nd ed. UK: BMJ Books, London2001: 447-458
        • Higgins JPT
        • Thompson SG.
        Quantifying heterogeneity in a meta-analysis.
        Stat Med. 2002; 21: 1539-1558
        • Leeflang MMG
        • Deeks JJ
        • Rutjes AWS
        • Reitsma JB
        • Bossuyt PMM
        Bivariate meta-analysis of predictive values of diagnostic tests can be an alternative to bivariate meta-analysis of sensitivity and specificity.
        J Clin Epidemiol. 2012; 65: 1088-1097
      1. Chandler J, Higgins J, Deeks J, Davenport C, Clarke M. Cochrane Handbook for Systematic Reviews of Interventions. 2017.

        • Sanchez-Redondo J
        • Espinosa G
        • Varillas Delgado D
        • Cervera R
        Recurrent Thrombosis With Direct Oral Anticoagulants in Antiphospholipid Syndrome: A Systematic Literature Review and Meta-analysis.
        Clin Ther. 2019; : xxx
        • 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 Hemost. 2016; 22: 239-247
        • Schulman S
        • Angerås U
        • Bergqvist D
        • Eriksson B
        • Lassen MR
        • Fisher W
        • et al.
        Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients.
        J Thromb Haemost. 2010; 8: 202-204
        • Parry TJ
        • Huang Z
        • Chen C
        • Connelly MA
        • Perzborn E
        • Andrade-Gordon P
        • et al.
        Arterial antithrombotic activity of rivaroxaban, an orally active factor Xa inhibitor, in a rat electrolytic carotid artery injury model of thrombosis.
        Blood Coagul Fibrinolysis. 2011; 22: 720-726
        • Wagner N
        • Dressel T
        • Schäfer K
        • Konstantinides S
        Effect of the factor Xa inhibitor rivaroxaban on arterial thrombosis in wild-type and apolipoprotein E-deficient mice.
        Thromb Res. 2012; 130: 793-798
        • Baker WL
        • Beyer-Westendorf J
        • Bunz TJ
        • Eriksson D
        • Meinecke A-K
        • Sood NA
        • et al.
        Effectiveness and safety of rivaroxaban and warfarin for prevention of major adverse cardiovascular or limb events in patients with non-valvular atrial fibrillation and type 2 diabetes.
        Diabetes Obes Metab. 2019; 21: 2107-2114
        • Perzborn E
        • Strassburger J
        • Wilmen A
        • Pohlmann J
        • Roehrig S
        • Schlemmer K-H
        • et al.
        In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939–an oral, direct Factor Xa inhibitor.
        J Thromb Haemost. 2005; 3: 514-521
        • Celinska-Löwenhoff M
        • Zabczyk M
        • Iwaniec T
        • Plens K
        • Musial J
        • Undas A
        Reduced plasma fibrin clot permeability is associated with recurrent thromboembolic events in patients with antiphospholipid syndrome.
        Rheumatology (Oxford). 2018; 57: 1340-1349
        • Koupenova M
        • Kehrel BE
        • Corkrey HA
        • Freedman JE
        Thrombosis and platelets: an update.
        Eur Heart J. 2017; 38: 785-791
        • Perzborn E
        • Heitmeier S
        • Laux V
        Effects of Rivaroxaban on Platelet Activation and Platelet-Coagulation Pathway Interaction: In Vitro and In Vivo Studies.
        J Cardiovasc Pharmacol Ther. 2015; 20: 554-562
        • Anand SS
        • Caron F
        • Eikelboom JW
        • Bosch J
        • Dyal L
        • Aboyans V
        • et al.
        Major Adverse Limb Events and Mortality in Patients With Peripheral Artery Disease: The COMPASS Trial.
        J Am Coll Cardiol. 2018; 71: 2306-2315
        • Connolly SJ
        • Eikelboom JW
        • Bosch J
        • Dagenais G
        • Dyal L
        • Lanas F
        • et al.
        Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial.
        Lancet. 391. London, England, 2018: 205-218
        • 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. 2010; 7: 15-18
        • 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: 848-853
        • Tektonidou MG
        • Andreoli L
        • Limper M
        • Tincani A
        • Ward MM
        Management of thrombotic and obstetric antiphospholipid syndrome: a systematic literature review informing the EULAR recommendations for the management of antiphospholipid syndrome in adults.
        RMD Open. 2019; 5e000924
        • Woller SC
        • Stevens SM
        • Kaplan DA
        • T Rondina M
        Protocol Modification of Apixaban for the Secondary Prevention of Thrombosis Among Patients With Antiphospholipid Syndrome Study.
        Clin Appl Thromb Hemost. 2018; 24: 192
        • Ruffatti A
        • Tonello M
        • Del Ross T
        • Cavazzana A
        • Grava C
        • Noventa F
        • et al.
        Antibody profile and clinical course in primary antiphospholipid syndrome with pregnancy morbidity.
        Thromb Haemost. 2006; 96: 337-341
        • 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: 237-242
        • 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: 883-891
        • Ruiz-Irastorza G
        • Khamashta MA
        • Hunt BJ
        • Escudero A
        • Cuadrado MJ
        • Hughes GR V
        Bleeding and recurrent thrombosis in definite antiphospholipid syndrome: analysis of a series of 66 patients treated with oral anticoagulation to a target international normalized ratio of 3.5.
        Arch Intern Med. 2002; 162: 1164-1169
        • Rosove MH
        • Brewer PMC
        Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients.
        Ann Intern Med. 1992; 117: 303-308
        • Tektonidou MG
        • Ioannidis JP
        • Boki KA
        • Vlachoyiannopoulos PG
        • Moutsopoulos HM
        Prognostic factors and clustering of serious clinical outcomes in antiphospholipid syndrome.
        QJM. 2000; 93: 523-530
        • Taraborelli M
        • Reggia R
        • Dall'Ara F
        • Fredi M
        • Andreoli L
        • Gerosa M
        • et al.
        Longterm Outcome of Patients with Primary Antiphospholipid Syndrome: A Retrospective Multicenter Study.
        J Rheumatol. 2017; 44: 1165-1172