Subscribe to RSS
DOI: 10.1055/s-0041-1725057
Arterial Thrombosis in Patients with Antiphospholipid Syndrome: A Review and Meta-Analysis
Authors
Funding This work was supported by a grant from Hospital Clinic, IDIBAPS and University of Barcelona (Estada Retribuïda per ampliació d'estudis).

Abstract
There is a scarcity of high-quality randomized controlled trials (RCTs) comparing antithrombotic regimens for secondary prevention of arterial thrombosis (AT) in antiphospholipid syndrome (APS). We reviewed different antithrombotic regimens used for this purpose. We searched for studies on management of AT in APS on PubMed and Web of Science. Eleven studies (5 RCTs, 3 prospective, and 3 retrospective cohort studies) comparing different regimens and reporting outcomes specifically for patients with index AT events were identified. Treatments were vitamin K antagonists (VKA; 9 studies), non-VKA oral anticoagulant (NOAC; 3 studies), single antiplatelet therapy (SAPT; 7 studies), dual antiplatelet therapy (DAPT; 2 studies), and VKA combined with SAPT (4 studies). We performed a meta-analysis for the outcomes: recurrent AT, any (arterial or venous) recurrent thromboembolism, and major bleeding. Recurrent AT was reduced with VKA plus SAPT versus VKA (risk ratio [RR]: 0.43; 95% confidence interval [CI]: 0.22–0.85) and with DAPT versus SAPT (RR: 0.29; 95% CI: 0.09–0.99). Any recurrent thromboembolism was reduced with VKA plus SAPT versus VKA alone (RR: 0.41; 95% CI: 0.24–0.69) and versus SAPT alone (RR: 0.36; 95% CI: 0.13–0.96). There were no significant differences between other treatments for thromboembolism and for none of the comparisons regarding major bleeding. In a sensitivity analysis, excluding low-quality studies, VKA was more effective than NOAC to prevent recurrent AT (RR: 0.25; 95% CI: 0.07–0.93). Combined antithrombotic therapy might be more effective than single agents as secondary prophylaxis in APS with AT, and does not seem to compromise with safety, but the quality of evidence is generally low. NOACs should be avoided for patients with APS and AT.
Publication History
Article published online:
10 May 2021
© 2021. Thieme. All rights reserved.
Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA
-
References
- 1
Miyakis S,
Lockshin MD,
Atsumi T.
et al.
International consensus statement on an update of the classification criteria for
definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4 (02) 295-306
Reference Ris Wihthout Link
- 2
Wilson WA,
Gharavi AE,
Koike T.
et al.
International consensus statement on preliminary classification criteria for definite
antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999;
42 (07) 1309-1311
Reference Ris Wihthout Link
- 3
Duarte-García A,
Pham MM,
Crowson CS.
et al.
The epidemiology of antiphospholipid syndrome: a population-based study. Arthritis
Rheumatol 2019; 71 (09) 1545-1552
Reference Ris Wihthout Link
- 4
Hwang JJ,
Shin SH,
Kim YJ.
et al.
Epidemiology of antiphospholipid syndrome in Korea: a nationwide population-based
study. J Korean Med Sci 2020; 35 (05) e35
Reference Ris Wihthout Link
- 5
Kearon C,
Parpia S,
Spencer FA.
et al.
Antiphospholipid antibodies and recurrent thrombosis after a first unprovoked venous
thromboembolism. Blood 2018; 131 (19) 2151-2160
Reference Ris Wihthout Link
- 6
Tektonidou MG,
Andreoli L,
Limper M.
et al.
EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann
Rheum Dis 2019; 78 (10) 1296-1304
Reference Ris Wihthout Link
- 7
Tektonidou MG,
Ioannidis JPA,
Boki KA,
Vlachoyiannopoulos PG,
Moutsopoulos HM.
Prognostic factors and clustering of serious clinical outcomes in antiphospholipid
syndrome. QJM 2000; 93 (08) 523-530
Reference Ris Wihthout Link
- 8
Dufrost V,
Risse J,
Reshetnyak T.
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 (10) 1011-1021
Reference Ris Wihthout Link
- 9
Oku K,
Amengual O,
Yasuda S,
Atsumi T.
How to identify high-risk APS patients: clinical utility and predictive values of
validated scores. Curr Rheumatol Rep 2017; 19 (08) 51
Reference Ris Wihthout Link
- 10
Fujieda Y,
Atsumi T,
Amengual O.
et al.
Predominant prevalence of arterial thrombosis in Japanese patients with antiphospholipid
syndrome. Lupus 2012; 21 (14) 1506-1514
Reference Ris Wihthout Link
- 11
Taraborelli M,
Reggia R,
Dall'Ara F.
et al.
Longterm outcome of patients with primary antiphospholipid syndrome: a retrospective
multicenter study. J Rheumatol 2017; 44 (08) 1165-1172
Reference Ris Wihthout Link
- 12
Pengo V,
Ruffatti A,
Legnani C.
et al.
Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J
Thromb Haemost 2010; 8 (02) 237-242
Reference Ris Wihthout Link
- 13
Galli M,
Luciani D,
Bertolini G,
Barbui T.
Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin
antibodies in the antiphospholipid syndrome: a systematic review of the literature.
Blood 2003; 101 (05) 1827-1832
Reference Ris Wihthout Link
- 14
Schulman S,
Svenungsson E,
Granqvist S.
Duration of Anticoagulation Study Group.
Anticardiolipin antibodies predict early recurrence of thromboembolism and death among
patients with venous thromboembolism following anticoagulant therapy. Am J Med 1998;
104 (04) 332-338
Reference Ris Wihthout Link
- 15
Ruiz-Irastorza G,
Cuadrado MJ,
Ruiz-Arruza I.
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 (02) 206-218
Reference Ris Wihthout Link
- 16
Keeling D,
Mackie I,
Moore GW,
Greer IA,
Greaves M.
British Committee for Standards in Haematology.
Guidelines on the investigation and management of antiphospholipid syndrome. Br J
Haematol 2012; 157 (01) 47-58
Reference Ris Wihthout Link
- 17
Limper M,
de Leeuw K,
Lely AT.
et al.
Diagnosing and treating antiphospholipid syndrome: a consensus paper. Neth J Med 2019;
77 (03) 98-108
Reference Ris Wihthout Link
- 18
Jackson WG,
Oromendia C,
Unlu O,
Erkan D,
DeSancho MT.
Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking.
Recurrent thrombosis in patients with antiphospholipid antibodies and arterial thrombosis
on antithrombotic therapy. Blood Adv 2017; 1 (25) 2320-2324
Reference Ris Wihthout Link
- 19
Levine SR,
Brey RL,
Tilley BC.
et al;
APASS Investigators.
Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with
ischemic stroke. JAMA 2004; 291 (05) 576-584
Reference Ris Wihthout Link
- 20
Yamazaki M,
Kadohira Y,
Maekawa M.
et al.
Combined antiplatelet agents might help prevent arterial thrombosis in antiphospholipid
syndrome. J Thromb Haemost 2009; 7 (Suppl. 02) 720-721
Reference Ris Wihthout Link
- 21
Malec K,
Broniatowska E,
Undas A.
Direct oral anticoagulants in patients with antiphospholipid syndrome: a cohort study.
Lupus 2020; 29 (01) 37-44
Reference Ris Wihthout Link
- 22
Jadad AR,
Moore RA,
Carroll D.
et al.
Assessing the quality of reports of randomized clinical trials: is blinding necessary?.
Control Clin Trials 1996; 17 (01) 1-12
Reference Ris Wihthout Link
- 23
Wells G,
Shea B,
O'Connell D.
et al.
The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies
in meta-analyses. 2013 . Accessed October 9, 2020 at: http://wwwohrica/programs/clinical_epidemiology/oxfordasp
Reference Ris Wihthout Link
- 24
Crowther MA,
Ginsberg JS,
Julian 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 (12)
1133-1138
Reference Ris Wihthout Link
- 25
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; 7 (01) 15-18
Reference Ris Wihthout Link
- 26
Arauz A,
Roa LF,
Hernandez B.
et al.
Aspirin versus anticoagulation in young patients with cerebral infarction secondary
to primary antiphospholipid syndrome [in Spanish]. Rev Neurol 2011; 53 (10) 584-590
Reference Ris Wihthout Link
- 27
Pyo JY,
Jung SM,
Lee SW,
Song JJ,
Lee SK,
Park YB.
Subsequent thrombotic outcomes in patients with ischemic stroke with antiphospholipid
antibody positivity. Yonsei Med J 2017; 58 (06) 1128-1134
Reference Ris Wihthout Link
- 28
Ohnishi N,
Fujieda Y,
Hisada R.
et al.
Efficacy of dual antiplatelet therapy for preventing recurrence of arterial thrombosis
in patients with antiphospholipid syndrome. Rheumatology (Oxford) 2019; 58 (06) 969-974
Reference Ris Wihthout Link
- 29
Pengo V,
Denas G,
Zoppellaro G.
et al.
Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood
2018; 132 (13) 1365-1371
Reference Ris Wihthout Link
- 30
Ordi-Ros J,
Sáez-Comet L,
Pérez-Conesa M.
et al.
Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome: a randomized
noninferiority trial. Ann Intern Med 2019; 171 (10) 685-694
Reference Ris Wihthout Link
- 31
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 (03) 301-306
Reference Ris Wihthout Link
- 32
Cervera R,
Piette JC,
Font J.
et al;
Euro-Phospholipid Project Group.
Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of
disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002; 46 (04) 1019-1027
Reference Ris Wihthout Link
- 33
Cervera R,
Boffa MC,
Khamashta MA,
Hughes GRV.
The Euro-Phospholipid project: epidemiology of the antiphospholipid syndrome in Europe.
Lupus 2009; 18 (10) 889-893
Reference Ris Wihthout Link
- 34
Ricarte IF,
Dutra LA,
Abrantes FF.
et al.
Neurologic manifestations of antiphospholipid syndrome. Lupus 2018; 27 (09) 1404-1414
Reference Ris Wihthout Link
- 35
Uthman I,
Noureldine MHA,
Ruiz-Irastorza G,
Khamashta M.
Management of antiphospholipid syndrome. Ann Rheum Dis 2019; 78 (02) 155-161
Reference Ris Wihthout Link
- 36
Soltész P,
Veres K,
Lakos G,
Kiss E,
Muszbek L,
Szegedi G.
Evaluation of clinical and laboratory features of antiphospholipid syndrome: a retrospective
study of 637 patients. Lupus 2003; 12 (04) 302-307
Reference Ris Wihthout Link
- 37
Kearon C,
Akl EA,
Ornelas J.
et al.
Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest
2016; 149 (02) 315-352
Reference Ris Wihthout Link
- 38
Cuadrado MJ,
Bertolaccini ML,
Seed PT.
et al.
Low-dose aspirin vs low-dose aspirin plus low-intensity warfarin in thromboprophylaxis:
a prospective, multicentre, randomized, open, controlled trial in patients positive
for antiphospholipid antibodies (ALIWAPAS). Rheumatology (Oxford) 2014; 53 (02) 275-284
Reference Ris Wihthout Link
- 39
Verro P,
Levine SR,
Tietjen GE.
Cerebrovascular ischemic events with high positive anticardiolipin antibodies. Stroke
1998; 29 (11) 2245-2253
Reference Ris Wihthout Link
- 40
Wang CR,
Liu MF.
Rituximab usage in systemic lupus erythematosus-associated antiphospholipid syndrome:
a single-center experience. Semin Arthritis Rheum 2016; 46 (01) 102-108
Reference Ris Wihthout Link
- 41
Ruiz-Irastorza G,
Khamashta MA,
Hunt BJ,
Escudero A,
Cuadrado MJ,
Hughes GRV.
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 (10) 1164-1169
Reference Ris Wihthout Link
- 42
Derksen RH,
de Groot PG,
Kappelle LJ.
Low dose aspirin after ischemic stroke associated with antiphospholipid syndrome.
Neurology 2003; 61 (01) 111-114
Reference Ris Wihthout Link
- 43
Finazzi G,
Marchioli R,
Brancaccio V.
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 (05) 848-853
Reference Ris Wihthout Link
- 44
Khamashta MA,
Cuadrado MJ,
Mujic F,
Taub NA,
Hunt BJ,
Hughes GR.
The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med
1995; 332 (15) 993-997
Reference Ris Wihthout Link
- 45
Rosove MH,
Brewer PMC.
Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70
patients. Ann Intern Med 1992; 117 (04) 303-308
Reference Ris Wihthout Link
- 46
Lopes LC,
Spencer FA,
Neumann I.
et al.
Bleeding risk in atrial fibrillation patients taking vitamin K antagonists: systematic
review and meta-analysis. Clin Pharmacol Ther 2013; 94 (03) 367-375
Reference Ris Wihthout Link
- 47
Chai-Adisaksopha C,
Crowther M,
Isayama T,
Lim W.
The impact of bleeding complications in patients receiving target-specific oral anticoagulants:
a systematic review and meta-analysis. Blood 2014; 124 (15) 2450-2458
Reference Ris Wihthout Link