Efficacy of aspirin for the primary prevention of thrombosis in patients with antiphospholipid antibodies: An international and collaborative meta-analysis

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Autoimmunity Reviews xxx (2013) xxx–xxx

AUTREV-01469; No of Pages 11

Contents lists available at ScienceDirect

Autoimmunity Reviews

j ourna l homepage: www.e lsev ie r .com/ locate /aut rev

Review

Efficacy of aspirin for the primary prevention of thrombosis in patientswith antiphospholipid antibodies: An international andcollaborative meta-analysis

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Laurent Arnaud a,b,c,⁎,1, Alexis Mathian a,b,c,1, Amelia Ruffatti d, Doruk Erkan e, Maria Tektonidou f,Ricard Cervera g, Ricardo Forastiero h, Vittorio Pengo i, Marc Lambert j, Maria Angeles Martinez-Zamora k,Juan Balasch k, Stephane Zuily l, Denis Wahl l,2, Zahir Amoura a,b,c,2

a Department of Internal Medicine, French National Reference Center for Systemic Lupus and Antiphospholipid Syndrome, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, 47-83 bd de l'hôpital, 75013Paris, Franceb Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 945, Paris, Francec Université Pierre et Marie Curie, UPMC Univ Paris 06, Paris, Franced Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Padua, Padua, Italye Hospital for Special Surgery, Weill Cornell Medical College, New York, USAf First Department of Internal Medicine, School of Medicine, National University of Athens, Athens, Greeceg Department of Autoimmune Diseases, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Catalonia, Spainh Department of Physiology, Favaloro University, Buenos Aires, Argentinai Clinical Cardiology, Department of Cardiac Thoracic and Vascular Sciences, University of Padova, Padova, Italyj Internal Medicine Department, Universitary Hospital, Lille, Francek Institut Clínic of Gynecology, Obstetrics and Neonatology, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Faculty of Medicine, University of Barcelona, Barcelona, Spainl Nancy University Hospital, Université de Lorraine, INSERM U961, Vandœuvre-Les-Nancy, France

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⁎ Corresponding author at: Service deMédecine InterneE-mail address: [email protected] (L. Arnaud

1 Laurent Arnaud & Alexis Mathian contributed equally2 Denis Wahl & Zahir Amoura contributed equally to th

1568-9972/$ – see front matter © 2013 Published by Elsehttp://dx.doi.org/10.1016/j.autrev.2013.10.014

Please cite this article as: Arnaud L, et al, EfficAn international and co..., Autoimmun Rev (

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Article history:Received 1 October 2013Accepted 25 October 2013Available online xxxx

Keywords:AspirinThrombosisMeta-analysisAntiphospholipid antibodies

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RRECWe performed a meta-analysis to determine whether aspirin has a significant protective effect on risk of first

thrombosis among patients with antiphospholipid antibodies (aPL+). Observational and interventional studiesidentified from the Medline, Embase and Cochrane databases were selected if they assessed the incidence offirst thrombosis in aPL+patients treatedwith aspirin versus thosewithout. Pooled effect estimateswere obtainedusing a random-effectsmodel. Of 1211 citation retrieved, 11 primary studies (10 observational and 1 intervention-al) met inclusion criteria, including a total of 1208 patients and 139 thrombotic events. The pooled odds ratio (OR)for the risk of first thrombosis in patients treatedwith aspirin (n = 601)was 0.50 (95%CI: 0.27 to 0.93) comparedto those without aspirin (n = 607), with significant heterogeneity across studies (I2 = 46%, p = 0.05). Subgroupanalysis showed a protective effect of aspirin against arterial (OR: 0.48 [95%CI: 0.28–0.82]) but not venous (OR:0.58 [95% CI: 0.32–1.06]) thrombosis, as well as in retrospective (OR: 0.23 [0.13–0.42]) but not prospective studies(OR: 0.91 [0.52–1.59]). Subgroup analysis according to underlying disease revealed a significant protective effect ofaspirin for asymptomatic aPL+ individuals (OR: 0.50 [0.25–0.99]), for systemic lupus erythematosus (SLE) (OR:0.55 [0.31–0.98]) and obstetrical antiphospholipid syndrome (APS) (OR: 0.25 [0.10–0.62]). This meta-analysisshows that the risk of first thrombotic event is significantly decreased by low dose aspirin among asymptomaticaPL individuals, patients with SLE or obstetrical APS. Importantly, no significant risk reduction was observedwhen considering only prospective studies or those with the best methodological quality.

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1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

2.1. Literature search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.2. Study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.3. Data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

2, GroupeHospitalier Pitié-Salpêtrière, 47-83 bd de l'Hôpital, 75013 Paris, France. Tel.:+33 1 42 17 80 40; fax:+33 1 42 17 80 44.).to this work.is work.

vier B.V.

acy of aspirin for the primary prevention of thrombosis in patientswith antiphospholipid antibodies:2013), http://dx.doi.org/10.1016/j.autrev.2013.10.014

http://dx.doi.org/10.1016/j.autrev.2013.10.014

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2.4. Disease definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.5. Contact with authors and management of duplicate studies or patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.6. Quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.7. Cumulative meta-analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.8. Statistical analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.1. Literature search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.2. Publication bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.3. Selected studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.4. Assessment of methodological quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.5. Risk of first thrombosis associated with aPL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.6. Risk of first thrombosis according to pathogenic backgrounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.7. Cumulative meta-analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.8. Hemorrhagic risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Appendix A. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Appendix B. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Appendix C. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Appendix D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

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1. Introduction

Antiphospholipid antibodies (aPL) are a heterogeneous family of auto-antibodies directed against phospholipid and/or phospholipid-bindingproteins, which include, among others, lupus anticoagulants (LA), anti-cardiolipin antibodies (aCL) and anti-β2GPI antibodies (anti-β2GPI)[1,2]. aPL predispose to pregnancy morbidity and vascular thrombosis,which clinically define the antiphospholipid syndrome [3]. They can bedetected in a variety of situations, including auto-immune diseases suchas systemic lupus erythematosus (SLE), pre-surgical testing or blood do-nation in the general population, or during investigations for recurrentspontaneous abortion, fetal death or premature birth. They may also bedetected during infections but in that case are mostly transient.The exact prevalence of aPL in the general population aswell as in SLE pa-tients is currently debated due to previous aPL assay standardizationand threshold issues [4–8]. Based on a limited number of studies, theincidence of a first thrombotic event is estimated to range from 0 to 1for 100 patient-years in asymptomatic aPL+ individuals, from 2 to 4 for100 patient-years in aPL+ patients with SLE and up to 7 for 100patient-years in those with obstetrical APS associated with SLE [9–11].There is a general agreement on long term anticoagulation to preventrecurrences of thrombosis in patients with APS [12]. However, there islimited evidence regarding the adequate primary prevention of thrombo-sis in aPL carriers [13]. Aspirin has been shown effective for the primaryprevention of arterial thrombotic events in high-risk individuals in thegeneral population [14]. The use of low-dose aspirin has recently been ad-vocated in aPL+ patients at high-risk for thrombosis such as those withSLE or positive LA or persistently positive aCL at medium-high titers orin the presence of other thrombotic risk factors [9]. Additionally, lowdose aspirin may also prevent venous thrombosis as it has been recentlyreported in the secondary prevention of venous thromboembolism inthe general population [15]. Yet, the prescription of low dose aspirin toprevent the first thrombosis in aPL carriers remains very controversialbecause of the conflicting results among the previous studies [13].We therefore conducted a systematic review of the literature and meta-analysis to assess the efficacy of low-dose aspirin for the primary preven-tion of thrombosis in aPL+ patients.

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2. Methods

Thismeta-analysiswas performed in accordancewith the recommen-dations of the Meta-analysis of Observational Studies in Epidemiology(MOOSE) group [16].

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R2.1. Literature search

Two main investigators (L.A. & A.M.) searched EMBASE (1974–July2012), MEDLINE (1966–July 2012) and the Cochrane Database ofSystematic Reviews (The Cochrane Library, 2012, issue 7) for originalarticles without language restrictions. Search strategy combined freetext search, exploded MESH/EMTREE terms and all synonyms of thefollowing Medical Subject Headings terms: antiphospholipid antibodies,systemic lupus erythematosus, obstetrical antiphospholipid syndrome,lupus-like syndrome, lupus coagulation inhibitor, anticardiolipin antibod-ies, beta 2-Glycoprotein I, aspirin, and thrombosis (see the detailed searchstrategy in Appendix A). We also searched for additional articles fromthe reference list of relevant papers obtained from the electronic search.In addition, the gray literaturewas explored by hand searching the con-ference abstracts of the American College of Rheumatology and theEuropean League Against Rheumatism from January 1999 to July 2012.

2.2. Study selection

Selection criteria were determined before data collection. Inclusioncriteria included: (1) either observational and interventional studies;(2) reporting on primary prophylaxis (no prior thrombosis); (3) withcontinuous treatment with low-dose aspirin (4) in patients with aPL.For each study, a 2 × 2 table was constructed based on treatment withaspirin and occurrence of thrombosis. For the studies published byForastiero et al. [17], Hereng et al. [18], and Cervera et al. [19], the 2 × 2table was updated by personal communications of the authors. Studieswith intermittent prophylaxis (i.e., only in high risk periods)were exclud-ed [20]. Reviews, editorials, guidelines, letters, case reports, articles on dif-ferent outcomes and sub-studies of eligible studies were also excluded.Whenever disagreement occurred, it was resolved by discussion betweenthe 2 main investigators until a consensus was reached. A log of reasonsfor rejection of citations identified from the searches was kept.

2.3. Data extraction

Data were simultaneously and independently extracted by the 2main investigators. The recorded information for each selected study in-cluded: study design; patients' characteristics and underlying disease, ifavailable (asymptomatic aPL carrier, SLE, obstetrical APS); testmethodsand thresholds for defining a positive aPL according or not to interna-tional standards [5,21–23]; methods that objectively verified thethromboembolic events in accordance with Sapporo's (before 2006)

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[23] or Sydney's (after 2006) [5] consensus conference criteria; and thenumber of arterial or venous thrombotic events among individualstreated with aspirin versus those not treated.

2.4. Disease definitions

SLE was defined according to the 1997 ACR criteria for SLE [24] andAPS according to Sapporo's (before 2006) or Sydney's (after 2006)consensus conference criteria [5,23]. Asymptomatic aPL+ carrierswere defined as individuals with aPL without history of thrombosis orobstetrical APS or defined SLE.

2.5. Contact with authors and management of duplicate studies or patients

All authors of selected studieswere contacted by email to check and/or update the event counts recorded and asked to provide additionalinformation regarding the detailed number of arterial and venousthrombotic events; all but one responded. When we identified patientsthat had been included in multiple papers, the analysis was limited tothe study with the largest number of patients in order to avoid duplica-tions [25–28]. Because 10 duplicate patients were included in bothstudies by Pengo [29] and Ruffatti [25] we decided to include thesetwo studies in the meta-analysis, as excluding one of those wouldhave discarded an important number of unique patients. When it wasimpossible to extract data for a subgroup analysis (even after theauthors were contacted), the study was excluded.

2.6. Quality assessment

Themethodological quality of included articles was reviewed by the2 main investigators. Any information about authors, journals, and in-stitutions was deleted for this purpose. Studies were evaluated inde-pendently by means of an original scoring system adapted from themeta-analyses by Wahl et al. [30–32]. The quality assessment formencompassed 39 items distributed in 5 categories: clinical criteria (SLEpatients classified or not according to the American College of Rheuma-tology criteria, obstetrical APS classified or not according to Sapporo's orSidney's criteria); methods for outcome diagnosis (detailed descriptionof clinical, laboratory and imaging tests); laboratory assessment ofaPL (test methods and thresholds according or not to internationalstandards); modalities of aspirin treatment (daily dose mentioned ornot); quality of design (single-centre versus multicenter studies); ran-domized controlled trial versus prospective or retrospective cohortstudies, and confounders (adequate description of cardiovascular riskfactors, other thrombophilic disorders, co-prescription of chloroquineor hydroxychloroquine). We tested correlations (using Spearman's co-efficient) between study quality scores and study effect estimates(expressed as log (OR)) as a way to assess relationships betweenstudy quality and magnitude of effect estimate.

2.7. Cumulative meta-analyses

To assess the contribution of individual studies to the pooled estimate,we performed cumulative meta-analyses according to: (i) descendingquality score, therefore allowing examination of the impact of the studiesof lesser quality on the pooled estimate (for this analysis, study names areblinded but available from main author upon request); (ii) increasingdate of publication, to allow assessment of the changes in associationbetween exposure to aspirin and occurrence of thrombosis in patientsover time; and (iii) increasing study size to reveal how many patientsare needed before statistical significance is obtained.

2.8. Statistical analyses

In the primary analysis we considered the efficacy of aspirin for theprimary prevention of all thrombotic events (i.e., both arterial and


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venous) in aPL+ patients. Accordingly, we constructed 2 × 2 tables foreach outcome from each study. We used the odds ratio (OR) as the mea-sure of association in this meta-analysis and we obtained pooled-risk es-timates by using a random-effects model, according to the method ofDerSimonian and Laird (fixed-model effect was tested but not selectedbecause of study heterogeneity, data not shown). Publication biaswas ex-amined using a funnel plot and Egger's regression test [33]. Heterogeneity(Cochran's chi-2 and I2 tests) was considered statistically significant atp b 0.10 and I2 N 50%. Separate a priori subgroup analyses were plannedfor arterial versus venous thrombotic events, for prospective versus retro-spective studies, as well as for the different pathogenic backgrounds,when possible. Spearman's coefficient was used for testing correlations.The agreement between the two primary reviewers for quality scorewas measured using the intra-class correlation coefficient (ICC) withJMP 8 software (SAS Institute Inc., Cary, USA). Themeta-analysis was per-formed with the use of the software RevMan version 5.0 (The CochraneCollaboration, 2008, Copenhagen, Denmark).

3. Results

3.1. Literature search

Our literature search identified 1211 citations, of which 11 uniquestudies [17–19,25,27,29,34–37] were included in this meta-analysis(Fig. 1). The reasons for the exclusion of some articles after a full textreview [20,25,26,28,38–45] are shown in Fig. 1.

3.2. Publication bias

Visual examination of the funnel plot (Appendix B) only revealedminor asymmetry and Egger's test (p = 0.38) did not show anystatistical evidence for publication bias.

3.3. Selected studies

The characteristics of the 11 studies included in the meta-analysis[17–19,25,27,29,34–37] are shown in Table 1.

Included studies were 6 prospective [17,19,25,27,29,34] and 4 retro-spective [18,35–37] cohort studies and a single randomized controlledtrial [34]. The article published by Erkan et al. in 2007 [34] reports onthe results of both a prospective cohort study and a randomizedcontrolled trial (APLASA study), and therefore accounts for two studies.The publication period runs from 2001 to 2012. Sample sizes variedfrom 65 to 238 aPL+ patients for a total of 1208. Six studies weremulticentric [19,25,29,34,35]. All studies but one included SLE patients.Five studies excluded obstetrical APS. The length of follow-up rangedfrom 2.3 to 8.7 years. The percentage of female ranged from 68.1% to100%. The mean/median age at study entry varied from 29.3 to47.8 years. The presence of aCL, LA, and anti-β2GPI was assessed in11, 11 and five [17,25,27,29,37] studies, respectively. The number ofpatients lost to follow-up was reported in 6 studies [18,19,25,34,36].Confounding factors, such as cardiovascular risk factors andthrombophilic disorders were reported in seven [18,25,29,34,36,37] andthree [17,29,36] studies, respectively. The prescription of chloroquineand hydroxychloroquine was mentioned in 5 studies [18,27,34,37] butthe analysis of their independent effect on thrombosis rate was not per-formed by the authors. Only one trial monitored the compliance usingparticipants' self-report [34].

3.4. Assessment of methodological quality

The average quality score of included studies was 64 of 100, rangingfrom 51 to 80. Inter-observer reliability between the two main investi-gators for quality scoring was very good (ICC: 0.87, 95%CI: 0.58–0.96,p b 0.001). We found a significant correlation between quality scoresand log (OR) of primary studies (r = 0.74, p = 0.009).



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Fig. 1. Flow-chart for study selection.

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3.5. Risk of first thrombosis associated with aPL

Among the 1208 aPL+ patients from the 11 included studies, 601(49.8%) received prophylaxiswith aspirin. Forty-seven thrombotic events(7.8%) occurred in those receiving aspirin versus 92 events (15.2%) inthose who did not (p b 0.0001). Three out of eleven included studies(27%) reported a significant association between aspirin prophylaxisand the overall risk of first thrombosis. By pooling the 11 included studies(Fig. 2), we found an overall OR of 0.50 for the risk of first thrombosis inaPL+ patients treated with aspirin versus those who were not treated(95%CI: 0.27 to 0.93). We found no significant correlation between thepublication year and the risk of thrombosis among individual studies(r = −0.03, p = 0.93). We found significant but limited statisticalheterogeneity across studies (I2 = 46%, p = 0.05), as also suggested bythe visual inspection of the L'Abbé plot (Appendix C). Subgroup analysisaccording to the type of thrombotic event (Fig. 3) showed a protective

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Table 1Studies addressing primary prophylaxis of thrombosis with low dose aspirin in patients with a

Author, year, (Reference) Study type Numberenrolled

Population studied

Obstetrical APSb

number (%)Sn

Erkan 2001 [35] Retro 65 65 (100) NForastiero 2005 [17]h Pros 108 33 (30.6) 2Tarr 2007 [27] Pros 81 NA 8Erkan 2007 [34]h RCT 98 0 (0.0) 6

Erkan 2007 [34]h Pros 74 0 (0.0) 2

Hereng 2008 [18]h Retro 103 0 (0.0) 3Cervera 2009 [19]h Pros 121 121 (100) NTektonidou 2009 [37]h Retro 129 0 (0.0) 1Pengo 2011 [29]h Pros 104 0 (0.0) 1Ruffatti 2011 [26]h Pros 238 32 (13.4) 6Martinez-Zamora 2012 [36]h Retro 87 57 (65.5) 0

APS, antiphospholipid syndrome; SLE, systemic lupus erythematosus; Retro, retrospective cohora At study entry.b Including transient ischemic attack and catastrophic antiphospholipid syndrome.c Including pulmonary embolism.d For the group treated with aspirin.e For the group not treated with aspirin.f For obstetric APS.g For asymptomatic carrier.h Some data were reported through personal communications with the first author in 2011


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effect of aspirin when considering arterial (OR: 0.48 [95%CI: 0.28–0.82])but not venous (OR: 0.58 [95%CI: 0.32–1.06]) thrombosis separately. Fi-nally, we observed a significant decreased in the risk of first thrombosisamong aPL+ individuals treated with aspirin in the subgroup analysisconsidering only retrospective studies (OR: 0.23 [95%CI: 0.13–0.42]), butnot prospective studies (OR: 0.91 [95%CI: 0.52–1.59]) (Fig. 4).

3.6. Risk of first thrombosis according to pathogenic backgrounds

The underlying disease associated with the presence of aPL may in-fluence the risk of thrombosis and explain heterogeneity among studies.Subgroup analysis according to the pathogenic background revealed asignificant protective effect of aspirin for asymptomatic aPL+ patients(OR: 0.50 [0.25–0.99]), for those with systemic lupus erythematosus(SLE) (OR: 0.55 [0.31–0.98]), as well as for those with obstetricalantiphospholipid syndrome (APS) (OR: 0.25 [0.10–0.62]) (Fig. 5).

ntiphospholipid antibodies.

Agea

yr, mean ± SDor median (range)

Patients treatedwith aspirinnumber (%)

Follow-up duration yr,mean ± SD or median(range)

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umber (%)

A 29.3 ± 5 31 (47.7) 8.1 ± 3.50 (18.5) 42 (3–85) 31 (28.7) 3.8 (0.3–10)1 (100) 32.6 ± 11.0 52 (64.2) 5.04 (65.3) 43.1 ± 12.8d

42.7 ± 14.0e48 (49.0) 2.30 ± 0.95

6 (35.1) 47.8 ± 14.8d

46.2 ± 14.1e61 (82.4) 2.46 ± 0.76

7 (35.9) 41.7 ± 16.7 75 (72.8) 5.3 ± 2.1A 40 (0–82) 50 (41.3) 5.029 (100) 31.0 ± 13 72 (55.8) 8.74 (13.5) 45 ± 15.0 37 (35.6) 4.59 (29.0) 40.9 ± 11.1 123 (51.7) 2.92 ± 1.0(0.0) 32.8 ± 3.5f

31.9 ± 5.6g21 (24.1) 7.3 ± 3.5f 8.2 ± 4.3g

t study; RCT, randomized controlled trial; Pros, prospective cohort study;NA, not available.

or 2012, except for Ref. [18] for which data were provided by Dr Marc Lambert.



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Fig. 2. Forest plot for main analysis.


3.7. Cumulative meta-analyses

Additionally, we performed cumulativemeta-analysis (i.e., adding thestudies one at a time according to a specified criterion [e.g., date of publi-cation, size or quality] and updating the OR as each new study is added),as a manner to assess the influence of this criterion on the overall risk.When arranged by ascending publication date, we found that the riskestimate of first thrombosis was stable from the year 2009 (Appendix D,panel A). When ordered by increasing study size, we found that the im-pact of the largest studies was minor when the total number of includedpatients reached 500 (Appendix D, panel B). The cumulative meta-analysis of studies arranged by descending quality scores demonstrateda decreasing pooled OR for the risk of first thrombosis, as lower-qualityscore studies were successively added to the higher-quality score studies(Appendix D, panel C). Sensitivity analysis performed by including the50% of studies with the highest methodological quality did not demon-strate a protective effect of aspirin (OR: 0.92 [95%CI: 0.50–1.69]).

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Fig. 3. Forest plot for artery versu


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3.8. Hemorrhagic risk

No major bleeding occurred in the 4 studies for which hemor-rhagic events were reported [18,34,37]. Additionally, three patientstreated with aspirin experienced minor bleeding in the APLASAstudy [34].

4. Discussion

Our meta-analysis of 11 studies including 1208 aPL+ patients and139 thrombotic events revealed that aPL+ patients treated with longterm low-dose aspirin have a 50% risk reduction for the occurrence ofa first thrombotic event than those who did not receive this treatment.Additionally, subgroup analysis according to the pathogenic back-grounds revealed that the risk reduction was significant among asymp-tomatic aPL+ individuals as well as among aPL+ patients with SLE orobstetrical APS.

s venous subgroup analysis.



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Fig. 4. Forest plot for subgroup analysis according to study design.


Up to now, a single randomized, double-blind, placebo-controlledclinical trial, namely the Antiphospholipid Antibody Acetylsalicylic Acid(APLASA) study [34] addressed our question of interest. This study,

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Fig. 5. Forest plot for subgroup analysis acc


Pwhich showed no protective effect of aspirin, was terminated earlybecause no thrombotic event occurred in the placebo group, which wasattributed to the relatively short follow-up duration, the good control of

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additional vascular risk factors and the inclusion of a significant propor-tion of individualswith a low risk aPL profile [9]. Additionally, 10 observa-tional studies [17–19,25,27,29,35–37] also addressed our question ofinterest by examining asymptomatic aPL+ individuals, patients withSLE and aPL, or patients with obstetrical APS. Three of these studiesshowed a significant decrease in the risk of first thrombosis amongpatients treated with aspirin [18,35,37] while a non-significant decreasewas observed in five studies [19,25,28,29,34,36] and a non-significantincrease in two studies [17,34] (Figs. 3 & 4).

As expected, significant statistical heterogeneitywasobserved acrossincluded studies. We therefore used a random-effects model and hadplanned a priori subgroup analyses to investigate the sources of this het-erogeneity. First, we grouped studies according to their design. Wefound that the risk of first thrombosis was significantly decreasedwhen considering retrospective but not prospective studies (Fig. 4),which can have different meanings. On the one hand, retrospectivestudies are more susceptible to biases than prospective ones. Therefore,selection or measurement biases may account for the difference ob-served between study designs. In the other hand, aPL may be transient.We therefore cannot exclude that the status of aPLmay have changed atsome time for the prospective studies, even though repeated aPL mea-surementswere performed inmost of these studies. Importantly,we ob-served no significant publication bias, but we found a strong correlationbetween the methodological quality scores and the risk estimates of in-cluded studies. Additionally, we did not observe a significant protectiveeffect of low-dose aspirin in the cumulative meta-analysis according toquality scores and the sensitivity analysis, when considering only stud-ies with the best methodology. Importantly, the methodological qualityscores were assessed based on themethodology reported in the articles.Therefore, the quality scores may have been underestimated for somestudies as the authors may not have fully reported on the methodologythat was used. Altogether, these results strongly suggest that additionalstudies with better methodology are urgently needed.

Another important feature is that the laboratory methods employedfor the measurement of aPL have been heterogeneous across includedstudies, and enrolled subjects have been classified according to updatinglaboratory criteria. Additionally, concomitant pro- and anti-thromboticrisk factors have been infrequently taken into account across these stud-ies. For instance, hypertension was found to be an independent predictorof thrombosis in the retrospective study by Ruffatti [25], whereas arterialevents have been associated with the coexistence of metabolic syndrome[46] or smoking and oral contraceptives in primary APS [47]. On the con-trary, hydroxychloroquine usemay be protective for thrombosis in SLE asit is shown in several observational studies [40,48]. ORs provided in thismeta-analysis are generally unadjusted for other thrombotic risk factorsas well as for potential protective factors.

Patients had heterogeneous pathogenic backgrounds, includingasymptomatic aPL, SLE, and obstetrical APS. Importantly, subgroupanalyses according to these disease subsets revealed a significant pro-tective effect of aspirin across those three pathogenic backgrounds(Fig. 5). While this meta-analysis strengthens the recently publishedrecommendations of the 13th aPL task force about the use of low-doseaspirin for the primary prevention of thrombosis in SLE patients andaPL+ individuals, one should keep in mind that these recommenda-tions were rated weak recommendations by the task-force itself, be-cause these were only based on low- to moderate-quality evidence [9].

Recommendations from the 13th aPL task force [9] have alsohighlighted the importance of considering both the risks for recurrenceand the risk for major bleeding. Because bleeding events were scarcelyreported in included studies ourmeta-analysis could not formally assessthe benefit/risk ratio of aspirin, while the latter carries a small, but non-insignificant risk of bleeding [49]. Yet, nomajor bleeding occurred in thefour studies for which these data were reported, andminor bleeding oc-curred only in 3 patients treated with aspirin during the APLASA study[34]. Studying primary prevention trials with aspirin and the risk ofbleeding, aspirin prophylaxis has been proposed only for patients who


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are at high risk for future thrombosis (e.g., N3% per year, concomitantcardiovascular disease risk factors) [50,51]. Regarding this issue, the13th aPL task force recommends that asymptomatic aPL carriers shouldbe divided in patients with high risk profile (LA positivity or triple pos-itivity [LA + aCL + anti-β2-GPI] or isolated persistently positive aCLat medium-high titers) and patients with low risk profile (isolated, inter-mittently positive aCL or anti-β2-GPI at low-medium titers) [9], but wewere not able to describe which proportion of high risk versus low riskasymptomatic carriers was studied in the papers included in the meta-analysis. Regarding the hemorrhagic risk of aspirin in SLE, Wahl et al.have performed anumerical simulation showing that prophylactic aspirincould be effective in reducing the number of thrombotic events comparedto inducing bleeding episodes [44]. A similar analysis remains to be con-ducted in obstetrical APS, as the benefit/risk ratio of continuous adminis-tration of low dose aspirin remains unknown in this specific population.

Finally we would like to balance the conclusion of this meta-analysis,as limited data suggest that intermittent prophylaxis with aspirin or hep-arinmay be effective in some cases and should therefore be formally eval-uated. In theAPLASA study [34], thrombotic eventsmostly occurredwhenhigh-risk aPL profile patients were exposed to additional risk factors forthrombosis, while receiving low dose aspirin. In a 3-year prospectivestudy [20] of 178 asymptomatic aPL carriers receiving low molecularweight heparin or aspirin only during high risk periods, Giron-Gonzaleset al. recorded no episode of thrombosis. Together, these observations ad-vocate the need for a formal evaluation of an intermittent prophylaxiswith aspirin or heparin only during high risk periods, in asymptomaticaPL carriers.

Taking into account all published studies irrespective of the studydesign, we did observe a decreased risk for a first thrombotic eventamong individuals treated with low-dose aspirin. However, no sig-nificant risk reductionwas observedwhen considering only prospec-tive studies or those with the best methodological quality. Wetherefore believe that high-quality randomized controlled trials,stratifying aPL+ patients according to their thrombotic risk, takinginto account additional pro-thrombotic and protective confoundingfactors, and comparing continuous and intermittent prophylaxisduring high-risk periods are needed to derive further high-gradeevidence-based guidelines.

Take-home messages

• The use of low dose aspirin to prevent a first thrombosis in patientswith antiphospholipid antibodies (aPL) remains controversial.

• Our meta-analysis of 11 primary studies including a total of 1208patients compared the occurrence of a first thrombotic event inaPL patients with versus without low-dose aspirin.

• We observed a significant decrease in the risk of arterial but notvenous thrombosis in aPL patients treated with low-dose aspirin.

• The risk of first thrombotic event was significantly decreased bylow dose aspirin among asymptomatic aPL individuals, patientswith systemic lupus or obstetrical antiphospholipid syndrome.

• No significant risk reduction was observed when considering onlyprospective studies or those with the best methodological quality.

Acknowledgments

None.

Competing interests

No author has any conflict of interest to disclose.

Contributions

Laurent ARNAUD, Alexis MATHIAN, Stephane ZUILY, Denis WAHL &Zahir AMOURA designed the research. Amelia RUFFATTI, Doruk ERKAN,



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Maria TEKTONIDOU, Ricard CERVERA, Ricardo FORASTIERO, VittorioPENGO, Marc LAMBERT, Maria Angeles MARTINEZ-ZAMORA, JuanBALASCH, Laurent ARNAUD, Alexis MATHIAN, Stephane ZUILY, DenisWAHL & Zahir AMOURA performed the research. Laurent ARNAUD,Alexis MATHIAN, Stephane ZUILY, Denis WAHL & Zahir AMOURA ana-lyzed the data. Laurent ARNAUD, Alexis MATHIAN, Doruk ERKAN,

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Maria TEKTONIDOU, Denis WAHL & Zahir AMOURA wrote the paper.All authors approved the final manuscript.

Funding

None.

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Appendix A

Search strategyTwo main investigators (L.A. & A.M.) searched EMBASE (1974–

July 2012), MEDLINE (1966–July 2012) and the Cochrane Databaseof Systematic Reviews (The Cochrane Library, 2012, issue 7) for orig-inal articles without language restrictions. Search strategy combinedfree text search, exploded MESH/EMTREE terms and all synonyms ofthe followingMedical Subject Headings terms: antiphospholipid antibod-ies, systemic lupus erythematosus, obstetrical antiphospholipid syn-drome, lupus-like syndrome, lupus coagulation inhibitor, anticardiolipinantibodies, beta 2-Glycoprotein I, aspirin, and thrombosis. The spe-cific search strategy for PubMed was: ((“Lupus Erythematosus,Systemic”[Mesh]) OR (“Lupus”[all fields]) OR (“AntiphospholipidSyndrome”[Mesh]) OR (“Antiphospholipid Syndrome”[all fields])OR (“lupus-like”[all fields]) OR (“beta 2-Glycoprotein I”[Mesh]) OR(“Antibodies, Antiphospholipid”[Mesh]) OR (“Antiphospholipid”[all

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fields])) AND ((“thrombosis”[all fields]) OR (“thrombosis”[Mesh]))AND ((“aspirin”[Mesh]) OR (“aspirin”[all fields])). The specific searchstrategy for Embase was: (((‘systemic lupus erythematosus’/exp OR ‘sys-temic lupus erythematosus’) OR (‘antiphospholipid syndrome’/exp OR‘antiphospholipid syndrome’) OR (‘lupus like syndrome’/exp OR ‘lupuslike syndrome’) OR (‘beta2 glycoprotein 1 antibody’/exp OR ‘beta2 glyco-protein 1 antibody’) OR (‘phospholipid antibody’/exp OR ‘phospholipidantibody’)) AND (‘thrombosis’/exp OR ‘thrombosis’) AND ((‘aspirin’/expOR ‘aspirin’) OR (‘acetylsalicylic acid’/exp OR ‘acetylsalicylic acid’))).

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Funnel-Plot for all studies included in meta-analysisVisual inspection of the funnel-plot for all studies included in the

meta-analysis does not suggest significant publication bias. The dashedline shows the pooled estimate of all included studies.

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Appendix C

L'Abbé Plot of all studies included in meta-analysisThe observed risk (proportion) for first thrombotic events in the as-

pirin group is plotted against the observed risk in the control group.

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Visual inspection of the L'Abbé plot suggests moderate heterogeneitybetween included studied. Circle size represents study sample size.Studies located to the right of the diagonal line (OR = 1.0) suggest aprotective effect of aspirin. The dotted line represents the estimatedoverall aspirin treatment effect (OR = 0.50).

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Appendix D

Cumulative meta-analyses according to year of publication (A), study size (B) and methodological quality (C).

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Efficacy of aspirin for the primary prevention of thrombosis in patients with antiphospholipid antibodies: An international and collaborative meta-analysis