Arterial Thrombosis in Patients with Antiphospholipid

Arterial Thrombosis in Patients with AntiphospholipidSyndrome: A Review and Meta-AnalysisJesus Aibar Q1Q1

Q1, MD, PhD1,2 Sam Schulman, MD, PhD2,3

1Department of Internal Medicine, Hospital Clínic, IDIBAPS,University of Barcelona, Barcelona, Spain

2Department of Medicine, Thrombosis and Atherosclerosis ResearchInstitute, McMaster University, Hamilton, Ontario, Canada

3Department of Obstetrics and Gynecology, I.M. Sechenov FirstMoscow State Medical University, Moscow, Russia

Semin Thromb Hemost 2021;00:1–15.

Address for correspondence Sam Schulman, MD, PhD, ThrombosisService, HHS-General Hospital, 237 Barton Street East, Hamilton ON,L8L 2� 2, Canada (e-mail: [email protected]).

Antiphospholipid syndrome (APS) is an acquired autoimmunedisease that is characterized by the presence of recurrentthrombotic events (venous, arterial, and/or microvascular)and/or pregnancy morbidity. The classification criteria forresearch studies also require at least one laboratory criterion—lupus anticoagulant (LA; also called nonspecific inhibitor),cardiolipin (aCL) antibodies immunoglobulin G (IgG) and/or

IgM isotype, and/or β2-glycoprotein I antibodies (aβ2GPI) IgGand/or IgM isotype, with confirmation 12 weeks after theinitial sample.1 APS is classified according to the 2006 Sydneyinternational consensus criteria,1 which were a revision of theSapporo criteria.2 APS occurs as a primary condition or can beassociatedwithsystemic lupus erythematosus (SLE)oranotherautoimmune disease.

Keywords

► antiphospholipidsyndrome

► arterial thrombosis► stroke► recurrence► bleeding

Abstract There is a scarcity of high-quality randomized controlled trials (RCTs) comparingantithrombotic regimens for secondary prevention of arterial thrombosis (AT) inantiphospholipid syndrome (APS). We reviewed different antithrombotic regimensused for this purpose.We searched for studies onmanagement of AT in APS on PubMedand Web of Science. Eleven studies (5 RCTs, 3 prospective, and 3 retrospective cohortstudies) comparing different regimens and reporting outcomes specifically for patientswith index AT events were identified. Treatments were vitamin K antagonists (VKA; 9studies), non-VKA oral anticoagulant (NOAC; 3 studies), single antiplatelet therapy(SAPT; 7 studies), dual antiplatelet therapy (DAPT; 2 studies), and VKA combined withSAPT (4 studies). We performed a meta-analysis for the outcomes: recurrent AT, any(arterial or venous) recurrent thromboembolism, and major bleeding. Recurrent ATwas reduced with VKA plus SAPT versus VKA (risk ratio [RR]: 0.43; 95% confidenceinterval [CI]: 0.22–0.85) and with DAPT versus SAPT (RR: 0.29; 95% CI: 0.09–0.99). Anyrecurrent 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). Therewere no significant differences between other treatments for thromboembolism andfor none of the comparisons regarding major bleeding. In a sensitivity analysis,excluding low-quality studies, VKA was more effective than NOAC to prevent recurrentAT (RR: 0.25; 95% CI: 0.07–0.93). Combined antithrombotic therapy might be moreeffective than single agents as secondary prophylaxis in APSwith AT, and does not seemto compromise with safety, but the quality of evidence is generally low. NOACs shouldbe avoided for patients with APS and AT.

Issue Theme Recent Advances inThrombosis and Hemostasis—Part VII;Guest Editor: Sam Schulman, MD, PhD.

© 2021. Thieme. All rights reserved.Thieme Medical Publishers, Inc.,333 Seventh Avenue, 18th Floor,New York, NY 10001, USA

DOI https://doi.org/10.1055/s-0041-1725057.ISSN 0094-6176.

1

mailto:[email protected]

In a recent population-based study of patients with APS inthe United States, the overall annual incidence of APS was 2.1per 100,000 population (age- and sex-adjusted), and the prev-alence was 50 per 100,000 population.3 The incidence wasthe same amongmales and females. However, in a nationwidepopulation-based study performed inKorea, the incidence ratewas 0.75 per 100,000 person-years (95% confidence interval[CI]: 0.73–0.78); incidence in males: 0.59 (95% CI: 0.56–0.62)and females: 0.91 (95% CI: 0.87–0.96). Moreover, the incidencerates between males and females exhibited different patterns.Males had a peak incidence rate at 70 to 79 years of age, andfemalespresented incidencepeaksat 30 to39years andat70to79 years of age.4 Venous thromboembolism was the mostcommon clinical manifestation in the above-mentioned epi-demiological study,3,4 but serious arterial events were notuncommon, including stroke (35%) and peripheral arterialthrombosis (8%).

Several studies have evaluated the incidence of recurrentarterial and venous thrombosis after a first event in patientswith APS. There is evidence that after a first arterial or venousthrombosis, patients with APS have a higher risk of a newthrombosis than patients without APS.5 Moreover, patientswith APS and a first arterial thrombosis have a higher risk ofrecurrence than those with a first venous thrombosis.6–8

Furthermore, the risk of venous or arterial thrombosis isincreased in patients with positive LA, with medium or highlevels of aCL of the IgG or IgM type, and with double or triplepositivity of antiphospholipid antibodies (aPLs).9–14

Treatment of the first venous thrombosis in patients withdefinite APS should, according to different guidelines, bewith avitamin K antagonist (VKA) with a therapeutic range of inter-national normalized ratio (INR) of 2.0 to 3.0.15,16 The treatmentof choice for afirst arterial thrombosis is still amatter ofdebate.According to the European League Against Rheumatism(EULAR) recommendations for themanagementofAPSinadultspublished in 20196 and 2012 Guidelines on the Investigationand Management of APS,16 in patients with APS and a firstarterial thrombosis (excluding ischemic stroke) thetreatment iswith VKAwith a therapeutic range of INR 2 to 3. Unfortunately,randomized controlled trials (RCTs) of high quality in APSwitharterial thrombosis, comparing high- or moderate-intensityanticoagulation with VKA versus antiplatelet agents or acombination of both are lacking.15,17,18 In patients with strokeor transient ischemic attack (TIA), there is no evidence support-ingone treatment (VKAvs. antiplatelet agents vs. a combinationof both) over the other.17 Experts recommend therapy witheither antiplatelet agents or VKA (INR range: 2–3).17 The aimofthis review is to specifically analyze studies including patientswith definite APSwith recurrent arterial thrombosis to try andidentify the best treatment options for secondary prevention ofarterial thrombosis.We therefore performeda literature searchand a meta-analysis of the study-level data.

Methods

Search StrategyWe searched PubMed, the Cochrane database, and the Web ofScience, including all records from 1965 through January 31,

2020.MeSHand keyword termsusedwere APS, arterial throm-bosis, stroke, and recurrent thrombosis. Only articles publishedin English were considered for the review. We reviewed thetitles and abstracts of all the articles obtained and includedstudies thatdescribed the incidenceof recurrentarterial throm-bosis in patients with APS, who were over 18 years of age. Wealso reviewed the bibliographic references of all systematicreviews obtained to identify additional studies related toour search.

Inclusion and Exclusion CriteriaWe included full papers as well as abstracts, as long as therequired data were available. RCTs and prospective or retro-spective cohort studies comparing different oral antithrom-botic treatment regimens were eligible. The study populationhad to include patientswith arterial thrombosis but could alsoconsist of patients with other clinical manifestations providedthat the outcomes were reported separately for those witharterial thrombosis. Studies comparing a single treatmentregimen with historical data from other publications onanother regimen were excluded.

Treatment RegimensThe antiplatelet agents were aspirin (most of the cases),ticlopidine, clopidogrel, cilostazol, dipyridamole, beraprostsodium, sarpogrelate hydrochloride, and dilazep dihydrochlor-ide. Dual antiplatelet therapy (DAPT) was any combination ofthose. In the studies comparing VKAwith other regimens, thetherapeutic rangewas INR 2.0 to 3.0 with the exception for theAntiphospholipid Antibodies and Stroke Study (APASS), whichused INR1.4 to 2.8, and the studybyYamazaki et al,whichusedINR 2.0 to 2.5.19,20 Non-VKA oral anticoagulant (NOAC) wasmainly rivaroxaban, with the exception of one study, in whichalso apixaban and dabigatran were used.21

Outcome MeasuresThe outcomes were recurrent arterial thrombosis, anythromboembolism (arterial or venous thromboembolism),as well as major bleeding as defined by the original authors.Arterial events included stroke, TIA, myocardial infarction,peripheral arterial thromboembolism, systemic visceralarterial embolism, and central retinal artery occlusion.

Quality Assessment of StudiesFor the assessment of the quality of studies, we used theJadad score for RCTs,22 and the Newcastle–Ottawa Scale forcohort studies.23

Statistical AnalysisWe performed the analysis based on intention-to-treat andcalculated risk ratio (RR) and 95% CI. Meta-analysis wasperformed, using the random-effects model, when therewere at least two eligible studies comparing the same pairof treatment regimens and reporting the same type ofoutcome. The reason for this model was that we expected ahigh degree of heterogeneity. We quantified heterogeneityusing I2, where I2>50% corresponds to high and I2¼25 to 50%corresponds to moderate heterogeneity. Due to the small

Seminars in Thrombosis & Hemostasis Vol. 00 No. 0/2021 © 2021. Thieme. All rights reserved.

Arterial Thrombosis in Antiphospholipid Syndrome Aibar, Schulman2

number of studies for each comparison, it was not meaningfulto test for publication bias, using funnel plots. All tests weretwo-sided and we considered a p-value of <0.05 statisticallysignificant. For the meta-analysis, we used Review Manager(RevMan), version 5.3 (Copenhagen; The Nordic CochraneCentre, The Cochrane Collaboration, 2014).

Results

According to our initial search criteria, 2,763 studies wereobtained, of which 2,690 were excluded after reading the titleand abstract. Of the remaining 73 articles, 62 did not fulfill ourinclusion criteria after a complete text review, so that only 11studies could be incorporated in our review18–21,24–30 (seeflow diagram;►Fig. 1). One of the studies was identified fromscreening of references.20 ►Table 1 shows the characteristicsof the includedstudies.Of these, threewereprospectivecohortstudies, three retrospective cohort studies, and the remainingfive were RCTs. The total number of patients with APS andarterial thrombosis was 1,278, ranging between 20 and 720 inthe 11 studies, of which 4 also had included cases that hadindex venous thromboembolism. Regarding studies with

arterial index events, 5 studies included only patients withstroke,19,20,25–27 2 studies included patients with any arterialthrombosis (stroke,myocardial infarction, arterial ischemia inlegs, central retinal artery occlusion, and other acute arterialthrombosis [renal, splanchnic, etc.],with strokebeing themostcommon[72and90%of the cases]),18,28and4 studies includedpatientswith arterial andvenous thrombosis orboth.21,24,30,31

Threestudies comparedmore than twotreatment regimens.Of the 11 articles included in the study, 3 studies comparedsingle antiplatelet therapy (SAPT) with VKA, 1 compared VKAwith a target INR 2 to 3 versus VKA with a target INR 3 to 4,1 comparedSAPTversus combined therapywithVKAandSAPT,1 compared SAPT versus VKA versus combined therapy withVKA and SAPT, 1 evaluated SAPTversus DAPTversus combinedtherapy with SAPT and VKA, 1 compared SAPT versus VKAversus DAPTversus combined therapywithVKA and SAPT, and3 studies compared a NOAC with VKA.

The mean age of the patients included was in 10 of thestudies less than 50 years. Most of the studies had morefemales than males included, with a total mean of 57%females. Five studies provided information on proportionof patients that were triple positive (LAþ aCLþ aβ2GPI),

Fig. 1 Flow diagram of search results.


Arterial Thrombosis in Antiphospholipid Syndrome Aibar, Schulman 3

Table

1Cha

racteristics

oftheinclud

edstud

ies

Stud

y(first

author,ye

ar)

APS

definition

N (num

ber

ofce

nters)

Design

Indicationfor

trea

tmen

tAge,

yFe

males,

%Triple

pos

itive,

%Prim

aryAPS

/seco

ndary

toSL

E,%/%

Trea

tmen

tsFo

llow-up

years

Crowther,20

0324

Sydn

eycriteria

114(13)

RCT

Arterialo

rve

nous

thrombo

sis

4260

Unk

nown

86/14

VKAINR2–

3vs.

VKAINR3–

42.7

Levine

,20

0419

Stroke

þaP

Lpo

sitive

720(44)

Prospe

ctive

withinRC

TStroke

6242

Unk

nown

Noda

taVKAvs.S

APT

2

Yamazak

i,20

0920

Noda

ta60

(Noda

ta)

RCT

Stroke

Noda

taNoda

taNoda

taNoda

taSA

PTvs.D

APT

vs.

VKAplus

SAPT

3

Oku

ma,

2009

25Sydn

eycriteria

20(1)

RCT

Stroke

4850

Noda

ta65

/35

SAPT

vs.V

KA

plus

SAPT

3.9(2)

Arauz

,201

126

Sapp

oro

criteria

92(1)

Prospe

ctive

coho

rtstud

yStroke

3471

Noda

ta10

0/0

SAPT

vs.V

KA

4.5

Jack

son,

2017

18Sydn

eycriteria

139(26)

Retrospec

tive

coho

rtstud

yAny

arterial

thrombo

sis

4366

3666

/34(any

autoim

mun

e)SA

PTvs.V

KAvs.

VKAplus

SAPT

4.24

Pyo,

2017

27Sydn

eycriteria

46(1)

Retrospec

tive

coho

rtstud

yStroke

4461

3758

/20(2%Be

hcet)

SAPT

vs.V

KA

4.3

Ohn

ishi,2

0192

8Sydn

eycriteria

90(1)

Retrospec

tive

coho

rtstud

yAny

arterial

thrombo

sis

4573

Noda

ta41

/59

SAPT

vs.V

KAvs.

VKAplus

SAPT

vs.D

APT

8

Peng

o,20

1829

Sydn

eycriteria

120(14)

RCT

Arterialo

rve

nous

thrombo

sis

ormicrothrombo

sis

4664

100

59/21(20%

othe

rau

toim

mun

e)Rivarox

aban

vs.V

KA

1.5

Ordi-R

os,20

1930

Sydn

eycriteria

190(6)

RCT

Arterialo

rve

nous

thrombo

sis

4964

6169

/31

Rivarox

aban

vs.V

KA

3

Malec

,20

2021

Sydn

eycriteria

176(1)

Prospe

ctive

coho

rtstud

yArterialo

rve

nous

thrombo

sis

4483

26Noda

taNOACvs.VKA

4.3

Abbrev

iation

s:APS

,antipho

spho

lipid

synd

rome;

DAPT

,dua

lantiplateletthe

rapy

;INR,

internationa

lnormalized

ratio;N

OAC,n

on-VKAoralan

tico

agulan

t;RC

T,rand

omized

controlle

dtrial;SA

PT,singlean

tiplatelet

therap

y;SLE,

system

iclupu

serythe

matos

us;VKA,vitamin

Kan

tago

nist.



ranging from 26 to 100%. The proportion of patients withprimary APS ranged from 41 to 84% in the seven studies thatcontained this information.

Quality of the StudiesWe assessed two of thefive RCTs as having a low quality withonly 1 point on the Jadad scale (►Fig. 2).20,25 For the sixcohort studies there was generally a lack of accounting forpatients lost from follow-up and poor comparability of thecharacteristics of different treatment groups without anyattempt to adjust for the differences (►Fig. 3). In APASS, theCox analysis adjusted for differences only in comparisonsbetween aPL-positive and aPL-negative patients but notbetween patients treated with VKA or aspirin.19 Thedocumentation on the outcome of interest compared withat inception was deficient, either because some recurrentevents were only based on clinical history,18 or lack ofdescription how initial events28 or recurrent events wereascertained.27 Thus, overall, the majority of the studies wereof low to moderate quality, with the exception for the study

comparing standard versus high-intensity VKA,24 and two ofthree studies comparing NOAC with VKA.29,30

Thrombotic OutcomesThe thrombotic outcomes per study and treatment group areshown in ►Table 2. The rate of recurrent arterial thrombosisranged from 0 to 72.7%, and the annualized rate ranged from0 to 18.6%/year with a mean of 4.0%/year. In 11 study armsusing a single antithrombotic agent, the mean annualizedrate of AT was 4.8%/year (range: 0–18.6) compared with amean of 2.3%/year (range: 0–5.6) in five study arms withcombined antithrombotic agents, and the weighted meanswere 3.8 versus 2.0%/year.

There was a significant reduction of recurrent arterialthrombosis with VKA plus SAPT versus VKA (RR: 0.43; 95%CI: 0.22–0.85) in the only study that had this comparison andreported arterial outcomes separately (►Fig. 4).28 There wasalso a significant reduction of arterial thrombosis with DAPTversus SAPT (RR: 0.29; 95% CI: 0.09–0.99) in two studieswithlow heterogeneity (I2¼0%).20,28

Fig. 3 Quality assessment of the Q2Q2Q2 included studies according to the Newcastle–Ottawa Scale.

Fig. 2 Jadad scores of the included randomized controlled trials.



Table

2Initialthrom

boticev

ents

andthrombo

ticev

ents

during

follo

w-up,acco

rdingto

trea

tmen

tregimen

Stud

y(first

author,ye

ar)

NTo

talnum

ber

pertrea

tmen

tarm

(N)an

dnum

ber(%

)with

initialarterial

even

tPa

tien

tswitharterial

index

even

t(N

)an

dthrombo

ticev

ents,n(%

),during

follo

w-up

Crowther,20

0324

114

VKAINR3–

4(N

¼56

)14

(25%

)VKAINR2–

3(N

¼58

)13

(22.4%

)VKAINR3–

4(N

¼14

)1(7.1%)arterialþ2(14.3%

)ve

nous

VKAINR2–

3(N

¼13

)1(7.7%)arterialþ0ve

nous

Levine

,20

0419

720

SAPT

(N¼35

9)35

9(100

%)

VKA(N

¼36

1)36

1(100

%)

SAPT

(N¼35

9)80

(22.3%

)arterial

orve

nous

VKA(N

¼36

1)94

(26%

)arterial

orve

nous

Yamazak

i,20

0920

60SA

PT(N

¼20

)20

(100

%)

DAPT

(N¼20

)20

(100

%)

VKAþSA

PT(N

¼20

)20

(100

%)

SAPT

(N¼20

)3(15%

)arterial

DAPT

(N¼20

)0(0%)

VKAþSA

PT(N

¼20

)0(0%)

Oku

ma,

2009

2520

SAPT

(N¼11

)11

(100

%)

VKAþSA

PT(N

¼9)

9(100

%)

SAPT

(N¼11

)8(72.7%

)arterialþ0ve

nous

VKAþSA

PT(N

¼9)

2(22.2%

)arterialþ0ve

nous

Arauz

,201

126

92SA

PT(N

¼38

)38

(100

%)

VKA(N

¼54

)54

(100

%)

SAPT

(N¼38

)0

VKA(N

¼54

)8(14.8%

)arterialþ0ve

nous

Jack

son,

2017

1813

9SA

PT(N

¼43

)43

(100

%)

VKA(N

¼38

)38

(100

%)

VKAþSA

PT(N

¼58

)58

(100

%)

SAPT

(N¼43

)16

(37.2%

)arterial

orve

nous

VKA(N

¼38

)9(23.7%

)arterial

orve

nous

VKAþSA

PT(N

¼58

)4(6.9%)arterial

orve

nous

Pyo,

2017

2746

SAPT

(N¼22

)22

(100

%)

VKA(N

¼24

)24

(100

%)

SAPT

(N¼22

)6(27.3%

)arterial

orve

nous

VKA(N

¼24

)8(33.3%

)arterial

orve

nous

Ohn

ishi,2

0192

890

SAPT

(N¼41

)41

(100

%)

VKA

(N¼13

)13

(100

%)

VKAþSA

PT(N

¼21

)21

(100

%)

DAPT

(N¼15

)15

(100

%)

SAPT

(N¼41

)16

(39%

)arterialþ

2(4.9%)ve

nous

VKA(N

¼13

)10

(77%

)arterialþ

1(7.7%)ve

nous

VKAþSA

PT(N

¼21

)7(33.3%

)arterialþ

1(4.8%)ve

nous

DAPT

(N¼15

)2(13.3%

)arterialþ

1(6.7%)ve

nous

Peng

o,20

1829

120

NOAC(N

¼59

)21

(35.6%

)VKA(N

¼61

)22

(36.2%

)NOAC(N

¼21

)4(19%

)arterialþ0ve

nous

VKA(N

¼22

)0arterialþ0ve

nous

Ordi-R

os,20

1930

190

NOAC(N

¼95

)37

(39%

)VKA(N

¼95

)34

(35.8%

)NOAC(N

¼37

)7(18.9%

)arterialþ1(2.7%)ve

nous

VKA(N

¼34

)2(5.9%)arterialþ1(2.9%)ve

nous

Malec

,20

2021

176

NOAC(N

¼82

)22

(26.8%

)VKA(N

¼94

)20

(21.27

%)

NOACs(N

¼22

)2(9%)arterialþ1(4.5%)ve

nous

VKA(N

¼20

)2(10%

)arterialþ2(10%

)ve

nous

Abbrev

iation

s:DAPT

,du

alan

tiplatelettherap

y;INR,internationa

lnormalized

ratio;NOAC,no

n-VKAoral

antico

agulan

t;SA

PT,sing

lean

tiplatelettherap

y;VKA,vitamin

Kan

tago

nist.



Fig. 4 Forest plots of arterial thrombosis. Comparisons between single antiplatelet therapy (SAPT) versus vitamin K antagonist (VKA) (A), dualantiplatelet therapy (DAPT) versus SAPT (B), VKA plus SAPT versus SAPT (C), VKA plus SAPT versus VKA (D), VKA international normalized ratio(INR) 2–3 versus VKA INR 3–4 (E), DAPT versus VKA plus SAPT (F), VKA versus non-VKA oral anticoagulant (NOAC) (G).



Fig. 5 Forest plots of any thrombosis. Comparisons between single antiplatelet therapy (SAPT) versus vitamin K antagonist (VKA) (A), dualantiplatelet therapy (DAPT) versus SAPT (B), VKA plus SAPT versus SAPT (C), VKA plus SAPT versus VKA (D), VKA international normalized ratio(INR) 2–3 versus VKA INR 3–4 (E), DAPT versus VKA plus SAPT (F), VKA versus non-VKA oral anticoagulant (NOAC) (G).



For the composite of arterial and venous thromboembo-lism, therewas a significant reduction of eventswith VKAplusSAPT versus VKA alone (RR: 0.41; 95% CI: 0.24–0.69) intwo studies with low heterogeneity (I2¼0%) (►Fig. 5).18,28

Likewise, there was a reduction with VKA plus SAPT versusSAPT alone (RR: 0.36; 95% CI: 0.13–0.96) in four studieswith high heterogeneity (I2¼64%).18,20,25,28 There was atrend to reduced events with DAPT versus SAPT (RR: 0.40;95% CI: 0.15–1.08) in two studies with low heterogeneity(I2¼0%).20,28

In seven studies, patients with arterial thrombosis asindex event had recurrence mostly as arterial thrombosisagain, in three studies therewere no data, and only one studyshowedmore recurrences as venous thrombosis than arteri-al thrombosis.

Bleeding OutcomeMajor bleeding events were reported and separated fromother bleeding in seven studies (►Table 3) and there was nosignificant difference in this outcome between any of thetreatment regimens compared (►Fig. 6).

HeterogeneityModerate to high heterogeneity was seen in some of thecomparisons and seemed to be due to very favorable resultsregarding any thrombotic recurrence and low risk of bleedingfor SAPT in the study byArauz et al,26possibly due to the lowermean age (34 years) versus the other studies. Furthermore, forthe outcome of recurrent arterial thrombosis, the heterogene-ity could have been due to the much higher proportionof secondary APS in the study by Ohnishi et al (55%)28 versusthe other studies.

Sensitivity AnalysisA sensitivity analysis was performed for treatment regimenswith both high-quality RTCs and low-quality RCTs or low-quality cohort studies represented, excluding the low-qualitystudies. This situation only pertained to the comparison ofNOACs with VKA. After excluding the study by Malec et al,21

there was a significant reduction of arterial thrombosis withVKA versus NOAC (RR: 0.25; 95% CI: 0.07–0.93) and a trend toreductionof thecomposite thromboticoutcome(RR:0.33;95%CI: 0.11–1.03), without any difference in riskofmajor bleeding(2 studies, I2¼0%) (►Fig. 7).

Discussion

Arterial Thrombotic Manifestations of APSIn vascular APS, the most common presenting manifesta-tions, according to the Euro-Phospholipid Project,32,33 astudy performed in a cohort of 1,000 APS patients, weredeepvein thrombosis (DVT; 32%), pulmonary embolism (9%),and superficial thrombophlebitis in the legs (9%). Among thearterial thrombotic manifestations, stroke (13%), TIA (7%),and myocardial infarction (3%) were the most common.32 Ithas been suggested that more than 20% of strokes in patientunder 45 years are associated with APS.34,35 In a retrospec-tive study including 218 patients with primary APS and 288

with APS secondary to SLE, Soltész et al reported thatthrombotic manifestations were venous (DVT and pulmo-nary embolism) in 37%, coronary and carotid in 34%, andcerebrovascular in 40%.36 In a Japanese retrospective studywith 141 patients, arterial thrombosis was the presentingmanifestation in 66% (mainly as stroke) versus venousthrombosis in 33%.10 In a Korean nationwide population-based studywith 3,088 newly diagnosed APS patients, strokeor TIA was the most common manifestation (28%) followedby DVT (20%) and pulmonary embolism (17.5%).4

In the studies in our meta-analysis that recruited patientswith either arterial or venous thrombosis as indexevent, 64 to89%ofpatientspresentedwithvenous thrombosis.21,24,30,31 Inthe study by Pengo et al,31 stroke was the first APS manifesta-tion in 13% of the patients. Malec et al showed that 24% of thepatients had stroke (or TIA) as first APS manifestation.21 Thus,the proportionof APS patientswith arterial thrombosis asfirstevent varies from approximately 20% up to 74%, probablydepending on the type of patients referred, the profile of thecenter, and other selection bias.

Management of Arterial ThrombosisIn this meta-analysis of 11 studies, comparing seven differenttherapeutic constellations for the management of APS patientswith arterial thrombosis as first presenting manifestation, wemade some potentially interesting observations. For theprevention of recurrent arterial thrombosis, DAPT seemed tobe more effective than SAPT and similarly VKA plus SAPTappeared more effective than VKA alone (albeit based on onlyone small study). Recurrent arterial thrombosis or venousthromboembolism gave the impression of being reduced withVKA plus SAPT both when compared with VKA alone and toSAPT alone, and DAPT demonstrated a trend to better effectcomparedwith SAPT. Thus, it is possible that patients with APSand arterial thrombosis may benefit from a combination ofantithrombotic agents, with reservations for the low quality ofmost of the included studies and the small number of patientsand events. None of our comparisons of treatment regimensidentifieda significantdifference in the riskofmajor bleeding. Itis reasonable to assume that with the hypercoagulable stateassociated with APS, the risk of recurrent thrombotic eventsoutweighs the risk of bleeding complications even with themore aggressive treatment regimens. Furthermore, our sensi-tivityanalysiswithonlystudiesofhighquality showedthatVKAis superior to NOAC for reducing the risk of recurrent AT aswellas (borderline significance) for the composite of arterial andvenous thromboembolism.

The treatment of thrombosis in APS has been studiedduring the past three decades. Factors that can modify theresponse to the treatment include aPL profile (double, triplepositivity, LA), primary versus secondary APS, increasingnumber of criteria for definite APS, the site of thrombosis(arterial or small vessel), male sex, and the presence of othercardiovascular risk factors.8,35

Guideline RecommendationsAccording to the EULAR recommendations, a NOAC could beconsidered for patients who are not able to maintain a



Table

3Blee

ding

ratesdu

ring

follo

w-up,

acco

rdingto

trea

tmen

tregim

en

Stud

y(first

author,ye

ar)

Major

blee

dingrates

CRNMBrates

Crowther,20

0324

VKAINR3–

4(n

¼56

)3(5.4%)

3.6%

annu

alrisk

VKAINR2–

3(n

¼58

)4(6.9%)

2.2%

annu

alrisk

VKAINR3–

4Noda

taVKAINR2–

3Noda

ta

HR:

1.0;

95%CI:0.2–

4.8;

p¼0.96

Levine

,20

0419

SAPT

Noda

taVKAINR2–

3Noda

taSA

PTNoda

taVKAINR2–

3Noda

ta

Yamazak

i,20

0920

SAPT

(n¼20

)0

DAPT

(n¼20

)0

VKAþSA

PT(n

¼20

)0

SAPT

0DAPT

0VKAþSA

PT0

Oku

ma,

2009

25SA

PT(n

¼11

)1(9%)

VKAþSA

PT(n

¼9)

0SA

PT0

SAPT

þVKA

1

Arauz

,201

126

SAPT

(n¼38

)0

VKA(n

¼54

)2(3.7%)

SAPT

0VKA

2(3.7%)

Jack

son,

2017

18SA

PTNoda

taVKA

Noda

taVKAþSA

PTNoda

taSA

PTNoda

taVKA

Noda

taVKAþSA

PTNoda

ta

Pyo,

2017

27SA

PTNoda

taVKA

Noda

taSA

PTNoda

taVKA

Noda

ta

Ohn

ishi,2

0192

8SA

PT(n

¼41

)5(12.2%

)VKA(n

¼13

)0

VKAþSA

PT(n

¼21

)2(9.5%)

DAPT

(n¼15

)2(13.3%

)SA

PTNoda

taVKA

Noda

taVKAþSA

PTNoda

taDAPT

Noda

ta

Peng

o,20

1829

NOAC(n

¼59

)4(7%)

VKA(n

¼61

)2(3%)

NOAC

Noda

taVKA

Noda

ta

HR:

2.5;

95%CI:0.5–

13.6;p¼0.3

Ordi-R

os,20

1930

NOAC(n

¼95

)6(6.3%)

VKA(n

¼95

)7(7.4%)

NOAC9(9.5%)

VKA5(5.3%)

HR:0

.88;

95%CI:0.30

–2.63;

p¼0.82

HR:2

.35;

95%CI:0.72

–7.61;

p¼0.16

0

Malec

,20

2021

NOAC(n

¼82

)(m

ajorblee

ding

andCRNMBrates)

14(17%

)4.96

per10

0pa

tien

t-years(95%

CI:2.82

–8.12)

VKA(n

¼94

)(m

ajor

blee

ding

andCRNMBrates)

11(12%

)2.42

per10

0pa

tien

t-years(95%

CI:1.27

–4.21)

HR:1

.51;

95%CI:1.53

–8.63;

p¼0.00

3

Abbrev

iation

s:CI,co

nfide

nceinterval;C

RNMB,

clinicallyreleva

ntno

n-majorblee

ding

;DAPT

,dua

lantiplatelettherap

y;HR,h

azardratio;INR,interna

tion

alno

rmalized

ratio;N

OAC,n

on-VKAoral

antico

agulan

t;SA

PT,sing

lean

tiplatelettherap

y;VKA,vitamin

Kan

tago

nist.

a OnlyICH

sinc

eQ3

Q3un

clea

rifothe

rblee

dsweremajor.



Sam

Cross-Out

Fig. 6 Forest plot of major bleeding. Comparisons between single antiplatelet therapy (SAPT) versus vitamin K antagonist (VKA) (A), dualantiplatelet therapy (DAPT) versus SAPT (B), VKA plus SAPT versus SAPT (C), VKA plus SAPT versus VKA (D), VKA international normalized ratio(INR) 2–3 versus VKA INR 3–4 (E), DAPT versus VKA plus SAPT (F), VKA versus non-VKA oral anticoagulant (NOAC) (G).



therapeutic INR despite good adherence to VKA or those withallergy or intolerance to VKA.6 NOACs should, however, not beused inpatientswith triple aPL positivity because of high riskofrecurrences,6,8,29 as also is evident from our analysis. High-intensityVKA (INR� 3) is not recommended after afirst venousthrombosis inAPSpatients. However, inpatientswith recurrentvenous thrombosis despite adequate treatment with VKA, itmay be considered to increase the range to INR 3 to 4, add low-dose aspirin (LDA), or switch to low-molecular-weight heparin.6

Regarding the duration of anticoagulation in patients withunprovoked first venous thrombosis, it is recommended tocontinue indefinitely. However, in patients with provoked firstvenous thrombosis, the recommended duration of anticoagu-lation is thesameas inpatientswithoutAPS.37 Inpatientswithahigh-risk aPL profile or additional risk factor for recurrence,long-term anticoagulant treatment is recommended also forprovoked venous thrombosis.6

For treatment of arterial thrombosis, a multitude oftherapeutic regimens have been recommended (►Table 4).

A Dutch consensus paper from 2019 suggests clopidogrel,aspirin, VKA (INR range: 2.5–3.5), or combined therapy withVKA (INR range: 2.0–3.0) plus antiplatelet therapy.17 Thecombination is, however, not favored as thefirst choicebasedon increased risk of bleeding in a study in patients without aprevious thrombotic event.38

The EULAR guidelines recommend for patients withdefinite APS and a first arterial thrombosis to use VKA overtreatmentwith LDA. This is basedon two studies, oneofwhichincluded and followed 24 patients with some only tested oncefor aCL, and only seven of the patients received VKA.39

The second study did not separate outcomes according tothe type of index event.40 The result from our meta-analysispoints instead slightly, although without statistical signifi-cance, in favor of SAPT. Regarding VKA, both a therapeutic INRrange of 2 to 3 and of 3 to 4 are recommended with risk ofbleeding and recurrent thrombosis to be taken into account.Finally, treatment with VKA (INR range: 2–3) plus LDA issuggested as an alternative.6 By contrast, the Report of a

Fig. 7 Sensitivity analysis excluding low-quality studies. Forest plots of (A) arterial thrombosis, (B) any thrombosis, and (C) major bleeding.

Table 4 Recommended treatment for arterial thrombosis in antiphospholipid syndrome according to different guidelines andconsensus documents

Study (author, year) Clopidogrel LDA VKA, INR 2–3 VKA, INR 3–4 VKA, INR 2–3, plus LDA

Limper, 2001917 þ þRuiz-Irastorza, 201115,a (þ) (þ) (þ) þ þTektonidou, 20196,15 þ þ (þ)

Abbreviations: INR, international normalized ratio; LDA, low-dose aspirin; VKA, vitamin K antagonist.aSomemembers of the Task Force (MC, DE, RD, SK, and VP Q4Q4

Q4) supported other options such as antiaggregant therapy alone or anticoagulant therapywith the INR range of 2.0–3.0.



Task Force at the 13th International Congress on Antiphos-pholipid Antibodies in 2011 recommended for patients withdefinite APS and arterial thrombosis either VKA (INR>3.0) orLDA plus VKA (INR range: 2–3).15 Some members of the TaskForce were of the opinion that LDA alone or VKA (INR range:2–3) would also be acceptable.

We have here analyzed 11 studies that recruited patientswith APS and arterial thrombosis and with separate outcomereporting for patients with index arterial thrombosis, withsome of the studies also including patients with venousthrombosis. In slight contrast tomost of the above-mentionedrecommendations, we found that combination therapy (VKAplus SAPT or DAPT) seems to provide better secondaryprophylactic effect than any single agent. Some interestingstudies were not included in this meta-analysis because theylacked a control group or used historical cohorts as a controlgroup such as the studies byRuiz-Irastorza et al41 andDerksenet al42 or because they did not specify thrombotic recurrencesaccording to the thrombotic index event (arterial or venousthrombosis) such as the WAPS study43 or the studies byTaraborelli et al,11 Khamashta et al,44 and Rosove et al.45

None of the guidelines or consensus statements providesuggestions or recommendations on duration of antithrom-botic therapy specifically for arterial thrombosis. There are,however, general recommendations to continue indefinitelyfor patients with definite APS and thrombosis (grade 1C),15

and that a decision to discontinue anticoagulation in patientswith APS should be taken at an expert center.17 We did notattempt to explore this question in our analysis.

Bleeding on Management of Arterial Thrombosis inAPS PatientsBleeding still remains a major concern of treatment with anyanticoagulant and obviously raises concerns when combinedantithrombotic therapy issuggested. TreatmentwithVKAhasahigh bleeding risk because of narrow therapeutic range, and alarge number of food and drug interactions. Several studieshave assessed the risk of bleeding in patients receiving VKA.46

Chai-Adisaksopha et al evaluated the risk of bleeding inpatients on NOACs, concluding that these were associatedwith less major bleeding, intracranial bleeding, clinicallyrelevant nonmajor bleeding (CRNMB), fatal bleeding, and totalbleeding than VKA (RR: 0.76, p<0.01) without an increase inthe riskofgastrointestinalbleeding.47►Table 4 shows the ratesof bleeding in the studies included in our review according tothedifferent regimensof treatment.Of the11studies analyzed,only eight studies evaluated bleeding episodes. Of these, sevenstudies reported major bleeding and one of them jointlyreported major bleeding and CRNMB.21 ►Fig. 6 shows theRRs for major bleeding according to the different treatmentscompared. As can be observed, there were no statisticallysignificant differences between the any of the treatmentsanalyzed.

Limitations

There are several limitations to our meta-analysis. First, thecriteria used for the diagnosis of APS varied with one study

using the Sapporo criteria, others the Sydney criteria, and thelargest study recruiting patients with only a single test foraPL.19 Second, several of the studies hadvery small numbers ofpatients in the different treatment groups resulting in highimprecision in the risk estimates. Third, we combined studieswith different designs and there was also heterogeneityregarding proportions of caseswith indexeventbeing a stroke,of triple positive cases, and of primary versus secondary APS.Fourth, for some pairs of treatment regimens there was onlyone study with estimable results and ideally a meta-analysisshould include results from at least four studies.

Conclusions

Arterial thrombosis is a common manifestation in patientswithAPSwith the incidence ranging from23 to 74%. Ischemicstroke is the most frequently studied arterial event. Inpatients with arterial thrombosis as first manifestation ofAPS, the recurrence is usually another arterial thrombosis.

Most studies report lower bleeding rates than recurrentthrombotic rates, probably because the included patientswith thrombotic events and APS are young with few comor-bidities and because of their hypercoagulable state.

It is difficult to give a strong recommendation regardingbest anticoagulant treatment in patients with arterialthrombosis as first manifestation of APS, due to the lowquality in several of the studies and the imprecision in therisk estimates. However, among all therapeutic regimensevaluated, it seems that the combined treatments with SAPTand VKA or with two antiplatelet agents might have betterefficacy and possibly without a reduction in safety. It wouldbe very interesting to see these two alternatives compared inawell-designed RCT. Such a RCT should test noninferiority ofDAPTversus VKA plus SAPT, since DAPT has the advantage ofeasier management.

FundingThis work was supported by a grant from Hospital Clinic,IDIBAPS and University of Barcelona (Estada Retribuïdaper ampliació d’estudis).

Conflict of InterestDr. Schulman reports research grants from Octapharmaand Boehringer-Ingelheim and honoraria from Alnylam,Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daii-chi-Sankyo, and Sanofi.

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Arterial Thrombosis in Patients with Antiphospholipid