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

Abstract

The antiphospholipid syndrome (APS) is defined by the presence of thrombosis and/or pregnancy morbidity in combination with the persistent presence of circulating antiphospholipid antibodies: lupus anticoagulant, anticardiolipin antibodies and/or anti-β2-glycoprotein I antibodies in medium to high titers. The management of thrombosis in patients with APS is a subject of controversy. This set of recommendations is the result of an effort to produce guidelines for therapy within a group of specialist physicians in Cardiology, Neurology, Hematology, Rheumatology and Internal Medicine, with a clinical and research focus on APS.

Keywords

anticardiolipin antiphospholipid aspirin hydroxychloroquine lupus anticoagulant prevention stroke thrombosis warfarin

Introduction

The antiphospholipid syndrome (APS) is defined by the presence of thrombosis and/or pregnancy morbidity in combination with the persistent presence of circulating antiphospholipid antibodies (aPL): lupus anticoagulant (LA), anticardiolipin antibodies (aCL) and/or anti β2 glycoprotein I antibodies (anti-β2 GPI) in medium to high titers. Specific clinical and immunological criteria have been developed to classify patients as having definite APS.¹

The management of thrombosis in patients with APS is a subject of controversy. On the one hand, APS is well known as an acquired thrombophilia affecting approximately 20% of young patients with venous thromboembolism or stroke,^2,3 with observational studies suggesting high recurrence rates in untreated patients.⁴ On the other hand, lifelong oral anticoagulation is associated with an increased rate of serious bleeding, which is higher as the international normalized ratio (INR) increases; the inconvenience of regular INR testing is also a factor influencing the quality of life. Thus, any therapeutic decision would potentially face the risk of either insufficient antithrombotic coverage or excessive exposure to major side effects. Moreover, there is also a potential need for primary thromboprophylaxis in individuals with aPL who have not yet suffered any thrombosis.

Recently, two systematic reviews^4,5 and an academic review,⁶ all published in high-impact journals, included treatment recommendations. However, some controversial management issues remain unresolved, particularly with respect to patients with APS and cerebral arterial events. Primary thromboprophylaxis has been less extensively investigated.

In the setting of the 13th International Congress on Antiphospholipid Antibodies, held in Galveston in April 2010, an international Task Force composed of clinicians and researchers with experience in the field jointly elaborated a consensus document on the primary and secondary thromboprophylaxis in individuals with aPL, after a systematic and critical review of the literature.

Methods

The group identified five key questions to be answered by the literature review:

What is the risk of first thrombosis in lupus patients with aPL, women with purely obstetric APS, and asymptomatic healthy aPL carriers?

What is the risk of recurrent events in untreated patients with APS and previous thrombosis (arterial and venous)?

What are the factors that influence the risk of vascular events (first or recurrent) in patients with aPL?

Is primary thromboprophylaxis with aspirin and/or hydroxychloroquine effective and safe?

What is the best treatment to prevent recurrent thrombosis in patients with aPL and arterial or venous events fulfilling and not fulfilling criteria for APS?

A systematic literature review using PUBMED and EMBASE was performed using the following strategies:

(Antiphospholipid syndrome OR antiphospholipid antibodies OR Lupus coagulation inhibitor OR anticardiolipin antibodies OR beta 2-Glycoprotein I) AND Thrombosis (all the 16 MeSH headings) NOT review NOT Children NOT Recurrent

(Antiphospholipid Syndrome OR Lupus Anticoagulant OR Phospholipid Antibody) AND (Therapy OR Anticoagulant Therapy)

(“Antiphospholipid Syndrome/drug therapy”[MeSH] OR “Antiphospholipid Syndrome/therapy”[MeSH]) AND “Thrombosis”[MeSH]

“Antibodies, Antiphospholipid”[MeSH] AND (“Thrombosis/drug therapy”[MeSH] OR “Thrombosis/therapy”[MeSH])

Antibodies, Antiphospholipid/blood*[MESH] AND recurrence[MESH].

Papers containing original data relevant to the clinical questions were selected. Additional papers were obtained by scanning the references of the selected articles. Data were extracted by three authors (GR-I, M-JC, IR-A) and summarized in tables. The tables and the complete reference list were then distributed among the members of the Task Force. The entire group met on 13 April 2010 in a preconference workshop of the 13th International Congress on Antiphospholipid Antibodies. A preliminary consensus document was agreed and distributed among the members of the Task Force for further discussion.

The strength of the recommendations and the level of evidence were rated from 1–2 and from A–C, respectively, using the American College of Chest Physicians system.⁷ According to this scoring system, strong recommendations (grade 1) were made when the results from the studies made the authors feel confident regarding the desirable effects of an intervention. Such a confidence is reflected by the expression ‘we recommend’. On the other hand, weak recommendations (grade 2) were made when there is uncertainty about the balance between desirable and undesirable effects. In this case, the expression ‘we suggest’ is used. The quality of evidence on which recommendations are based was graded from high (A level) to low (C level). A more detailed description of this scoring system is given in Table 1. In addition, some recommendations were agreed upon based on the experience of the authors, with little relevant supporting published evidence. In those cases, recommendations were labeled as ‘non-graded’. Finally, when consensus on an item was not achieved, the final label was ‘non-graded due to lack of consensus’.

Table 1

American College of Chest Physicians grades of recommendation (modified from Guyatt GH, et al)⁷

Grade of recommendation	Benefit vs. risk and burdens	Methodological quality of supporting evidence	Implications	Effects of further research
1A Strong recommendation High-quality evidence	Desirable effects clearly outweigh undesirable effects, or vice versa	Consistent evidence from RCTs without important limitations, or exceptionally strong evidence from observational studies	Recommendation can apply to most patients in most circumstances	Further research is very unlikely to change our confidence in the estimate effect
1B Strong recommendation Moderate-quality evidence	Desirable effects clearly outweigh undesirable effects, or vice versa	Evidence from RCTs with important limitations (inconsistent results, methodological flaws, indirect or imprecise), or very strong evidence from observational studies	Recommendation can apply to most patients in most circumstances	Higher-quality research may well have an important impact on our confidence in the estimate of effect and may change the estimate
1C Strong recommendation Low or very low-quality evidence	Desirable effects clearly outweigh undesirable effects, or vice versa	Evidence from at least one critical outcome from observational studies, case series, or from RCTs with serious flaws or indirect evidence	Recommendation can apply to most patients in many circumstances	Higher-quality research is likely to have an important impact on our confidence in the estimate of effect and may well change the estimate
2A Weak recommendation High-quality evidence	Desirable effects closely balanced with undesirable effects	Consistent evidence from RCTs without important limitations, or exceptionally strong evidence from observational studies	The best action may differ depending on circumstances or patient or society values	Further research is very unlikely to change our confidence in the estimate of effect
2B Weak recommendation Moderate-quality evidence	Desirable effects closely balanced with undesirable effects	Evidence from RCTs with important limitations (inconsistent results, methodological flaws, indirect or imprecise), or very strong evidence from observational studies	The best action may differ depending on circumstances or patient or society values	Higher-quality research may well have an important impact on our confidence in the estimate of effect and may change the estimate
2C Weak recommendation Low or very low-quality evidence	Desirable effects closely balanced with undesirable effects	Evidence from at least one critical outcome from observational studies, case series, or from RCTs with serious flaws or indirect evidence	Other alternatives may be equally reasonable	Higher-quality research is likely to have an important impact on our confidence in the estimate of effect and may well change the estimate

RCT, randomized controlled trial.

Recommendations

General background

aPL increase the risk for thrombotic events.⁸ However, the relationship between aPL and thrombosis is not ‘all or nothing’. Circulating aPL should be considered a thrombotic risk factor, with several other variables modulating the final clinical expression.⁹ Among these, the most important are the aPL profile (type, level and persistence), the coexistence of other thrombotic risk factors, and the presence of an underlying autoimmune disease.

The classical systematic reviews by Galli et al. established LA as the individual aPL most strongly related to thrombosis.^10,11 On the other hand, isolated anti-β2-GPI were weakly associated with clinical manifestations of APS.^11,12 This has been recently confirmed in a population-based case-control study of Dutch women under 50 years of age, 203 with myocardial infarction, 175 with ischemic stroke and 628 healthy controls:¹³ LA positivity increased the risk of stroke 48-fold, and the risk of myocardial infarction 11-fold. Anti-β2-GPI only doubled the risk of stroke, but not of myocardial infarction. The role of aCL in the absence of LA is more debated, with no associated increased risk for stroke or myocardial infarction in the Dutch study.¹³ It must be noted, though, that single aPL determinations were performed in this study.

Two observational studies suggested that patients with systemic lupus erythematosus (SLE) and isolated medium–high titer, persistently positive aCL (defined as more than 2/3 of serial determinations positive) had an increased risk for thrombosis, while those with occasional aCL positivity did not.^14,15 On the other hand, combined aPL positivity has been associated with increasing thrombotic risk,^16,17 with the so-called triple-positive population (LA plus aCL plus anti-β2-GPI) being the highest risk group.^15,18,19 Individuals with multiple positive aPL tend to have more stable antibody levels on repeated determinations.²⁰ This probably reflects the fact that aPL levels are routinely much higher in this group.⁹

The role of vascular risk factors in patients with APS has become more clear. aPL patients presenting with thrombosis frequently have one or several additional cardiovascular risk factors such as hypertension, smoking, hypercholesterolemia or estrogen use. The co-existent presence of these factors is associated with thrombosis.^21–25 Moreover, the interaction between aPL and smoking and oral contraceptives has been clarified in the case-control study by Urbanus et al.:¹³ the risk for suffering a stroke doubled among smoking LA-positive women, as compared with non-smokers; the risk of stroke among oral contraceptive users multiplied more than sevenfold. All LA-positive women who suffered a myocardial infarction smoked.

The influence of concomitant SLE may also impact the risk of thrombosis. SLE is a risk factor for thrombosis in isolation. Patients with SLE have a higher than expected incidence of vascular events,²⁶ not completely explained by traditional vascular risk factors.²⁷ The combination of SLE and aPL is particularly worrisome, since aPL positivity has been shown to increase the risk of thrombosis in patients with lupus,^14,15,28,29 and the diagnosis of SLE appears to further enhance the likelihood of vascular events in patients with aPL.^30–32 Observational studies suggest that manifestations of APS other than clinical classification criteria, such as heart valve lesions,¹⁵ livedo reticularis,³³ and thrombocytopenia^24,25 may be associated with thrombosis; however, such association is not considered strong enough to guide clinical decisions.

Thus, the presence of LA, particularly if combined with aCL and anti-β2-GPI (triple positivity), and the presence of isolated, persistently positive aCL at medium–high levels (although the latter has only been studied in patients with lupus) is considered a high-risk serological aPL profile (Table 2). A concomitant diagnosis of SLE and the coexistence of traditional thrombotic risk factors (smoking, arterial hypertension, hypercholesterolemia and estrogenic oral contraceptive use) further increase the risk for thrombosis. On the other hand, individuals with isolated aCL or anti-β2-GPI at low–medium titers, particularly if intermittently positive, could be considered at a low risk for future thrombosis (Table 2).

Table 2

High- and low-risk serological features in patients with antiphospholipid antibodies

High risk

LA positivity

Triple positivity (LA + aCL + anti-β2-GPI)

Isolated persistently positive aCL at medium–high titers*

Low risk

Isolated, intermittently positive aCL or anti-β2-GPI at low-medium titers

LA, lupus anticoagulant; aCL, anticardiolipin antibodies; anti-β2-GPI, anti-β2 glycoprotein I antibodies.

Only studied in patients with systemic lupus erythematosus.

1. General measures for aPL carriers

1.1. A strict control of cardiovascular risk factors should be accomplished in all individuals with a high-risk aPL profile, irrespective of the presence of previous thrombosis, concomitant SLE or additional APS features. Non-graded recommendation.

1.2. We recommend that all aPL carriers receive thromboprophylaxis with usual doses of low molecular weight heparin in high-risk situations, such as surgery, prolonged immobilization and the puerperium. 1C recommendation.

Rationale

There is no study addressing the effect of controlling cardiovascular risk factors on the risk of thrombosis in individuals with aPL. However, given the consistent association of these factors with vascular events in the general population as well as in APS patients (see ‘General background’), the recommendation of an adequate management of hypertension, obesity and dyslipidemia and the avoidance of smoking and estrogen-containing therapy is warranted.

In addition, observational studies suggest that standard thromboprophylaxis in high-risk periods, such as surgery or the puerperium, is effective.^24,25

2. Primary thromboprophylaxis in SLE patients with aPL

2.1. Clinicians should regularly assess patients with SLE for the presence of aPL. Non-graded recommendation.

2.2. We recommend that patients with SLE and positive LA or isolated persistent aCL at medium–high titers receive primary thromboprophylaxis with hydroxychloroquine (1B recommendation) and low-dose aspirin (2B recommendation).

Note: Some members of the Task Force (DE, RD, SK, VP) suggest hydroxychloroquine use in this setting with a grade 2B.

Rationale

As previously discussed, the simultaneous presence of SLE and aPL increases the risk for thrombosis.^14,15,28 ^, 32,34 As a consequence, the highest thrombosis rates in patients with aPL are reported in the subgroup with SLE (Table 3).^{15,19,25,28,30,31,35–40} In patients with lupus, LA is most strongly associated with thrombosis, but isolated persistently positive aCL at medium–high titers is also a risk factor (see ‘General background’).^14,15 APS has been shown to increase irreversible organ damage and decrease survival of patients with SLE.⁴¹ Thus, screening for aPL is recommended due to their prognostic significance and the potential indication for primary thromboprophylaxis.

Table 3

Primary thrombosis rates in patients with antiphospholipid antibodies

Author/year^ref	Type of study	N patients	Follow-up	Thrombosis rate
Patients with SLE and aPL
Tektonidou et al. 2009¹ ⁵	Ambispective cohort	144	104 months	2.09/100 patient-years
				62% arterial events
				60% with AAS at any time
Tarr et al. 2007³ ⁵	Prospective cohort	81	5 years	3.7% overall:
				1.9% aspirin (CVA)
				6.9% observational (CVA)
Martinez et al. 2006³ ⁶	Retrospective cohort	41	83.5 months	3.93/100 patient-years
				8 venous events
				6 arterial events (4 CVA)
Mok et al. 2005² ⁸	Prospective cohort	240	5 years	Arterial events:
		105 C		C: 1.46/100 patient-years
		76 Ch		Ch: 2.06/100 patient-years
		59 AA		AA: 1.84/100 patient-years
				Venous events:
				C: 1.34/100 patient-years
				Ch: 2.06/100 patient-years
				AA: 2.52/100 patient-years
Shah et al. 1998³ ⁷	Retrospective cohort	21	10 years	3.8% thrombosis in 10 years
				100% arterial events
				37% with AAS
Patients with obstetric APS (no SLE)
Ruffati et al. 2006³ ⁸	Ambispective cohort	37	6.3 years	0/100 patient-years
Quenby et al. 2005³ ⁹	Retrospective case-control	141	7.3 years	0.6/100 patient-years
				3 arterial events
				3 venous events
Patients with obstetric APS ± associated SLE
Pengo et al. 2010¹ ⁹	Retrospective cohort	11*	1–10 years	2/11
Pengo et al. 2010¹ ⁹	Retrospective cohort	11*	1–10 years	100% CVA
Erkan et al. 2001⁴⁰	Retrospective cohort	34	8.1 years	7.4/100 patient-years
			50% secondary APS	7 venous events
				12 arterial events
				1 catastrophic APS
Silver et al. 1994³¹	Retrospective cohort	39*	3.7 years	7.7% thrombosis in 3.7 years
				2 arterial events
				1 venous event
Asymptomatic aPL carriers
Giron-Gonzalez et al. 2004² ⁵	Retrospective cohort	178*	36 months	0
Giron-Gonzalez et al. 2004² ⁵	Retrospective cohort	178*	100% thromboprophylaxis in high-risk periods	0
Finazzi et al. 1996³⁰	Prospective cohort	243*	5 years	0.95/100 patient-years

C, Caucasian; Ch, Chinese; AA, African American; aPL, antiphospholipid antibodies; APS, antiphospholipid syndrome; CTD, connective tissue disease; SLE, systemic lupus erythematosus; CVA, cerebrovascular accident.

NA, not available.

Some of these patients had SLE, the exact proportion is not reported in the study.

A recent systematic review has found moderate-quality evidence that antimalarials have antithrombotic effects in patients with SLE.⁴² Such effects are further supported by a case-control study that found a significant reduction of thromboembolic events over 2-year follow-up in SLE patients treated with hydroxychloroquine.⁴³ In the subgroup of lupus patients with aPL, observational studies also point to a protective effect of hydroxychloroquine against thrombosis.^15,44

Moreover, moderate and high-quality evidence provides support that antimalarials decrease damage accrual and increase the survival of lupus patients, respectively, with little associated toxicity.⁴² Thus, hydroxychloroquine is currently recommended as baseline therapy in all lupus patients without known contraindications.⁴²

Observational studies suggest that thromboprophylaxis with low-dose aspirin is effective in patients with SLE and aPL.^15,35,45 A decision analysis showed a good balance between thrombotic events prevented/bleeding episodes induced in patients with lupus and positive aCL or LA.⁴⁶ On the other hand, the APLASA clinical trial, enrolling 65% of patients with SLE, did not find differences among aPL-positive patients treated with either low-dose aspirin or placebo.³² However, the event rate in the placebo group in this study was zero, which was attributed to the short follow-up, the good control of vascular risk factors and the inclusion of individuals (over 40%) with a low-risk aPL profile (Table 4).

Table 4

Primary intervention studies in patients with antiphospholipid antibodies

Author, year^ref	Type of study/ follow-up	N	Intervention	Results
Patients with SLE and aPL
Tektonidou et al. 2009¹ ⁵	Retrospective/ 104 months	144	AAS HCQ	HR per month: AAS 0.98 (95% CI 0.96–0.99) and HCQ 0.99 (95% CI 0.98–1.00) Increased duration of AAS and HCQ use associated with decreased thrombosis
Tarr et al. 2007³ ⁵	Prospective/ 5 years	81	52 AAS 1 clopidogrel 1 warfarin 29 observation	Lower incidence of arterial thrombosis in prophylaxis group vs. observational group: 1/52 (1.9%) vs. 2/29 (6.9%)
Mok et al. 2005⁴⁴	Retrospective/ 11 years	83	NA	Patients taking HCQ were at a lower risk for thrombotic events (OR 0.21, 95% CI 0.06–0.81)
Wahl et al. 2000⁴ ⁶	Decision analysis		Observation AAS Anticoagulation	Benefit of primary prophylaxis with AAS outweighs risks in aPL-positive SLE patients
Patients with obstetric APS (no SLE)
Ruffati et al. 2006³ ⁸	Longitudinal/ 6.3 years	37	Heparin during pregnancy	No events
Patients with obstetric APS ± associated SLE
Erkan et al. 2001⁴⁰	Retrospective/ 8.1 years	65	31 AAS (32% CTD) 34 observation (44% CTD)	Lower incidence of thrombosis with AAS: 1.3/100 pts/year vs. 7.4/100 pts/year or 10% vs. 59%
aPL carriers ± obstetric APS ± SLE
Hereng et al. 2008⁴ ⁵	Retrospective 64 months	103	75 AAS 28 Observation HCQ in CTD	Lower frequency of thrombotic events in AAS group: 12% vs. 35.7% overall 11% vs. 4% in SLE
Hereng et al. 2008⁴ ⁵	Retrospective 64 months	36% SLE or other CTD	75 AAS 28 Observation HCQ in CTD
Ruffati et al. 2009² ⁴	Retrospective 56.3 months	370	134 long-term prophylaxis with AAS 5 long-term prophylaxis with warfarin 48 prophylaxis only during high-risk periods with AAS/heparin or both	Combined long-term and high-risk periods prophylaxis protective against thrombosis
Ruffati et al. 2009² ⁴	Retrospective 56.3 months	35% SLE
Erkan et al. 2007³²	RCT 2.3 years Observational 2.4 years	98 65% SLE 74 35% SLE	48 AAS 50 Placebo 61 AAS 13 Placebo	AAS not effective in preventing thrombosis compared with placebo: HR: 1.04 (95% CI 0.69–1.56) 0 thrombosis rate with placebo in both studies
Erkan et al. 2002² ³	Case-control	133	AAS and/or HCQ (HCQ only in patients with CTD)	Probability of thrombotic events decreased by taking AAS ± HCQ
			77 cases (31% CTD)
			56 controls (78% CTD)
Asymptomatic aPL carriers
Giron-Gonzalez et al. 2004² ⁵	Retrospective 36 months	178	AAS 325 mg/day in pregnancy Enoxaparin in high-risk situations	No thrombotic events

aPL, antiphospholipid antibodies; APS, antiphospholipid syndrome; CTD, connective tissue disease; SLE, systemic lupus erythematosus; AAS, aspirin; HCQ, hydroxychloroquine; HR, hazard ratio; CI, confidence interval; NA, not available.

No studies have analyzed whether the combination of both therapies (antimalarials plus low-dose aspirin) increases the efficacy of primary thromboprophylaxis in this group of patients with SLE and aPL.

3. Primary thromboprophylaxis in aPL-positive individuals without SLE

3.1. In non-SLE individuals with aPL and no previous thrombosis, we suggest long-term thromboprophylaxis with low-dose aspirin in those with a high-risk aPL profile, especially in the presence of other thrombotic risk factors. 2C recommendation.

Rationale

The actual risk of thrombosis in aPL-positive individuals without SLE is not well established, since reported incidence data vary considerably (Table 3). APS-associated obstetric morbidity in the absence of SLE has not been clearly associated with a higher risk of thrombosis.^31,39 In the study by Ruffatti et al., women with obstetric APS who had thrombosis during the subsequent follow-up had all suffered previous thromboembolic events and were triple aPL positive.³⁸ Likewise, the risk of thrombosis in healthy individuals with aPL as an incidental finding seems low.²⁵ The APLASA clinical trial, performed in a mixed population of individuals with and without a concomitant connective tissue disease, did not find differences between placebo and low-dose aspirin³² (see previous section for comments regarding this study).

Based on this evidence, universal thromboprophylaxis with aspirin cannot be recommended for asymptomatic carriers of aPL. However, there is some concern that those with a high-risk aPL profile (Table 2), especially if combined with additional thrombotic risk factors, could be at a higher risk for subsequent vascular events; thus, therapy with aspirin could be considered in such individuals.

4. Secondary thromboprophylaxis

4.1. We recommend that patients with either arterial or venous thrombosis and aPL who do not fulfill criteria for APS be managed in the same manner as aPL-negative patients with similar thrombotic events. 1C recommendation.

4.2. We recommend that patients with definite APS and a first venous event receive oral anticoagulant therapy to a target INR 2.0–3.0. 1B recommendation.

Rationale

A recent systematic review has concluded, based on subgroup analyses, that patients with aPL and thrombosis who do not fulfill laboratory criteria for APS have rates of recurrent events with standard therapy similar to aPL-negative patients.⁴

For patients with definite APS who present with non-recurrent venous thromboembolism, standard anticoagulation to a target INR 2.0–3.0 is effective in preventing further events, while higher-intensity anticoagulation has not been demonstrated to decrease the rate of recurrences in two randomized controlled trials.^47,48 Although the quality of these studies was limited by the insufficient anticoagulation in a substantial number of patients randomized to the high-intensity arm, the low frequency of recurrent events seen in all groups supports the efficacy of standard intensity anticoagulation in this clinical setting.⁴

4.3. Patients with definite APS and arterial thrombosis should be treated with warfarin at an INR >3.0 or combined antiaggregant-anticoagulant (INR 2.0–3.0) therapy. Non-graded recommendation due to lack of consensus.

Note: Some members of the Task Force (MC, DE, RD, SK, VP) believe that other options such as antiaggregant therapy alone or anticoagulant therapy to a target INR 2.0–3.0 would be equally valid in this setting.

Rationale

A systematic review has concluded, based on observational studies, that patients fulfilling criteria for definite APS with arterial or recurrent events are at a high risk for recurrences when treated with oral anticoagulation to a target INR 2.0–3.0, while the rate of recurrent thrombosis was low when the INR was effectively over 3.0.⁴ Deaths due to bleeding were much less frequent than deaths due to recurrent thrombosis.⁴ Several observational studies published after 2007 support these conclusions (Table 5). A prospective study of 59 aPL-positive Canadian individuals found that recurrent events were more frequent in patients presenting with arterial events. A previous arterial thrombosis was a strong predictor of a new arterial event.⁴⁹ A prospective follow-up of 1000 European patients with APS⁵⁰ also found recurrent arterial events being more frequent than venous (56 versus 51 recurrent events, respectively), even though venous thromboses were twice more frequent than arterial as the presenting manifestation of APS (785 versus 389, respectively).⁵¹ It was also observed that patients with recurrent events were less likely to be on oral anticoagulation to a target INR >3.0 than on lower intensity anticoagulation or aspirin. Unfortunately, the actual therapy at the moment of thrombosis was not documented. Twenty-seven deaths due to thrombosis and six deaths due to hemorrhage were seen.⁵⁰ A small retrospective analysis of a cohort of 59 APS patients from Singapore⁵² observed 19 new thromboses in 14 patients, more frequently arterial. At the time of recurrent thrombosis the actual INR was <3.0 in all patients but one (Table 5). A retrospective analysis of a cohort of 160 patients with APS, all of them triple-positive, found a high frequency of recurrent events, most frequently arterial.¹⁹ Warfarin to a target INR 2.0–3.0 was statistically more effective than low-dose aspirin or no therapy; however, a 30% recurrence rate was found among patients on warfarin (target INR 2.0–3.0) during a mean follow-up of 6 years.¹⁹

Table 5

Recurrent thrombosis rates in studies published after 2007

Author/year^ref	Study design	N patients	Type of previous thrombosis	Treatment	Outcomes	Comments/Limitations
Neville et al. 2009⁴ ⁹	Prospective cohort Median follow-up 7.4 years	59 aPL- positive individuals	16 V 14 A	NA	Recurrent events more frequent in patients with previous arterial events vs. venous events (13 vs. 8 events, respectively). Previous arterial event strong predictor of new arterial event (adjusted OR 10.4) Smoking (adjusted OR 4.4) and diabetes (adjusted OR 9.9) strong predictors of new arterial events	Treatment NA
Tan et al. 2009⁵²	Retrospective cohort Mean follow-up 8.8 years	59 patients with APS (44 with CTD)	29 V 29 A 1 V + A	W	19 thrombosis (14 A, 5 V) in 14 patients. Actual INR <2: 12 (8A, 4V) Actual INR 2.0-3.0: 6 (6A) Actual INR >3.0: 1 (1V) 6 episodes of major bleeding Actual INR <3.0: 2 Actual INR ≥3.0: 4	Retrospective data HCQ treatment NA Vascular risk factors NA
Cervera et al. 2009⁵⁰	Prospective cohort Follow-up 5 years	1000 patients with APS (47% SLE)	A and V	None AAS W (INR 2.0–3.0) W (INR >3.0)	166 recurrent events: No treatment: 27/166 (17%) AAS: 49/166 (29%) W (INR 2.0–3.0): 69/166 (41%) W (INR >3.0): 21/166 (13%) 27 deaths due to thrombosis vs. 6 deaths due to hemorrhage	Actual INR at thrombosis NA Venous thrombosis most frequent presenting events, arterial thrombosis most frequent recurrent events
Pengo et al. 2010¹ ⁹	Retrospective cohort Mean follow-up 6 years	160 patients with APS and triple aPL positivity (18% SLE)	76 V 69 A 11 Obst	None AAS W (INR 2.0-3.0)	Recurrent VTE 59% Recurrent arterial 68% Recurrent events in 36/123 (30%) on W (mean INR 2.3) vs. 19/37 (50%) on none or AAS Adjusted HR for thrombosis (no-W vs. W): 2.4 (95%CI 1.3–4.1) 0.8%-year major bleeds with W
Okuma et al. 2010⁵³	Randomized controlled trial Mean follow-up 3.9 years	20 patients with APS (7 SLE)	20 stroke	AAS AAS + W (INR 2.0–3.0)	Cumulative non-stroke survival 25% (AAS) vs. 74% (AAS + W) (p = 0.026) 1 non-fatal hemorrhage in each group	aPL profile NA

aPL, antiphospholipid antibodies; APS, antiphospholipid syndrome; CTD, connective tissue disease; SLE, systemic lupus erythematosus; V, venous; A, arterial; W, warfarin; AAS, aspirin; INR, international normalized ratio; OR, odds ratio; HR, hazard ratio; CI, confidence interval; NA, not available.

In addition to these observational studies, a small randomized controlled trial, enrolling 20 Japanese APS patients with stroke with a mean age below 50 years, compared combined therapy with warfarin (target INR 2.0–3.0) plus low-dose aspirin with aspirin alone.⁵³ Combined therapy was statistically more effective, with a low frequency and severity of bleeding in both groups (Table 5). This study is subject to important limitations (lack of data regarding aPL profiles, lack of data on the actual number and type of events in each group, one patient with atrial fibrillation treated with aspirin only); however, it is the only randomized controlled trial focused on arterial events in APS and opens the door to the use of combined antiaggregant–anticoagulant drugs as first-line therapy in patients with APS and stroke.

Some authors (GR-I, M-JC, IR-A, RB, SM, SP, MT, MK) agree that more intense therapy, such as oral anticoagulation to an INR higher than 3.0 or combined therapy with warfarin, INR 2.0–3.0, and low-dose aspirin should be indicated in patients with APS presenting with arterial thrombosis. Other members of the panel (MC, RD, DE, SK, VP) believe that other options (antiaggregant therapy alone or warfarin INR 2.0–3.0) are equally valid alternatives. We all agree that the evidence supporting any option must be considered low quality (grade C).

4.4. An estimation of the patient’s bleeding risk should be performed before prescribing high-intensity anticoagulant or combined antiaggregant-anticoagulant therapy. Non-graded recommendation.

Rationale

Estimating the patient’s bleeding risk is essential before starting long-term anticoagulant therapy, particularly in patients who are candidates to receive high-intensity anticoagulation or combined therapy. The risk of major bleeding increases with rising INRs; however, the relationship is not linear, with a sharp increase at INRs >4.0–5.0.⁵⁴ Concomitant aspirin therapy doubles the risk of bleeding in patients on oral anticoagulants.^54,55 A dose of 100 mg/day is safer than higher doses.⁵⁴ Age over 75 years, history of severe bleeding, polypharmacy, insufficient education on anticoagulant therapy, malignancy⁵⁴ and the presence of leukoaraiosis⁵⁶ have all been related to a higher frequency of hemorrhages.

4.5. Non-SLE patients with a first non-cardioembolic cerebral arterial event, with a low-risk aPL profile and the presence of reversible trigger factors, could individually be considered candidates to treatment with antiplatelet agents. Non-graded recommendation.

Rationale

The authors agree that the relative influence of aPL in the development of thrombosis may vary among individual patients. As discussed in the general background, patients with SLE and those with strongly positive LA, especially if accompanied by other aPL (triple-positive patients), seem to be at the highest risk for thrombosis, whether first or recurrent, while those with isolated low–medium titer aCL or anti-β2-GPI seem to be at the other end of the spectrum, even if fulfilling laboratory criteria for APS. The low risk of recurrent stroke seen in some cohorts of APS patients treated with low-dose aspirin, with a minority of them being concurrently positive for aCL and LA,⁵⁷ may reflect the different clinical behavior of this subgroup.

Thus, even with the current lack of clinical data to support this recommendation, the authors agree that patients with non-cardioembolic stroke and a low-risk aPL profile (non-SLE with single, not persistent, low–medium level aCL or anti-β2-GPI positivity), especially in the presence of a reversible risk factor such as smoking or estrogenic therapy, could be individually considered candidates to antiaggregant treatment instead of prolonged high-intensity anticoagulation.

Taking into account the high prevalence of cardiac valve abnormalities seen in patients with APS,⁵⁸ it would be important to exclude a cardioembolic source according to established guidelines.^59,60 However, in a recent study by the APASS group, within a well-recognized cohort with stroke and low-risk aPL profile treated with aspirin or warfarin, the simultaneous presence of either valvular thickening or patent foramen ovale – detected by transesophageal echocardiography – and aPL – in a single determination – did not increase the risk of subsequent events.⁶¹ Thus, further studies in patients fulfilling laboratory APS criteria are needed before recommending specific screening of cardioembolic sources in the subpopulation with low-risk aPL profile.

5. Duration of treatment

5.1. We recommend indefinite antithrombotic therapy in patients with definite APS and thrombosis. 1C recommendation.

5.2. In cases of first venous event, low-risk aPL profile and a known transient precipitating factor, anticoagulation could be limited to 3–6 months. Non-graded recommendation.

Rationale

In patients with venous thromboembolism, it has been shown that the presence of single aCL increases the risk of recurrent thromboembolism within 6 months of anticoagulation withdrawal.⁶² In the retrospective study by Khamashta et al.,⁶³ the frequency of thrombosis rose sharply shortly after stopping anticoagulant therapy. Moreover, long-term therapy (whether antiaggregant or anticoagulant) is recommended in the general population with stroke,⁶⁴ and recent guidelines suggest indefinite oral anticoagulation for all patients with unprovoked venous thromboembolism in whom the bleeding risk is low.⁶⁵ Thus, the general rule of indefinite (lifelong) antithrombotic therapy generally applies to patients with APS and thrombosis, whether venous or arterial.

However, stopping oral anticoagulation 3–6 months after a venous thromboembolism due to a transient risk factor is adequate in the general population.⁶⁵ What if this clinical scenario is completed with single, not persistent, low–medium titers aCL or anti-β2-GPI: what we previously defined as low-risk aPL profile? (Table 2). There are no data to answer this question. However, as in the case of arterial events, the authors agree that this subgroup of patients would be candidates for less aggressive therapy, which may include a shorter duration of anticoagulant treatment. A recent Spanish series of six patients with venous thromboembolism with single aCL positive at least two times observed no episodes of recurrent thrombosis after a mean follow-up of 21 months after stopping oral anticoagulation following the eventual negativization of aCL.⁶⁶ Of note, four of these patients presented reversible risk factors for venous thrombosis.

A negative ultrasound screening for residual thrombosis as well as a negative D-dimers test after 3 months of anticoagulant therapy identify a population at low risk for recurrent thromboembolic events after stopping anticoagulation.^67,68 Although patients with aPL have been excluded from most of these studies, additional evaluation including these techniques could aid in taking the decision of withdrawing anticoagulation in this subgroup of patients with APS.

6. Refractory and difficult cases

6.1. In patients with difficult management due to recurrent thrombosis, fluctuating INR levels, major bleeding or a high risk for major bleeding, alternative therapies could include long-term low molecular weight heparin, hydroxychloroquine or statins. Non-graded recommendation.

Rationale

The utility of several alternative treatments for APS has been suggested by several studies, most of them observational. A small, low-quality randomized controlled trial has shown that combination therapy with low-dose aspirin and warfarin to an INR 2.0–3.0 is more effective than aspirin alone in the secondary prevention of stroke in patients with APS⁵³ (see ‘Secondary thromboprophylaxis’ section). However, no comparative studies against warfarin alone are available.

Very limited data suggest that long-term low molecular weight heparin can be an effective and safe alternative to warfarin in patients with APS.⁶⁹ Whether the response is similar in arterial and venous thrombosis and whether there is need for combining antiaggregant drugs are unresolved questions.

Statins have been shown to inhibit NF-κB, an important mediator of platelet activation and tissue factor over-expression induced by aPL.⁷⁰ Fluvastatin has been shown to inhibit aPL-induced tissue factor production in mouse models and in cultured human endothelial cells.⁷⁰ In a recent pilot trial in nine patients with APS treated with fluvastatin 40 mg/day for 30 days, decreased levels of inflammatory and thrombogenic mediators were seen after treatment.⁷¹ Among non-APS patients, a decreased risk of venous thromboembolism has been shown in healthy people with normal cholesterol levels treated with rosuvastatin.⁷² Thus, beyond lipid-lowering activity, statins could have an adjuvant role in preventing thrombosis in patients with aPL/APS, importantly, with no intrinsic additional risk of bleeding.

The antithrombotic properties of hydroxychloroquine in patients with aPL and SLE has already been noted⁴² (see section ‘Primary thromboprophylaxis in patients with systemic lupus erythematosus’). Studies have shown that hydroxychloroquine reduces aPL-induced platelet activation and clotting and inhibits the formation of aPL-β₂ GPI–phospholipid bilayer complexes.⁷⁰ Although clinical studies in patients with APS without SLE are lacking, hydroxychloroquine could be used as an adjuvant agent in patients with APS with difficult management, taking into account the excellent safety profile and the lack of associated bleeding.⁴²

Final remarks

These recommendations, summarized in Table 6, are the result of a focused effort to produce guidelines for therapy within a group of specialist physicians in Cardiology, Neurology, Hematology, Rheumatology and Internal Medicine, with a clinical and research focus on APS. We realize that most of our recommendations are based on weak or incomplete data (evidence level C), therefore they are subject to modification as better studies are completed. Indeed, consensus was not achieved for some recommendations. However, therapy of patients with APS cannot be delayed until high-quality evidence becomes available.

Table 6

Summary of recommendations

Recommendation	Grade of recommendation
1. General measures for aPL carriers
1.1. A strict control of cardiovascular risk factors should be accomplished in all individuals with a high-risk aPL profile, irrespective of the presence of previous thrombosis, concomitant SLE or additional APS features.	Non-graded
1.2. We recommend that all aPL carriers receive thromboprophylaxis with usual doses of low molecular weight heparin in high-risk situations, such as surgery, prolonged immobilization and puerperium.	1C
2. Primary thromboprophylaxis in SLE patients with aPL
2.1. Clinicians should regularly assess patients with SLE for the presence of aPL.	Non-graded
2.2. We recommend that patients with SLE and positive LA or isolated persistent aCL at medium–high titers receive primary thromboprophylaxis with hydroxychloroquine (1) and low-dose aspirin (2).	1B (1)* 2B (2)
3. Primary thromboprophylaxis in aPL-positive individuals without SLE
3.1. In non-SLE individuals with aPL and no previous thrombosis, we suggest long-term primary thromboprophylaxis with low-dose aspirin in those with a high-risk aPL profile, especially in the presence of other thrombotic risk factors.	2C
4. Secondary thromboprophylaxis
4.1. We recommend that patients with either arterial or venous thrombosis and aPL who do not fulfill criteria for APS be managed in the same manner as aPL-negative patients with similar thrombotic events.	1C
4.2. We recommend that patients with definite APS and a first venous event receive oral anticoagulant therapy to a target INR 2.0–3.0.	1B
4.3. Patients with definite APS and arterial thrombosis should be treated with warfarin at an INR >3.0 or combined antiaggregant–anticoagulant (INR 2.0–3.0) therapy.**	Non-graded due to lack of consensus
4.4. An estimation of the patient’s bleeding risk should be performed before prescribing high-intensity anticoagulant or combined antiaggregant–anticoagulant therapy.	Non-graded
4.5. Non-SLE patients with a first non-cardioembolic cerebral arterial event, with a low-risk aPL profile and the presence of reversible trigger factors could individually be considered candidates to treatment with antiplatelet agents.	Non-graded
5. Duration of treatment
5.1. We recommend indefinite antithrombotic therapy in patients with definite APS and thrombosis	1C
5.2. In cases of first venous event, low-risk aPL profile and a known transient precipitating factor, anticoagulation could be limited to 3–6 months.	Non-graded
6. Refractory and difficult cases
6.1. In patients with difficult management due to recurrent thrombosis, fluctuating INR levels, major bleeding or a high risk for major bleeding, alternative therapies could include long-term low molecular weight heparin, hydroxychloroquine or statins.	Non-graded

Some members of the Task Force (DE, RD, SK, VP) support a grade 2B for the recommendation of hydroxychloroquine use in this setting.

Some members of the Task Force (MC, DE, RD, SK, VP) believe that other options such as antiaggregant therapy alone or anticoagulant therapy to a target INR 2.0–3.0 would be equally valid in this setting.

In this set of recommendations, we acknowledge that the house of APS has more rooms than we initially believed. The categorization of different risk subgroups, using both clinical and immunological features (first versus recurrent thrombosis, arterial versus venous events, SLE versus non-SLE, single versus multiple aPL positivity, etc.), opens the door for more tailored therapy. Future advances in the detection of ‘real’ pathogenic aPL, such as antibodies against the domain I of β2-GPI,⁷³ will hopefully provide us with new tools to better define the risk profile of patients with APS.

Footnotes

Funding

Dr Ruiz-Irastorza is supported by the Department of Education, Universities and Research of the Basque Government.

Conflict of interest

The authors declare that they have no conflicts of interest.

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