Treatment of antiphospholipid syndrome

Introduction

Antiphospholipid syndrome (APS) is characterized by vascular thrombosis and/or pregnancy morbidity occurring in patients with persistent antiphospholipid antibodies (aPL). Prevention of thrombosis and proper management of women during pregnancy are the major goals of therapy in patients with aPL. Treatment of APS has long been the subject of intense debate, due to the diversity of clinical presentations and medical specialties involved. A consensus document has been issued by the APS Treatment Trends Task Forces, created as part of the International Congress on aPL. The main aim of the task force was to systematically review the current and potential future treatment strategies for aPL-positive patients. More recently, the EULAR recommendations for the management of APS in adults have been released. A summary of the above mentioned recommendations is shown in Table 65.1 .

This chapter reviews the available evidence and recommendations for primary thromboprophylaxis in aPL-positive individuals with no prior thrombotic events, secondary prophylaxis in patients with a previous thrombotic event, and the treatment of refractory or difficult cases. Strategies for the management of APS during pregnancy are also discussed.

Primary thromboprophylaxis

It is still an open question whether prophylactic treatment is needed in subjects with aPL who have no history of thrombosis. The net benefit of active therapy against placebo has never been clearly proven. However, we suggest a careful thrombotic risk assessment as part of good clinical practice and general measures to control cardiovascular risk factors for all patients with aPL (Table 1). The avoidance of smoking and controlling body weight, high blood pressure, and hypercholesterolemia should be considered as main management goals in all subjects with aPL and these concepts are part of the updated EULAR recommendations for the management of APS in adults. Estrogen-containing oral contraceptive pills or estrogen replacement therapy should be avoided due to their prothrombotic effects.

Autoimmune conditions, mainly systemic lupus erythematosus (SLE), are considered by themselves as an additional risk factor for thrombosis. Thus, primary thromboprophylaxis should be considered with low-dose aspirin (75–100 mg/day) in all patients with an underling systemic autoimmune conditions and persistent aPL at medium–high titers (immunoglobulin (Ig)M or IgG >40 IgG antiphospholipid units (GPL) or IgM antiphospholipid units (MPL) or >99th percentile). In patients with SLE and with persistently positive aPL, primary thromboprophylaxis including low-dose aspirin (75–100 mg/day) and/or hydroxychloroquine (200–400 mg/day) is strongly recommended. This suggestion is made based on studies that have shown that hydroxychloroquine protects against thrombosis in patients with lupus, including those with aPL.

Although no study has specifically investigated whether the addition of antiplatelet agents offers additional protection, aspirin is generally considered to be an effective option in the setting of primary thromboprophylaxis. Thus, given the general recommendation of hydroxychloroquine therapy in patients with lupus, the addition of low-dose aspirin (LDA) should be decided on an individual basis. Specifically, the addition of low-dose aspirin may be appropriate in selected cases, such as for patients with a high risk aPL profile (e.g., triple positivity for lupus anticoagulant (LA), anticardiolipin (aCL), and anti-β2-glycoprotein I (β2GPI)) and/or other concomitant cardiovascular risk factors, and for SLE patients with a history of obstetric APS.

However, although low-dose aspirin seems a logical thromboprophylaxis approach, supportive evidences are still anecdotal. The Physician Health Study demonstrated no protection against deep venous thrombosis in men with anticardiolipin antibodies receiving low-dose aspirin. However, more recent evidence suggests a protective role for low-dose aspirin for venous thrombosis, at least in the general population.

In asymptomatic carriers of aPL without an underlying connective tissue disease, the decision regarding thromboprophylaxis should be best based on the aPL profile. Aspirin thromboprophylaxis (75–100 mg/day) is suggested for those with a high-risk profile, such as patients with lupus anticoagulant, particularly triple-positive individuals.

A prospective, multicenter, randomized, open, controlled trial in patients positive for antiphospholipid antibodies (ALIWAPAS) aimed to examine the efficacy and safety of LDA versus LDA plus low-intensity warfarin in the primary thrombosis prevention of aPL-positive patients with SLE and/or obstetric morbidity. No differences in the number of thromboses were observed between patients treated with LDA versus those treated with LDA plus low-intensity warfarin. More episodes of bleeding were detected in the LDA plus warfarin group. The authors concluded that the LDA plus warfarin regime was significantly less safe and not as acceptable as LDA alone.

At least two score systems have been proposed as thrombotic risk assessment tools in patients with aPL. The Global Anti-Phospholipid Syndrome Score (GAPSS) was developed by our group and independently validated as an effective tool to help physicians in stratifying patients according to their thrombotic risk. Patients with a GAPSS score ≥10 might be considered to be at a higher risk of thrombotic event and might require a closer follow-up, especially in high-risk situations (e.g., surgery, immobilization). Proper management of removable risk factors, such as hyperlipidemia and hypertension, is highly recommended to reduce the thrombotic risk.

Prevention of recurrent thrombosis

At present, the management of APS patients with previous thrombosis is based on long-term antithrombotic therapy because the rate of recurrent thrombosis is high (29% per year without treatment). Some questions remain on whether patients with APS should receive the same therapy as the general population with similar manifestations and whether arterial and venous events should be treated in a different way.

Two randomized, controlled trials have compared high [target international normalized ratio (INR) 3.0–4.0] with standard (target INR 2.0–3.0) intensity of anticoagulation for secondary thromboprophylaxis in patients with APS. No significant differences in terms of efficacy or safety between the regimens were observed in these trials. However, both of them suffered from a main bias due to the overrepresentation of patients with first venous thromboembolism. Thus, we recommend indefinite anticoagulant therapy with vitamin K antagonist (VKA) to a target INR of 2.0–3.0 for patients with APS and first venous event. A reduction in the duration of treatment with VKA can be considered only in patients with a low-risk aPL profile and clear provoking factors (e.g., surgery, prolonged immobilization) at the time of the thrombosis.

The management of arterial events is more controversial and debate persists. The APS and Stroke Study (APSSS) concluded that patients with stroke and aPL not fulfilling classification criteria would be best treated as the general population, with low-dose-aspirin. However, it is our current approach that patients with definite APS with arterial disease and/or recurrent events merit a more aggressive approach, which might include VKA with a target INR of 3.0–4.0. Occasionally, combined anticoagulant-antiaggregant therapy may also be considered. In fact, recurrences are very infrequent (0.016–0.031 events per patient per year) among patients receiving effective oral anticoagulation to an INR of 3.0–4.0. However, the physician has to be aware that high-intensity oral anticoagulation therapy carries an inevitable risk of serious hemorrhage, although this risk does not appear higher than that observed in other thrombotic conditions warranting oral anticoagulation.

The management of venous thromboembolism (VTE) is a rapidly changing scenario. The direct oral anticoagulants (DOAC) (dabigatran etexilate, rivaroxaban, apixaban, and edoxaban) have been shown to be effective in the management of VTE and they do not require laboratory monitoring. However, despite some pilot experiences were showing promising results for the use of DOAC in the management of VTE in APS, there is still an ongoing debate about their safety. A phase II/III trial to assess the efficacy and safety of rivaroxaban in APS patients with previous VTE showed that endogenous thrombin potential (ETP) for rivaroxaban did not reach the non-inferiority threshold; however, as there was no increase in thrombotic risk compared with standard-intensity warfarin, rivaroxaban was considered an effective and safe alternative in patients with APS and previous venous thromboembolism. Nevertheless, more recently, a recent RCT of rivaroxaban versus warfarin in patients with APS with triple aPL positivity was prematurely terminated due to an excess of thromboembolic events (mostly arterial) in the rivaroxaban arm. Accordingly, rivaroxaban should not be used in patients with triple aPL positivity. Before further evidence will be available, DOACs may be considered in very selected patients, mainly with venous event, with difficulty achieving a target INR of 2–3 despite compliance with VKA or who have contraindications to VKA. Switching from treatment with VKA to DOACs due to low adherence to VKA or INR monitoring should be avoided.