Antithrombotic treatment for stroke associated with antiphospholipid antibodies

Abstract

The current mainstay of treatment of thrombotic antiphospholipid syndrome (APS) is long term warfarin; however, the optimal antithrombotic treatment for APS-related ischaemic stroke or transient ischaemic attacks (TIA) remains uncertain, as does the optimal intensity of anticoagulation. The risk of bleeding with increasing anticoagulant intensity needs to be balanced against the risk of profound permanent disability and death, or irreversible neurological deterioration as a result of recurrent stroke/TIA. Several experts recommend a target INR of 3.5 (range 3.0–4.0) for stroke associated with persistent antiphospholipid antibodies (aPL) which meet International consensus Updated Sapporo (Sydney) classification criteria, with a similar approach in patients with aPL-associated TIA. However, current guidelines recommend a target INR of 2.5 (2.0–3.0) in these patients. Prospective adequately powered clinical studies are required to determine the optimal antithrombotic approach including the potential role of oral direct inhibitors of coagulation for patients with aPL-associated stroke.

Keywords::

• antiphospholipid antibodies
• antiplatelet agents
• oral direct inhibitors
• stroke
• warfarin

The current mainstay of treatment of thrombotic antiphospholipid syndrome (APS) is long-term warfarin; however, the optimal antithrombotic treatment for APS-related ischemic stroke or other ischemic or possibly ischemic manifestations remains uncertain, as does the optimal intensity of anticoagulation. APS is defined as the presence of thrombosis (venous and/or arterial or microvascular) and/or pregnancy loss or late obstetric morbidity in association with persistently positive antiphospholipid antibodies (aPL) [1]. The most frequent site of arterial thrombosis in APS is in the cerebral vasculature resulting in stroke/transient ischaemic attacks (TIA). aPL are a heterogeneous group of autoantibodies, which include lupus anticoagulants (LA), and IgG and/or IgM anticardiolipin antibodies (aCL) and anti-β2-glycoprotein-I (aβ2-GPI) antibodies, of moderate or high positivity (>40 GPL or MPL units, or exceeding the 99th centile). The International consensus Updated Sapporo [Sydney] classification criteria define persistently positive aPL as those being present on two or more occasions at least 12 weeks apart [1].

Estimates vary for the true frequency of aPL in stroke. A study by the AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION), based on analysis of 120 full-text papers and calculation of the median frequency for positive aPL tests for clinical outcome, has estimated the overall frequency of aPL in stroke and TIA to be 13.5 and 7%, respectively. The authors highlighted that limitations of the literature analyzed included that all three criteria aPL tests were performed in only 11% of papers, about one-third used a low-titer aCL cut-off, aPL confirmation was performed in only one-fifth and the study design was retrospective in nearly half. They concluded that best estimates of the incidence of aPL-associated events should be confirmed with appropriately designed population studies [2].

Retrospective and observational studies suggest that stroke associated with aPL has a high risk of recurrence, and consequently, the potential for severe disability or death, and therefore, should be treated with long-term warfarin. In a meta-analysis of 16 studies (9/16; 56% were retrospective cohort studies, 3/16; 19% were prospective cohort studies and 4/16; 25% were randomized control trials), recurrence rates in patients with definite APS and previous venous thromboembolism were lower than in patients with arterial and/or recurrent events, both with and without therapy. Only 3.8% of recurrent events occurred at an international normalized ratio (INR) >3.0 [3]. aPL phenotype may also be important with regard to the risk of recurrence, with high-risk triple-positive patients (i.e., with LA, aCL and aβ2-GPI) on standard intensity anticoagulation showing a 30% recurrence rate over a 6-year follow-up period [4].

The key issue of the optimal intensity of anticoagulation with warfarin for APS-related stroke was addressed in two prospective randomized controlled trials. Crowther et al. and Finazzi et al. concluded that the optimal target INR for venous and/or arterial thromboembolism in APS is 2.5 (range 2.0–3.0) [5,6]. However, patients with arterial thrombosis were poorly represented in these trials. Patients with arterial thrombosis represented only 24% and 32% respectively in the two trials. Patients who developed recurrent thrombosis whist on therapeutic anticoagulation also represented poorly in the two studies. Of note, six patients who developed recurrence of thrombosis in the high intensity arm in the study by Crowther et al., three had subtherapeutic INRs and one had been off warfarin for a considerable period; the study by Finazzi et al. did not report on this issue. In the general stroke and TIA population, aspirin plus dipyridamole, or clopidogrel alone, are superior to aspirin alone [7]. The Antiphospholipid Antibodies and Stroke Study (APASS), a prospective cohort study within the Warfarin versus Aspirin Recurrent Stroke Study (WARSS), found no benefit of warfarin anticoagulation (target INR 1.4–2.8) over aspirin (325 mg/day) in stroke prevention [8]. APASS participants were those in WARSS who consented to enroll in APASS, with usable baseline blood samples drawn prior to randomization to WARSS and analyzed for aPL status within 90 days of the index stroke by a central independent laboratory. However, this study had several major limitations. First, the cohort was elderly, with the average age being 60 years; thus these patients would have been likely to have had multiple risk factors for the development of stroke, such as hypertension, diabetes and cardiovascular disease independent of aPL. In addition, laboratory criteria for aPL were questionable. The assessment of aPL was done only once, at the time of entry into the study; hence some patients may have had transient rather than persistent aPL required for a diagnosis of APS. Of 726 aPL-positive patients, 52.6% had low positive aCL, and furthermore, IgA aCL, which is not included in the Updated Sapporo (Sydney) Criteria, was also used as a diagnostic criterion. The lack of robust data on the optimal anticoagulant intensity is reflected in national and international guidelines. The Task Force at the 13th International Congress on Antiphospholipid Antibodies recommended that patients with definite APS and arterial thrombosis should be treated with warfarin at an INR >3.0 or combined antiplatelet–anticoagulant (INR 2.0–3.0) therapy [9]. This was a non-graded recommendation due to lack of consensus within the Task Force, with other suggested options, such as antiplatelet therapy alone or anticoagulant therapy to a target INR 2.0–3.0 [8]. Determination of the optimal anticoagulant intensity requires consideration of risk factors for bleeding as well as other etiologies for stroke, including atrial fibrillation and arterial dissection. Thrombosis is multifactorial, and thus, the presence of APS is likely to potentiate the risk of standard vascular risk factors for arterial thrombosis, such as hypertension and hyperlipidemia, which should be identified and actively managed.

Current British Committee for Standards in Haematology (BCSH) [7] and American College of Chest Physicians (ACCP) guidelines [10] do not recommend high-intensity anticoagulation in patients with stroke or TIA associated with aPL. This is based on the finding from the APASS study [8], the only prospective study in this group of patients, which had major limitations detailed above. In patients with a history of ischemic stroke or TIA associated with aPL, the ACCP recommends a variety of options: long-term treatment with aspirin (75–100 mg once daily), clopidogrel (75 mg once daily), aspirin/extended-release dipyridamole (25 mg/200 mg two-times a day) or cilostazol (100 mg two-times a day) or vitamin K-dependent oral anticoagulants at a target INR of 2.0–3.0 or a combination of clopidogrel plus aspirin, or triflusal. The BCSH takes a similar approach to the ACCP and also recommend that young adults (<50 years) with ischemic stroke associated with aPL use anticoagulation with warfarin at a target INR of 2.0–3.0 or antiplatelet agents.

There are limited therapeutic options for patients who have recurrent stroke despite high-intensity warfarin. These include addition of an antiplatelet agent or low molecular weight heparin including high-intensity low molecular weight heparin. The possibility that the INR may not reflect the true anticoagulant intensity in APS patients should be considered. This is due to variable responsiveness of reagents used in the INR test to LA, leading to potential instability of anticoagulation [11]. In this circumstance, measurement of amidolytic factor X levels may be useful to assess the true intensity of warfarin anticoagulation [7]. There is a significantly higher risk of bleeding with high-intensity anticoagulation with vitamin K antagonist and with combined anticoagulant and antiplatelet treatment. The risk of bleeding increases, when the INR exceeds 4, and the risk rises sharply with values >5 [12]. The annual rate for bleeding events (fatal or non-fatal requiring hospital admission) with warfarin alone was 4.3 and for warfarin plus aspirin 5.1. Murine models and human studies suggest involvement of the complement system in thrombotic APS and that complement inhibition may ameliorate aPL-induced thrombosis. In cases where anticoagulation has failed, other available therapeutic options include combining anticoagulation with immunosuppression and/or immunomodulation with modalities including rituximab, hydroxychloroquine and statins [13]. Hydroxychloroquine is a well-established treatment for patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis due to its anti-inflammatory effects, which is standard initial therapy in all patients who have no contraindications [14]. In addition to its anti-inflammatory activity, hydroxychloroquine may reduce blood coagulability, probably through reduced red cell sludging and blood viscosity and possibly through some inhibition of platelet reactivity [15]. More recently, it has been shown to protect against thrombosis and increase survival in patients with SLE and consensus guidelines for the management of APS support the use of hydroxychloroquine as an adjuvant therapy to anticoagulation in patients with recurrent thrombosis despite anticoagulation [9]. Statins inhibit the enzyme HMG-CoA reductase, which has a central role in inhibition of hepatic cholesterol production. These agents are widely prescribed to reduce cardiovascular risk; however, it is increasingly apparent that statins have pleiotropic effects including anti-inflammatory and antithrombotic actions [16,17]. Rituximab is a chimeric monoclonal antibody against CD20 and has been used in several autoimmune diseases including SLE [18]. There are reported cases of use of rituximab in patients with catastrophic APS. There is growing evidence that complement activation plays a role in thrombosis in this group of patients. Complement inhibition with eculizumab, used successfully in some cases of catastrophic APS, is thus also an option to explore in anticoagulation-failed refractory cases of ischemic stroke associated with aPL [19].

The new-generation oral anticoagulants or oral direct inhibitors (ODI) of coagulation, dabigatran (a direct thrombin inhibitor), and rivaroxaban and apixaban, both direct factor Xa inhibitors, have shown promising results in the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation in Phase III clinical trials [20–22]. Dabigatran, rivaroxaban and apixaban are approved by NICE and the US FDA for the prevention of stroke or systemic embolization in patients with atrial fibrillation. ODI have also undergone Phase III trials for the treatment of acute deep vein thrombosis and pulmonary embolism and secondary prevention of VTE and rivaroxaban has been licensed for these indications. ODI represent a major therapeutic advance as, unlike warfarin, they do not require regular monitoring of their anticoagulant effects, do not interact with dietary constituents and alcohol and have few reported drug interactions [23]. Unlike warfarin, which reduces the activity of the major naturally occurring anticoagulants activated protein C and S, ODI have no effect on these factors. aPL could increase the counterbalancing effect of warfarin through reduction of protein C and S activity, potentially shifting the equilibrium further away from anticoagulation [24]. We are currently conducting a prospective randomized controlled trial of warfarin versus rivaroxaban in patients with thrombotic APS with venous thromboembolism (Rivaroxaban in Antiphospholipid Syndrome [RAPS]) trial [25]. It should be appreciated that clinical trials of therapeutic dose rivaroxaban versus warfarin have used warfarin at a target INR of 2.5 (i.e., range 2.0–3.0) as the comparator, which may not be always appropriate in APS patients.

What is the optimal antithrombotic approach to patients with aPL-associated ischemic stroke? The risk of bleeding with increasing anticoagulant intensity clearly needs to be balanced against the risk of profound permanent disability and death, or irreversible neurological deterioration as a result of recurrent strokes. Current national guidelines (UK and USA) recommend a target INR of 2.5 (2.0–3.0) in these patients [7,10], however, the evidence base for this is flawed. The lack of consensus within the Task Force at the 13th International Congress on Antiphospholipid Antibodies [9] is testament to the lack of substantive data to guide whether warfarin at a target INR of >3.0 is more efficacious in the prevention of aPL-associated recurrent stroke. This lack of consensus is reflected within the authorship of this editorial. Appropriate studies are required to investigate the potential role of ODI in the management of aPL-associated stroke.

Financial & competing interests disclosure

H Cohen (chief investigator, RPAS) and SJ Machin received a grant (19708) from Arthritis Research UK for RAPS trial. Bayer plc is providing rivaroxaban for RAPS without charge and funding for specific pharmacovigilance functions. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.