The new generation non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) are established as therapeutic alternatives to warfarin and other VKAs, and becoming the standard of care for a wide range of indications, including the treatment of venous thromboembolism (VTE), and the prevention of stroke and systemic embolism in non-valvular atrial fibrillation. NOACs represent a major advance in anticoagulation as, unlike VKAs, they are fixed dose with predictable effect and therefore do not require regular anticoagulant monitoring. In addition, they are not affected by changes in diet and alcohol intake and have fewer drug interactions that affect anticoagulant intensity, which would be expected to result in improved quality of life for patients. Of note, animal studies have shown NOAC-related reproductive toxicity and that NOACs are secreted into milk; these agents are therefore contraindicated in pregnancy and during breastfeeding.
The potential use of NOACs in patients with thrombotic antiphospholipid syndrome (APS), where warfarin remains the current mainstay of treatment although it presents particular problems in this patient group, has sparked considerable interest. APS may occur alone, or with another autoimmune disease. Approximately 30-40% of patients with systemic lupus erythematosus (SLE) have antiphospholipid antibodies (aPL) and 30-40% of this group will develop thrombotic APS, which is considered to be a major adverse prognostic factor in patients with SLE. Appropriate management of thrombotic APS is of key importance to minimise its deleterious clinical impact.
It is likely that patients with thrombotic APS were included in the study populations in the phase III clinical trials of NOACs versus warfarin in patients with VTE. However, aPL status not systematically documented in these trials, and the results may therefore not be directly generalisable to patients with APS, where there remains an unmet need. The RAPS; (Rivaroxaban in Antiphospholipid Syndrome; www://www.isrctn.com/ISRCTN68222801) randomised controlled trial (RCT) of rivaroxaban versus warfarin in APS patients, with or without SLE, who have had previous VTE and are on warfarin, target INR 2.5 (range 2.0-3.0), has completed recruitment. The TRAPS (Rivaroxaban in Thrombotic Antiphospholipid Syndrome; wwws://clinicaltrials.gov/ct2/show/NCT02157272) RCT, open to recruitment, is comparing rivaroxaban with warfarin in high-risk (i.e. triple aPL positive) APS patients.
It should be appreciated that clinical trials of NOACs versus warfarin in patients with VTE have used warfarin at a target INR of 2.5 (range 2.0–3.0) as the comparator. The optimal dose of NOACs in patients who experience recurrent VTE whilst on standard intensity VKA is not known. There is a notable lack of appropriate prospective clinical studies to guide optimal antithrombotic treatment, in particular with regard to anticoagulant intensity, in APS patients with ischaemic stroke or cerebral ischaemic lesions. The role of NOACs in these patients, and those with arterial thromboembolism in other sites, needs to be explored. In conclusion, definition of the role of NOACs in patients with thrombotic APS should be based on the results of prospective, appropriately designed and adequately powered clinical studies.
Disclosure of Interest H. Cohen Grant/research support from: Bayer, Speakers bureau: Bayer (honoraria diverted to local Charity)