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Antiphospholipid syndrome (APS) is an autoimmune condition characterized by thrombosis and pregnancy morbidity.1 Thrombotic APS variably involves arterial, venous, and microvascular circulations. The pathophysiology of thrombotic APS is thought to involve the generation of autoantibodies that bind to the major B-cell epitope on domain I of the β2-glycoprotein. This binding and subsequent thrombus formation occurs through intermediary processes that likely include oxidative stress,2 complement activation,3 and neutrophils4 invoking a “2-hit” process of initial endothelial disruption followed by thrombus formation.5 Laboratory diagnostic criteria for APS include the presence of any one of the qualifying antibody isotypes (anticardiolipin IgG or IgM, anti–β2-glycoprotein-1 IgG or IgM) and titers, or the presence of a lupus anticoagulant (LA) initially and again at least 12 weeks later. Anticoagulant therapy is the mainstay of treatment for thrombotic APS, and due to the high risk for thrombosis progression and recurrence, indefinite anticoagulation is often considered.6 Even with use of vitamin K antagonists (VKA) the annual rate of recurrent thrombosis is at least 1.5%7 and potentially as high as 30% over 5 years.8,9 Direct oral anticoagulants (DOACs) offer a simpler therapeutic regimen with greater convenience than VKA therapy, and are approved for the treatment and secondary prevention of venous thromboembolism (VTE).10,11 There remains great interest to offer APS patients an alternative to VKA therapy, provided that this is safe and effective. The limited available evidence from prospective and retrospective studies was presented in a systematic review12 and a patient-level meta-analysis.13 Concerningly, these analyses reported recurrent thrombosis rates around 15% among APS patients treated with DOACs with as high as a 4-fold increased risk for recurrence among those patients that have all 3 APS lab tests positive—“triple positivity.”13 These publications have significant limitations (eg, meta-analyses include multiple case reports with an n = 1 that potentially amplify selection and publication biases, patients that experienced thrombosis on other anticoagulants prior to receiving a DOAC were included, and studies were retrospective). There are 5 small randomized controlled trials involving DOAC treatment of patients with APS and a history of thrombosis. The first (RAPS) randomized 116 patients with APS and a history of VTE to either rivaroxaban 20 mg daily or dose-adjusted warfarin (target International Normalized Ratio [INR], 2.5).14 The investigators reported that the percentage change in endogenous thrombin potential at 42 days for rivaroxaban was inferior to that of warfarin; but no thromboembolic events occurred over the 210-day follow-up in either group. The authors concluded that rivaroxaban might be an effective and safe alternative in patients with APS and previous VTE. The TRAPS (Rivaroxaban in Thrombotic Antiphospholipid Syndrome) study compared rivaroxaban 20 mg daily to warfarin (target INR, 2.5) among patients with triple-positive APS and prior VTE or arterial thrombosis.15 TRAPS was terminated prematurely by the data safety monitoring board because the rate of thromboembolic events was 12% among those randomized to rivaroxaban (4 ischemic strokes and 3 myocardial infarctions) compared to 0% among those

Direct oral anticoagulants in antiphospholipid syndrome with venous thromboembolism: Impact of the European Medicines Agency guidance