Direct oral anticoagulants versus Vitamin K antagonists in antiphospholipid syndrome: A systematic review and meta-analysis

Background: Randomized controlled trials (RCTs) comparing the efficacy and safety of direct oral anticoagulants (DOACs) versus Vitamin K antagonists (VKAs) in patients with thrombotic antiphospholipid syndrome (APS) have yielded inconsistent results, partly due to the inherent challenges of conducting RCTs in populations with rare medical conditions. We conducted a systematic review and meta-analysis to evaluate the comparative effects of DOACs versus VKAs in thrombotic APS. Methods: RCTs and observational studies comparing DOACs versus VKAs in patients with thrombotic APS were included. The primary endpoint was a composite of arterial (ATE) and venous thrombotic events (VTE). Incidence rate ratios (IRRs) and associated 95 % confidence intervals (CI) were used to account for different follow-up durations. GRADE was used for rating the certainty of evidence. Findings: Twelve studies, four randomized and eight observational, encompassing a total of 1307 APS patients were included. The use of DOACs was associated with an increase in the primary endpoint (IRR 2.33; 95 % CI 1.18–4.58; GRADE=moderate) driven by increased ATE (IRR 2.70; 95 % CI 1.42–5.13; GRADE=low), compared with the use of VKA. VTE (IRR 0.98; 95 % CI 0.59–1.64; GRADE=low), major (IRR 0.83; 95 % CI 0.48–1.43; GRADE=low) and non-major (IRR 1.32; 95 % CI 0.81–2.14; GRADE=very low) bleeding did not differ significantly between groups. Compared with VKAs, DOACs were associated with an increase in myocardial infarction (IRR 4.71; 95 % CI 1.00–22.21; GRADE=very low) and stroke (IRR 7.48; 95 % CI 1.27–44.13; GRADE=very low). The increased risk of arterial thrombotic events with DOACs was consistently observed in a dedicated analysis of RCTs and was mitigated by the concomitant use of single antiplatelet therapy. Interpretation: In patients with thrombotic APS, the use of DOACs is associated with increased thrombotic events compared with VKAs, mainly driven by arterial thrombotic events. A single antiplatelet therapy combined with DOACs maight offer a promising alternative to VKAs, warranting further dedicated investigations. Primary Funding Source: The study was not funded. Protocol registration: This study is registered in PROSPERO (CRD42024582033).