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

Abstract

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).

Keywords: Antiphospholipid syndrome; Bleeding; DOACs; Thrombotic events; VKAs.