Direct oral anticoagulants versus vitamin K antagonists after venous thrombosis in antiphospholipid syndrome: Recurrence, safety, and exploratory phenotype analysis. A real-life cohort study

Background: Evidence comparing direct oral anticoagulants (DOACs) with vitamin K antagonists (VKAs) remains uncertain, particularly in patients whose index event is venous thromboembolism (VTE). Objective: To compare the effectiveness and safety of DOACs versus VKAs after an index VTE in APS and, as an exploratory objective, to identify APS features associated with recurrent thrombosis (rTEs). Methods: We conducted a retrospective cohort study of 84 consecutive adults fulfilling 2023 ACR/EULAR APS classification criteria and followed between 2010 and 2025 after an index VTE. Patients received VKAs (n = 54) or DOACs (n = 30). The primary efficacy outcome was rTEs during treatment; bleeding was the primary safety outcome. Time-to-event and propensity-score methods were used to address differences between treatment groups. Phenotype analyses were considered exploratory. Results: Over 686.2 patient-years, 25 rTEs occurred. Recurrence was more frequent with DOACs than with VKAs (46.7% vs. 20.4%; p = 0.012), with incidence rates of 12.2 and 1.9 events per 100 patient-years, respectively. In multivariable Cox analysis, DOACs exposure was associated with earlier recurrence (HR 4.1, 95% CI 1.7-10.3; p = 0.002), and the association remained in propensity-score analyses. Microvascular involvement was more frequent among patients with rTEs (40.0% vs. 13.6%; p = 0.007). Bleeding rates were low and did not differ significantly between groups. Conclusions: In this single-centre cohort restricted to APS patients with an index VTE, DOACs exposure was associated with more frequent and earlier recurrent thrombosis than VKAs therapy, without an evident bleeding advantage. Microvascular involvement may mark a higher-risk phenotype, but this exploratory finding requires confirmation in larger prospective cohorts.