Comparative effectiveness and outcomes of direct oral anticoagulants vs. Vitamin K antagonists (VKA) in atrial arrhythmias patients with isolated lupus anticoagulant without antiphospholipid syndrome: a real-world cohort analysis

BACKGROUND: Direct oral anticoagulants (DOACs) are preferred over VKA for stroke prevention in atrial fibrillation/flutter (AF), but concerns exist regarding their use in antiphospholipid syndrome (APS). The safety and effectiveness of DOACs in AF patients with isolated lupus anticoagulant (LA) who do not meet APS criteria remain uncertain. METHODS: Using the TriNetX global research network, we conducted a new-user, active-comparator cohort study of adults with AF/flutter (ICD-10 I48, on or after 2010) and laboratory-documented LA positivity (ICD-10 D68.62 or confirmatory ratio-based dRVVT/lupus-sensitive aPTT assays) established on or before anticoagulant initiation, excluding coded APS (D68.61) and documented positive anticardiolipin or anti-β2-glycoprotein I antibodies. The index date was the first qualifying DOAC or VKA prescription after AF diagnosis. Propensity score matching (1:1) balanced >100 covariates including prior stroke/TIA, prior bleeding, prior venous thromboembolism, renal function, and comorbidities. Co-primary outcomes were incident ischemic stroke and incident bleeding at 5 years, analyzed with Kaplan-Meier methods and Cox proportional hazards models. RESULTS: After matching, 1152 patients were included (576 per group; mean follow-up ≈2.6 years). Incident ischemic stroke was similar between DOAC and VKA users (5.8% vs. 6.0%; HR 0.93, 95% CI 0.54-1.60; p = 0.80). The incident bleeding composite was directionally lower with DOACs without reaching significance (18.0% vs. 22.6%; HR 0.79, 95% CI 0.57-1.10; p = 0.17), as were severe intracranial bleeding (2.0% vs. 3.3%; HR 0.61, 95% CI 0.29-1.29) and the intracranial/GI hemorrhage composite (9.1% vs. 12.1%; HR 0.75, 95% CI 0.51-1.12). In a pre-specified full-cohort analysis retaining prior events, the bleeding advantage reached nominal significance (26.6% vs. 33.0%; HR 0.77, 95% CI 0.62-0.95). All-cause mortality did not differ (21.2% vs. 22.0%; HR 0.96, 95% CI 0.75-1.23; p = 0.73), and there were no significant differences in myocardial infarction, venous thromboembolism, or composite arterial events. An apixaban-specific analysis was consistent. CONCLUSIONS: In this new-user cohort of AF patients with isolated lupus anticoagulant, DOAC therapy was not associated with higher rates of ischemic stroke, arterial events, venous thromboembolism, or mortality compared with VKA, and bleeding outcomes were directionally lower with DOACs without reaching statistical significance. These hypothesis-generating findings suggest DOACs may be a reasonable option in this population, pending confirmation in prospective studies.