Background The use of direct oral anticoagulants (DOACs) in antiphospholipid syndrome (APS) remains a topic of discussion. Current guidelines favor warfarin for high-risk APS, but the optimal approach for single antibody–positive APS (anticardiolipin [aCL], lupus anticoagulant [LAC], or beta-2 glycoprotein I [B2GP1]) is unclear.Methods We performed three parallel, retrospective cohort studies using the TriNetX global network. Adult patients (≥18 years) with APS and isolated positivity for aCL, LAC, or B2GP1 antibodies were identified. For each antibody cohort, patients newly initiated on DOACs were compared to those started on warfarin. Propensity score matching was performed 1:1 for demographics and key comorbidities. Statistical analysis utilized Kaplan-Meier survival curves with log-rank tests and hazard ratios (HR) with 95% confidence intervals; p < 0.05 was considered significant.Results In the aCL-positive cohort, there were no statistically significant differences between DOAC and warfarin groups for gastrointestinal (GI) bleed (HR 1.35, 95% CI 0.80–2.30, p=0.26), hemoperitoneum (HR 2.09, 95% CI 0.38–11.41, p=0.39), intracranial hemorrhage (ICH) (HR 0.79, 95% CI 0.33–1.88, p=0.59), iron deficiency anemia (HR 1.25, 95% CI 0.77–2.03, p=0.37), blood transfusion (HR 1.40, 95% CI 0.70–2.82, p=0.34), ischemic stroke (HR 0.70, 95% CI 0.31–1.57, p=0.38), peripheral arterial thrombosis (HR 0.56, 95% CI 0.21–1.52, p=0.25), deep vein thrombosis (DVT) (HR 1.69, 95% CI 0.95–3.01, p=0.07), pulmonary embolism (PE) (HR 0.76, 95% CI 0.35–1.65, p=0.48), outpatient visits (HR 0.88, 95% CI 0.52–1.51, p=0.64), emergency visits (HR 0.77, 95% CI 0.48–1.22, p=0.27), and all-cause mortality (HR 0.94, 95% CI 0.68–1.31, p=0.72). However, DOACs were associated with a higher risk of myocardial infarction (MI) (HR 2.48, 95% CI 1.01–6.09, p=0.040) and a lower risk of hospitalization (HR 0.378, 95% CI 0.175–0.817, p=0.010) compared to warfarin.

In the LAC-positive cohort, DOAC therapy was associated with significantly lower risks for GI bleed (HR 0.72, 95% CI 0.58–0.88, p=0.001), hemoperitoneum (HR 0.18, 95% CI 0.06–0.53, p<0.001), ICH (HR 0.50, 95% CI 0.32–0.77, p=0.001), blood transfusion (HR 0.76, 95% CI 0.57–1.00, p=0.049), ischemic stroke (HR 0.50, 95% CI 0.37–0.67, p<0.001), peripheral arterial thrombosis (HR 0.59, 95% CI 0.43–0.80, p=0.001), DVT (HR 0.79, 95% CI 0.69–0.91, p=0.001), hospitalization (HR 0.75, 95% CI 0.66–0.86, p<0.001), and all-cause mortality (HR 0.61, 95% CI 0.53–0.71, p<0.001), compared to warfarin. Iron deficiency anemia was more frequent with DOACs (HR 1.22, 95% CI 1.05–1.42, p=0.010). There were no significant differences for MI (HR 1.24, 95% CI 0.85–1.80, p=0.27), PE (HR 0.85, 95% CI 0.70–1.04, p=0.12), outpatient visits (HR 1.05, 95% CI 0.90–1.22, p=0.53), or emergency visits (HR 0.92, 95% CI 0.82–1.03, p=0.13).

In the B2GP1 ab–positive cohort, DOACs were associated with a lower risk of ischemic stroke (HR 0.21, 95% CI 0.06–0.74, p=0.007). There were no significant differences between DOAC and warfarin groups in GI bleed (HR 0.79, 95% CI 0.42–1.48, p=0.47), hemoperitoneum (HR 1.79, 95% CI 0.30–10.75, p=0.52), ICH (HR 0.93, 95% CI 0.29–3.06, p=0.91), iron deficiency anemia (HR 0.96, 95% CI 0.58–1.59, p=0.88), blood transfusion (HR 0.50, 95% CI 0.21–1.23, p=0.13), MI (HR 0.61, 95% CI 0.24–1.53, p=0.28), peripheral arterial thrombosis (HR 1.05, 95% CI 0.39–2.79, p=0.93), DVT (HR 0.80, 95% CI 0.39–1.66, p=0.55), PE (HR 0.79, 95% CI 0.33–1.89, p=0.60), hospitalization (HR 1.06, 95% CI 0.55–2.04, p=0.86), outpatient visits (HR 1.00, 95% CI 0.50–2.00, p=0.997), emergency visits (HR 0.96, 95% CI 0.62–1.49, p=0.86), and all-cause mortality (HR 0.89, 95% CI 0.60–1.31, p=0.55)Conclusions In this large, real-world analysis of APS patients with single-positive antibody profiles, DOACs demonstrated non-inferior safety and efficacy to warfarin for most clinically relevant thrombotic, bleeding, and mortality outcomes. Notably, DOACs were associated with a lower risk of ischemic stroke in B2GP1-positive APS and a broad reduction in adverse outcomes among LAC-positive patients. Acute MI risk was increased with DOACs in aCL-positive patients. These results support the consideration of DOACs as a therapeutic alternative to warfarin in select single-positive APS populations, but highlight the need for prospective studies to clarify subgroup-specific risks.

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2025
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