Comparative safety and effectiveness of apixaban versus warfarin in antiphospholipid syndrome with chronic kidney disease: A real-world propensity-matched cohort study

Abstract Background: Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by recurrent arterial and/or venous thrombosis and is associated with significant long-term morbidity and mortality. Patients with APS and concomitant chronic kidney disease (CKD) represent a particularly high-risk population, as both conditions independently increase the risk of thrombotic and bleeding complications. Warfarin remains the recommended anticoagulant for high-risk APS based on current guidelines, but its use in CKD is complicated by labile INRs, frequent monitoring, and drug-diet interactions, as well as an elevated risk of both bleeding and thrombotic events. Direct oral anticoagulants (DOACs), such as apixaban, offer advantages including fixed dosing, fewer dietary interactions, and no requirement for regular laboratory monitoring. However, data on the safety and efficacy of DOACs in APS, particularly among patients with CKD, remain limited and somewhat conflicting, with randomized trial data notably lacking for this subgroup. Given the unique clinical challenges faced by APS patients with CKD, there is a critical need to evaluate real-world outcomes of apixaban versus warfarin in this population to inform evidence-based decision-making. Methods: We conducted a retrospective cohort study using the TriNetX US Collaborative Network. Adult patients (≥18 years) with a diagnosis of APS and stage 3–5 CKD who were newly initiated on apixaban or warfarin were identified. Patients receiving other oral anticoagulants or antiplatelet agents were excluded. Propensity score matching (1:1) was performed based on demographics and relevant comorbidities, yielding 523 patients per group. Outcomes were compared using Kaplan-Meier analysis, reporting hazard ratios (HRs) and log-rank p-values.. Results: A total of 1,054 matched patients (mean age 66 years; 56% female) were included. Compared to warfarin, apixaban was associated with a significantly lower risk of major bleeding, defined as a composite of gastrointestinal, intracranial, and other clinically significant hemorrhages (HR 0.46, 95% CI 0.26–0.80, p=0.005) and Intracranial hemorrhage (ICH) ( HR 0.14, 95% CI 0.02–1.12, p=0.030), with no observed hemoperitoneum events in the apixaban group. There were no significant differences between groups in the risk of gastrointestinal bleed (HR 0.72, 95% CI 0.38–1.34, p=0.292), intracerebral hemorrhage (HR 0.27, 95% CI 0.03–2.46, p=0.216), iron deficiency anemia (HR 1.06, 95% CI 0.67–1.68, p=0.818), or requirement of blood transfusion (HR 0.91, 95% CI 0.39–2.10, p=0.816). For thrombotic and arterial outcomes, there were no significant differences in deep vein thrombosis (HR 0.85, 95% CI 0.45–1.58, p=0.598), pulmonary embolism (HR 0.74, 95% CI 0.31–1.79, p=0.503), ischemic stroke (HR 0.50, 95% CI 0.19–1.33, p=0.156), acute myocardial infarction (HR 0.72, 95% CI 0.30–1.77, p=0.472), or peripheral arterial thrombosis/limb ischemia (HR 0.36, 95% CI 0.10–1.34, p=0.112). There were also no significant differences in healthcare utilization outcomes, including emergency room visits (HR 1.02, 95% CI 0.67–1.55, p=0.923), outpatient visits (HR 0.68, 95% CI 0.31–1.50, p=0.340), or hospitalizations (HR 0.94, 95% CI 0.60–1.46, p=0.768). Notably, all-cause mortality was significantly lower in the apixaban group (HR 0.51, 95% CI 0.34–0.74, p=0.000) compared to warfarin. Conclusion: In this large, multicenter, real-world cohort of patients with APS and stage 3–5 chronic kidney disease, apixaban use was associated with significantly lower rates of major bleeding, ICH, and all-cause mortality compared to warfarin, while rates of thrombotic and arterial events were similar between groups. There were no significant differences in gastrointestinal bleeding, anemia, blood transfusion, or healthcare utilization outcomes. These findings suggest that apixaban may offer a safe and effective alternative to warfarin for anticoagulation in APS patients with CKD, a population often excluded from randomized trials, potentially expanding therapeutic options in this high-risk group. Nonetheless, prospective, randomized studies are needed to confirm these observations and to further delineate the role of DOACs in APS patients with varying degrees of renal dysfunction and antibody positivity.