Abstract
Background: Antiphospholipid syndrome (APS) is a major cause of arterial thrombosis and recurrent vascular events, often requiring lifelong anticoagulation. While warfarin remains the standard of care, the role of adding low-dose aspirin (ASA) for secondary prevention remains debated, especially given concerns about increased bleeding risk. Current guideline recommendations are largely based on limited clinical trial data, and real-world evidence comparing combination therapy to warfarin alone is lacking. Clarifying the impact of adjunctive aspirin on both thrombotic and bleeding outcomes in APS patients is crucial for guiding optimal management.
Methods: We conducted a retrospective cohort study using the TriNetX Network. Two cohorts were defined: (1) APS patients with arterial thrombosis on warfarin and Aspirin 81 mg, and (2) APS patients with arterial thrombosis on warfarin without ASA. Inclusion criteria required age ≥18 years, diagnosis of APS (ICD-10: D68.61), arterial thrombotic events (e.g., cerebral infarction, myocardial infarction, arterial embolism), and INR values between 2.0 and 3.0. Patients on other antiplatelet or direct oral anticoagulants were excluded in both cohorts. Propensity score matching (1:1) was performed to balance demographics and comorbidities. Outcomes were assessed over a 4-year follow-up period and included thrombotic events, bleeding complications, mortality, and healthcare utilization. Hazard ratios (HR) were calculated with 95% confidence intervals (CI).
Results: After 1:1 propensity score matching, 2,144 patients were included in each cohort. The mean follow-up duration was 1,479 days in the aspirin group and 1,589 days in the non-aspirin group. Kaplan-Meier survival analysis demonstrated that patients receiving aspirin in addition to warfarin had significantly increased hazards for multiple adverse outcomes.
The risk of the following was higher in the aspirin group: gastrointestinal bleeding (HR 1.44, 95% CI 1.14–1.81, p=0.002), hemoperitoneum (HR 3.20, 95% CI 1.44–7.13, p=0.003), iron deficiency anemia (HR 1.35, 95% CI 1.12–1.63, p=0.001), and requirement of blood transfusion (HR 1.34, 95% CI 1.02–1.77, p=0.037). The intracranial hemorrhages outcome had an HR of 1.40 (95% CI 1.01–1.93, p=0.041).
The hazard ratio for ischemic stroke was 1.52 (95% CI 1.10–2.08, p=0.009), and for acute myocardial infarction, HR was 2.10 (95% CI 1.47–3.00, p<0.001). Peripheral arterial events showed no significant difference (HR 1.07, 95% CI 0.68–1.66, p=0.775).
For hospitalization, the HR was 1.75 (95% CI 1.34–2.28, p<0.001), and for outpatient visits, HR was 1.84 (95% CI 1.27–2.67, p=0.001). Emergency department visits were also more frequent in the aspirin group (HR 1.31, 95% CI 1.11–1.55, p=0.001). There was no significant difference in all-cause mortality between the two groups (HR 1.02, 95% CI 0.90–1.16, p=0.779).
Conclusions: In this large, real-world cohort of APS patients with arterial thrombosis, adding low-dose aspirin to warfarin was linked to a significantly higher risk of major bleeding—including gastrointestinal hemorrhage, hemoperitoneum, iron deficiency anemia, and blood transfusion—without any reduction in all-cause mortality. Importantly, rates of ischemic stroke and acute myocardial infarction were also higher in the aspirin group. This unexpected increase in arterial events may reflect residual confounding by indication, as patients perceived to be at greater thrombotic risk were more likely to receive combination therapy. Despite careful propensity score matching, unmeasured differences in disease severity and clinical decision-making may have contributed to these findings. These findings raise important questions about routinely combining aspirin with warfarin in APS patients with arterial thrombosis, as it appears to increase bleeding risk without improving survival. Further prospective studies are needed to determine the most effective and safest antithrombotic approach for this high-risk group.
