A subanalysis of the ARTESiA trial has provided a detailed characterisation of major bleeding events in patients with subclinical atrial fibrillation (SCAF) treated with apixaban versus aspirin.¹ While apixaban increased the overall risk of major bleeding, this was primarily driven by gastrointestinal events, with no significant difference in fatal or intracranial bleeding rates compared to aspirin.

This prespecified subanalysis examined data from the Apixaban for the Reduction of Thromboembolism in Patients With Device-Detected Subclinical Atrial Fibrillation (ARTESiA) trial. This international, double-blind, double-dummy randomised clinical trial included 3,961 patients (mean age 76.8 years; 64% male) with device-detected SCAF and a CHA₂DS₂-VASc score of ≥3. Participants were randomised to receive either apixaban (5 mg twice daily, or 2.5 mg when indicated) or aspirin (81 mg once daily). The primary outcome for this analysis was major bleeding, as defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria, over a mean follow-up of 3.5 years.

Major bleeding occurred more frequently in the apixaban group than in the aspirin group (86 vs 47 patients, respectively), corresponding to rates of 1.71 versus 0.94 per 100-patient-years (hazard ratio [HR], 1.80; 95% CI, 1.26–2.57).

The higher rate was driven by gastrointestinal bleeding, which occurred in 0.89% of apixaban patients versus 0.40% of aspirin patients per 100 patient-years (HR, 2.23; 95% CI, 1.32–3.78). However, rates of intracranial bleeding (0.33 vs 0.40 per 100 patient-years; HR, 0.82; 95% CI, 0.43–1.57) and fatal bleeding (0.10% vs 0.16% per 100 patient-years; HR, 0.63; 95% CI, 0.20–1.91) were similar between the two groups.

Major bleeding events in the apixaban arm were less likely to occur at critical sites compared to the aspirin arm (27.9% vs 46.8%; p=0.03), including intracranial sites (18.6% vs 42.6%; p=0.003). The majority of major bleeding events in both groups were classified as nonemergencies, characterised by a decrease in haemoglobin of ≥2 g/dL. Factors significantly associated with an increased risk of major bleeding included nonsteroidal anti-inflammatory drug (NSAID) use (HR, 10.25), cancer (HR, 2.87), increasing age (HR, 1.47 per 5-year increase), and randomisation to apixaban (HR, 1.84).

This analysis provides crucial context for the primary ARTESiA findings. According to the investigators, "in patients with SCAF, apixaban increased major gastrointestinal bleeding compared with aspirin but intracranial and fatal bleeding events were similar between groups; most bleeding events were nonemergencies characterized by a decrease in hemoglobin." These findings can help clinicians in shared decision-making when balancing the stroke reduction benefits of apixaban against its bleeding risks in this patient population.

References

1. Siegal DM, Sticherling C, Healey JS, et al. Major Bleeding With Apixaban vs Aspirin: A Subanalysis of the ARTESiA Randomized Clinical Trial. JAMA Cardiol. Published online November 12, 2025. https://doi.org/10.1001/jamacardio.2025.4151

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