Among AF patients with breakthrough ischemic stroke on oral anticoagulation, having at least one identifiable causal factor was associated with higher 90-day mortality (22.7% vs 18.4%, P=0.032).
Cohort (n=1,649)
Yes
What are the causal factors of breakthrough ischemic stroke in AF patients on oral anticoagulation, and do they affect 90-day outcomes?
Nearly half of AF patients with breakthrough ischemic stroke on oral anticoagulation have identifiable contributing factors, which are associated with higher 90-day mortality and stroke recurrence.
Absolute Event Rate: 22.7% vs 18.4%
p-value: p=0.032
Abstract Background and aims Oral anticoagulants (OACs), including vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs), reduce ischemic stroke risk in atrial fibrillation(AF), yet 1–2% of patients still experience breakthrough strokes annually, not fully explained only by poor adherence. Clarifying underlying mechanisms is essential to improve prevention strategies. Methods ASPERA(NCT06823466) is a multicenter ambispective study; this analysis includes the retrospective arm of AF patients with neuroimaging-confirmed ischemic stroke despite ongoing therapeutic OAC between 2020 and 2025, with collection of baseline characteristics, comorbidities, treatments, and 90-day outcomes. Results Among 1,649 patients (median age 80.4 years, 52.2% females) most were treated with DOACs (77.3%). Causal factors for breakthrough ischemic stroke included drug-to-drug interactions potentially affecting OAC efficacy (26.4%), competing etiologies (24.3%), and active cancer (4.4%). Overall, 180 (10.9%) had more than one potential cause and 724 (43.9%) of patients had at least one of those factors. Patients with almost one identifiable factor had a higher prevalence (P 0.01) of arterial hypertension (87.3% vs 76.3%), diabetes mellitus (30.1% vs 24.3%), and dyslipidemia (58.1% vs 45.8%) and a higher rate of minor stroke (NIHSS≤5) presentation (33.8% vs 26.7%, P = 0.002) compared with those without. These patients also showed higher 90-day mortality (22.7% vs 18.4%, P = 0.032) and stroke recurrence rates (4.8% vs 2.4%, P = 0.007). Conclusions Approximately half of patients experiencing ischemic stroke despite ongoing oral anticoagulation have an identifiable mechanism that may have contributed to the event. Improved recognition and characterization of these factors may help reduce the risk of breakthrough stroke and warrant investigation in prospective studies. Conflict of interest A. Zini declares consulting and speaker fees from Bayer, Boehringer-Ingelheim, Alexion, Daiichi Sankyo, Pfizer, PIAM, and Amgen; and advisory board fees from Boehringer-Ingelheim, Daiichi Sankyo, Bayer, and AstraZeneca. L. Pantoni declares consultancy fees from Medtronic, PIAM, and Amicus. S. Sacco reports consultant fees from Novartis, Novo Nordisk, Boehringer Ingelheim, Teva, Allergan, Pfizer Canada, Abbott Canada, Lundbeck, AstraZeneca, and Eli Lilly; and compensation for other services from Novartis. The other authors have nothing to disclose.
Santis et al. (2026) conducted a cohort in Atrial fibrillation with breakthrough ischemic stroke (n=1,649). Presence of at least one identifiable causal factor vs. No identifiable causal factors was evaluated on 90-day mortality (p=0.032). Among AF patients with breakthrough ischemic stroke on oral anticoagulation, having at least one identifiable causal factor was associated with higher 90-day mortality (22.7% vs 18.4%, P=0.032).