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The mechanisms underlying these events remain unclear. We aimed to identify potential causes of breakthrough ischemic stroke and assess their impact on outcomes, with a focus on drug interactions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>ASPERA-R is a multicenter retrospective study including patients with ischemic stroke despite ongoing OAC therapy for AF (February 2020\u2013February 2025). Ongoing treatment was defined by DOAC last intake within 48\u00a0h or therapeutic INR levels for VKAs. Potential causes included interacting drugs, active cancer, and competing etiologies. Ninety-day outcomes were compared between patients with and without\u2009\u2265\u20091 potential cause using adjusted Cox regression. Inverse probability-weighted analyses (IPW) evaluated the impact of interacting drugs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 1649 patients (median age 80.4\u00a0years [IQR 73.2\u201385.6]; 860 [52.2%] female), most were on DOACs (1275;\u00a077.3%), and 724 (43.9%) had\u2009\u2265\u20091 potential cause. Interacting drugs were identified in 28.4%, competing etiologies in 24.3%, and cancer in 4.4% cases. Patients with one or more potential cause had a higher risk of recurrent ischemic stroke at 90\u00a0days (HR 2.04, 95% CI 1.18\u20133.53) compared with those without, with no differences in other outcomes. In the IPW analyses, interacting drugs were associated with increased myocardial infarction risk (HR 3.26, 95% CI 1.30\u20138.17).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Potential causes are identifiable in about half of breakthrough strokes and are associated with higher risk of recurrence compared with those without. Improved detection and management of these factors may reduce recurrence risk, warranting individualized approaches.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00415-026-14039-x","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T02:05:55Z","timestamp":1786932355000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Decoding the causes of ischemic stroke despite ongoing oral anticoagulation and their clinical impact: the ASPERA-R study"],"prefix":"10.1007","volume":"273","author":[{"given":"Federico","family":"De 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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. B. Casolla declares speaker fees from ACTICOR Biotech and Sanofi-Aventis France. H. Budincevic declares speaker fees from Bayer, Boehringer Ingelheim, Viatris, Novartis, Pliva-Teva, Abbott, Medis, Eli Lilly, Berlin Chemie, Pfizer, and Roche. R. Ornello reports speaker fees from AbbVie, Bayer, Eli Lilly, Lundbeck, Novartis, Organon, Pfizer, and Teva. S. Sacco reports consultant fees from Novartis, Novo Nordisk, Boehringer Ingelheim, Teva, Allergan, Pfizer Canada, Abbott Canada, Lundbeck, AstraZeneca, and Eli Lilly and declares compensation for other services from Novartis. All other authors report no relevant disclosures.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki. The ASPERA study protocol has been registered and approved by the Ethics Committee of the Abruzzo Region (CETRA) with protocol number 033054\/25; it is publicly accessible on the ClinicalTrials.gov database with code NCT06823466.","order":2,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Informed consent was obtained from all individual participants included in the study.","order":3,"name":"Ethics","label":"Consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"526"}}