Early versus Late starting of Direct Oral Anticoagulants after breakthrough ischemic stroke: A Target Trial Analysis from the ASPERA-R Study

BACKGROUND AND PURPOSE: Randomized trials support early initiation of direct oral anticoagulants (DOACs) after atrial fibrillation (AF)-related ischemic stroke, but patients with breakthrough ischemic stroke occurring despite ongoing anticoagulation have been largely under-represented. We evaluated the effectiveness and safety of early versus delayed DOAC initiation after breakthrough ischemic stroke. METHODS: We performed a target trial emulation comparing early versus delayed DOAC initiation in patients with breakthrough ischemic stroke. Treatment strategies were prespecified using severity-adapted timing thresholds based on baseline National Institutes of Health Stroke Scale (NIHSS) scores. The study population was drawn from the retrospective arm of the international, multicentre ASPERA study and included patients with AF who experienced an ischemic stroke while receiving continuous anticoagulation. To emulate random assignment and avoid immortal time bias, a cloning-censoring-weighting approach with inverse probability weighting was applied. Primary outcomes were 90-day new ischemic events and moderate-to-severe bleeding. Risk ratios (RRs), absolute risk differences (RDs), and hazard ratios (HRs) were estimated using weighted regression and Cox models. RESULTS: Among 833 patients (median age 81 years), 336 were assigned to early and 497 to delayed DOAC initiation. At 90 days, early initiation was associated with a lower risk of new ischemic events (RR 0.44, 95% CI 0.21-0.90; RD -3.64%, 95% CI -6.40 to -0.87; HR 0.43, 95% CI 0.21-0.91). Moderate-to-severe bleeding occurred less frequently with early initiation (RR 0.10, 95% CI 0.01-0.76). Early initiation was also associated with lower 90-day all-cause and vascular mortality. A Net Early Benefit Score integrating ischemic and bleeding risks was positive across all NIHSS strata. CONCLUSIONS: In patients with breakthrough ischemic stroke, early severity-adapted DOAC initiation was associated with lower risks of recurrent ischemic events and mortality at 90 days without an increase in major bleeding. These findings support early anticoagulation initiation in this high-risk population.

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Journal
International Journal of Stroke
Published
2026-06-19
DOI
https://doi.org/10.1177/17474930261463051
Primary Topic
Atrial Fibrillation Management and Outcomes
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article
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article

Early versus Late starting of Direct Oral Anticoagulants after breakthrough ischemic stroke: A Target Trial Analysis from the ASPERA-R Study

Valeria Terruso, Leonardo Pantoni, Mauro Silvestrini, Piergiorgio Lochner et al.
International Journal of Stroke
Atrial Fibrillation Management and Outcomes
article

Early versus Late starting of Direct Oral Anticoagulants after breakthrough ischemic stroke: A Target Trial Analysis from the ASPERA-R Study

Valeria Terruso, Leonardo Pantoni, Mauro Silvestrini, Piergiorgio Lochner, Carlos Hervás, Giuseppe Scopelliti, Maria Rosaria Bagnato, Lucio D’Anna, Francesca Gabriele, Rachele Tortorella, Francesca Bernocchi, Alexandros A. Polymeris, Alberto Fior, Giacomo Urbinati, Giovanni Frisullo, Antonio De Mase, Myriam Perla Mazloum, Miguel Serôdio, Luisa Vinciguerra, Marco Rossi, Ghil Schwarz, Paola Forti, Andrea Zini, Paolo Candelaresi, Sandra Ahmed, Maria Guarino, Tara Latimer, Maria Sessa, Blanca Fuentes, Marialuisa Zedde, Francesco Mele, Giovanna Viticchi, Pier Andrea Rizzo, Ilaria Cova, Martina Gaia Di Donna, Maria Giulia Mosconi, Mariana A de Souza, Giovanni Merlino, Simona Sacco, Hossam Shokri, Lorenzo Barba, Maria Grazia Piscaglia, Angelo Cascio Rizzo, Ahmed ElSayed, Giuseppe Reale, Simona Scalise, Emanuele Spina, Matteo Paolucci, Stefano Forlivesi, Matteo Foschi, Valentina Barone, Diana Aguiar de Sousa, Raffaele Ornello, Barbara Casolla, Markus Otto, Hrvoje Budinčević, Vincenzo Andreone, Aldobrando Broccolini, Federico De Santis, Bernardo Antunes, Ricardo Rigual, Giovanni Di Mauro, Marcella Caggiula, Mauro Gentile, Ahmed Nasreldein, Federico Mazzacane, Vincenzo Laterza, Gabriele Prandin, Giuseppe Rinaldi, L. S. Costa, Sandeep Buddha, Viktoria Musienko, Kristina Kacani, Liqun Zhang, Benjamin Landau, Roumeisa Khalil, Luca Antonelli, Mona AlBanna, Samah Ali Ismail, Ahmed Abdelalim, Ahmed Elbassiouny, Tamer Roushdy, Nicola Loizzo, Mariarosaria Valente, Federica Ferrari, Muhammad Elboghdany, Ludovica Maria Miserocchi, Djeghlal Noufel-Anis, Marina Mannino, Pietro Caliandro, Domenico Maisano, Soma Banerjee, Laura Tudisco, Petra Crnac, Ana Catarina Gaspar Fonseca, Gaurav Desai, Aurelia Zauli, Laura Gonzalez-Martín
article en

Abstract

BACKGROUND AND PURPOSE: Randomized trials support early initiation of direct oral anticoagulants (DOACs) after atrial fibrillation (AF)-related ischemic stroke, but patients with breakthrough ischemic stroke occurring despite ongoing anticoagulation have been largely under-represented. We evaluated the effectiveness and safety of early versus delayed DOAC initiation after breakthrough ischemic stroke. METHODS: We performed a target trial emulation comparing early versus delayed DOAC initiation in patients with breakthrough ischemic stroke. Treatment strategies were prespecified using severity-adapted timing thresholds based on baseline National Institutes of Health Stroke Scale (NIHSS) scores. The study population was drawn from the retrospective arm of the international, multicentre ASPERA study and included patients with AF who experienced an ischemic stroke while receiving continuous anticoagulation. To emulate random assignment and avoid immortal time bias, a cloning-censoring-weighting approach with inverse probability weighting was applied. Primary outcomes were 90-day new ischemic events and moderate-to-severe bleeding. Risk ratios (RRs), absolute risk differences (RDs), and hazard ratios (HRs) were estimated using weighted regression and Cox models. RESULTS: Among 833 patients (median age 81 years), 336 were assigned to early and 497 to delayed DOAC initiation. At 90 days, early initiation was associated with a lower risk of new ischemic events (RR 0.44, 95% CI 0.21-0.90; RD -3.64%, 95% CI -6.40 to -0.87; HR 0.43, 95% CI 0.21-0.91). Moderate-to-severe bleeding occurred less frequently with early initiation (RR 0.10, 95% CI 0.01-0.76). Early initiation was also associated with lower 90-day all-cause and vascular mortality. A Net Early Benefit Score integrating ischemic and bleeding risks was positive across all NIHSS strata. CONCLUSIONS: In patients with breakthrough ischemic stroke, early severity-adapted DOAC initiation was associated with lower risks of recurrent ischemic events and mortality at 90 days without an increase in major bleeding. These findings support early anticoagulation initiation in this high-risk population.

International Journal of Stroke
Ain Shams University (EG), Marche Polytechnic University (IT), University of Udine (IT), North Bristol NHS Trust (GB), University of Lisbon (PT), University of Trieste (IT), Cairo University (EG), University of Basel (CH), Universidade Politécnica de Viana do Castelo (PT), University of L'Aquila (IT), Hospital Universitario La Paz (ES), King Fahd Medical City (SA), Charing Cross Hospital (GB), University Hospital of Basel (CH), Agostino Gemelli University Polyclinic (IT), Foundation Center (US), Klinička bolnica "Sveti Duh" (HR), Ospedale Antonio Cardarelli (IT), Luigi Sacco Hospital (IT), Azienda Sanitaria Unità Locale di Reggio Emilia (IT), Ospedale degli Infermi (IT), Ospedale "Santa Maria delle Croci" di Ravenna (IT), Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT), Unidade Local de Saúde de São José (PT), Hospital de São José (PT), Ospedale Vincenzo Cervello (IT), Urology Foundation (GB), St George's Hospital (GB), Azienda Ospedaliero-Universitaria Careggi (IT), Ospedale Santa Maria (IT), Casa di Cura Columbus (IT), Azienda USL di Bologna (IT), Istituto delle Scienze Neurologiche di Bologna (IT), Hôpital Pasteur (FR), Azienda Ospedaliera Ospedale Maggiore (IT), Naval Medical Research Unit EURAFCENT (EG), Hospital de Santa Maria (PT), Ospedale Vito Fazzi (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Ospedale Civile di Venezia (IT), Imperial College London (GB), University of Osijek (HR), Universidad Autónoma de Madrid (ES), Martin Luther University Halle-Wittenberg (DE), Assiut University (EG), Saarland University (DE)
Good health and well-being
Openalex Percentile: Top 8%
Atrial Fibrillation Management and Outcomes
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