Anticoagulation to prevent ischemic stroke and neurocognitive impairment in atrial fibrillation: the BRAIN-AF randomized clinical trial

Individuals with atrial fibrillation (AF) are at increased risk of stroke, cognitive impairment and dementia. Observational studies suggest that anticoagulation may reduce the risk of cognitive decline in patients with AF and elevated thromboembolic risk, implicating subclinical cerebral emboli as a potential mechanistic link. Whether anticoagulation prevents cognitive deterioration in patients with AF at low risk of stroke remains uncertain. Here we conducted a multicenter, double-blind, placebo-controlled trial in which participants with AF and low thromboembolic risk (CHA<sub>2</sub>DS<sub>2</sub>-VASc scores of 0 or 1, excluding female sex) were randomized 1:1 to receive rivaroxaban 15 mg daily or placebo. The primary outcome was a composite of cognitive decline (≥2-point drop in Montreal Cognitive Assessment), stroke or transient ischemic attack with a motor deficit or aphasia. The trial was halted after meeting the predetermined futility criterion following a planned interim analysis, with 1,235 of the intended 1,424 participants (919 men; 316 women) enrolled. Over a median follow-up of 3.7 years, the primary outcome occurred in 256 (20.7%) participants, at an annual rate of 7.0% with rivaroxaban versus 6.4% with placebo, yielding a hazard ratio of 1.10 (95% confidence interval (0.86-1.40); P = 0.46). Conditional power analysis indicated a 1.2% probability of achieving a statistically significant treatment effect if the trial had been continued to its planned total of 410 events. Major bleeding occurred in two patients treated with rivaroxaban (0.09% per year) and five patients treated with placebo (0.21% per year). In conclusion, despite the high incidence of cognitive decline observed among patients with AF and low stroke risk, the BRAIN-AF trial, which tested a low dose of rivaroxaban to prevent stroke, transient ischemic attack and cognitive decline in patients with prior AF, was stopped early due to futility. ClinicalTrials.gov registration: NCT02387229 .

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Publication Details

Journal
Nature Medicine
Published
2026-01-01
DOI
https://doi.org/10.1038/s41591-025-04101-y
Citations
2
Primary Topic
Atrial Fibrillation Management and Outcomes
Type
article
Field-Weighted Citation Impact
60.13

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article

Anticoagulation to prevent ischemic stroke and neurocognitive impairment in atrial fibrillation: the BRAIN-AF randomized clinical trial

Christian Bocti, Mario Talajic, Yaariv Khaykin, Gernot Schram et al.
2 citations
Nature Medicine
Atrial Fibrillation Management and Outcomes
60.13
article

Anticoagulation to prevent ischemic stroke and neurocognitive impairment in atrial fibrillation: the BRAIN-AF randomized clinical trial

Christian Bocti, Mario Talajic, Yaariv Khaykin, Gernot Schram, François St-Maurice, Hélène Mayrand, Jeff S. Healey, Isabelle Nault, Michael Heffernan, R Chehayeb, Stephen B. Wilton, Normand Racine, Léna Rivard, Simon Kouz, Pablo B. Nery, Winston Tsui, Ratika Parkash, Sandra E. Black, PETER LEONG SIT, Atul Verma, Jorge Wong, Fadi Massoud, Ronald A.F. Fowlis, Sylvain Lanthier, Jaimie Manlucu, Blandine Mondésert, FRANCIS PICHETTE, Alexandre Raymond-Paquin, L. Macle, Yan Deschaintre, Stanley Nattel, Valérie Gaudreault, Vidal Essebag, RAKESH BHARGAVA, Martín Aguilar, Roopinder K. Sandhu, B. Thibault, Ricardo Bessoudo, Céline Chayer, JULIA CADRIN-TOURIGNY, Peter G. Guerra, John Vyselaar, Umjeet Jolly, Paul Dorian, Clarence Khoo, André Roussin, M. Tremblay-Gravel, Greg Curnew, Isabelle Greiss, Miguel Barrero, J.C. Tardif, F. Sandrin, P. G. Khairy, Alain Robillard, TunZan Maung, Ariane Lemieux, Jean-François Roux, David Laflamme, Kenneth Quadros, Yves Pesant, Marie-Claude Guertin, Jason Andrade, Saul Vizel, Peiman Marzban, Stéphanie Bourgeois, David Conen, William Liang, Anil Gupta, Gilbert Gosselin, Mariève Cossette, François Deslongchamps, Katia Dyrda, Luc Cormier, Louis-Philippe David, A. Shekhar Pandey, on behalf of the BRAIN-AF investigators, Anmol Kapoor, Teresa Kus, Fabian Alejandro Azzari, Thalia S. Field, Judith Brouillette, Denis Roy, Rafik Tadros, Louis Bherer
article en
2 citations

Abstract

Individuals with atrial fibrillation (AF) are at increased risk of stroke, cognitive impairment and dementia. Observational studies suggest that anticoagulation may reduce the risk of cognitive decline in patients with AF and elevated thromboembolic risk, implicating subclinical cerebral emboli as a potential mechanistic link. Whether anticoagulation prevents cognitive deterioration in patients with AF at low risk of stroke remains uncertain. Here we conducted a multicenter, double-blind, placebo-controlled trial in which participants with AF and low thromboembolic risk (CHA<sub>2</sub>DS<sub>2</sub>-VASc scores of 0 or 1, excluding female sex) were randomized 1:1 to receive rivaroxaban 15 mg daily or placebo. The primary outcome was a composite of cognitive decline (≥2-point drop in Montreal Cognitive Assessment), stroke or transient ischemic attack with a motor deficit or aphasia. The trial was halted after meeting the predetermined futility criterion following a planned interim analysis, with 1,235 of the intended 1,424 participants (919 men; 316 women) enrolled. Over a median follow-up of 3.7 years, the primary outcome occurred in 256 (20.7%) participants, at an annual rate of 7.0% with rivaroxaban versus 6.4% with placebo, yielding a hazard ratio of 1.10 (95% confidence interval (0.86-1.40); P = 0.46). Conditional power analysis indicated a 1.2% probability of achieving a statistically significant treatment effect if the trial had been continued to its planned total of 410 events. Major bleeding occurred in two patients treated with rivaroxaban (0.09% per year) and five patients treated with placebo (0.21% per year). In conclusion, despite the high incidence of cognitive decline observed among patients with AF and low stroke risk, the BRAIN-AF trial, which tested a low dose of rivaroxaban to prevent stroke, transient ischemic attack and cognitive decline in patients with prior AF, was stopped early due to futility. ClinicalTrials.gov registration: NCT02387229 .

Nature MedicineVol. 32(1)
University of New Brunswick (CA), Western University (CA), St. Michael's Hospital (CA), Dalhousie University (CA), Sunnybrook Health Science Centre (CA), University of British Columbia (CA), University of Ottawa (CA), University of Alberta (CA), McMaster Divinity College (CA), Université du Québec à Rimouski (CA), University of Toronto (CA), BP (Canada) (CA), Summit Pacific College (CA), Hamilton General Hospital (CA), Montreal Heart Institute (CA), Saint John Regional Hospital (CA), St. Boniface Hospital (CA), Oakville-Trafalgar Memorial Hospital (CA), London Health Sciences Centre (CA), McGill University Health Centre (CA), Centre Hospitalier Universitaire de Sherbrooke (CA), Research Manitoba (CA), Southlake Regional Health Center (CA), Health Sciences Centre (CA), Population Health Research Institute (CA), St Mary's Hospital Centre (CA), Hôpital Maisonneuve-Rosemont (CA), Huntington Society of Canada (CA), Cégep de Rimouski (CA), Cegep regional de Lanaudiere (CA), Cégep de Lévis (CA), The Coordinating Center (US), Centre Intégré Universitaire de Santé et de Services Sociaux du Saguenay–Lac-Saint-Jean (CA), Oakville Public Library (CA), CARE Canada (CA), Hôpital Charles-Le Moyne (CA), Greenfield Research (Canada) (CA), Centre intégré universitaire de santé et de services sociaux de la Mauricie-et-du-Centre-du-Québec (CA), Hôtel-Dieu de Québec (CA), La Boîte à lettres (CA), Institut universitaire de cardiologie et de pneumologie de Québec (CA), Hôpital du Sacré-Cœur de Montréal (CA), Centre Hospitalier de l’Université de Montréal (CA), Cambridge Cardiac Care Centre (CA), Future Vehicle Technologies (Canada) (CA), Centre Intégré de Santé et de Services Sociaux des Laurentides (CA), Centre intégré de santé et de services sociaux de Chaudière-Appalaches (CA), Canadian Heart Research Centre (CA), Dr. Georges-L.-Dumont University Hospital Centre (CA), MPB Technologies & Communications (Canada) (CA), Centre for Family Medicine (CA), Université Laval (CA), Libin Cardiovascular Institute of Alberta (CA), Université de Montréal (CA), Hamilton Health Sciences (CA), McMaster University (CA)
Alzheimer's Association, Eli Lilly and Company, Pfizer, AstraZeneca, Heart and Stroke Foundation of Canada, Biogen, Focused Ultrasound Foundation, University of Rochester, Canarie, Boston Scientific Corporation, Fondation Brain Canada, Weston Brain Institute, Compute Canada, Fondation Leducq, Queen's University, Eisai, Novo Nordisk, Université de Montréal, Servier, Fondation Institut de Cardiologie de Montréal, Institut de Cardiologie de Montréal, Merck Canada, Esperion Therapeutics, National Institutes of Health, Genentech, Erasmus Research Institute of Management, Canadian Institutes of Health Research, Networks of Centres of Excellence of Canada, Novo Nordisk Canada, Biosense Webster
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