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Randomized Controlled Trial
. 2025 Feb;24(2):140-151.
doi: 10.1016/S1474-4422(24)00475-7.

Apixaban versus aspirin for stroke prevention in people with subclinical atrial fibrillation and a history of stroke or transient ischaemic attack: subgroup analysis of the ARTESiA randomised controlled trial

Ashkan Shoamanesh  1 , Thalia S Field  2 , Shelagh B Coutts  3 , Mukul Sharma  4 , David Gladstone  5 , Robert G Hart  4 , Giuseppe Boriani  6 , David J Wright  7 , Christian Sticherling  8 , David H Birnie  9 , Michael R Gold  10 , Julia W Erath  11 , Valentina Kutyifa  12 , Rajibul Mian  4 , Alexander P Benz  13 , Christopher B Granger  14 , William F McIntyre  4 , Stuart J Connolly  4 , Jens Cosedis Nielsen  15 , Marco Alings  16 , Lena Rivard  17 , Renato D Lopes  14 , Jeff S Healey  4 ; ARTESiA study investigators
Affiliations
Randomized Controlled Trial

Apixaban versus aspirin for stroke prevention in people with subclinical atrial fibrillation and a history of stroke or transient ischaemic attack: subgroup analysis of the ARTESiA randomised controlled trial

Ashkan Shoamanesh et al. Lancet Neurol. 2025 Feb.

Abstract

Background: People with subclinical atrial fibrillation are at increased risk of stroke, albeit to a lesser extent than those with clinical atrial fibrillation, leading to an ongoing debate regarding the benefit of anticoagulation in these individuals. In the ARTESiA trial, the direct-acting oral anticoagulant apixaban reduced stroke or systemic embolism compared with aspirin in people with subclinical atrial fibrillation, but the risk of major bleeding was increased with apixaban. In a prespecified subgroup analysis of ARTESiA, we tested the hypothesis that people with subclinical atrial fibrillation and a history of stroke or transient ischaemic attack, who are known to have an increased risk of recurrent stroke, would show a greater benefit from oral anticoagulation for secondary stroke prevention compared with those without a history of stroke or transient ischaemic attack.

Methods: ARTESiA is a double-blind, double-dummy, randomised controlled trial conducted at 247 sites in 16 countries across Europe and North America. Adults aged 55 years or older with device-detected subclinical atrial fibrillation lasting from 6 min to 24 h and a CHA2DS2-VASc score of 3 or higher were randomly assigned using an interactive web-based system to oral apixaban 5 mg twice per day or oral aspirin 81 mg once per day. The primary efficacy outcome was stroke or systemic embolism, and the primary safety outcome was major bleeding, assessed as absolute risk differences. Analyses were by intention to treat. ARTESiA is registered with ClinicalTrials.gov (NCT01938248) and is completed; this report presents a prespecified subgroup analysis in people with a history of stroke or transient ischaemic attack.

Findings: Between May 7, 2015, and July 30, 2021, 4012 people with subclinical atrial fibrillation were randomly allocated either apixaban (n=2015) or aspirin (n=1997). A history of stroke or transient ischaemic attack was present in 346 (8·6%) participants (172 assigned to apixaban and 174 to aspirin), among whom the annual rate of stroke or systemic embolism was 1·20% (n=7; 95% CI 0·48 to 2·48) with apixaban versus 3·14% (n=18; 1·86 to 4·96) with aspirin; (hazard ratio [HR] 0·40, 95% CI 0·17 to 0·95). In participants without a history of stroke or transient ischaemic attack (n=3666; 1843 assigned to apixaban and 1823 to aspirin), the annual rate of stroke or systemic embolism was 0·74% (n=48; 95% CI 0·55 to 0·98) with apixaban versus 1·07% (n=68; 95% CI 0·83 to 1·36) with aspirin (HR 0·69, 95% CI 0·48 to 1·00). The absolute risk difference in incidence of stroke or systemic embolism at 3·5 years of follow-up was 7% (95% CI 2 to 12) in participants with versus 1% (0 to 3) in participants without a history of stroke or transient ischaemic attack. The annual rate of major bleeding in participants with a history of stroke or transient ischaemic attack was 2·26% with apixaban (n=13; 95% CI 1·21 to 3·87) versus 1·16% with aspirin (n=7; 0·47 to 2·39; HR 1·94, 95% CI 0·77 to 4·87). The absolute risk difference in major bleeding events at 3·5 years was 3% (-1 to 8) in individuals with a versus 1% (-1 to 2) in those without a history of stroke or transient ischaemic attack.

Interpretation: Treatment with the direct-acting oral anticoagulant apixaban in people with subclinical atrial fibrillation and a history of stroke or transient ischaemic attack led to a 7% absolute risk reduction in stroke or systemic embolism over 3·5 years, compared with a 1% absolute risk reduction for individuals without a previous history of stroke or transient ischaemic attack. The corresponding absolute increase in major bleeding was 3% and 1%, respectively. Apixaban could be considered for secondary stroke prevention in people with subclinical atrial fibrillation and a history of stroke or transient ischaemic attack.

Funding: The Canadian Institutes of Health Research, Bristol-Myers Squibb-Pfizer Alliance, Heart and Stroke Foundation of Canada, Canadian Stroke Prevention and Intervention Network, Hamilton Health Sciences, Accelerating Clinical Trials Network, Population Health Research Institute, and Medtronic.

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Conflict of interest statement

Declaration of interests AS reports grants, consulting fees, and honoraria from Bayer AG and Daiichi Sankyo; and being on two data safety monitoring boards and advisory boards for Bayer AG. TSF reports payment for expert testimony from Plaintiff and Canadian Medical Protective Agency; personal fees from Bayer and Novartis; advisory board participation for HLS Therapeutics and AstraZeneca; and being a board member for DESTINE Health and Vancouver General Hospital and University of British Columbia Hospital Foundation. MS reports research support paid to their institution from Bayer, Bristol Myers Squibb/Janssen, and AstraZeneca/Alexion; personal consulting fees from AstraZeneca and Bayer; and board membership on the Canadian Stroke Consortium Board and Bayer Advisory Board. DG reports Bayer site fees paid to their institution for participation in the OCEANIC-AF trial. GB reports speaker fees from Bayer, Boston Scientific, BMS, Daiichi Sankyo, Sanofi, and Janssen, unrelated to this manuscript. CS reports consulting fees from Medtronic, Boston Scientific, and Biotronik; and honoraria from Microport and Biotronik. DHB reports patient site and National Leadership fees from the Population Health Research Institute for ARTESiA paid to their institution. MRG reports consulting fees from Boston Scientific, Medtronic, and Abbott; and speaker fees from Abbott and Boston Scientific. JWE reports honoraria from Bayer Vital and Pfizer; and travel support from Bayer Vital. VK reports grants from Boston Scientific, ZOLL, Biotronik, Spire, and the National Institutes for Health; consulting fees from ZOLL; and honoraria from Abbott, Medtronic, ZOLL, and Biotronik. APB reports lecture fees from Bristol-Myers Squibb and AstraZeneca; and participation in educational programmes supported by Boston Scientific. CBG reports grants from Alnylam, Boehringer Ingelheim, Bristol Myers Squibb, US Food and Drug Administration, Janssen, Lilly, Novartis, Pfizer, Philips, and Roche; consulting fees from Alnylam, Boehringer Ingelheim, Bristol Myers Squibb, US Food and Drug Administration, Janssen, Lilly, Novartis, Pfizer, Philips, Roche, Merck, NIH, NephroSynergy, Novo Nordisk, Novartis, Pfizer, Philips, REATA, Roche, and Veralox; honoraria from AbbVie, Abiomed, Amgen, Alnylam Pharmaceuticals, Anthos, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardionomic, Cadrenal, CeleCore Therapeutics, HengRui, Janssen, Medscape, Medtronic, Merck, NIH, NephroSynergy, Novo Nordisk, Novartis, Pfizer, Philips , REATA, Roche, and Veralox; data safety monitoring boards/advisory board Bayer, Novartis, Novo Nordisk, Veralox, Cardionomics, and Janssen, Merck; and stock interests in Tenac.io. WFM reports grant from Trimedica; consulting fees from Trimedica and Atricure; and honoraria from iRhythm. JCN reports institutional research grants from the Novo Nordisk Foundation and the Danish Heart Foundation; and being the executive editor for Europace. RDL reports consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Briston-Myers Squibb, Novo Nordisk, and Pfizer; speaking fees for AstraZeneca, Daiichi Sankyo, Novo Nordisk, and Pfizer; and institutional grant support from Amgen, Bristol-Myers Squibb, GSK, Medtronic Pfizer, and Sanofi. JSH reports funding for the ARTESiA trial from BMS/Pfizer and Medtronic, and for the ATLAS and LAAOS-4 trials from Boston Scientific; advisory board fees from Boston Scientific; speaker fees from BMS/Pfizer, Boston Scientific, and Medtronic; expert witness fees from Bayer; and data safety monitoring boards participation for the PRAETORIAN DFT trial from Boston Scientific.

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