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Randomized Controlled Trial
. 2025 Dec 1;10(12):1305-1314.
doi: 10.1001/jamacardio.2025.4151.

Major Bleeding With Apixaban vs Aspirin: A Subanalysis of the ARTESiA Randomized Clinical Trial

Deborah M Siegal  1   2 , Christian Sticherling  3 , Jeff S Healey  4   5 , William F McIntyre  4   5 , Lene S Christensen  6 , Ratika Parkash  7 , Thomas Vanassche  8 , David Conen  4   5 , Michael Gold  9 , Christopher B Granger  10 , Jens Cosedis Nielsen  11   12 , Marc Carrier  1   2 , Daniel M Wojdyla  10 , Julia W Erath  13 , Lena Rivard  14 , Valentina Kutyifa  15 , David J Wright  16 , Renato D Lopes  10
Affiliations
Randomized Controlled Trial

Major Bleeding With Apixaban vs Aspirin: A Subanalysis of the ARTESiA Randomized Clinical Trial

Deborah M Siegal et al. JAMA Cardiol. .

Abstract

Importance: The Apixaban for the Reduction of Thromboembolism in Patients With Device-Detected Subclinical Atrial Fibrillation (ARTESiA) randomized clinical trial showed that in patients with subclinical atrial fibrillation (SCAF) apixaban, compared with aspirin, reduced stroke/systemic embolism but increased major bleeding.

Objectives: To characterize major bleeding events (site and severity) and identify factors associated with major bleeding.

Design, setting, and participants: This was a prespecified subanalysis of the ARTESiA population who received treatment. This was an international, double-blind, double-dummy randomized clinical trial. Included were patients with 1 or more episodes of SCAF lasting 6 minutes to 24 hours with stroke risk factors (CHA2DS2-VASc score ≥3) or prior stroke without other risk factors. Study data were analyzed from August to November 2024.

Interventions: Apixaban, 5 mg, twice daily (2.5 mg twice daily when indicated) or aspirin, 81 mg, once daily.

Main outcomes and measures: Major bleeding adjudicated by a blinded committee according to International Society on Thrombosis and Hemostasis criteria.

Results: A total of 3961 patients (mean [SD] age, 76.8 [7.6] years; 2535 male [64%]) were included in this analysis. After a mean (SD) follow-up of 3.5 (1.8) years, 1 or more major bleeding episodes occurred in 133 patients, 86 of 1989 taking apixaban and 47 of 1972 taking aspirin (1.71 vs 0.94 per 100-patient-years; hazard ratio [HR], 1.80; 95% CI, 1.26-2.57). The rates of intracranial (0.33 vs 0.40 per 100 patient-years; HR, 0.82; 95% CI, 0.43-1.57) and fatal (0.10% vs 0.16% per 100 patient-years; HR, 0.63; 95% CI, 0.20-1.91) bleeding were similar in the apixaban and aspirin groups, whereas the rate of gastrointestinal bleeding was higher in the apixaban group (0.89% vs 0.40% per 100 patient-years; HR, 2.23; 95% CI, 1.32-3.78). Among 133 index major bleeding events, those that occurred with apixaban were less likely to occur at critical sites (27.9% [24 of 86] vs 46.8% [22 of 47]; P = .03) including intracranial (18.6% [16 of 86] vs 42.6% [20 of 47]; P = .003). Most major bleeding events were nonemergencies characterized by decreased hemoglobin greater than or equal to 2 g/dL. Factors associated with major bleeding included nonsteroidal anti-inflammatory drug (NSAID) use (HR, 10.25; 95% CI, 6.57-15.99), cancer (HR, 2.87; 95% CI, 1.49-5.53), randomization to apixaban (HR, 1.84; 95% CI, 1.29-2.63), and age (HR, 1.47; 95% CI, 1.28-1.67, per 5-year increase).

Conclusions and relevance: Results of this subanalysis of the ARTESiA randomized clinical trial found that although the rate of major gastrointestinal bleeding was higher in patients with SCAF who were treated with apixaban vs aspirin, rates of fatal and intracranial bleeding were not different. Most major bleeding events were nonemergencies characterized by a decrease in hemoglobin level greater than or equal to 2 g/dL. NSAID use, cancer, randomization to apixaban, and increasing age were associated with an increased risk of major bleeding.

Trial registration: ClinicalTrials.gov Identifier: NCT01938248.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Siegal reported being supported by a Tier 2 Canada Research Chair in Anticoagulant Management of Cardiovascular Disease; receiving honoraria paid indirectly to institute from AstraZeneca and Servier; and receiving consulting fees paid indirectly to institute from VarmX and Perosphere outside the submitted work. Dr Healey reported receiving grants from Medtronic and BMS/Pfizer during the conduct of the study and personal fees from Boston Scientific outside the submitted work. Dr McIntyre reported receiving consulting fees from Atricure, speaker fees from iRhythm, and the National New Investigator Award from Heart and Stroke Foundation of Canada and the Population Health Research Institute Career Award. Dr Parkash reported receiving grants from Medtronic and Abbott during the conduct of the study. Dr Vanassche reported receiving personal fees from BMS/Pfizer, Daiichi Sankyo, Boehringer Ingelheim, and Bayer in the form of limited honorarium for advisory boards and/or lecture outside the submitted work. Dr Gold reported receiving consulting fees from Boston Scientific cardiac implantable electronic device (CIED) and Medtronic CIED outside the submitted work. Dr Granger reported receiving grants from Pfizer, BMS, Boehringer Ingelheim, Bayer, Janssen, Daiichi Sankyo, Anthos; personal fees from Pfizer, BMS, Boehringer Ingelheim, Bayer, Janssen, Daiichi Sankyo, Anthos; having a patent pending for Tenac.io; consulting fees from AbbVie, Abiomed, Alnylam Pharmaceuticals, Amgen, Anthos, Astra Zeneca, Bayer Corporation, Boehringer Ingelheim, Boston Scientific Corporation, Bristol Myers Squibb, Cardionomics, CeleCor Therapeutics, Janssen Pharmaceutical, Merck, Novo Nordisk, Novartis, Pfizer, Philips, Roche; having a salary funded by Duke research grants sponsored by Alnylam Pharmaceuticals, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen Pharmaceuticals, National Heart, Lung, and Blood Institute, Novartis, Pfizer, Philips; and having equity in Tenac.io. Dr Carrier reported receiving personal fees from Anthos, Regeneron, BMA, Pfizer, and Sanofi with payments made to institution outside the submitted work. Dr Wojdyla reported receiving grants from Pfizer during the conduct of the study. Dr Erath reported receiving lecture fees and travel grants from Pfizer and consultant fees from Zoll Medical outside the submitted work. Dr Kutyifa reported receiving grants from Boston Scientific, Biotronik, the National Institutes of Health, Spire and personal fees from ZOLL, and Biotronik outside the submitted work. Dr Wright reported receiving personal fees from Medtronic and grants from Boston Scientific outside the submitted work. Dr Lopes reported receiving grants from Bristol Myers Squibb, Glaxo Smith Kine, Medtronic, Pfizer, Sanofi and personal fees from Merck, Novo Nordisk, and Portola during the conduct of the study. No other disclosures were reported.

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