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Randomized Controlled Trial
. 2025 Sep 16;14(18):e042147.
doi: 10.1161/JAHA.125.042147. Epub 2025 Aug 22.

Apixaban Versus Aspirin to Reduce Cognitive Decline After Cryptogenic Stroke and Atrial Cardiopathy: ARCADIA-Cognition Study

Ronald M Lazar  1 , George Howard  2 , Michael T Brewer  1 , Christy Cassarly  3 , Qi Pauls  3 , Stephanie Kemp  4 , David L Tirschwell  5 , Kevin N Sheth  6 , Max Wintermark  7 , Hooman Kamel  8 , W T Longstreth Jr  9   10 , Mitchell S V Elkind  11   12 , Joseph P Broderick  13 , Maarten G Lansberg  4
Affiliations
Randomized Controlled Trial

Apixaban Versus Aspirin to Reduce Cognitive Decline After Cryptogenic Stroke and Atrial Cardiopathy: ARCADIA-Cognition Study

Ronald M Lazar et al. J Am Heart Assoc. .

Abstract

Background: ARCADIA (Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke), a secondary stroke prevention study comparing apixaban versus aspirin for cryptogenic stroke and biomarkers of atrial cardiopathy, ended prematurely for futility. In the ARCADIA-Cognition study we hypothesized that cognitive decline would be slower in the apixaban arm due to less microembolization.

Methods: ARCADIA subjects on study drug and eligible for magnetic resonance imaging participated in ARCADIA-CSI (ARCADIA-Cognition and Silent Infarction). Cognitive tests were administered centrally by telephone ≥3 months after the ARCADIA index stroke and yearly thereafter. Composite Z scores were the means of 5 standardized cognitive tests. Trajectories of the composite Z score and the individual test scores were compared between treatment arms using a mixed-effects model.

Results: Of 799 screened patients at 75 sites, 310 were enrolled in ARCADIA-CSI. Of these, 296 completed at least 1 cognitive exam, and 47 subjects were excluded from the primary analysis for baseline dementia. For the 249 subjects included in the analysis, there were 582 cognitive assessments. Baseline characteristics were balanced between the apixaban (n=128) and aspirin (n=121) arms. Mean age was 68 (SD: 10.4) years, median modified Rankin Scale score 1 (interquartile range, 0-2), 52% female, and 19% Black. During median follow-up of 378 (interquartile range, 183-735) days, the annual change in the overall standardized composite score was 0.084 (95% CI, 0.017-0.149) in the aspirin arm and 0.107 (95% CI, 0.041-0.174) in the apixaban arm (P=0.62).

Conclusions: Cognitive trajectories did not differ between apixaban and aspirin. Further studies should address infarct location and volume and concurrent pathology to determine optimal treatment to mitigate cognitive decline with atrial disease.

Registration: URL: http://clinicaltrials.gov; Unique Identifier: NCT03192215.

Keywords: Apixaban; aspirin; atrial cardiopathy; cognition; covert infarction.

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Conflict of interest statement

Dr Elkind reports receiving study drug in kind from the BMS‐Pfizer Alliance for Eliquis and ancillary funding from Roche for the National Institutes of Health‐funded ARCADIA trial; and royalties from UpToDate for the chapter on cryptogenic stroke.

Dr Kamel reports a multiple principal investigator role in the ARCADIA trial, which received in‐kind study drug from the BMS‐Pfizer Alliance for Eliquis and ancillary study support from Roche Diagnostics; a Deputy Editor role for JAMA Neurology; clinical trial steering/executive committee roles for the STROKE‐AF (Medtronic), LIBREXIA‐AF (Janssen), and LAAOS‐4 (Boston Scientific) trials; consulting or end point adjudication committee roles for AbbVie, AstraZeneca, Arthrosi Therapeutics, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk; and household ownership interests in TETMedical, Spectrum Plastics Group, and Ascential Technologies.

Dr Lansberg reports research grants from National Institute of Neurological Disorders and Stroke.

Dr Lazar reports research grants from National Institute of Neurological Disorders and Stroke (National Institutes of Health) and the McKnight Brain Research Foundation. He serves as a consultant to DiaMedica, Inc and iMIND.

Dr Longstreth reports a multiple‐principal investigator role in the ARCADIA trial and research grants from National Institutes of Health.

Dr Sheth reports research grants from National Institute of Neurological Disorders and Stroke, American Heart Association, and Hyperfine. He serves on a Data Safety and Monitoring Board for Phillips and Sense. He serves on scientific advisory boards for BrainQ, Bexorg, Astrocyte, and Rhaeos and holds a patent that licensed to Alva Health.

Dr Tirschwell reports a multiple‐PI role in the ARCADIA trial.

Other authors report no conflicts of interest.

Figures

Figure 1
Figure 1. Consolidated Standards of Reporting Trials diagram.
Figure 2
Figure 2. The composite cognitive trajectories (slopes) and 95% CIs for the apixaban (orange) and aspirin (blue) arms over the course of cognitive test administrations.
Higher scores represent better performances. A Z score=0.0 represents the 50th percentile.
See this image and copyright information in PMC

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