Major Adverse Cognitive Events (MACE-Cog): A New “MACE” Framework for Cognitive Outcomes in Cardiovascular Diseases and Stroke

Cardiovascular diseases, particularly stroke, are leading causes of dementia. Several common cardiac interventions such as coronary artery bypass grafting and transcatheter aortic valve implantation are also associated with cognitive decline. However, cognitive outcomes continue to be poorly collected in clinical trials of cardiovascular diseases. In this article, we review the limitations of current approaches to cognitive assessment in cardiovascular disease studies. When assessed, there is wide variation in cognitive tasks used, and tasks have limited population-specific validation, are subject to floor and ceiling effects, and may suffer from sociocultural and linguistic biases. Many tasks are not available in multilingual formats and often rely on face-to-face testing with trained coordinators. All conventional cognitive outcomes in cardiovascular trials are associated with substantial incompletion, especially among older and more impaired individuals, the very people most important to capture. This nonrandom missingness generates survivor and attrition biases, an unacceptable situation for any trial outcome. Last, the meaning of measured cognitive outcomes is often unclear for patients, caregivers, clinicians, and regulators. To help address these limitations, we propose a new framework, major adverse cognitive events (MACE-Cog), to better capture cognitive outcomes in stroke and other cardiovascular populations. As an inclusive construct reflecting the multidimensional nature of cognitive decline, major adverse cognitive events do not rely solely on performance on cognitive testing but also consider inability to complete cognitive testing due to cognitive-behavioral factors, reported symptoms of cognitive decline, impairment in activities of daily living as a result of cognitive impairment, new clinical diagnoses of dementia, and care home admission. We hope that the proposed composite outcome and multiple use cases presented spark progress in cardiovascular research toward more inclusive approaches to the study of cognitive outcomes that move beyond the confines of cognitive tests alone.

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Publication Details

Journal
Circulation
Published
2026-07-27
DOI
https://doi.org/10.1161/circulationaha.125.077180
Primary Topic
Dementia and Cognitive Impairment Research
Type
article
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article

Major Adverse Cognitive Events (MACE-Cog): A New “MACE” Framework for Cognitive Outcomes in Cardiovascular Diseases and Stroke

Morgan D. Barense, Eric Edward Smith, Sajeevan Sujanthan, Ruth Masterson Creber et al.
Circulation
Dementia and Cognitive Impairment Research
article

Major Adverse Cognitive Events (MACE-Cog): A New “MACE” Framework for Cognitive Outcomes in Cardiovascular Diseases and Stroke

Morgan D. Barense, Eric Edward Smith, Sajeevan Sujanthan, Ruth Masterson Creber, James Kennedy, Aravind Ganesh, Jennifer S. Rabin, Katie N. Dainty, Terence J. Quinn, Douglas S. Lee, Krista L. Lanctôt, Raed A. Joundi, Rajesh Kharbanda, Ryan T. Muir, Mario Gaudino, Bijoy K. Menon, Tolulope T. Sajobi, Stephen Edward Fremes, Michael D. Hill, Richard H. Swartz
article en

Abstract

Cardiovascular diseases, particularly stroke, are leading causes of dementia. Several common cardiac interventions such as coronary artery bypass grafting and transcatheter aortic valve implantation are also associated with cognitive decline. However, cognitive outcomes continue to be poorly collected in clinical trials of cardiovascular diseases. In this article, we review the limitations of current approaches to cognitive assessment in cardiovascular disease studies. When assessed, there is wide variation in cognitive tasks used, and tasks have limited population-specific validation, are subject to floor and ceiling effects, and may suffer from sociocultural and linguistic biases. Many tasks are not available in multilingual formats and often rely on face-to-face testing with trained coordinators. All conventional cognitive outcomes in cardiovascular trials are associated with substantial incompletion, especially among older and more impaired individuals, the very people most important to capture. This nonrandom missingness generates survivor and attrition biases, an unacceptable situation for any trial outcome. Last, the meaning of measured cognitive outcomes is often unclear for patients, caregivers, clinicians, and regulators. To help address these limitations, we propose a new framework, major adverse cognitive events (MACE-Cog), to better capture cognitive outcomes in stroke and other cardiovascular populations. As an inclusive construct reflecting the multidimensional nature of cognitive decline, major adverse cognitive events do not rely solely on performance on cognitive testing but also consider inability to complete cognitive testing due to cognitive-behavioral factors, reported symptoms of cognitive decline, impairment in activities of daily living as a result of cognitive impairment, new clinical diagnoses of dementia, and care home admission. We hope that the proposed composite outcome and multiple use cases presented spark progress in cardiovascular research toward more inclusive approaches to the study of cognitive outcomes that move beyond the confines of cognitive tests alone.

CirculationVol. 154(4)
Engineering and Physical Sciences Research Council (GB), Sunnybrook Health Science Centre (CA), University Health Network (CA), Pediatric Oncology Group (CA), Cornell University (US), Columbia University Irving Medical Center (US), Toronto Rehabilitation Institute (CA), North York General Hospital (CA), Oxford Health NHS Foundation Trust (GB), Baycrest Hospital (CA), John Radcliffe Hospital (GB), Population Health Research Institute (CA), Shamnur Shivashankarappa Institute of Medical Sciences & Research Centre (IN), National Institute for Health and Care Research (GB), University of Oxford (GB), Institute of Health Services and Policy Research (CA), O'Brien Institute (AU), BGC Engineering (Canada) (CA), Society of Environmental Toxicology and Chemistry (US), Norwegian Womens Public Health Association (NO), Oxford BioMedica (United Kingdom) (GB), San Diego Cardiac Center (US), Institute for Clinical Evaluative Sciences (CA), International Neuromodulation Society (US), University of Glasgow (GB)
Quality Education
Openalex Percentile: Top 8%
Dementia and Cognitive Impairment Research
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