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      Assessment of Vascular Event Prevention and Cognitive Function Among Older Adults With Preexisting Vascular Disease or Diabetes : A Secondary Analysis of 3 Randomized Clinical Trials

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          Key Points

          Question

          Do null results on cognitive function in cardiovascular trials exclude worthwhile benefit?

          Findings

          In this secondary analysis of 3 randomized clinical trials including 45 029 participants undergoing cognitive assessment, the prevention of nonfatal cardiovascular events in 4.5% of survivors in the Heart Protection Study, by randomization to statin, yielded an estimated cognitive function difference equivalent to avoiding 0.15 years of aging. By contrast, the trial was powered to detect a difference in cognitive aging of at least 1 year.

          Meaning

          Nonsignificant findings, even from large trials, should not be taken as good evidence of a lack of worthwhile benefit on cognitive function of prolonged use of cardioprotective therapies.

          Abstract

          This secondary analysis of 3 randomized clinical trials estimates the effect on cognitive aging of the avoidance of vascular events and evaluates whether reports of nonsignificant results exclude worthwhile benefit among patients with vascular disease.

          Abstract

          Importance

          Acquisition of reliable randomized clinical trial evidence of the effects of cardiovascular interventions on cognitive decline is a priority.

          Objectives

          To estimate the association of cognitive aging with the avoidance of vascular events in cardiovascular intervention trials and understand whether reports of nonsignificant results exclude worthwhile benefit.

          Design, Setting, and Participants

          This secondary analysis of 3 randomized clinical trials in participants with preexisting occlusive vascular disease or diabetes included survivors to final in-trial follow-up in the Heart Protection Study (HPS), Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), and Treatment of HDL (High-Density Lipoprotein) to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trials of lipid modification for prevention of cardiovascular events. Data were collected from February 1994 through January 2013 and analyzed from January 2015 through December 2018.

          Exposures

          Incident vascular events and diabetes and statin therapy.

          Main Outcomes and Measures

          Cognitive function was assessed at the end of a mean (SD) of 4.9 (1.5) years of follow-up using a 14-item verbal test. Associations of the incidence of vascular events and new-onset diabetes during the trials, with cognitive function at final in-trial follow-up were estimated and expressed as years of cognitive aging (using the association of the score with age >60 years). The benefit on cognitive aging mediated through the effects of lowering low-density lipoprotein cholesterol levels on events was estimated by applying these findings to nonfatal event differences observed with statin therapy in the HPS trial.

          Results

          Among 45 029 participants undergoing cognitive assessment, mean (SD) age was 67.9 (8.0) years; 80.7% were men. Incident stroke (n = 1197) was associated with 7.1 (95% CI, 5.7-8.5) years of cognitive aging; incident transient ischemic attack, myocardial infarction, heart failure, and new-onset diabetes were associated with 1 to 2 years of cognitive aging. In HPS, randomization to statin therapy for 5 years resulted in 2.0% of survivors avoiding a nonfatal stroke or transient ischemic attack and 2.4% avoiding a nonfatal cardiac event, which yielded an expected reduction in cognitive aging of 0.15 (95% CI, 0.11-0.19) years. With 15 926 participants undergoing cognitive assessment, HPS had 80% power to detect a 1-year (ie, 20% during the 5 years) difference in cognitive aging.

          Conclusions and Relevance

          The expected cognitive benefits of the effects of preventive therapies on cardiovascular events during even the largest randomized clinical trials may have been too small to be detectable. Hence, nonsignificant findings may not provide good evidence of a lack of worthwhile benefit on cognitive function with prolonged use of such therapies.

          Trial Registration

          isrctn.com and ClinicalTrials.gov Identifiers: ISRCTN48489393, ISRCTN74348595, and NCT00461630

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          Most cited references9

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          A major role for cardiovascular burden in age-related cognitive decline.

          Chengxuan Qiu, Laura Fratiglioni (2015)
          The incidence of dementia and cardiovascular disease (CVD) increases with age. Current evidence supports the role for both atherosclerosis and arteriosclerosis as a common pathophysiological ground for the heart-brain connection in ageing. Cognitive decline and CVDs share many vascular risk factors (VRFs) such as smoking, hypertension, and diabetes mellitus; furthermore, CVDs can contribute to cognitive decline by causing cerebral hypoperfusion, hypoxia, emboli, or infarcts. Mixed dementia, resulting from both cerebrovascular lesions and neurodegeneration, accounts for the majority of dementia cases among very old individuals (≥75 years). An accumulation of multiple VRFs, especially in middle age (40-59 years of age), can substantially increase dementia risk. The suggested declining trend in dementia risk, occurring in parallel with the decreasing incidence of cardiovascular events in high-income countries, supports the role of cardiovascular burden in dementia. Accordingly, strategies to promote cardiovascular health, especially if implemented from early life, might help to delay the onset of dementia. In this Review, we discuss the literature investigating the association of cardiovascular burden with cognitive decline and dementia over the life-course.
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            Cognitive Test Scores in UK Biobank: Data Reduction in 480,416 Participants and Longitudinal Stability in 20,346 Participants

            Donald Lyall, Breda Cullen, Mike Allerhand … (2016)
            UK Biobank includes 502,649 middle- and older-aged adults from the general population who have undergone detailed phenotypic assessment. The majority of participants completed tests of cognitive functioning, and on average four years later a sub-group of N = 20,346 participants repeated most of the assessment. These measures will be used in a range of future studies of health outcomes in this cohort. The format and content of the cognitive tasks were partly novel. The aim of the present study was to validate and characterize the cognitive data: to describe the inter-correlational structure of the cognitive variables at baseline assessment, and the degree of stability in scores across longitudinal assessment. Baseline cognitive data were used to examine the inter-correlational/factor-structure, using principal components analysis (PCA). We also assessed the degree of stability in cognitive scores in the subsample of participants with repeat data. The different tests of cognitive ability showed significant raw inter-correlations in the expected directions. PCA suggested a one-factor solution (eigenvalue = 1.60), which accounted for around 40% of the variance. Scores showed varying levels of stability across time-points (intraclass correlation range = 0.16 to 0.65). UK Biobank cognitive data has the potential to be a significant resource for researchers looking to investigate predictors and modifiers of cognitive abilities and associated health outcomes in the general population.
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              The neuropathology of older persons with and without dementia from community versus clinic cohorts.

              Mark Bennett, Joseph Boyle, Tom Schneider … (2008)
              Community-based cohorts of older persons may differ neuropathologically from clinic-based cohorts. This study investigated age-related pathologies in persons with and without dementia and included autopsied participants from two community-based cohorts, the Rush Religious Orders Study (n=386) and the Memory and Aging Project (n=195), and one clinic-based cohort, the Clinical Core of the Rush Alzheimer's Disease Center (n=392). Final clinical diagnoses included no cognitive impairment (n=202), mild cognitive impairment (MCI) (n=150), probable Alzheimer's disease (AD) (n=474), possible AD (n=88), and other dementias (n=59). Postmortem diagnoses included pathologic AD, cerebral infarcts, and Lewy body disease. Community-based persons with clinical AD had less severe AD pathology (p<0.001) and had more cerebral infarcts (p<0.001) compared to clinic-based persons. Additionally, community-based persons with MCI had more infarcts compared to clinic-based persons. Overall, there was a higher proportion of Lewy bodies and atypical pathologies in the clinic-based compared to the community-based cohorts (p<0.001). Community-based persons with probable AD show less severe AD pathology and more often have infarcts and mixed pathologies; those with MCI more often have infarcts and mixed pathologies. Overall, clinic-based persons have more Lewy bodies and atypical pathologies. The spectrum of pathologies underlying cognitive impairment in clinic-based cohorts differs from community-based cohorts.
              Article 0 comments Cited 96 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): JAMA Netw Open
                Journal ID (iso-abbrev): JAMA Netw Open
                Journal ID (pmc): JAMA Netw Open
                Title: JAMA Network Open
                Publisher: American Medical Association
                ISSN (Electronic): 2574-3805
                Publication date (Electronic): 1 March 2019
                Publication date Collection: March 2019
                Publication date (Corrected, electronic): 15 March 2019
                Publication date PMC-release: 1 March 2019
                Volume: 2
                Issue: 3
                Electronic Location Identifier: e190223
                Affiliations
                [1 ]Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
                [2 ]Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
                [3 ]National Clinical Research Center of Cardiovascular Diseases, Fuwai Hospital, Beijing, China
                [4 ]National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
                Author notes
                Article Information
                Accepted for Publication: December 26, 2018.
                Published: March 1, 2019. doi:10.1001/jamanetworkopen.2019.0223
                Correction: This article was corrected on March 15, 2019, to fix a typographical error in the title.
                Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Offer A et al. JAMA Network Open .
                Corresponding Author: Sarah Parish, DPhil, Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, United Kingdom ( sarah.parish@ 123456ndph.ox.ac.uk ).
                Author Contributions: Drs Offer and Parish had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Offer, Landray, Armitage, Collins, and Parish contributed equally to the manuscript.
                Concept and design: Haynes, Landray, Armitage, Collins, Parish.
                Acquisition, analysis, or interpretation of data: Offer, Arnold, Clarke, Bennett, Bowman, Bulbulia, Haynes, Li, Hopewell, Landray, Armitage, Parish.
                Drafting of the manuscript: Offer, Parish.
                Critical revision of the manuscript for important intellectual content: All authors.
                Statistical analysis: Offer, Arnold, Parish.
                Obtained funding: Bowman, Landray, Armitage, Collins.
                Administrative, technical, or material support: Bowman, Bulbulia, Haynes, Li, Landray, Armitage, Collins.
                Supervision: Armitage, Collins, Parish.
                Conflict of Interest Disclosures: Drs Offer, Arnold, Bennett, Haynes, and Parish reported receiving grants from the Medical Research Council (MRC), the British Heart Foundation (BHF), Cancer Research UK (CRUK), Merck, and Roche during the conduct of the study. Dr Clarke reported receiving grants from the MRC, the BHF, Merck, and Roche during the conduct of the study. Dr Bowman reported receiving grants from the MRC and the BHF during the conduct of the study and grants from Merck outside the submitted work. Dr Bulbulia reported receiving grants from the MRC during the conduct of the study. Dr Hopewell reported receiving grants from the BHF, the MRC, CRUK, Merck, and Roche during the conduct of the study and grants from Merck and the Medicines Company (MEDCO) outside the submitted work. Dr Landray reported receiving grants from the MRC, the BHF, CRUK, Merck, Roche, and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre during the conduct of the study and grants from MEDCO, Boehringer Ingelheim, Novartis, and Pfizer outside the submitted work. Dr Armitage reported receiving grants from the MRC, the BHF, CRUK, and Merck during the conduct of the study and grants from Bayer, Solvay, Abbott, Alzheimers’ Research UK, MEDCO, the BHF, and the NIHR outside the submitted work. Dr Collins reported receiving grants and personal fees from the BHF and from UKBIOBANK during the conduct of the study and grants from CRUK, the MRC, Merck, the NIHR, Wellcome Trust, Pfizer, and MEDCO during the conduct of the study. In addition, Drs Collins and Parish reported having a patent for a statin-related myopathy genetic test issued and licensed, with royalties paid to University of Oxford and the MRC, from Boston Heart Diagnostics (Drs Collins and Parish have waived any personal reward). No other disclosures were reported.
                Funding/Support: This work was supported by grant MRC_MC_U137686853 from the UK MRC; grant CH/1996001/9454 from the BHF; grants from Merck, Roche, and CRUK to the University of Oxford; grant FS/14/55/30806 from the BHF (Dr Hopewell); and the BHF Centre of Research Excellence, Oxford (Dr Hopewell).
                Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
                Group Information: A complete list of the Heart Protection Study investigators is found in the Heart Protection Study Collaborative Group 11 ; a complete list of the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine investigators in Armitage et al 12 ; and a complete list of the Treatment of HDL (High-Density Lipoprotein) to Reduce the Incidence of Vascular Events investigators in HPS2-THRIVE Collaborative Group. 13
                Additional Contributions: Lixin Jiang, MD Chinese Academy of Medical Sciences, coordinated the Treatment of HDL (High-Density Lipoprotein) to Reduce the Incidence of Vascular Events (HPS2-THRIVE) in China and established the cognitive testing in it. She was not personally compensated for this work.
                Additional Information: Requests for data sharing will be handled in line with the data access and sharing policy of the Nuffield Department of Population Health, University of Oxford (available at https://www.ndph.ox.ac.uk/about/data-access-policy).
                Article
                Publisher ID: zoi190022
                DOI: 10.1001/jamanetworkopen.2019.0223
                PMC ID: 6484650
                PubMed ID: 30821829
                SO-VID: 0b022b66-3429-481d-8cb3-12a7c8306468
                Copyright © Copyright 2019 Offer A et al. JAMA Network Open .
                License:

                This is an open access article distributed under the terms of the CC-BY License.

                History
                Date received : 26 July 2018
                Date: 21 December 2018
                Date accepted : 26 December 2018
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                Categories
                Subject: Research
                Subject: Original Investigation
                Subject: Online Only
                Subject: Neurology

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