Chung, Sheng-Chia

Denaxas, Spiros

Fitzpatrick, Natalie K

Providencia, Rui

Rossor, Martin

Torralbo, Ana

Ytsma, Cai

English

UCL Discovery

J A C C : A D V A N C E S V O L . - , N O . - , 2 0 2 3ª 2 0 2 3 T H E A U T H O R S . P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E AM E R I C A NC O L L E G E O F C A R D I O L O G Y F OU N D A T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E RT H E C C B Y L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y / 4 . 0 / ) .I S S N 2 7 7 2 - 9 6 3 XLettersRESEARCH LETTERCognitive Impairmentand Dementia inAtrial FibrillationA Population Study of 4.3 Million IndividualsMild cognitive impairment (MCI) is an early stage incognitive function decline that is greater than thatobserved in healthy aging but of insufficient severityto fulfil the criteria of dementia. Causes for MCI areheterogeneous, and while MCI may be reversible insome individuals, it may reflect an early dementia-associated disease processes, with annual conver-sion rate of z20%.1 Factors associated with thedevelopment, or protection from, MCI in atrial fibril-lation (AF) patients, and subsequent development ofdementia, have not been fully elucidated.We investigated the association of AF with MCI andsubsequent dementia using routinely collected UKprimary electronic health record (EHR) data.We used the UK-based linked EHR of 4.3 millionindividuals between January 1, 1998, and May 31,2016. All individuals with incident AF were included,and the index date was defined as the date of the firstrecorded AF diagnosis. For each case, we randomlyselected 1 AF-free individual as a control from thestudy cohort who was matched to the sex and age atdiagnosis of the individual with incident AF. AF wasdefined as I48 of the International Statistical Classi-fication of Diseases-10th Revision (ICD-10) and cor-responding Read version 2 terms (Read V2) from theClinical Practice Research Datalink.2 The primaryoutcome of the study was the incidence of MCI,What is the clinical question being addressed?We investigated the risk of MCI after AF diag-nosis in the United Kingdom.What is the main finding?Our study showed that AF was associated with a 45%increase on the risk of MCI and that cardiovascularrisk factors and multicomorbidity appear to associatewith this outcome.defined as ICD-10 codes G31.8 and F06.7 and corre-sponding Read terms. Follow-up ceased with death,end of registration with the practice, cessation of thecontribution of data to the CPRD, or end of the studyperiod. We studied the association between AF andMCI in relevant subgroups including age at AF diag-nosis, sex, socioeconomic categories, stroke andtreatment of digoxin, oral anticoagulants, and amio-darone treatment. We investigated the associationbetween AF and MCI in Cox proportional hazardsmodel controlled for competing risk. Competingevents (eg, death) were treated as censored observa-tions. Adjustment was performed for age, sex, cal-endar year at study entry, socioeconomic status,smoking, hypertension, diabetes, obesity, hyper-cholesterolaemia, hearing loss, thyroid disease,depression, atherosclerotic heart disease, peripheralartery disease, heart failure, stroke, cancer, chronickidney disease, liver disease, and chronic obstructivepulmonary disease. We applied the same method tostudy the subsequent dementia incidence in partici-pants developed MCI.We analyzed data for 4,309,245 eligible individualsin the United Kingdom and identified 233,833 (5.4%)individuals with incident AF and a total of 233,747non-AF (Figure 1). The mean age was 74.2 years in bothAF and non-AF patients. During a median of 5.3 yearsof follow-up, there were 4,269 total incident MCIcases from both AF and non-AF patients. Persons withAF had a higher risk of MCI than non-AF individuals,with an adjusted HR of 1.45 (95% CI: 1.35-1.56). Be-sides AF, risk factors such as older age, female sex,higher socioeconomic deprivation, clinical history ofdepression, stroke, and multimorbidity were associ-ated with a greater risk of MCI (risk ratio ranging from1.08 (age in years) to 1.44 (history of depression atbaseline), all P < 0.001).Analyses showed similar results in the populationstratified by age at AF diagnosis, sex, socioeconomicdeprivation, and history of stroke. Patients withincident AF receiving digoxin treatment did notexperience an increased risk of MCI (HR: 0.97; 95% CI:0.53-1.78). Similarly, whereas MCI risk was higher inAF patients not receiving oral anticoagulant treat-ment and amiodarone treatment, AF patientsreceiving oral anticoagulant treatment and amiodar-one treatment were not at risk of MCI.FIGURE 1 Study Population and Risk Factors for Incident Dementia Following a Diagnosis of Mild Cognitive Impairment(Left) Characteristics of participants with AF and age- and sex-matched controls; (right) adjusted HR associated with each risk factor for the incidence of dementia afterthe diagnosis of mild cognitive impairment. AF ¼ atrial fibrillation; COPD ¼ chronic obstructive pulmonary disease; IMD ¼ Index of Multiple Deprivation.Letters J A C C : A D V A N C E S , V O L . - , N O . - , 2 0 2 3- 2 0 2 3 : 1 0 0 6 5 52Among individuals who developed MCI, there were1,117 dementia diagnosis on or after MCI diagnosisduring the study period. Individuals with AF alsoassociated with higher risk of dementia among thosewho developed MCI (multiple-adjusted HR: 1.25(95% CI: 1.09-1.42). Risk factors associated with sub-sequent dementia risk were sex, smoking, asthma,chronic kidney disease, and multicomorbidity(Figure 1).Our study showed that AF was associated with a45% increased risk of MCI in a real-world nationallyrepresentative cohort. The results showed that age,greater sociodemographic deprivation, and clinicalhistory of stroke were associated with a higher risk ofMCI but did not modify the association between AFand MCI. Both AF and MCI were frequently diagnosedin individuals aged over 74 years when multi-comorbidity was present, and we found diabetes,hypercholesterolemia, depression, and peripheralartery disease are also associated with an elevatedrisk of MCI. Progression from MCI to dementia ap-pears to be, at least partially, mediated by cardio-vascular risk factors and the presence of multiplecomorbidities. Silent brain infarcts are frequent in theAF population and have been previously associatedwith cognitive dysfunction.3,4Some limitations need to be acknowledged: as forall electronic health record studies, possible lack ofdata granularity and level of detail in the dataset is apotential limitation. Risk of unmeasured risk factors orcomorbidities is also something that needs to be bornein mind. We hope to have minimized this issue withdetailed characterization of the sample and presenta-tion of 16 frequently associated comorbidities.Underreporting of cognitive impairment, due to thesubtility/unspecificity of symptoms and sub-optimaluse of cognitive testing is a problem for research forthe field, also identified for EHR.5 However, ICD-10have been previously used in MCI studies withacceptable performance.6 Finally, an increase in risk ofMCI was not observed in individuals with AF receivingdigoxin, or amiodarone treatment, with risk in thesepatients being comparable to their non-AF peers.However, the observational design of this study andvery wide confidence interval for these subgroups ofpatients (accounting for only 10%-20% of the AFsample) does not allow us tomake any solid inferencesabout causality, a potential protective role of thesedrugs or unmeasured confounders.Our findings emphasize the association of multi-comorbidity and cardiovascular risk factors with AFdevelopment of MCI and progression to dementiain the AF population. These data provide supportto the previous hypothesis of integrated AFcare7 (combining anticoagulation, symptom, andcomorbidity-management) as a way of preventingcognitive deterioration and progression to dementia,highlighting the need for a confirmatory clinical trial.J A C C : A D V A N C E S , V O L . - , N O . - , 2 0 2 3 Letters- 2 0 2 3 : 1 0 0 6 5 53Sheng-Chia Chung, PhDMartin Rossor, MDAna Torralbo, PhDCai Ytsma, MScNatalie K. Fitzpatrick, MScSpiros Denaxas, PhD*Rui Providencia, MD, PhD*Institute of Health informatics ResearchUniversity College London222 Euston RoadNW1 2DA London, United KingdomE-mail: r.providencia@ucl.ac.ukhttps://doi.org/10.1016/j.jacadv.2023.100655The study was approved by the Medicines and Healthcare Products RegulatoryAuthority (United Kingdom) Independent Scientific Advisory Committee[18_228]. Dr Chung is supported by the National Institute of Health and CareResearch (NIHR) grants NIHR131227 & NIHR129463. Dr Providencia is supportedby the University College London British Heart Foundation Research Acceler-ator AA/18/6/34223 and NIHR grant NIHR129463. All other authors have re-ported that they have no relationships relevant to the contents of this paper todisclose.The authors attest they are in compliance with human studies committees andanimal welfare regulations of the authors’ institutions and Food and DrugAdministration guidelines, including patient consent where appropriate. Formore information, visit the Author Center.REF ER ENCES1. Langa KM, Levine DA. The diagnosis and management of mild cognitiveimpairment: a clinical review. JAMA. 2014;312:2551–2561.2. Chung SC, Sofat R, Acosta-Mena D, et al. Atrial fibrillation epidemiology,disparity and healthcare contacts: a population-wide study of 5.6 million in-dividuals. Lancet Reg Health Eur. 2021;7:100157.3. Conen D, Rodondi N, Müller A, et al. Relationships of Overt and Silent brainlesions with cognitive function in patients with atrial fibrillation. J Am CollCardiol. 2019;73:989–999.4. Kühne M, Krisai P, Coslovsky M, et al. Silent brain infarcts impact oncognitive function in atrial fibrillation. Eur Heart J. 2022;43:2127–2135.5. Maserejian N, Krzywy H, Eaton S, et al. Cognitive measures lacking in EHRprior to dementia or Alzheimer’s disease diagnosis. Alzheimers Dement.2021;17:1231–1243.6. Mattke S, Jun H, Chen E, et al. Expected and diagnosed rates ofmild cognitive impairment and dementia in the U.S. Medicare population:observational analysis. Alzheimers Res Ther. 2023;15:128.7. Yang PS, Sung JH, Jang E, et al. The Effect of integrated caremanagement on dementia in atrial fibrillation. J Clin Med. 2020;9:1696.

Cognitive Impairment and Dementia in Atrial Fibrillation

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Cognitive Impairment and Dementia in Atrial Fibrillation

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