Access Document
Total Page:16
File Type:pdf, Size:1020Kb
BMJ Confidential: For Review Only The association between anticholinergic medication and dementia incidence varies with pattern of exposure and medication class: A nested case-control study using the Clinical Practice Research Datalink Journal: BMJ Manuscript ID BMJ.2017.042315 Article Type: Research BMJ Journal: BMJ Date Submitted by the Author: 10-Nov-2017 Complete List of Authors: Richardson, Kathryn; University of East Anglia, ; Fox, Chris; Norwich Medical School, Department of Psychological Sciences Maidment, Ian; University of Aston, Steel, Nicholas; University of East Anglia, Norwich Medical School Loke, Yoon; University of East Anglia, School of Medicine Arthur, Antony; University of East Anglia, School of Health Sciences University of East Anglia, Norwich Research Park myint, phyo; University of Aberdeen, ; University of East Anglia, Norwich Medical School Grossi, Carlota; University of East Anglia, School of Health Sciences Mattishent, Katharina; University of East Anglia, Norwich Medical School Bennett, Kathleen; Royal College of Surgeons in Ireland (RCSI), Population Health Sciences Campbell, Noll; Purdue University College of Pharmacy, Department of Pharmacy Practice Boustani, Malaz; Indiana University, Center for Aging Research Robinson, Louise; Institute for Health and Society, Newcastle University Brayne, Carol; University of Cambridge, Institute of Public Health Matthews, Fiona; Newcastle University, Institute for Health and Society, Biomedical Research Building, Campus for Ageing and Vitality Savva, George; Quadram Institute Bioscience, Analytical Sciences Unit; University of East Anglia, School of Health Sciences Keywords: dementia, pharmacoepidemiology, anticholinergic, Primary care https://mc.manuscriptcentral.com/bmj Page 1 of 70 BMJ 1 2 3 The association between anticholinergic medication and dementia incidence varies with 4 pattern of exposure and medication class: A nested case-control study using the Clinical 5 Practice Research Datalink 6 7 Kathryn Richardson, Chris Fox, Ian Maidment, Nicholas Steel, Yoon K Loke, Antony Arthur, Phyo K 8 9 Myint, Carlota M Grossi, Katharina Mattishent, Kathleen Bennett, Noll Campbell, Malaz Boustani, 10 Louise Robinson, Carol Brayne, Fiona E Matthews, George M Savva 11 Confidential: For Review Only 12 Kathryn Richardson, School of Health Sciences, University of East Anglia, Norwich, NR4 7TJ, UK 13 Research Fellow in Statistics 14 Chris Fox, Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, 15 16 Clinical Professor 17 Ian Maidment, School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK 18 Senior Lecturer in Clinical Pharmacy 19 20 Nicholas Steel, Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ 21 Clinical Professor in Public Health 22 Yoon K Loke, Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ 23 Professor of Medicine and Pharmacology 24 25 Antony Arthur, School of Health Sciences, University of East Anglia, Norwich, NR4 7TJ, UK 26 Professor of Nursing Science, 27 Phyo K Myint, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, AB25 2ZD, UK 28 Clinical Chair in Medicine of Old Age, 29 30 Carlota M Grossi, School of Health Sciences, University of East Anglia, Norwich, NR4 7TJ, UK 31 Senior Research Associate, 32 Katharina Mattishent, Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ 33 34 Clinical Research Fellow, 35 Kathleen Bennett, Division of Population Health Sciences, Royal College of Surgeons in Ireland, 36 Dublin, Ireland Associate Professor in Pharmacoepidemiology 37 38 Noll Campbell, Department of Pharmacy Practice, College of Pharmacy, Purdue University, US 39 Assistant Professor 40 Malaz Boustani, School of Medicine, University of Indiana, Indiana United States 41 Professor of Medicine 42 43 Louise Robinson, Newcastle University Institute for Ageing, Newcastle University, NE4 5PL, UK 44 Professor of Primary Care and Ageing 45 Carol Brayne, Professor of Public Health Medicine, Cambrdge Institute of Public Health, University of 46 Cambridge, CB2 0SR, UK 47 48 Fiona E Matthews, Institute for Health and Society, Newcastle University, NE4 5PL, UK 49 Professor of Epidemiology 50 51 George M Savva, School of Health Sciences, University of East Anglia, NR4 7TJ, UK 52 Senior Lecturer in Applied Statistics 53 54 Correspondence to: K Richardson [email protected] 55 Word count: 4999 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 2 of 70 1 2 3 4 5 6 7 8 Key words: dementia, Alzheimer’s disease, pharmacoepidemiology, case-control study, 9 anticholinergic, medication use, antimuscarinic 10 11 Confidential: For Review Only 12 13 14 "What this paper adds" 15 16 Section 1: What is already known on this subject 17 18 • Use of medications with strong anticholinergic activity is associated with impaired 19 cognition in the short term. 20 21 • Published observational studies have found associations between anticholinergic use 22 and future cognitive decline and dementia incidence, but whether this is causal and 23 24 is directly attributable to anticholinergic activity is still unknown. 25 26 Section 2: What this study adds 27 28 • Our study confirms the previously observed association, but only for specific classes 29 of definite anticholinergics. Anticholinergic antidepressants, antiparkinsonians and 30 urologicals are linked to future dementia incidence, but antihistamines and 31 antispasmodics are not. 32 33 • Use of anticholinergic antidepressants and urologicals are positively associated with 34 dementia diagnosis 15-20 years after the exposure. 35 • Clinical practice and future research to reduce potentially harmful medication should 36 focus on risks associated with specific classes of anticholinergic medication. 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 3 of 70 BMJ 1 2 3 ABSTRACT 4 5 6 OBJECTIVES: To estimate how duration and level of exposure to different classes of 7 8 anticholinergic medication is associated with subsequent incident dementia. 9 DESIGN: Case-control study 10 11 SETTING:Confidential: General practices in the United For Kingdom Review contributing to the ClinicalOnly Practice 12 13 Research Datalink. 14 PARTICIPANTS: 40,770 patients aged 65-99 years and diagnosed with dementia between 15 16 April 2006 and July 2015, and 283,933 controls without dementia matched 7:1 on date, sex, 17 age, deprivation, and years of data history. 18 19 INTERVENTIONS: Daily defined doses (DDD) of anticholinergic medications coded according 20 to the Anticholinergic Cognitive Burden (ACB) scale; in total and grouped by subclass; 21 22 prescribed between 4-20 years prior to dementia diagnosis. 23 24 MAIN OUTCOME MEASURES: Odds ratios for incident dementia, adjusted for a wide range 25 of demographics and health-related covariates. 26 27 RESULTS: 14,453 (35%) cases and 86,403 (30%) controls were prescribed at least one potent 28 (ACB score 3, ACB3) anticholinergic during the exposure period. The adjusted odds ratio 29 30 (aOR) for ‘any ACB3’ was 1.11 (95% confidence interval 1.08 to 1.14), and an increasing odds 31 of dementia was significantly associated with an increasing average ACB score. When 32 33 considered by class, ACB3 antihistamines or antispasmodics were not significantly linked to 34 35 dementia. Within ACB3 antidepressants, urologicals, and antiparkinsonians, risks increased 36 with exposure with this increase observed for exposure 15-20 years before diagnosis. 37 38 CONCLUSIONS: In the largest study to date, a robust association between some classes of 39 anticholinergic medication use and future dementia incidence was observed. This could be 40 41 caused by a class-specific effect, or by medications being used for very early symptoms of 42 dementia. Future pharmacological and clinical research must examine subgroups of 43 44 anticholinergics as opposed to anticholinergic effects per se or summing scales for 45 46 anticholinergic exposure. 47 48 TRIAL REGISTRATION: EUPAS8705 (ENCePP e-register of studies) 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 4 of 70 1 2 3 Introduction 4 5 Dementia is a leading cause of disability and death worldwide (1), and its prevention is a 6 7 global public health priority. Dementia is caused by a number of different 8 9 neurodegenerative processes that contribute to irreversible cognitive decline and 10 11 Confidential: For Review Only 12 associated symptoms, progressive loss of independence and daily functioning. Mixed 13 14 dementias are more prevalent than is often recognised, with symptoms often more closely 15 16 linked to overall pathological burden as opposed to any specific disease process (2,3). No 17 18 19 disease modifying treatments for dementia exist, however, age-specific dementia incidence 20 21 across populations is declining, suggesting that changing lifestyles or environment may lead 22 23 to a meaningful change in dementia prevalence (4). Hence identifying and reducing 24 25 26 exposure to risk factors that can affect any aspect of long term brain health is important for 27 28 dementia prevention and cognitive health in the population (5). 29 30 31 Multiple medication use is increasing in middle aged and older populations (6,7), but the 32 33 potential harms of long term medication use are not well understood. Medications with 34 35 36 anticholinergic activity (henceforth anticholinergics) block the neurotransmitter 37 38 acetylcholine in the central or peripheral