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      Anticholinergic drugs and risk of dementia: case-control study

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          Abstract

          Objectives

          To estimate the association between the duration and level of exposure to different classes of anticholinergic drugs and subsequent incident dementia.

          Design

          Case-control study.

          Setting

          General practices in the UK contributing to the Clinical Practice Research Datalink.

          Participants

          40 770 patients aged 65-99 with a diagnosis of dementia between April 2006 and July 2015, and 283 933 controls without dementia.

          Interventions

          Daily defined doses of anticholinergic drugs coded using the Anticholinergic Cognitive Burden (ACB) scale, in total and grouped by subclass, prescribed 4-20 years before a diagnosis of dementia.

          Main outcome measures

          Odds ratios for incident dementia, adjusted for a range of demographic and health related covariates.

          Results

          14 453 (35%) cases and 86 403 (30%) controls were prescribed at least one anticholinergic drug with an ACB score of 3 (definite anticholinergic activity) during the exposure period. The adjusted odds ratio for any anticholinergic drug with an ACB score of 3 was 1.11 (95% confidence interval 1.08 to 1.14). Dementia was associated with an increasing average ACB score. When considered by drug class, gastrointestinal drugs with an ACB score of 3 were not distinctively linked to dementia. The risk of dementia increased with greater exposure for antidepressant, urological, and antiparkinson drugs with an ACB score of 3. This result was also observed for exposure 15-20 years before a diagnosis.

          Conclusions

          A robust association between some classes of anticholinergic drugs and future dementia incidence was observed. This could be caused by a class specific effect, or by drugs being used for very early symptoms of dementia. Future research should examine anticholinergic drug classes as opposed to anticholinergic effects intrinsically or summing scales for anticholinergic exposure.

          Trial registration

          Registered to the European Union electronic Register of Post-Authorisation Studies EUPAS8705.

          Related collections

          Most cited references 42

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          Data Resource Profile: Clinical Practice Research Datalink (CPRD)

          The Clinical Practice Research Datalink (CPRD) is an ongoing primary care database of anonymised medical records from general practitioners, with coverage of over 11.3 million patients from 674 practices in the UK. With 4.4 million active (alive, currently registered) patients meeting quality criteria, approximately 6.9% of the UK population are included and patients are broadly representative of the UK general population in terms of age, sex and ethnicity. General practitioners are the gatekeepers of primary care and specialist referrals in the UK. The CPRD primary care database is therefore a rich source of health data for research, including data on demographics, symptoms, tests, diagnoses, therapies, health-related behaviours and referrals to secondary care. For over half of patients, linkage with datasets from secondary care, disease-specific cohorts and mortality records enhance the range of data available for research. The CPRD is very widely used internationally for epidemiological research and has been used to produce over 1000 research studies, published in peer-reviewed journals across a broad range of health outcomes. However, researchers must be aware of the complexity of routinely collected electronic health records, including ways to manage variable completeness, misclassification and development of disease definitions for research.
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            Dementia prevention, intervention, and care

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              Evaluating medication effects outside of clinical trials: new-user designs.

               Wayne Ray (2003)
              Recent clinical trials demonstrating that hormone replacement therapy (HRT) does not prevent coronary heart disease in women have again raised doubts concerning observational studies. Although much of the explanation probably lies in what might be called the "healthy HRT user" effect, another contributing factor may be that most observational studies included many prevalent users: women taking HRT for some time before study follow-up began. This practice can cause two types of bias, both of which plausibly may have contributed to the discrepancy between observational and randomized studies. First, prevalent users are "survivors" of the early period of pharmacotherapy, which can introduce substantial bias if risk varies with time, just as in studies of operative procedures that enroll patients after they have survived surgery. This article provides several examples of medications for which the hazard function varies with time and thus would be subject to prevalent user bias. Second, covariates for drug users at study entry often are plausibly affected by the drug itself. Investigators often do not adjust for these factors on the causal pathway, which may introduce confounding. A new-user design eliminates these biases by restricting the analysis to persons under observation at the start of the current course of treatment. This article thus argues that such designs should be used more frequently in pharmacoepidemiology.
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                Author and article information

                Affiliations
                [1 ]School of Health Sciences, University of East Anglia, Norwich NR4 7TJ, UK
                [2 ]Norwich Medical School, University of East Anglia, Norwich, UK
                [3 ]School of Life and Health Sciences, Aston University, Birmingham, UK
                [4 ]School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK
                [5 ]Division of Population Health Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
                [6 ]Department of Pharmacy Practice, College of Pharmacy, Purdue University, West Lafayette, IN, USA
                [7 ]School of Medicine, Indiana University, Indianapolis, IN, USA
                [8 ]Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK
                [9 ]Cambridge Institute of Public Health, University of Cambridge, Cambridge, UK
                [10 ]Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK
                Author notes
                Correspondence to: K Richardson k.richardson@ 123456uea.ac.uk
                Contributors
                Role: research fellow
                Role: professor
                Role: senior lecturer
                Role: professor
                Role: professor
                Role: professor
                Role: professor
                Role: senior research associate
                Role: research fellow
                Role: associate professor
                Role: assistant professor
                Role: professor
                Role: professor
                Role: professor
                Role: professor
                Role: senior lecturer
                Journal
                BMJ
                BMJ
                BMJ-UK
                bmj
                The BMJ
                BMJ Publishing Group Ltd.
                0959-8138
                1756-1833
                2018
                25 April 2018
                : 361
                rick042315
                10.1136/bmj.k1315
                5915701
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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                Medicine

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