Multiple adverse outcomes associated with antipsychotic use in people with dementia: population based matched cohort study (2024)

1. Pearl L H Mok, research fellow1 2,
2. Matthew J Carr, research fellow1 2 3,
3. Bruce Guthrie, professor4,
4. Daniel R Morales, Wellcome Trust clinical research fellow5,
5. Aziz Sheikh, professor6 7,
6. Rachel A Elliott, professor3 8,
7. Elizabeth M Camacho, senior research fellow8,
8. Tjeerd van Staa, professor9,
9. Anthony J Avery, professor3 10,
10. Darren M Ashcroft, professor1 2 3

1. ¹Centre for Pharmacoepidemiology and Drug Safety, Division of Pharmacy and Optometry, University of Manchester, Manchester, M13 9PT, UK
2. ²Manchester Academic Health Science Centre, Manchester, UK
3. ³NIHR Greater Manchester Patient Safety Research Collaboration, University of Manchester, Manchester, UK
4. ⁴Advanced Care Research Centre, Usher Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
5. ⁵Population Health and Genomics, University of Dundee, Dundee, UK
6. ⁶Usher Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
7. ⁷Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
8. ⁸Manchester Centre for Health Economics, Division of Population Health, Manchester, UK
9. ⁹Division of Informatics, Imaging and Data Sciences, University of Manchester, Manchester, UK
10. ¹⁰Centre for Primary Care, School of Medicine, University of Nottingham, Nottingham, UK

1. Correspondence to: P L H Mok pearl.mok{at}manchester.ac.uk

• Accepted 29 February 2024

Abstract

Objective To investigate risks of multiple adverse outcomes associated with use of antipsychotics in people with dementia.

Design Population based matched cohort study.

Setting Linked primary care, hospital and mortality data from Clinical Practice Research Datalink (CPRD), England.

Population Adults (≥50 years) with a diagnosis of dementia between 1 January 1998 and 31 May 2018 (n=173 910, 63.0% women). Each new antipsychotic user (n=35 339, 62.5% women) was matched with up to 15 non-users using incidence density sampling.

Main outcome measures The main outcomes were stroke, venous thromboembolism, myocardial infarction, heart failure, ventricular arrhythmia, fracture, pneumonia, and acute kidney injury, stratified by periods of antipsychotic use, with absolute risks calculated using cumulative incidence in antipsychotic users versus matched comparators. An unrelated (negative control) outcome of appendicitis and cholecystitis combined was also investigated to detect potential unmeasured confounding.

Results Compared with non-use, any antipsychotic use was associated with increased risks of all outcomes, except ventricular arrhythmia. Current use (90 days after a prescription) was associated with elevated risks of pneumonia (hazard ratio 2.19, 95% confidence interval (CI) 2.10 to 2.28), acute kidney injury (1.72, 1.61 to 1.84), venous thromboembolism (1.62, 1.46 to 1.80), stroke (1.61, 1.52 to 1.71), fracture (1.43, 1.35 to 1.52), myocardial infarction (1.28, 1.15 to 1.42), and heart failure (1.27, 1.18 to 1.37). No increased risks were observed for the negative control outcome (appendicitis and cholecystitis). In the 90 days after drug initiation, the cumulative incidence of pneumonia among antipsychotic users was 4.48% (4.26% to 4.71%) versus 1.49% (1.45% to 1.53%) in the matched cohort of non-users (difference 2.99%, 95% CI 2.77% to 3.22%).

Conclusions Antipsychotic use compared with non-use in adults with dementia was associated with increased risks of stroke, venous thromboembolism, myocardial infarction, heart failure, fracture, pneumonia, and acute kidney injury, but not ventricular arrhythmia. The range of adverse outcomes was wider than previously highlighted in regulatory alerts, with the highest risks soon after initiation of treatment.

Footnotes

• Contributors: All authors conceived and designed the study and acquired, analysed, or interpreted the data. BG, DRM, TvS, AJA, and DMA reviewed the clinical codes. PLHM conducted the statistical analyses and wrote the first draft of the manuscript. All authors critically revised the manuscript for important intellectual content and approved the final version. AJA, DMA, RAE, BG, DRM, AS, and TvS obtained the funding. PLHM is the guarantor. The corresponding author (PLHM) attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

• Funding: This study was funded by the National Institute for Health and Care Research (NIHR, RP-PG-1214-20012). MJC, AJA, and DMA were supported by the NIHR Greater Manchester Patient Safety Translational Research Centre (PSTRC-2016-003) at the time of this study and are now supported by the NIHR Greater Manchester Patient Safety Research Collaboration (NIHR204295). The funders had no role in the study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the article for publication. PLHM has full access to all data and all authors have full access to the statistical reports and tables in the study. PLHM takes responsibility for the integrity of the data and the accuracy of the data analysis.

• Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: BG reports research grants from the National Institute for Health and Care Research (NIHR). DRM was awarded a Wellcome Trust Clinical Research Development Fellowship (214588/Z/18/Z). AS reports a research grant from the NIHR. RAE reports research grants from the NIHR and NHS England, and travel costs to attend a roundtable dinner discussion on medication errors, House of Commons, Westminster, on 29 March 2022. TvS reports research grants from the NIHR. AJA is national clinical director for prescribing for NHS England and reports research grants from the NIHR. DMA reports research grants from the NIHR, AbbVie, Almirall, Celgene, Eli Lilly, Janssen, Novartis, UCB, and the Leo Foundation. All other authors declare no support from any organisation for the submitted work (except those listed in the funding section); no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

• Transparency: The lead author (PLHM: the manuscript’s guarantor) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

• Dissemination to participants and related patient and public communities: This study used anonymised electronic health records from the CPRD and it is therefore not possible to disseminate the findings directly to individuals whose data we used. This study is part of a National Institute for Health and Care Research (NIHR) funded programme (RP-PG-1214-20012): Avoiding patient harm through the application of prescribing safety indicators in English general practices (PRoTeCT). We have experienced patient and public involvement members aligned to the programme who we will consult in the results dissemination. In addition, senior author DMA is director of NIHR Greater Manchester Patient Safety Research Collaboration (GMPSRC), and co-authors MJC and AJA are affiliated with it. The Patient Safety Research Collaboration has a community of public contributors including patients, carers, and people accessing health and social care services. The authors will work with this network to disseminate findings.

• Provenance and peer review: Not commissioned; externally peer reviewed.

Data availability statement

Electronic health records are, by definition, considered sensitive data in the UK by the Data Protection Act and cannot be shared via public deposition because of information governance restriction in place to protect patient confidentiality. Access to Clinical Practice Research Datalink (CPRD) data is subject to protocol approval via CPRD’s research data governance process. For more information see https://cprd.com/data-access. Linked secondary care data from Hospital Episodes Statistics, mortality data from the Office for National Statistics, and index of multiple deprivation data can also be requested from CPRD.

http://creativecommons.org/licenses/by/4.0/

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/.