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Predictive factors of discontinuation and switch of cholinesterase inhibitors in community-dwelling patients with Alzheimer’s disease

A 2-year prospective, multicentre, cohort study

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Abstract

Background: The efficacy of cholinesterase inhibitors (ChEIs), especially over the long term, is still under discussion. There is a lack of data concerning the optimal drug treatment duration and the reasons for discontinuation, particularly outside the clinical trial setting.

Objective: To identify predictive factors of discontinuation and switch of ChEIs in a real-world setting.

Methods: A multicentre cohort study of 686 patients with mild-to-moderate ambulatory Alzheimer’s disease who were diagnosed in 16 Alzheimer’s disease expert centres in 2000–2 and who were assessed twice yearly for 2 years. The main outcome measure was ChEI discontinuation and switch (analysed using Cox survival analyses).

Results: After 2 years, of the 611 subjects treated with a ChEI at baseline, 100 subjects had switched or discontinued ChEI therapy (incidence rate 12.7 [95% CI 10.2, 15.2] per 100 person-years). The incidences of switching and discontinuation were 9.2 (95% CI 7.0, 11.3) and 3.6 (95% CI 2.3, 4.8) per 100 person-years, respectively. In the multivariate analysis, predictive factors for switching were an ineffective ChEI dose (adjusted hazard ratio [HRa] = 6.91, 95% CI 3.08, 15.49), rapid cognitive decline (HRa = 4.10, 95% CI 1.85, 9.05), hospitalization unrelated to Alzheimer’s disease (HRa = 2.33,95% CI 1.07, 5.09) and anxiety (HRa= 2.08, 95% CI 1.16, 3.73). Predictive factors of discontinuation were: hospitalization related (HRa = 9.14, 95% CI 2.69, 31.07) or unrelated (HRa = 4.23, 95% CI 1.54, 11.59) to Alzheimer’s disease, use of an anticholinergic drug (HRa = 4.26, 95% CI 1.46, 12.45) and weight loss (HRa = 3.77, 95% CI 1.15, 12.33).

Conclusions: This study highlights four types of predictors of switch or discontinuation, reflecting disease progression, reconsideration of ChEI benefits, adverse drug reactions to ChEIs and inappropriate concurrent use of anticholinergic drugs. Attention should be paid to anticholinergic agents and prescribers should be given better information about these drugs.

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Acknowledgements

REAL.FR was supported by a grant from the Clinical Research Hospital Program from the French Ministry of Health (PHRC N° 98-47N, PHRC N° 0101001). This funding organization was not involved in the design and conduct of the study, collection of data, management, analysis, interpretation of data and preparation or review and approval of the manuscript.

REAL.FR Group: Principal Investigator: Prof. B. Vellas (Toulouse); Co-Investigators: Prof. M. Rainfray, Dr S. Richard-Harston (Bordeaux); Prof. A. Franco, Dr P. Couturier (Grenoble); Prof. F. Pasquier, Dr M.A. Mackowiak-Cordoliani (Lille); Dr B. Frigard, Dr H. Idiri, Dr K. Gallouj (Wasquehal); Dr B. Michel (Marseille); Prof. Cl. Jeandel (Montpellier); Prof. J. Touchon, Dr F. Portet, Dr S. Lerouge (Montpellier); Prof. Ph. Robert, Dr P. Brocker, C. Bertogliati (Nice); Prof. B. Forette, Dr L. Teillet, Dr L. Lechowski (Paris); Prof. J. Belmin, D.S. Pariel-Madjlessi (Paris); Prof. M. Verny, Dr M.A. Artaz (Paris); Prof. F. Forette, Dr A.S. Rigaud, Dr F. Latour (Paris); Prof. P. Jouanny, Dr S. Belliard, Dr O. Michel (Rennes); Dr C. Girtanner, Dr Thomas-Anterion (Saint Etienne); Study coordinators: F. Cortes, S. Gillette-Guyonnet, Prof. F. Nourhashemi, Dr P.J. Ousset (Toulouse); Epidemiologist: Prof. S. Andrieu (Toulouse); Data analysis: C. Cantet (Toulouse).

The authors have no conflicts of interest that are directly relevant to the contents of this study.

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Authors and Affiliations

  1. Department of Epidemiology and Public Health, Toulouse University Hospital, Université de Toulouse UPS, Inserm U558, Gérontopôle, Toulouse, France

    Virginie Gardette, Sandrine Andrieu & Alain Grand

  2. Pharmacoepidemiology Unit, Université de Toulouse UPS, EA3696, Toulouse, France

    Maryse Lapeyre-Mestre

  3. nserm U558, Toulouse, France

    Nicola Coley

  4. Department of Geriatric Medicine, Toulouse University Hospital, Inserm U558, Gérontopôle, Toulouse, France

    Christelle Cantet, Pierre-Jean Ousset & Bruno Vellas

  5. Department of Clinical Pharmacology, Toulouse University Hospital, Université de Toulouse UPS, Pharmacoepidemiology Unit, EA3696, Toulouse, France

    Jean-Louis Monstastruc

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  1. Virginie Gardette
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Gardette, V., Andrieu, S., Lapeyre-Mestre, M. et al. Predictive factors of discontinuation and switch of cholinesterase inhibitors in community-dwelling patients with Alzheimer’s disease. CNS Drugs 24, 431–442 (2010). https://doi.org/10.2165/11318010-000000000-00000

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