Initial Cholinesterase Inhibitor Therapy Dose and Serious Events in Older Women and Men

Paula A. Rochon, MD, MPH; Andrea Gruneir, PhD; Sudeep S. Gill, MD, MSc; Wei Wu, MSc; Lynn Zhu, PhD; Nathan Herrmann, MD; Chaim M. Bell, MD, PhD; Peter C. Austin, PhD; Nathan M. Stall, MD; Lisa McCarthy, PharmD, MSc; Vasily Giannakeas, MPH; Amanda Alberga, MPH; Dallas P. Seitz, MD, PhD; Sharon-Lise Normand, PhD; Jerry H. Gurwitz, MD; Susan E. Bronskill, PhD


J Am Geriatr Soc. 2018;66(9):1692-1699. 

In This Article

Abstract and Introduction


Objectives: To examine dose-related prescribing and short-term serious events associated with initiation of cholinesterase inhibitor (ChEI) therapy.

Design: Retrospective, population-based cohort study.

Setting: Ontario, Canada.

Participants: Women (n=47,829) and men (n=32,503) aged 66 and older who initiated a ChEI between April 1, 2010, and June 30, 2016.

Measurements: All-cause serious events (emergency department (ED) visits, inpatient hospitalizations, death) within 30 days of ChEI initiation. Multivariable Cox proportional hazards models were used to estimate adjusted rates of serious events.

Results: Overall, 4.8% of older adults were dispensed a lower-than-recommended ChEI starting dose, 87.9% a recommended dose, and 7.3% a higher-than-recommended starting dose. Eight thousand six hundred seventy-one (10.8%) individuals experienced a serious event within 30 days of initiating therapy, primarily ED visits (8,540, 10.6%). Relative to those initiated on a recommended starting dose, those initiated on a higher dose had a significantly increased rate of serious events (women adjusted hazard ratio (aHR) 1.50, 95% confidence interval (CI) =1.38–1.63; men aHR 1.31, 95% CI=1.19–1.45). Similar patterns were found for ED visits and inpatient hospitalizations but not death. The relative effect of higher-than-recommended starting dose dispensed vs. recommended starting dose dispensed was greater in women than it was in men: the number needed to harm was 22 (95% confidence interval (CI)=18–29) for women and 36 (95% CI= 26–61) for men.

Conclusion: Serious events immediately after initiation of ChEIs were associated with starting ChEI dose. This association was stronger in women.


Globally, almost 50 million people live with dementia.[1] Cholinesterase inhibitors (ChEIs) are some of the only medications approved for the symptomatic management of Alzheimer's disease and related dementias. Accordingly, ChEI therapies are widely used despite evidence of limited efficacy[2–4] and known adverse events,[2] including gastrointestinal problems (abdominal pain, diarrhea, nausea, vomiting, anorexia, weight loss[2]), syncope, and dizziness.[5]

The adage "start low and go slow"[6] is a prescribing strategy accepted in geriatric medicine to minimize adverse events that individuals starting a new drug therapy experience because adverse events are often dose related and usually occur soon after drug initiation.[7] Despite this, randomized controlled trials, including those for ChEIs, seldom report dose-related risk of drug therapy.[8] Consequently, appropriate dose-related considerations are lacking in drug prescribing guidelines, low doses of drugs are not manufactured, and older adults often split their pills to achieve the desired low dose.[9] The importance of "start low and go slow" may be magnified when prescribing for older women[6] because they are thought to be at greater risk of adverse events than men.[10,11]

Despite wide-spread use of ChEIs over 2 decades, little is known about the short-term effects of serious events associated with their initiation or how appropriate initial dose selection and consideration of sex differences may mitigate these events. We examined dose-related prescribing and short-term serious events associated with initiation of ChEI therapy in a large population-based cohort of older adults with dementia.