Upper Gastrointestinal Bleeding in Elderly Adults with Dementia Receiving Cholinesterase Inhibitors: A Population‐Based Cohort Study

Alzheimer's disease (AD) is a leading cause of disability in elderly adults worldwide.1 Cholinesterase inhibitors (ChEIs) are first-line drugs used in the treatment of AD; they inhibit the breakdown of acetylcholine by blocking acetylcholinesterase in the central and peripheral nervous systems. ChEIs are linked to the risk of adverse cardiovascular events, but few studies have assessed the association between ChEIs and upper gastrointestinal (GI) bleeding. Two clinical trials have reported higher rates of GI bleeding in individuals taking donepezil than in those taking placebo, but these trials did not have enough power to detect statistically significant differences between groups.2, 3 Two case reports revealed recurrent upper GI bleeding after the use of donepezil4 and melena after the use of rivastigmine.5 The present population-based study assessed whether the use of ChEIs was associated with risk of upper GI bleeding in elderly adults with dementia. This retrospective population-based cohort study was based on healthcare administrative claims databases6 in Ontario, Canada. All Ontario residents aged 66 and older newly diagnosed with dementia between April 1, 1999, and March 31, 2011, were included, except for those who had been hospitalized for upper GI bleeding in the 5 years before cohort entry. The exposed cohort included new users of donepezil, rivastigmine, or galantamine. The date of the first dispensed ChEI during the study period was used as the cohort entry date. Individuals were deemed to have discontinued ChEIs and were censored if they did not refill their ChEI prescription within a period of 1.5 times the total days' supply of the previous prescription. Each individual was followed until the first of death, drug discontinuation (for ChEI users), exposure to a ChEI (for unexposed subjects), 5 years of follow-up, end of the follow-up period (March 31, 2012), or until they reached the outcome of interest. Unexposed individuals were those who were not dispensed any ChEI in the year before cohort entry and over the entire study period. These subjects were randomly assigned a cohort entry date based on the distribution of cohort entry dates in the exposed cohort. The primary outcome of this study, hospital admission for upper GI bleeding, was identified using validated International Classification of Diseases, Ninth and Tenth Revision codes.7 High-dimensional propensity score8 matching was used to balance potential confounders9 between the exposed and unexposed groups. Cox proportional hazards models were used to estimate the association between the use of ChEIs and upper GI bleeding. All analyses were performed using SAS statistical software for UNIX version 9.2 (SAS Institute, Inc., Cary, NC). The research ethics board at Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada approved the study. Two hundred three thousand two hundred seventy-nine eligible individuals with dementia were identified. At baseline, 122,316 patients (60.2%) were dispensed one of the three ChEIs; 82,675 (67.5%) received donepezil, 12,900 (21.9%) received galantamine, and 26,741 (10.6%) received rivastigmine. After propensity score matching, 48,723 ChEI users were successfully matched to nonusers; their baseline characteristics were successfully balanced between groups (Table 1). Over 200,000 person-years of follow-up, 2,104 admissions were observed for upper GI bleeding: 785 in ChEI users (10.6 events per 1,000 person-years of follow-up) and 1,319 in nonusers (9.6 events per 1,000 person-years of follow-up). The Cox proportional hazards model suggested an insignificant association between ChEI use and upper GI bleeding in elderly adults with dementia (hazard ratio = 1.03, 95% confidence interval = 0.92–1.16). Although it is plausible that ChEIs may result in peripheral cholinergic adverse events, this large population-based study found no significant association between ChEI use and upper GI bleeding in elderly adults. Lack of a significant association between ChEIs and upper GI bleeding may be because adverse GI events resulting from ChEIs are typically transient and decrease with continued use of the drugs.10 This study has potential limitations. First, use of administrative databases precludes the ability to capture clinically important information such as disease severity and GI pathology. Second, given the small proportion of the subjects who received rivastigmine or galantamine, the effect of individual ChEIs on upper GI bleeding could not be meaningfully compared with that of the nonuser cohort. Future research is needed to estimate the incidence of upper GI bleeding in chronic users of ChEIs and in high-risk individuals, such as those living in long-term care residences or with a history of upper GI hemorrhage. Conflict of Interest: Dr. Mamdani has served as an advisory board member for Astra Zeneca, Bristol-Myers Squibb, Eli Lilly and Company, Glaxo Smith Kline, Hoffman La Roche, Novartis, Novo Nordisk, and Pfizer. This study was supported by a grant from the Ontario Ministry of Health and Long-Term Care Drug Innovation Fund and the Institute for Clinical Evaluative Sciences, a nonprofit research institute sponsored by the Ministry. Author Contributions: Thavorn, Mamdani: concept and design. Thavorn, Gomes, Camacho, Yao, Juurlink, Mamdani: study cohort creation. Yao, Gomes, Camacho: statistical analyses. Thavorn, Mamdani: drafting of manuscript. Thavorn, Gomes, Camacho, Yao, Juurlink, Mamdani: critical revision and finalizing of manuscript. Sponsor's Role: The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding sources.

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