News Author: Laurie Barclay, MD

May 20, 2009 — Cholinesterase inhibitors are associated with previously underrecognized serious adverse events in older adults with dementia, which must be carefully balanced against the generally modest benefits of these drugs, according to the results of a population-based cohort study reported in the May 11 issue of the Archives of Internal Medicine.

"Cholinesterase inhibitors are commonly prescribed to treat dementia, but their adverse effect profile has received little attention," write Sudeep S. Gill, MD, MSc, from the Institute for Clinical Evaluative Sciences in Toronto, Ontario, Canada, and colleagues. "These drugs can provoke symptomatic bradycardia and syncope, which may lead to permanent pacemaker insertion. Drug-induced syncope may also precipitate fall-related injuries, including hip fracture."

To evaluate the association between use of cholinesterase inhibitors and syncope-related outcomes, the investigators used healthcare databases from Ontario, Canada, with enrollment from April 1, 2002, to March 31, 2004. The study cohort consisted of 19,803 community-dwelling older adults with dementia who were prescribed cholinesterase inhibitors and 61,499 control subjects who were not using these medications.

Compared with control subjects, patients who were prescribed cholinesterase inhibitors had more frequent hospital visits for syncope (31.5 vs 18.6 events per 1000 person-years; adjusted hazard ratio [HR], 1.76; 95% confidence interval [CI], 1.57 - 1.98). Participants receiving cholinesterase inhibitors also had a higher frequency of other syncope-related events vs control subjects.

These events included hospital visits for bradycardia (6.9 vs 4.4 events per 1000 person-years; HR, 1.69; 95% CI, 1.32 - 2.15), permanent pacemaker insertion (4.7 vs 3.3 events per 1000 person-years; HR, 1.49; 95% CI, 1.12 - 2.00), and hip fracture (22.4 vs 19.8 events per 1000 person-years; HR, 1.18; 95% CI, 1.04 - 1.34).

Additional analyses in which participants were matched either on their baseline comorbidity status or use of propensity scores yielded similar findings.

"Use of cholinesterase inhibitors is associated with increased rates of syncope, bradycardia, pacemaker insertion, and hip fracture in older adults with dementia," the study authors write. "The risk of these previously underrecognized serious adverse events must be weighed carefully against the drugs' generally modest benefits."

Limitations of this study include retrospective, observational design; additional risk factors for syncope in many patients; possible residual confounding and hidden bias; failure to compare individual cholinesterase inhibitors or to examine dose-response relationships; lack of evaluation of fall-related injuries other than hip fracture; and exclusion of patients with a recent history of syncope.

"Older adults with dementia are vulnerable to adverse drug effects, and future RCTs [randomized controlled trials] evaluating treatments targeted to this population should therefore provide comprehensive documentation of common and serious outcomes such as falls (syncopal or otherwise) and injuries," the study authors conclude.

The Clinical Teachers Association of Queen's Endowment Fund and a Chronic Disease New Emerging Team program grant from the Canadian Institutes of Health Research (CIHR) supported this study. The New Emerging Team program receives joint sponsorship from the Canadian Diabetes Association; the Kidney Foundation of Canada; the Heart and Stroke Foundation of Canada; and the CIHR Institutes of Nutrition, Metabolism and Diabetes, and Circulatory and Respiratory Health. Some of the study authors have disclosed various financial relationships with Bayer Canada, the Ontario Ministry of Health, the University of Toronto, and the CIHR.

Arch Intern Med. 2009;169:867-873.


Clinical Context


Cholinesterase inhibitors are widely used to treat Alzheimer's disease and other forms of dementia, although previous trials have questioned their efficacy in relationship to their cost. In a randomized trial by Courtney and colleagues, which was published in the June 26, 2004, issue of the Lancet, use of donepezil was associated with modest improvements in cognition and function scores vs placebo during the first 2 years of treatment. However, rates of institutionalization and progression of disability were similar between donepezil and placebo at 3 years, and the 2 treatment groups also experienced similar rates of behavioral and psychological symptoms.

Donepezil was not associated with a higher rate of adverse events in the study by Courtney and colleagues, but this might have been the result of a small sample size. The current study uses a large patient cohort to examine the potential for serious adverse events associated with treatment with cholinesterase inhibitors.


Study Highlights


  • Researchers used public health databases from Ontario, Canada, which capture nearly all health-related events. They focused on residents 66 years or older with a previous diagnosis of dementia.
  • The study authors compared community-dwelling subjects who had received cholinesterase inhibitors vs patients who had not (control group). Control subjects needed to have recent contact with their clinician, and patients with a history of syncope in the last year were excluded from analysis.
  • Hospital and emergency department records were reviewed for the diagnoses of syncope, bradycardia, complete atrioventricular block, and hip fracture unrelated to a traumatic injury or cancer.
  • The study period lasted from 2002 to 2004. Researchers examined the relationship between the use of cholinesterase inhibitors and the above diagnoses. They adjusted for multiple covariates that could act as confounders, including demographic, disease, and pharmaceutic variables.
  • 19,803 adults received cholinesterase inhibitors (13,641 received donepezil; 3448, galantamine; and 2714, rivastigmine). These subjects were compared vs 61,499 control subjects.
  • The average number of hospital visits for syncope in subjects receiving cholinesterase inhibitors and in control subjects was 31.5 and 18.6 per 1000 person-years, respectively. The adjusted HR of 1.76 for this outcome was significant.
  • Subjects receiving cholinesterase inhibitors also experienced significantly higher rates of bradycardia (HR, 1.69) and pacemaker insertion (HR, 1.49).
  • The average rates of hip fracture in subjects receiving cholinesterase inhibitors and in control subjects were 22.4 and 19.8 per 1000 person-years, respectively. The adjusted HR of 1.18 for this outcome was also significant.
  • Additional analyses with a scale of all potential comorbidities failed to alter the main outcome of the study. Researchers also examined the relationship between 2 outcomes thought to be completely unrelated to the use of cholinesterase inhibitors (pulmonary embolism and cataract extraction) as a means to demonstrate that their positive findings were valid. Cholinesterase inhibitors had no association with pulmonary embolism or cataract extraction.


Clinical Implications


  • In a previous randomized study, use of donepezil for the treatment of Alzheimer's disease was associated with modest improvements in cognition and function scores but did not reduce rates of institutionalization, progression of disability, or behavioral symptoms vs placebo.
  • In the current cohort study, the use of cholinesterase inhibitors in older adults with dementia was associated with higher rates of syncope, bradycardia, pacemaker placement, and hip fracture.



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