NPC Archive Item: Cholinesterase inhibitors associated with syncope in patients with dementia

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18th May 2009

An observational study has found that cholinesterase inhibitors (donepezil, galantamine and rivastigmine▼) are associated with increased rates of syncope, bradycardia, permanent pacemaker insertion and hip fracture in older adults with dementia.

Prescribers should continue to follow the NICE-SCIE guideline on dementia. This incorporated a NICE technology appraisal relating to the cholinesterase inhibitors and memantine.  NICE recommend that cholinesterase inhibitors should be considered only for people with moderate Alzheimer’s disease, i.e. with a Mini-Mental State Examination (MMSE) score between 20 and 10 (the higher the score, the less severe the disease).  They are not recommended in other types of dementia or in mild cognitive impairment outside properly constructed clinical trials.

In patients with moderate Alzheimer’s disease, when treatment with cholinesterase inhibitors is being considered, the risk of adverse effects, including those outlined here, should be balanced against the limited benefits of these drugs. Treatment decisions should be individualised and the potential risks and modest benefits of treatment should be discussed with patients and/or their carers.

What is the background to this?
This observational study aimed to find out whether cholinesterase inhibitor use is associated with syncope (a brief loss of consciousness with spontaneous recovery) and bradycardia in patients with dementia. Syncope can have serious consequences: for example permanent pacemaker insertion and, because it is generally accompanied by falling, injury. Therefore, the study also considered the syncope-related outcomes of permanent pacemaker insertion and hip fracture.

What does this study claim?
Hospital visits for syncope were more frequent in people receiving cholinesterase inhibitors than in control subjects (31.5 vs 18.6 events per 1000 person-years; adjusted hazard ratio [HR] 1.76, 95% confidence interval [CI] 1.57 to 1.98). The syncope-related outcomes of hospital visits for bradycardia, permanent pacemaker insertion and hip fracture were also more common among people receiving cholinesterase inhibitors compared with controls (see study details below).

So what?
This observational study suggests that cholinesterase inhibitors are associated with increased risks of syncope, bradycardia, permanent pacemaker insertion and hip fracture in older adults with dementia living in the community. All observational studies are subject to residual confounding and hidden bias, and only flag up potential safety issues, not confirm them. Nevertheless, prescribers should be aware of these potential risks when treating patients with cholinesterase inhibitors.

The NICE Guideline Committee considered the evidence base relating to the use of cholinesterase inhibitors and concluded that, compared with placebo, they provide small but consistent gains in scores on cognitive and global scales for people with mild to moderately severe Alzheimer’s disease. The Committee noted, however, that the evidence available on the long-term effectiveness of the cholinesterase inhibitors on outcomes, such as quality of life and delayed time to nursing home placement, was limited and largely inconclusive. When they considered cost-effectiveness, the Committee concluded that the three cholinesterase inhibitors donepezil, galantamine and rivastigmine can be considered as options in the management of patients with Alzheimer’s disease of moderate severity only i.e. those with an MMSE score of between 10 and 20 points).

The limited benefits of the cholinesterase inhibitors should be balanced against the potential risk of serious adverse events. Treatment should be considered on an individual basis and involve a discussion with patients and their carers about the possible benefits and risks of cholinesterase inhibitors.

Please see the dementia section on NPC for more details on the management of patients with this condition

Study details

Gill SS, Anderson GM, Fischer HD, et al. Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: a population-based cohort study. Arch Intern Med 2009;169:867–73

Patients: Community dwelling Ontario residents aged 66 years or older with a prior diagnosis of dementia within the past 5 years from 1st April 2002 to 31st March 2004. Participants had no hospitalisations for syncope in the previous year.

Intervention: Investigation into the relationship between cholinesterase inhibitor use and syncope-related outcomes using Canadian Healthcare databases

Comparison: Outcomes were compared in 19,803 new users of cholinesterase inhibitors (13,641 donepezil, 3,448 galantamine, 2,714 rivastigmine) versus 61,499 who had not received any in the year prior to cohort entry. Cohort entry was defined as the date of the first dispensed cholinesterase inhibitor. The control cohort was matched to the drug cohort by year and quarter of cohort entry. Baseline characteristics were similar. Risk adjustment was used to account for differences in baseline risk.

Outcomes: First hospital visits for syncope, bradycardia or complete atrioventricular block were examined, together with permanent pacemaker insertion and hip fracture. Hip fractures were excluded if they were pathological, or associated with trauma or epilepsy.


Cholinesterase inhibitors vs controls (events per 1000 person-years)

Adjusted hazard ratio

Hospital visits for syncope

31.5 vs 18.6

1.76 (95% CI 1.57 to 1.98)

Hospital visits for bradycardia

6.9 vs 4.4

1.69 (95% CI 1.32 to 2.15)

Permanent pacemaker insertion

4.7 vs 3.3

1.49 (95% CI 1.12 to 2.00)

Hip fracture

22.4 vs 19.8

1.18 (95% CI 1.04 to 1.34)

Sponsorship: 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.

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