Stephanie Carrion
March 2009 CATS
Reference: Gill, S. et al. “Syncope and Its Consequences in Patients With Dementia
Receiving Cholinesterase Inhibitors.” Archives of Internal Medicine. Vol. 169(No. 9),
May 11, 2009: 867-873.
Question: Do cholinesterase inhibitors used for the treatment of dementia cause an
increase risk of syncope and bradycardia?
Methods: This population-based cohort study was conducted in Ontario, Canada, from
health care databases from April 1, 2002 through March 31, 2004. The population at the
time of the study included about 12 million people in the Ontario area, of which 1.4
million were 65 years or older. After a review of databases including the Ontario Drug
Benefit Program, emergency department records from the National Ambulatory Care
Reporting System (NACRS), hospitalization records from the Canadian Institutes for
Health Information Discharge Abstract Database (DAD), physician billing information
from the Ontario Health Insurance Plan (OHIP), and statistics from the Registered
Persons Database (RPDB), the researchers identified 19,803 community dwelling older
persons with a diagnosis of dementia, and another cohort of 61,499 patients without a
diagnosis of dementia who made up the control group. These databases are fairly
complete per the author’s report, for example, the ODB database is listed as having an
error rate of only 0.7%. Two cohorts of patients were identified from the pool of residents
aged 66 years or older: new users of cholinesterase inhibitors, and those who had not yet
received any prescriptions for cholinesterase inhibitors for the year prior to the study. The
authors then reviewed the records to determine the relationship between cholinersterase
inhibitor use and four outcomes: syncope, bradycardia, permanent pacemaker placement,
and hip fracture. There are only three cholinesterase medications use in the ODB and
included in this study: donepezil, galantamine, and rivastigmine. The study participants
also met the following inclusion criteria: documented diagnosis of dementia in past 5
years, no hospitalization for syncope in the past year, and community-dwelling
individuals only (no long-term care facility residents).
Results: The study participants were grouped into two cohorts: 19803 new users of
cholinesterase inhibitors, and 61499 control subjects. The two cohorts had comparable
baseline characteristics. The results were analyzed three ways, first, with the primary
analysis, then the modified comorbidity index, and lastly, a propensity score. The number
of hospital visits for syncope were more frequent in the cholinesterase cohort, 31.5 vs.
18.6 events per 1000 person-years or the adjusted HR of 1.76, with a 95% CI of 1.57-
1.98. The syncope-related outcomes were also more common in the cholinesterase cohort
including: 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). The additional analyses through
propensity-based matching and comorbidity-based matching were consistent with the
results of the primary analysis. In all, the authors noted increased rates of syncope,
bradycardia, pacemaker insertion, and hip fracture in dementia patients on cholinesterase
inhibitors.
Limitations: This study is an observational, cohort study, and as a result is subject to
residual confounding and hidden bias. While the databases were fairly complete, there is
the possibility of unknown or unmeasured factors not included in these databases having
an impact on the outcome. Also, the event rates for each individual drug were not
compared and instead, the cholinesterase inhibitors were compared as a class as these
medications have similar mechanisms of action. Dose-response relationships were not
examined. The effects of these medications on patients who already have a history of
sycnope were not evaluated. The only fall-related outcome studied was hip fracture.
Discussion: Emergency physicians see the chief complaint of syncope in the elderly, and
also in patients with dementia frequently. Often there is a long list of possible etiologies
for the syncopal event. These patients often have underlying cardiac disease, multiple
comorbidities, and polypharmacy. Many of these patients are on cholinesterase inhibitors
for enhancement of quality of life, however, these medications can have serious
consequences, including inducing bradycardia, leading to syncope, leading to the need for
pacemaker placement and possible complications related to the procedure, and even hip
fracture, with significant morbidity. While emergency medicine physicians do not make
the decision to start these medications, they frequently deal with the consequences. It is
important to understand the effects these medications can have on these patients notify
specialists patients are on these medications when admitted, and to educate patients and
their families when able and appropriate.
MH- Aged
MH- Aged, 80 and over
MH- Bradycardia/chemically induced/complications/epidemiology
MH- Case-Control Studies
MH- Cholinesterase Inhibitors/adverse effects/*therapeutic use
MH- Cohort Studies
MH- Databases, Factual
MH- Dementia/complications/*drug therapy
MH- Female
MH- Hip Fractures/epidemiology
MH- Hospitalization
MH- Humans
MH- Male
MH- Ontario/epidemiology
MH- Pacemaker, Artificial
MH- Syncope/*chemically induced/complications/*epidemiology