The influence of cholinesterase inhibitor therapy for dementia on risk of cardiac pacemaker insertion: a retrospective, population-based, health administrative databases study in Ontario, Canada

We believe that the observed overall protective nature of cholinesterase inhibitor exposure for pacemaker insertion may be the result of a complex interaction between: theoretical direct drug effects on the cardiac conduction system; an indirect effect via a central nervous system pathway; effects of a degenerative dementing illness on cardiac rhythm; presence and effects of co-morbidities not identified; altered symptom reporting or health-seeking behaviour of people with dementia; and person, family or health provider attitudes towards an invasive intervention such as a cardiac pacemaker insertion. Data for many of these factors are beyond the scope of this study.

Another possibility to explain the lack of association between cholinesterase inhibitor use and pacemaker insertion is that in the years following the approval of these drugs in the Canadian drug formulary, anecdotal cases have led to an increased awareness of the possible development of bradycardia and resulted in a more cautious approach to drug prescribing and symptom management.

Our results compare interestingly with previous studies. Gill found a slightly higher risk of pacemaker insertion (HR 1.49; 95% CI, 1.12-2.00) in demented patients treated with cholinesterase inhibitors [13] who also suffered a documented syncopal event. If the presence of dementia decreases the likelihood of pacemaker insertion, then cholinesterase inhibitor exposure in a study including patients both with and without dementia could be associated with a decreased risk of pacemaker insertion. Our study extends the observation to ALL demented patients who are exposed to cholinesterase inhibitor drugs. Similar to previous studies, [20,21] we found that patients taking amiodarone and/or digoxin were significantly more likely to undergo pacemaker insertion. This likely reflects the combination of complex pharmacodynamics and the prevalence of ‘tachy-brady’ syndrome (i.e. atrial fibrillation with co-existent conducting system disease) in this population [22,23].

Our study has several attributes that should be considered when interpreting its results. First, ours is a population-based analysis that captured all people exposed to these medications in the Canadian province with the largest population (13.3 M in 2011 [1]). This lets us avoid errors associated with biased sampling. Second, the data has face validity in that 30% of people with dementia were being treated with a cholinesterase inhibitor and almost all people (93.9%) prescribed a cholinesterase inhibitor had a code for dementia. Third, we used two analytical methodologies – case–control and prospective cohort – to examine the association of cholinesterase inhibitor exposure and pacemaker insertion. The fact that both analyses provided the same result supports our conclusion. Fourth, we cannot be certain how generalizable our results are to other jurisdictions. Although our analysis includes a very large sample over a long time-period, it is possible that subtleties native to other health jurisdictions would change the association between cholinesterase inhibitors and pacemaker insertion. Fifth, we only included a patient’s first period of exposure to a particular drug class. Patients who stopped a medication for more than approximately 6-months following dispensation would not have had the subsequent exposure to these medications captured by the study. Finally, dementia status and pacemaker insertion were determined by codes. While these codes have been shown in Medicare claims to have a sensitivity and specificity of 0.85 and 0.89, respectively [16], the accuracy of dementia codes and those for pacemaker insertion has not been confidently established in Ontario administrative datasets. However, errors in the assignment of these codes would – assuming that such errors are independent of cholinesterase status – bias the study’s association to the null. When studying conditions in older people, especially those who have multiple co-morbidities, and are taking multiple medications and may be classified as frail, caution has to be taken in assigning associations. More research is needed to clarify the clinical significance of the brady-arrhythmic effects of cholinesterase inhibitor drugs used to treat dementia.