Research Article: Cholinesterase Inhibitors and Hospitalization for Bradycardia: A Population-Based Study

Date Published: September 29, 2009

Publisher: Public Library of Science

Author(s): Laura Y. Park-Wyllie, Muhammad M. Mamdani, Ping Li, Sudeep S. Gill, Andreas Laupacis, David N. Juurlink, Carol Brayne

Abstract: Laura Park-Wyllie and colleagues examined the health records of more than 1.4 million older adults and show that initiation of cholinesterase inhibitor therapy is associated with a more than doubling of the risk of hospitalization for bradycardia.

Partial Text: Cholinesterase inhibitors such as donepezil, rivastigmine, and galantamine are widely prescribed to improve cognitive function in patients with Alzheimer disease—a condition expected to quadruple in prevalence over the next 50 y [1]. By inhibiting the synaptic metabolism of acetylcholine, these drugs enhance cortical cholinergic neurotransmission [2]. Although cholinesterase inhibitors are generally well tolerated, they may provoke adverse effects in some patients because their cholinergic effects are not confined to the central nervous system [2]. Symptoms of cholinergic excess are often nonspecific and include gastrointestinal upset, diarrhea, hypersalivation, and muscle cramps. In severe instances, these drugs can increase vagal tone and thereby precipitate bradycardia.

Between January 1, 2003 and March 31, 2008, we identified 27,333 hospitalizations for bradycardia among Ontario residents 67 y and older. Of these, 10,323 were excluded because they were hospitalized in the year prior to the index date, and 15,805 were excluded because they had not used cholinesterase inhibitors in the 9 mo prior to index date (Figure 2). Among the remaining patients, we further excluded 191 individuals exposed to cholinesterase inhibitors during the wash-out interval, and patients who had a pacemaker or could not be matched to at least one control (n≤5), leaving 1,009 eligible cases. Among these cases, 848 (84%) received a cholinesterase inhibitor in both the risk and reference periods, leaving 161 cases to inform our matched pairs analysis of individuals who had received a cholinesterase inhibitor in either the risk or reference period, but not both. Of these cases, 148 (92%) were fully matched to three controls and 157 (98%) were matched to at least two controls. We identified 466 matched controls from 42,833 potential controls.

Using the health care records of more than 1.4 million Ontario residents aged 67 y and older, we found that treatment with cholinesterase inhibitors was associated with a doubling in the risk of hospitalization for bradycardia. Importantly, although cholinesterase inhibitors are reversible precipitants of bradycardia, the drugs were resumed following discharge in greater than half the cases, presumably because the potential causative role of these drugs in the hospitalization was not appreciated. In many patients, cholinesterase inhibitors are associated with marginal improvement in cognition and global functioning [1],[33]. Consequently, recent guidelines suggest that cholinesterase inhibitors should not be standard of care for patients with dementia, but instead urge physicians to weigh each individual’s expected risks and benefits before initiating therapy. Our large-scale population-based assessment of the risk of bradycardia with cholinesterase inhibitors in clinical practice should help inform the risk-benefit assessment for clinicians and patients. A recent study used an alternate cohort design to examine a primary outcome of syncope in patients receiving cholinesterase inhibitors. In a secondary analysis, these investigators also observed an elevated risk of bradycardia (adjusted hazard ratio 1.69; 95% CI 1.32–2.15) associated with cholinesterase inhibitor use, which complements the findings of our study [34].



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