Cholinesterase Inhibitors and Incidence of Bradycardia in Patients with Dementia in the Veterans Affairs New England Healthcare System

OBJECTIVES: To quantify the association between cholinesterase inhibitors (ChE-Is) and a new diagnosis of bradycardia and to evaluate the clinical significance of bradycardia. DESIGN: Cox proportional hazards with time-dependent exposures were used to evaluate the association and examine the dose effect for donepezil and bradycardia. SETTING: New England Veterans Affairs Healthcare System. PARTICIPANTS: Patients with dementia who received care between January 1999 and June 2007 (N=11,328). MEASUREMENTS: Bradycardia was defined using three methods using a combination of International Classification of Diseases, Ninth Revision, codes and recorded heart rates of less than 60 beats per minute. RESULTS: A greater risk for bradycardia was found in patients taking any ChE-Is than in the no-treatment group (adjusted hazard ratio (HR)=1.4, 95% confidence interval (CI)=1.1-1.6). A dose-response effect was observed for donepezil, with the highest-dose group at greatest risk (HR=2.1, 95% CI=1.5-2.9). Results were consistent regardless of bradycardia definition. Patients with bradycardia were more likely to fall, experience syncope, or need a pacemaker implantation than those without. CONCLUSION: Using a large cohort, a modestly greater risk of bradycardia was found in patients with dementia taking ChE-Is than in those not taking these drugs. In patients taking donepezil, the risk of bradycardia may increase with increasing doses. Because of the potential clinical consequences, monitoring for bradycardia may be warranted in patients with dementia treated with ChE-Is.