Hernandez RK (MAVERIC, VA Boston Healthcare System), Farwell W
(MAVERIC, VA Boston Healthcare System), Cantor M , Lawler EV
(MAVERIC, VA Boston Healthcare System)
Cholinesterase inhibitors (ChE-Is) are widely used for the symptomatic treatment of Alzheimer’s disease and other dementias. Concern has been raised about a potential association with bradycardia. Our objective was to quantify this association and to examine the presence of a dose-response effect.
The study population was derived from all healthcare encounters and services for patients with dementia who received care in the New England VA Healthcare System between January 1999 and June 2007 (n = 11,328). Bradycardia was defined using three methods: ICD-9 codes only, ICD-9 codes or at least two recorded heart rates less than 60 beats per minute (bpm), and ICD-9 codes or one recorded heart rate less than 60 bpm. We used Cox proportional hazards modeling with time-dependent exposures to evaluate the crude and adjusted associations, taking into account confounders such as age, race, comorbidities and medications. We evaluated the dose effect for donepezil, the most commonly used ChE-I in the VA (90% of treated patients), and also used a case-crossover design to compare mean heart rate prior to treatment initiation with mean heart rate after initiation.
We found an increased risk for bradycardia among patients taking any ChE-Is, with an adjusted hazard ratio of 1.4 (95% 1.1-1.7). We observed a dose-response effect for donepezil, with the highest dose group at greatest risk for bradycardia compared to the no-treatment group (HR = 2.1; 95% CI 1.5-3.0); the lowest dose group had no increased risk (HR = 1.1; 95% CI 0.86-1.5). Results were consistent regardless of bradycardia definition. In the case-crossover cohort, there was a mean decrease of 1.4 bpm between 3 months before treatment initiation and 3 months after.
Using a large cohort with a long follow-up period, we found a modest increased risk of bradycardia among patients with dementia taking ChE-Is compared to those not treated with these drugs. Among patients taking donepezil, the risk of bradycardia may increase with increasing doses.
Our study suggests that close monitoring for bradycardia may be warranted for dementia patients treated with ChE-Is, particularly those treated with a donepezil dose of 10 or 15 mg/day.