NEW YORK (Reuters Health) – Because cholinesterase inhibitors induce can bradycardia, particularly at higher doses, physicians are being urged to closely monitor patients treated with these medications, especially those with dementia.

“The favorable safety profiles of cholinesterase inhibitors exhibited in clinical trials may not be reflected in the real-world population, particularly because these trials have excluded patients with certain cardiovascular disorders” and were generally short term, Dr. Elizabeth V. Lawler, at the Veteran Affairs Boston Healthcare System, and co-investigators note in the November Journal of the American Geriatrics Society.

Dementia is associated with a decline in levels of acetylcholine in the brain, the team explains, and cholinesterase inhibitors block hydrolysis of acetylcholine. While this effect slows cognitive decline, it is also believed to activate muscarinic receptors in the pacemaker cells of the heart, thereby decreasing heart rate.

Dr. Lawler and colleagues prospectively examined this association using the New England VA Healthcare System database for 1999 to 2007. The cohort included 11,328 patients with dementia (mean age 74 years, 97% male). None had a previous diagnosis of bradycardia or sinus syncope, or a pacemaker.

Twenty-eight percent were treated with one or more cholinesterase inhibitors (donepezil, n = 2888; galantamine, n = 324; rivastigmine, n = 218). Median follow-up ranged from 783 to 874 days for unexposed and exposed patients, respectively.

There were 288 events resulting in a diagnosis code for bradycardia in the exposed group and 599 in the unexposed group, for incidence rates per 1000 person-days of 0.17 and 0.07, respectively. The multivariate adjusted hazard ratio (HR) was 1.4.

Of those treated with donepezil, 712 were taking a low dose (5 mg/d), 1883 a medium dose (10 mg/d), and 293 a high dose (>/= 15 mg/d). HRs for bradycardia were statistically significant for the medium-dose (1.3) and the high-dose group (2.1).

The number needed to treat with a high dose to observe one additional case of bradycardia was 12. The numbers needed to treat with low and medium doses were 185 and 140, respectively.

Patients with bradycardia were more likely to fall (HR 2.6) and to experience syncope (HR 3.7). Patients taking cholinesterase inhibitors were also more likely to have a pacemaker implanted (0.73% vs 0.17%).

However, the risk of death was lower in patients with bradycardia (adjusted HR 0.64).

“Patients who appeared to be at the greatest risk of a decrease in heart rate were those with dementia diagnosed as nonspecific or Alzheimer’s disease; those taking beta-blockers; those who had fallen since diagnosis; and those with a history of MI, heart failure, or hypertension,” Dr. Lawler’s group reports.

Of concern, patients treated with cholinesterase inhibitors had a lower prevalence of electrocardiograms, Holter monitor testing, and cardiac electrophysiological stimulation.

The authors advise, “Closer surveillance for bradycardia may be warranted in patients treated with cholinesterase inhibitors.”

Also, they say, “The possible greater risk for bradycardia in patients taking 15 or 20 mg/d of donepezil should cause physicians to consider other treatment strategies.”

Reference:
J Am Geriatr Soc 2009;57:1997-2003.