Dementia Drugs Make the Ticker Sicker
Abstract & Commentary
By Allan J. Wilke, MD, Professor and Chair, Department of Integrative Medicine, Ross University (Bahamas) Limited, Freeport, Grand Bahama, The Bahamas. Dr. Wilke reports no financial relationship to this field of study.
Synopsis: Cholinesterase inhibitors place patients at risk for syncope, bradycardia, permanent pacemaker insertion, and hip fracture.
Source: Gill SS, et al. Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: A population-based cohort study. Arch Intern Med 2009; 169:867-873.
Cholinesterase inhibitors, donepezil (aricept®), rivastigmine (Exelon®), and galantamine (Razadyne®), and others do not limit their activity to the central nervous system. The cardiovascular system is one of the more sensitive to their effect, which is to raise the concentration and duration of action of acetylcholine. In the autonomic nervous system this can be manifested as increased vagal tone, and subsequently, bradycardia and AV node block. These, in turn, could result in syncope. Although product information for cholinesterase inhibitors (CIs) includes seizures, AV block, bradycardia, syncope, and urinary obstruction as serious adverse reactions, many physicians are unaware of these problems. These researchers from Canada used linked databases to explore the associations between the use of CIs and the development of syncope, bradycardia, permanent pacemaker insertion, and hip fractures. They assumed that bradycardia would predispose to syncope, which could result in hip fracture, and that bradycardia might prompt pacemaker insertion. The databases included pharmacy, emergency department, hospitalization, physician billing, and demographic records.
Between April 2002 and March 2004, they identified 75,140 individuals in Ontario who were 66 years or older and who had a diagnosis of dementia. They were divided into two groups, those newly prescribed a CI (13,641) and those who had not received any for the last year (61,499). The study excluded participants who had been diagnosed with dementia more than 5 years prior, who were long-term care patients, or who had been hospitalized for syncope in the year before the study started. Another exclusionary criterion was hip fractures that were caused by events or conditions other than falls (e.g., pathologic fractures, epilepsy, and trauma). The subjects and the controls were similar in baseline demographics (80 years old, 38% male), medical history, and medications, and made the same number of emergency department visits. Persons taking CIs were more likely to visit a hospital for syncope (hazard ratio [HR], 1.76) or bradycardia (HR, 1.69), undergo permanent pacemaker insertion (HR, 1.49), and suffer a hip fracture (HR, 1.18). In a comorbidity analysis, the results did not change. In an analysis of conditions unlikely to be associated with use of CIs (pulmonary embolism and cataract extraction), no relationship was found.
Commentary
This is not a randomized controlled trial, so it does not prove causation. However, it involves a population that is probably similar to yours, with a very large number of subjects and controls, and linked databases that likely registered all members of the population. The outcomes are biologically plausible, so I think the conclusions are believable.
Cholinesterase inhibitors have been available in the United States since the FDA approved tacrine (Cognix®) in 1993. In the ensuing 16 years, we've learned about their effectiveness (charitably, modest at best) and their adverse effects (primarily gastrointestinal, but also include seizures, urinary obstruction, headache, insomnia, fatigue, depression, and arthritis). Using the data the authors of this report provided, I calculated the number-needed-to-harm for three of the four outcomes of interest: syncope (143), bradycardia (870), and permanent pacemaker insertion (1852). These are large enough numbers, especially the last two, that the average physician might never witness the events in question. That does not lessen the impact of the adverse events over the entire population. Although the authors did not do an economic analysis of the adverse effects of CI use, I suspect that it is great. Greater still are the long-term effects on the individual, including being subjected to surgery with its inherent risks and the increased likelihood of death after a hip fracture. I also suspect that patients with pre-existing cardiovascular conditions are at greater risk than those without. We should be especially cautious prescribing CIs to individuals with first-degree AV block, given that CIs would likely exacerbate this arrhythmia. A recent article in JAMA documents the less-than-rosy long-term outcomes of patients who have this condition.1
As people age, they become less tolerant of the side effects of medications because of changes in body composition, liver enzymatic activity, and other factors. As people age, they develop more ailments and are prescribed more medications, increasing the likelihood of drug-drug interactions. In its most recent report, the CDC estimates that 53.9% of men and 63.8% of women 65 years and older were taking three or more prescribed drugs in the previous month.2 The risk-benefit equation that we should all consider when we prescribe a medication shifts as risks increase and benefits decrease. It is incumbent upon us as the "holders of the pen" to think twice before we prescribe a medication to an elderly patient. We need to ask ourselves, "Is there a compelling reason to prescribe this medication?" If not, put that pen back into your pocket.
References
1. Cheng S, et al. Long-term outcomes in individuals with prolonged PR interval or first-degree atrioventricular block. JAMA 2009;301:2571-2577.
2. National Center for Health Statistics Health, United States, 2008, with Chartbook. Hyattsville, MD: 2009.
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