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.
Cholinesterase inhibitors are commonly used to treat dementia. These drugs enhance the effects of acetylcholine, and reports suggest they may precipitate bradycardia in some patients. We aimed to examine the association between use of cholinesterase inhibitors and hospitalization for bradycardia.
Methods and Findings
We examined the health care records of more than 1.4 million older adults using a case-time-control design, allowing each individual to serve as his or her own control. Case patients were residents of Ontario, Canada, aged 67 y or older hospitalized for bradycardia between January 1, 2003 and March 31, 2008. Control patients (3∶1) were not hospitalized for bradycardia, and were matched to the corresponding case on age, sex, and a disease risk index. All patients had received cholinesterase inhibitor therapy in the 9 mo preceding the index hospitalization. We identified 1,009 community-dwelling older persons hospitalized for bradycardia within 9 mo of using a cholinesterase inhibitor. Of these, 161 cases informed the matched analysis of discordant pairs. Of these, 17 (11%) required a pacemaker during hospitalization, and six (4%) died prior to discharge. After adjusting for temporal changes in drug utilization, hospitalization for bradycardia was associated with recent initiation of a cholinesterase inhibitor (adjusted odds ratio [OR] 2.13, 95% confidence interval [CI] 1.29–3.51). The risk was similar among individuals with pre-existing cardiac disease (adjusted OR 2.25, 95% CI 1.18–4.28) and those receiving negative chronotropic drugs (adjusted OR 2.34, 95% CI 1.16–4.71). We found no such association when we replicated the analysis using proton pump inhibitors as a neutral exposure. Despite hospitalization for bradycardia, more than half of the patients (78 of 138 cases [57%]) who survived to discharge subsequently resumed cholinesterase inhibitor therapy.
Among older patients, initiation of cholinesterase inhibitor therapy was associated with a more than doubling of the risk of hospitalization for bradycardia. Resumption of therapy following discharge was common, suggesting that the cardiovascular toxicity of cholinesterase inhibitors is underappreciated by clinicians.
Please see later in the article for the Editors' Summary
Alzheimer disease and other forms of dementia principally affect people aged over 65. These conditions result in confusion, long term memory loss, irritability, and mood swings. As the population of developed countries ages, the prevalence of dementia is expected to increase significantly. It is forecast that the proportion of people with dementia in the US will quadruple by 2045.
A common treatment for Alzheimer disease is a class of drug called an acetylcholinesterase inhibitor or cholinesterase inhibitor. These include donepezil (brand name Aricept), rivastigmine (marketed as Exelon and Exelon Patch), and galantamine (branded Razadyne).
The benefit of taking cholinesterase inhibitors is generally small and they cannot reverse the effects of dementia. In about 50% of patients they delay the worsening of symptoms for between six months and a year, although a small number of patients may benefit more. They can have unpleasant side effects, which may include diarrhoea and muscle cramps.
Why Was This Study Done?
Existing evidence is inconclusive on whether cholinesterase inhibitors increase the risk of bradycardia, an abnormally slow resting heart rate of below 60 beats a minute, which can cause fatigue, dizziness, fainting, palpitations, shortness of breath, or death. In this paper, the authors use routinely collected health care data to investigate whether an older person taking a cholinesterase inhibitor is at increased risk of bradycardia.
What Did the Researchers Do and Find?
They began by supposing that cholinesterase inhibitors might induce bradycardia soon after a patient first began to take them. To investigate this, they obtained health care data on 1.4 million patients aged 67 or over in Ontario, Canada. They identified 161 patients who had visited a hospital for bradycardia and who had previously taken a cholinesterase inhibitor only within specific periods of time. They found that 139 had taken a cholinesterase inhibitor within the previous three months compared with 22 who had stopped taking it at least six months before.
They compared these cases with up to three “control” patients who matched each of the initial “case” group of 161 patients by age, sex, and risk of bradycardia on the basis of their general health. None of the 466 controls had visited a hospital for bradycardia by the “index date,” that is, the date of hospitalization of the case patient they matched. The researchers found 349 of the control patients had begun to take a cholinesterase inhibitor in the three months prior to the index date, compared with 117 who had stopped taking it at least six months before. A statistical analysis of these data showed that recent initiation of cholinesterase inhibitors was associated with approximately a doubling of the risk of hospitalization for bradycardia.
The authors repeated their procedure to see whether another class of drug, proton pump inhibitors, had a similar effect. As they had expected, it did not. They repeated the analysis for patients taking into account other drugs that slow the heart rate and found that their increased risk of bradycardia when taking a cholinesterase inhibitor persisted. The increase in risk was also similar in patients with pre-existing heart problems.
The researchers' data also showed that, excluding patients who while in the hospital had a pacemaker fitted to control their heart rate, over half of the patients released from hospital started taking a cholinesterase inhibitor again. Of these, a few returned to hospital with bradycardia within 100 days.
What Do These Findings Mean?
Recent guidelines suggest that doctors should not prescribe cholinesterase inhibitors for dementia patients as a matter of course, but weigh the potential risks and benefits. This paper provides evidence of an additional risk, of which at least some doctors are unaware. It was not possible to compare risk for different cholinesterase inhibitors because most patients took donepezil.
A population-based study like this cannot prove that cholinesterase inhibitors cause bradycardia. The authors used routinely collected data and so did not have information on all relevant risk factors, and thus there remains a possibility of bias due to unmeasured factors. In addition the authors had to make assumptions, for instance that patients took the drugs prescribed for them. They also considered only diagnoses of bradycardia made by a hospital doctor and not those made elsewhere, which means the incidence of bradycardia may have been underestimated. A strength of the study is the use of a case-time-control design, which has the advantage of reducing bias due to the different health conditions and lifestyle of individual patients, and also bias due to factors changing over time.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000157.
Wikipedia contains information on Alzheimer disease (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Information on bradycardia and its causes can be found in Wikipedia (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The UKs National Health Service provides information on dementia, including symptoms, causes, diagnosis, treatment, and prevention
MedlinePlus provides US-based health information (in English and Spanish)
The US National Institute on Aging provides information on health, relevant to older people, including Alzheimer Disease and dementia (in English and Spanish)
The US Alzheimers Association contains useful information on the disease, including on medication
The Public Health Agency of Canada website provides information on senior health (in English and French)
The UK-based Alzheimers Society provides advice on caring for people with dementia