Cholinesterase inhibitors and cardiovascular disease: a survey of old age psychiatrists' practice

SIR—The cholinesterase inhibitor (ChEI) drugs donepezil, rivastigmine and galantamine are currently approved for the symptomatic treatment of mild to moderate Alzheimer’s disease (AD). Although the target organ for these drugs is the brain, the heart is also rich in cholinesterases and their inhibition may adversely affect cardiac function. ChEIs are known to raise blood pressure and slow the pulse rate through both central and peripheral mechanisms; they also reduce cardiac beat-by-beat fluctuations [1]. These drugs may also increase the liability to falls in patients with AD and Lewy Body dementia, who have an increased incidence of orthostatic hypotension and carotid sinus hypersensitivity [2, 3]. The safety profile of these drugs in the mostly elderly patients with AD is not yet clear. Although the published clinical trials indicate that ChEIs are safe and well tolerated, they were carried out on relatively healthy subjects. It is not known to what extent the findings can be applied to the general AD population, significant numbers of whom suffer from concurrent cardiovascular disorders [4], and take multiple concomitant medications [5]. In a recent Canadian study of 6424 older adults newly prescribed donepezil, between half and three-quarters of this cohort would have been ineligible for enrollment into the randomised controlled trials that established the efficacy of this drug [6]. This study also found significantly higher rates of discontinuation in those with active cardiovascular disease. Syncope is reported as a common side effect of Donepazil in its summary of product characteristics with a reminder that the syncope may be due to cardiac side effects [7]. Concerns about the safety of ChEIs have also been raised by the recent finding of an increased mortality associated with active treatment in controlled trials of galantamine for Mild Cognitive Impairment (MCI: 1.4% versus 0.35%). Although no single cause of death predominated, half of these deaths were due to cardiovascular disorders [8]. This finding has resulted in a warning by the US Food and Drug Administration and its European equivalent in respect of MCI [9], but its relevance to patients with AD is unclear. The British National Formulary lists sick sinus syndrome and other supraventricular conduction problems such as atrial fibrillation and flutter as cautionary conditions in the prescribing of ChEIs [10]. Beyond this recommendation, however, there are currently no guidelines for the prescription of these drugs in the context of cardiovascular disease. From our own experience, we suspected there might be considerable variation in clinical practice regarding their use. To see if this was the case, we conducted a survey of old age psychiatrists in the Trent Region.