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. All old age psychiatrists in Leicestershire, Nottinghamshire, Derbyshire, Lincolnshire and the northern part of Northamptonshire were invited to complete a questionnaire regarding their usual ChEI prescribing practice in AD patients with a range of comorbid cardiovascular conditions: bradycardia, tachycardia, heart block, left and right bundle branch block, prolonged QT interval, sick sinus syndrome, hypertension, postural hypotension, atrial fibrillation, congestive heart failure, and angina. In each instance, they were asked if they would: prescribe as usual; prescribe with caution; or not prescribe. Where respondents indicated they would prescribe with caution, they were asked what specific measures they would take. They were also asked about the routine use of ECGs, and any training they had received in their interpretation. Questionnaires were distributed by post and in person at a regional meeting, and respondents were asked to record their actual practice and not ‘look up the answers’. Data are presented in terms of frequencies. Overall, 53/68 questionnaires were returned, a response rate of 76.5%. This sample consisted of mostly consultants (34), associate specialists (5), specialist registrars (5), staff grade doctors (5) and nurse prescribers (4). All of the respondents regularly prescribed ChEIs, and 74% (39/53) routinely do an ECG before prescribing. For Leicestershire clinicians, a routine ECG is an explicit part of the ChEI treatment protocol, and 88% (15/17) reported that they did so, compared to 63% (22/35) of clinicians elsewhere in the region. There was considerable regional variation with all prescribers in Lincolnshire (n = 6) and none of the prescribers in Northamptonshire (n = 3) routinely doing an ECG. Only 28% (15/53) of respondents had received any training in ChEI prescribing in patients with ECG abnormalities. All of those who had not received such training indicated that it would be useful. Seventy-four per cent (39/52) indicated that they have easy access to a cardiologist or physician opinion in the event of an ECG abnormality. Figure 1 shows the respondents’ prescribing practice in relation to specific cardiovascular conditions. It is evident that for all of these there is considerable variation in this practice. Where respondents indicated they would prescribe with caution, the commonest additional actions taken were to: monitor the patient and the ECG; investigate/treat the cardiovascular condition first; liaise with/refer to a physician; and discuss risks with the patient and family. Survey results. This survey confirms that in the Trent region there is no clinical consensus regarding ChEI prescription for AD in the context of cardiovascular comorbidity. There is no reason to suppose that our experience is any different from the national situation. This lack of agreement is a reflection of the lack of evidence provided by the clinical drug trials, from which this group of patients was largely excluded [7]. As a result, some patients will be exposed to significant risks if they are prescribed ChEIs without proper care and supervision. Conversely, some patients with relatively benign abnormalities will be deprived of the opportunity to benefit from these drugs if they are withheld inappropriately; for example, in our sample 21% of the clinicians said they would not prescribe to a patient with right bundle branch block only. How then should we proceed? Clearly, there is a need to establish an evidence base, by the systematic monitoring of patients with cardiovascular comorbidities who are prescribed a ChEI. In the meantime, we should use the clinical and pharmacological evidence that is available to develop some consensus guidelines as to what is best practice in the present state of knowledge. This would reduce inappropriate variability in prescribing, protect clinicians against charges of malpractice, and provide a framework for the discussion of risks and benefits with patients and their families. This last point is important, because it is currently very difficult for patients to give informed consent to treatment when the risks are unknown and there is no professional consensus to guide them. The content of these guidelines will need to be developed through expert discussion and agreement. We would propose that a pre-treatment ECG should be mandatory for patients being considered for ChEI treatment, both to identify clinically important abnormalities, and to provide a baseline against which to monitor change once treatment has commenced. Patients with moderate dementia commonly have cardiovascular comorbidity and are on multiple concurrent medications. The safety profile of ChEIs in this patient group is still being elucidated. The prescribing of ChEIs by old age psychiatric practitioners, in this patient group, is varied with no clinical consensus as to who should and should not receive these medications. Consensus guidelines are needed to ensure safe and equitable prescribing of ChEIs to this vulnerable group of patients. None

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