Comparative risk of cardiac arrhythmias associated with acetylcholinesterase inhibitors used in treatment of dementias – A narrative review

Abstract

Donepezil, galantamine, and rivastigmine are the three acetylcholinesterase inhibitors (AChEIs), out of a total of only four medications prescribed in the treatment of Alzheimer's Disease (AD) and related dementias. These medications are known to be associated with bradycardia given their mechanism of action of increasing acetylcholine (ACh). However, in March 2015, donepezil was added to the CredibleMeds “known‐risk” category, a list where medications have a documented risk for acquired long‐QT syndrome (ALQTS) and torsades de pointes (TdP) – a malignant ventricular arrhythmia that is a different adverse event than bradycardia (and is not necessarily associated with ACh action). The purpose of this article is to review the three AChEIs, especially with regards to mechanistic differences that may explain why only donepezil poses this risk; several pharmacological mechanisms may explain why. However, from an empirical point‐of‐view, aside from some case‐reports, only a limited number of studies have generated relevant information regarding AChEIs' and electrocardiogram findings; none have specifically compared donepezil against galantamine or rivastigmine for malignant arrhythmias such as TdP. Currently, the choice of one of the three AChEIs for treatment of AD symptoms is primarily dependent upon clinician and patient preference. However, clinicians should be aware of the potential increased risk associated with donepezil. There is a need to examine the comparative risk of malignant arrhythmias among AChEIs users in real‐world practice; this may have important implications with regards to changes in AChEI prescribing patterns.

Cardiac Changes in Parkinson’s Disease: Lessons from Clinical and Experimental Evidence

“…However, the cholinesterase inhibitor rivastigmine, has been shown to inhibit both acetylcholinesterase and butyrylcholinesterase, causing an overall increase in acetylcholine [132]. Importantly, donepezil was included in the "known-risk" category of the CredibleMeds list in March 2015, which means that it has a demonstrated risk of acquired enlargement of the QT segment and ventricular arrythmia different to bradycardia [133].…”

Inherited and Acquired Rhythm Disturbances in Sick Sinus Syndrome, Brugada Syndrome, and Atrial Fibrillation: Lessons from Preclinical Modeling

“…Congenital diseases may eventually manifest during adulthood in response to specific stresses, remaining undiscovered until a dramatic or fatal episode occurs, even in agonistic athletes routinely submitted to ECG to practice [102][103][104][105][106][107][108][109][110][111]. Acquired rhythm pathologies might be induced by several causes, among which drug cardiotoxicity, cardiomyopathies, myocarditis or systemic infections, valve diseases, and interventional/surgical maldeployment of cardiac valve replacements [112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128].…”

Use of Drugs With Risk of Heart Rate-Related Problems is Common in Norwegian Dementia Patients Treated With Acetylcholinesterase Inhibitors: A Prevalence Study Based on the Norwegian Prescription Database

“…Of the AChEIs, only donepezil is classified with a known risk of QT prolongation and TdP ( Crediblemeds, 2021 ). Still, the current knowledge on this topic is limited, and epidemiological studies to examine the comparative risk with use of the different AChEIs are missing ( Huang and Alsabbagh, 2020 ). Effects on the heart is a class effect of the AChEIs ( Editorial, 2006 ) and may result in bradycardia caused by blockage of cholinesterase connected to the vagal nerve, which can cause atrioventricular (AV) or sinoatrial block ( Huang and Alsabbagh, 2020 ).…”

“…Still, the current knowledge on this topic is limited, and epidemiological studies to examine the comparative risk with use of the different AChEIs are missing ( Huang and Alsabbagh, 2020 ). Effects on the heart is a class effect of the AChEIs ( Editorial, 2006 ) and may result in bradycardia caused by blockage of cholinesterase connected to the vagal nerve, which can cause atrioventricular (AV) or sinoatrial block ( Huang and Alsabbagh, 2020 ). The use of AChEIs has been associated with more than twofold risk of hospitalization due to bradycardia among elderly patients.…”