QT interval prolongation and Torsades de Pointes with donepezil, rivastigmine and galantamine

Abstract

Background: Acetylcholinesterase inhibitors (AChEis) including donepezil, galantamine and rivastigmine are used to treat Alzheimer’s disease (AD). This study aimed to evaluate evidence from the case report literature for an association between these agents and risk of QT interval prolongation and Torsades de Pointes (TdP) arrhythmia. Methods: Published literature was mined with predetermined MeSH terms for each of donepezil, galantamine and rivastigmine, to identify cases of QT interval prolongation and TdP. Case reports were analysed using causality scales and a QT interval nomogram. Results: A total of 13 case reports were found (10 for donepezil, 2 for galantamine and 1 for rivastigmine) with rate corrected QT interval (QTc) prolongation. Five cases with donepezil exhibited TdP. TdP was not reported in the cases with galantamine and rivastigmine. The use of a QT heart rate nomogram highlighted risk with donepezil compared with the other two drugs and the application of the Naranjo causality scale suggested probable or possible causation for all donepezil cases. All patients had at least two other risk factors for TdP, including modifiable risk factors such as electrolyte disturbances, bradycardia, co-administration of QT prolonging drugs. A number of recent cases involved recent changes in medication. Conclusion: Our evaluation of the case report literature suggests that there is evidence for a causal association between donepezil and QTc/TdP risk. Attention to risk factors for QTc prolongation/TdP should be exercised when prescribing donepezil and modifiable risk factors corrected. Owing to the low number of cases with galantamine and rivastigmine, further work is needed to establish whether these drugs may be more suitable than donepezil for patients with other risk factors for TdP. Plain language summary Evaluation of the link between Alzheimer’s drugs and altered electrical activity of the heart Alzheimer’s disease (AD) is responsible for most cases of dementia. A loss of nerve cells in the brain leads to memory loss and impaired cognition. Current AD treatments aim to optimise the communication between the remaining nerve cells in key parts of the brain. They do this by helping increase levels of chemicals called neurotransmitters that are responsible for nerve cell communication. One group of such drugs, called acetylcholinesterase inhibitors, increases brain levels of a neurotransmitter called acetylcholine (ACh). The three main drugs in this class are donepezil, galantamine and rivastigmine. This study investigated evidence in the literature associating these drugs with unwanted effects on the heart that may predispose to dangerous disturbances (‘arrhythmias’) to the normal cardiac rhythm, by slowing the speed with which heart tissue recovers from electrical excitation. Our analysis suggests that data from medical case reports are consistent with some ability of donepezil to delay electrical recovery from electrical excitation and produce arrhythmia, particularly in patients with other risk factors that may increase arrhythmia susceptibility. Information from preclinical studies indicates that this may arise from an off-target interaction of donepezil with a particular protein that is involved in generating cardiac electrical activity. A low number of reports with galantamine and rivastigmine precluded firm conclusions in respect of these drugs; further experimental work is warranted to determine whether, in some settings, either of these drugs may offer a safer treatment alternative to donepezil.