Proarrhythmic major adverse cardiac events with donepezil: A systematic review with meta-analysis
Tina Nham1, Michael Cristian Garcia2,3, Kai La Jennifer Tsang2,4
1Division of Geriatrics, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Insights
Donepezil, used for Alzheimer's disease, was not found to increase the risk of major adverse cardiac events (MACE) in a meta-analysis of randomized controlled trials. Longer-term studies are needed to fully assess cardiac safety.
Area of Science:
- Cardiology
- Pharmacology
- Neurology
Background:
- Donepezil is a commonly prescribed cholinesterase inhibitor for Alzheimer's disease.
- It is classified as a potential QT interval-prolonging medication based on limited data.
- This study evaluates the cardiac safety of donepezil using high-quality evidence.
Conclusions:
- Donepezil does not appear to be arrhythmogenic and is not associated with increased MACE.
- Further research on longer-term therapy is warranted to clarify clinical outcomes related to QT prolongation.
- Findings support informed prescribing practices regarding donepezil's cardiac safety profile.
Background:
Cholinesterase inhibitors (ChEIs) are regularly used in Alzheimer's disease. Of the three ChEIs approved for dementia, donepezil is among the most prescribed drugs in the United States with nearly 6 million prescriptions in 2020; however, it is classified as a "known risk" QT interval-prolonging medication (QTPmed). Given this claim is derived from observational data including single case reports, we aimed to evaluate high-quality literature on the frequency and nature of proarrhythmic major adverse cardiac events (MACE) associated with donepezil.
Methods:
We searched Medline, Embase, International Pharmaceutical Abstracts, and Cochrane Central from 1996 onwards for randomized controlled trials (RCTs) involving patients age ≥18 years comparing donepezil to placebo. The MACE composite included mortality, sudden cardiac death, non-fatal cardiac arrest, Torsades de pointes, ventricular tachyarrhythmia, seizure or syncope. Random-effects meta-analyses were performed with a treatment-arm continuity correction for single and double zero event studies.
Results:
Sixty RCTs (n = 12,463) were included. Twenty-five of 60 trials (n = 5886) investigated participants with Alzheimer's disease and 33 trials monitored electrocardiogram data. The mean follow-up duration was 31 weeks (SD = 36). Mortality was the most commonly reported MACE (252/331, 75.8% events), the remainder were syncope or seizures, with no arrhythmia events. There was no increased risk of MACE with exposure to donepezil compared to placebo (risk ratio [RR] 1.08, 95% CI 0.88-1.33, I2 = 0%) and this was consistent in the subgroup analysis of trials including participants with cardiovascular morbidities (RR 1.14, 95% CI 0.88-1.47). Subgroup analysis suggested a trend toward more events with donepezil with follow-up ≥52 weeks (RR: 1.32, 0.98-1.79).
Conclusions:
This systematic review with meta-analysis found donepezil may not be arrhythmogenic. Donepezil was not associated with mortality, ventricular arrhythmias, seizure or syncope, although longer durations of therapy need more study. Further research to clarify actual clinical outcomes related to QTPmed is important to inform prescribing practices.
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