Meta-analysis refutes arrhythmogenicity of drug for Alzheimer's disease therapy

Canadian researchers conducted a systematic review and meta-analysis of randomised controlled trials and concluded that taking donepezil does not affect the risk of serious cardiac arrhythmias. The publication appeared in the Journal of the American Geriatrics Society.

Donepezil belongs to cholinesterase inhibitors and increases the level of acetylcholine in the central nervous system. It is prescribed in Alzheimer's disease to symptomatically slow progression and reduce the severity of cognitive symptoms. As the drug can increase the tone of the vagus nerve, which parasympathetically innervates the heart, it is considered a potential arrhythmogen that prolongs the QT interval, although this effect has not been convincingly confirmed directly.

To obtain more complete information on this issue, Tina Nham (Tina Nham) from McMaster University and colleagues conducted a systematic search for randomised controlled trials of donepezil in adult patients in the databases Medline, Embase, International Pharmaceutical Abstracts and Cochrane Central. The final analysis included 60 papers with a total of 12463 patients with Alzheimer's disease and other types of dementia. The mean follow-up time was 31 weeks. The researchers were interested in a composite measure of major adverse cardiovascular events (MACE) that included all-cause mortality, sudden cardiac death, nonfatal cardiac arrest, pirouette ventricular tachycardia (torsade de pointes, a dangerous complication of QT interval prolongation), ventricular tachyarrhythmias (tachycardia or fibrillation), syncope, and seizures.

The most common MACE was death (252/331, or 75.8 per cent of events). The remainder represented syncopal states and seizures, and no arrhythmias were recorded. The use of donepezil did not increase the risk of MACE compared with placebo - the relative risk (RR) was 1.08 (95 per cent confidence interval 0.88-1.33; I2 = 0 per cent). A similar pattern was seen in a subgroup analysis of trials involving cardiac patients. Adverse events were slightly more common with longer follow-up (52 weeks or more), RR 1.32 (95 per cent confidence interval 0.98-1.79; I2 = 0 per cent).

The results indicate that donepezil is most likely nonarrhythmogenic. Its administration was not associated with mortality, ventricular arrhythmias, syncope, or seizures, although prolonged courses deserve further study. Studies are also needed to clarify the actual clinical outcomes associated with drugs that prolong the QT interval to help practitioners assess the risks of prescribing them, the paper's authors conclude.

Previously, another Canadian research team showed that donepezil increased the risk of hospitalisations associated with rhabdomyolysis (skeletal muscle damage).