Cardiovascular effects and risk of syncope related to donepezil in patients with Alzheimer’s disease
Bordier P, Garrigue S, Lanusse S, Margaine J, Robert F, Gencel L et al.;
Commented by , 23 Jun 2006
Aim of the study
Establish if the cholinesterase inhibitor (CI) donepezil has pharmacological effects on cardiac activity that can predispose to syncope.
Method
Prospective study of consecutive patients with mild to moderate Alzheimer’s disease (AD). Clinical characteristics, blood pressure (BP), heart rate (HR) and electrocardiogram (EKG) were recorded at baseline and after 1, 2 and 8 months on donepezil (5 mg for 1 month then 10 mg/day). Sequential data measurements were analysed by multivariate repeated-measures-analysis of variance followed by Scheffe’s procedure for multiple comparisons.
Results
Thirty patients were included, 26 completed one month of treatment and 22 completed 8 months. Mean age was 80 ±6 years, body weight 64 ±11 kg; 83% were women. The mean HR was 66 ±8 beats/min at baseline, decreasing to 62 ±9, 61 ±7 and 62 ±8 at 1, 2 and 8 months (all p = 0.002 vs baseline). The PR interval increased significantly (p = 0.02) in patients who were not taking negatively chronotropic or dromotropic drugs such as β-adrenoceptor antagonists, calcium channel antagonists, amiodarone, flecainide or propafenone: 155 ±23 ms at baseline, 158 ±21, 160 ±22, 163 ±24 ms on follow-up. There was no effect on BP, QRS duration and corrected QT interval. One patient developed syncope related to orthostatic hypotension.
Professor Gauthier's comments
CIs are known to cause bradycardia and syncope, but the relationship between the two is uncertain. This issue is very important in the context of recently reported asymmetric number of deaths between placebo and the CI galantamine in Mild Cognitive Impairment and donepezil in vascular dementia.
The current study and previous literature reviews (ref. 1) clearly show that the CI is safe when used in the symptomatic treatment of Alzheimer’s disease, although caution is required in patients with pre-treatment bradycardia and/or unexplained syncope, where an EKG should be done prior to initiating treatment, looking for sick sinus syndrome or clinically significant heart block.
There is also the possibility of drug interactions between CI and negatively chronotropic or dromotropic drugs, although in the study currently under discussion this was not a problem. It may well be, as the authors conclude, that the development of severe (and symptomatic) bradycardia when using donepezil or other CI is a manifestation of pre-existing conduction system disease.
It should be remembered that syncope are not uncommon in the non-AD dementias where CI is increasingly in use: syncopes are a "supportive feature" in the diagnosis of Dementia with Lewy bodies (ref. 2) and are a common side-effect of dopamine agonists used in Parkinson’s disease dementia. These are related to orthostatic hypotension rather than brady-arythmias (ref. 3).
Careful monitoring of BP in these patients in sitting and standing position will help control orthostatic hypotension, which should not be a deterrent to use a CI when clinically appropriate.
References
1. Gauthier S. Cholinergic adverse effects of cholinesterase inhibitors in Alzheimer's disease: epidemiology and management. Drugs Aging 2001; 18; 853-862
2. McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005; 65 (12); 1863-72. Epub 2005 October 19
3. Senard JM, Brefel-Courbon C, Rascol O, Montastruc JL. Orthostatic hypotension in patients with Parkinson's disease: pathophysiology and management. Drugs Aging 2001; 18 (7); 495-505