title: Cardiovascular effects and risk of syncope related to donepezil in patients with Alzheimer's disease.
abstract: BACKGROUND
  When otherwise unexplained, syncope in patients with Alzheimer's disease may be attributed to bradycardia caused by cholinesterase inhibitors. We studied prospectively the clinical events and cardiovascular changes occurring during treatment with donepezil in patients with Alzheimer's disease.
  
  
  METHODS
  Consecutive patients presenting with mild-to-moderate Alzheimer's disease were included in the study. Their clinical characteristics, blood pressure, heart rate and electrocardiogram were recorded before (baseline) and during treatment with donepezil. The drug was administered at a dosage of 5 mg/day for 1 month and 10 mg/day for the following 7 months, as tolerated. We compared the baseline observations with those made at 1, 2 and 8 months of donepezil treatment. We also examined the effects of negatively chronotropic or dromotropic drugs concomitantly administered with donepezil.
  
  
  RESULTS
  Thirty patients were included in the study, of whom 43% were taking negatively chronotropic or dromotropic drugs. The first month of therapy (donepezil 5 mg/day) was completed by 26 patients. During the 7-month high-dosage phase (10 mg/day), four patients dropped out of the study; thus, 22 patients completed the full 8 months of the study. The mean heart rate was 66 +/- 8 beats/min at baseline in the overall study population. This decreased significantly to 62 +/- 9, 61 +/- 7 and 62 +/- 8 beats/min at the 1, 2 and 8 month timepoints, respectively (all p = 0.002 vs baseline). Among patients not receiving negatively chronotropic or dromotropic drugs, heart rate decreased significantly over the course of the study (from 67 +/- 8 beats/min at baseline to 62 +/- 8 beats/min at 1 month, 62 +/- 7 beats/min at 2 months and 62 +/- 8 beats/min at 8 months [all p = 0.005 vs baseline]). There was no significant change in heart rate in patients who were receiving negatively chronotropic or dromotropic drugs. The PR interval increased over the course of the study in all patient groups, but these changes were only statistically significant in the group of patients who were not taking negatively chronotropic or dromotropic drugs (155 +/- 23ms at baseline vs 158 +/- 21, 160 +/- 22 and 163 +/- 24ms at the 1, 2 and 8 month timepoints; all p = 0.02 vs baseline). One patient developed syncope due to orthostatic hypotension; there were no cases of bradycardia-induced syncope. Gastrointestinal manifestations were reported in ten of the study patients. Abdominal pain and vomiting were the reasons for study termination in five of the eight patients who did not complete the trial.
  
  
  CONCLUSIONS
  A donepezil-induced decrease in heart rate and increase in PR interval were observed only in patients with Alzheimer's disease who were not treated with negatively chronotropic or dromotropic drugs. These changes were not associated with bradycardia-induced syncope.
authors.affiliation: Cardiovascular Hospital of Haut-Leveque, Bordeaux-Pessac, France. Phibordier@aol.com
authors.forename: Philippe
authors.initials: P
authors.lastname: Bordier
authors.forename: Stephane
authors.initials: S
authors.lastname: Garrigue
authors.forename: Stephane
authors.initials: S
authors.lastname: Lanusse
authors.forename: Julien
authors.initials: J
authors.lastname: Margaine
authors.forename: Frederic
authors.initials: F
authors.lastname: Robert
authors.forename: Laurent
authors.initials: L
authors.lastname: Gencel
authors.forename: Alexia
authors.initials: A
authors.lastname: Lafitte
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy*; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000009:adverse effects*; D000077265:Donepezil; D004334:Drug Administration Schedule; D004562:Electrocardiography / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007189:Indans / Q000009:adverse effects*; D008297:Male; D010880:Piperidines / Q000009:adverse effects*; D011446:Prospective Studies; D012306:Risk; D013575:Syncope / Q000139:chemically induced*
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil