title: Use of clarithromycin and adverse cardiovascular events among older patients receiving donepezil: a population-based, nested case-control study.
abstract: BACKGROUND
  Donepezil is a commonly used drug in older people that due to its procholinergic effects can provoke bradycardia and neurocardiogenic syncope. Donepezil is metabolized by the cytochrome P450 isozyme 3A4 (CYP3A4). Clarithromycin is a potent inhibitor of CYP3A4, and patients taking both of these drugs may be at increased risk of cardiac adverse events.
  
  
  OBJECTIVE
  The aim of this study was to evaluate the association between recent use of clarithromycin and adverse cardiovascular events in elderly patients receiving donepezil.
  
  
  METHODS
  A population-based, nested case-control study using provincial healthcare databases was conducted. The base cohort was made up of persons 66 years of age or older who were prescribed donepezil and also were prescribed clarithromycin, erythromycin, azithromycin, cefuroxime, moxifloxacin or levofloxacin. Cases were those members of the base cohort hospitalized for bradycardia, syncope or complete atrioventricular block. For each case patient, five controls were matched according to age, sex and residence (community or long-term care).
  
  
  RESULTS
  Between July 2002 and March 2010, 17,712 patients continuously receiving donepezil were prescribed one of the antibacterials. In 1400 person-years of follow-up, 59 cases were identified. As compared with azithromycin, there was no statistically significant association between use of clarithromycin in donepezil users and subsequent adverse cardiovascular events (odds ratio 0.67; 95% CI 0.28, 1.63). There was no significant risk associated with exposure to either cefuroxime or respiratory quinolones.
  
  
  CONCLUSIONS
  The use of clarithromycin in elderly donepezil users did not significantly increase the risk of adverse cardiovascular outcomes. However, our study cannot rule out a possible small increase in risk. Although antibacterials can be beneficial, care should be taken in selecting antibacterials for use in older people receiving donepezil.
authors.affiliation: Faculty of Medicine, University of Toronto, Toronto, ON, Canada. j.hutson@utoronto.ca.
authors.forename: Janine R
authors.initials: JR
authors.lastname: Hutson
authors.affiliation: Sunnybrook Health Sciences Centre, Institute for Clinical Evaluative Sciences, Toronto, ON, Canada.
authors.forename: Hadas D
authors.initials: HD
authors.lastname: Fischer
authors.affiliation: Sunnybrook Health Sciences Centre, Institute for Clinical Evaluative Sciences, Toronto, ON, Canada.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Sunnybrook Health Sciences Centre, Institute for Clinical Evaluative Sciences, Toronto, ON, Canada.|Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada.|Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gruneir
authors.affiliation: Sunnybrook Health Sciences Centre, Institute for Clinical Evaluative Sciences, Toronto, ON, Canada.
authors.forename: Nick
authors.initials: N
authors.lastname: Daneman
authors.affiliation: Sunnybrook Health Sciences Centre, Institute for Clinical Evaluative Sciences, Toronto, ON, Canada.|Department of Medicine, Queen's University, Kingston, ON, Canada.
authors.forename: Sudeep S
authors.initials: SS
authors.lastname: Gill
authors.affiliation: Faculty of Medicine, University of Toronto, Toronto, ON, Canada.|Sunnybrook Health Sciences Centre, Institute for Clinical Evaluative Sciences, Toronto, ON, Canada.|Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada.|Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada.
authors.forename: Paula A
authors.initials: PA
authors.lastname: Rochon
authors.affiliation: Sunnybrook Health Sciences Centre, Institute for Clinical Evaluative Sciences, Toronto, ON, Canada.|Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada.|Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada.
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Anderson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D054537:Atrioventricular Block / Q000139:chemically induced / Q000453:epidemiology; D001919:Bradycardia / Q000139:chemically induced / Q000453:epidemiology; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000453:epidemiology; D016022:Case-Control Studies; D002800:Cholinesterase Inhibitors / Q000009:adverse effects*; D017291:Clarithromycin / Q000009:adverse effects*; D015331:Cohort Studies; D065692:Cytochrome P-450 CYP3A Inhibitors; D000077265:Donepezil; D004347:Drug Interactions; D011307:Drug Prescriptions; D004791:Enzyme Inhibitors / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007189:Indans / Q000009:adverse effects*; D018942:Macrolides / Q000009:adverse effects; D008297:Male; D009864:Ontario / Q000453:epidemiology; D010880:Piperidines / Q000009:adverse effects*; D013575:Syncope / Q000139:chemically induced / Q000453:epidemiology
chemical_list: D000900:Anti-Bacterial Agents; D002800:Cholinesterase Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D007189:Indans; D018942:Macrolides; D010880:Piperidines; D000077265:Donepezil; D017291:Clarithromycin