title: A population-based study of the drug interaction between clopidogrel and angiotensin converting enzyme inhibitors.
abstract: OBJECTIVE
  Clopidogrel and angiotensin converting enzyme (ACE) inhibitors are commonly co-prescribed drugs. Clopidogrel inhibits carboxylesterase 1 (CES1), the enzyme responsible for converting prodrug ACE inhibitors (such as ramipril and perindopril) to their active metabolites. The clinical implications of this potential drug interaction are unknown. The clinical consequences of the potential drug interaction between clopidogrel and prodrug ACE inhibitors were examined.
  
  
  METHODS
  We conducted a nested case-control study of Ontarians aged 66 years and older treated with clopidogrel between September 1 2003 and March 31 2013 following acute myocardial infarction. Cases were subjects who died or were hospitalized for reinfarction or heart failure in the subsequent year, and each was matched with up to four controls. The primary outcome was a composite of reinfarction, heart failure or death. The primary analysis examined whether use of the prodrug ACE inhibitors ramipril or perindopril was more common among cases than use of lisinopril, an active ACE inhibitor.
  
  
  RESULTS
  Among 45 918 patients treated with clopidogrel following myocardial infarction, we identified 4203 cases and 14 964 controls. After adjustment, we found no association between the composite outcome and use of perindopril (adjusted odds ratio (aOR) 0.94, 95% confidence interval (CI) 0.76, 1.16) or ramipril (aOR 0.97, 95% CI 0.80, 1.18), relative to lisinopril. Secondary analyses of each element of the composite outcome yielded similar findings.
  
  
  CONCLUSIONS
  Following myocardial infarction, use of clopidogrel with ACE inhibitors activated by CES1 is not associated with an increased risk of adverse cardiovascular outcomes relative to lisinopril. These findings suggest that the recently described drug interaction between clopidogrel and prodrug ACE inhibitors is of little clinical relevance.
authors.affiliation: The Institute for Clinical Evaluative Sciences, Toronto, Ontario.|Department of Medicine, Faculty of Medicine, University of Toronto, Ontario.
authors.forename: Alex M
authors.initials: AM
authors.lastname: Cressman
authors.affiliation: The Institute for Clinical Evaluative Sciences, Toronto, Ontario.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Macdonald
authors.affiliation: The Institute for Clinical Evaluative Sciences, Toronto, Ontario.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Fernandes
authors.affiliation: The Institute for Clinical Evaluative Sciences, Toronto, Ontario.|Institute of Health Policy, Management and Evaluation, Toronto, Ontario.|The Leslie Dan Faculty of Pharmacy, Toronto, Ontario.|Applied Health Research Centre (AHRC), Li Ka Shing Knowledge Institute of St. Michael's, Toronto, Ontario.
authors.forename: Tara
authors.initials: T
authors.lastname: Gomes
authors.affiliation: The Institute for Clinical Evaluative Sciences, Toronto, Ontario.|Institute of Health Policy, Management and Evaluation, Toronto, Ontario.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Paterson
authors.affiliation: The Institute for Clinical Evaluative Sciences, Toronto, Ontario.|Institute of Health Policy, Management and Evaluation, Toronto, Ontario.|The Leslie Dan Faculty of Pharmacy, Toronto, Ontario.|Applied Health Research Centre (AHRC), Li Ka Shing Knowledge Institute of St. Michael's, Toronto, Ontario.|Dalla Lana School of Public Health, University of Toronto, Ontario.|Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Mamdani
authors.affiliation: The Institute for Clinical Evaluative Sciences, Toronto, Ontario.|Department of Medicine, Faculty of Medicine, University of Toronto, Ontario.|Institute of Health Policy, Management and Evaluation, Toronto, Ontario.|Sunnybrook Research Institute, Toronto, Ontario.|Department of Pediatrics, University of Toronto, Ontario, Canada.
authors.forename: David N
authors.initials: DN
authors.lastname: Juurlink
mesh_terms: D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016022:Case-Control Studies; D000077144:Clopidogrel; D016208:Databases, Factual; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006333:Heart Failure; D006801:Humans; D017706:Lisinopril / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy; D020913:Perindopril / Q000494:pharmacology* / Q000627:therapeutic use; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D017257:Ramipril / Q000494:pharmacology* / Q000627:therapeutic use; D012008:Recurrence; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D017706:Lisinopril; D017257:Ramipril; D013988:Ticlopidine; D020913:Perindopril
keywords: angiotensin converting enzyme inhibitors; clopidogrel; congestive heart failure; mortality; myocardial infarction