Clopidogrel Bioactivation and Risk of Bleeding in Patients Cotreated With Angiotensin-Converting Enzyme Inhibitors After Myocardial Infarction: A Proof-of-Concept Study

Research output: Contribution to journalJournal articleResearchpeer-review

  • K. E. Kristensen
  • H. J. Zhu
  • X. Wang
  • G. H. Gislason
  • C. Torp-Pedersen
  • H. B. Rasmussen
  • J. S. Markowitz
  • P. R. Hansen

View graph of relations

Clopidogrel is an oral antiplatelet prodrug, the majority of which is hydrolyzed to an inactive metabolite by hepatic carboxylesterase 1 (CES1). Most angiotensin-converting enzyme inhibitors (ACEIs) are also metabolized by this enzyme. We examined the effects of ACEIs on clopidogrel bioactivation in vitro and linked the results with a pharmacoepidemiological study. In vitro, ACEIs inhibited CES1-mediated hydrolysis of a model substrate, and trandolapril and enalapril increased formation of clopidogrel active metabolite. In 70,934 patients with myocardial infarction, hazard ratios for clinically significant bleeding in ACEI-treated patients cotreated with or without clopidogrel were 1.10(95% confidence interval (CI): 0.97-1.25, P = 0.124) and 0.90 (95% CI: 0.81-0.99, P = 0.025), respectively, as compared with patients who did not receive ACEIs. This difference was statistically significant (P = 0.002). We conclude that cotreatment with selected ACEIs and clopidogrel may increase the risk of bleeding. Combination of in vitro and pharmacoepidemiological studies may be a useful paradigm for assessment of drug-drug interactions.
LanguageEnglish
JournalClinical Pharmacology and Therapeutics
Volume96
Issue number6
Pages (from-to)713-722
ISSN0009-9236
DOIs
StatePublished - 2014

    Research areas

  • ACUTE CORONARY SYNDROMES COMPARATIVE PHARMACOKINETICS HUMAN CARBOXYLESTERASES ANTIPLATELET AGENTS PLATELET REACTIVITY NATIONWIDE COHORT DIABETES-MELLITUS CLINICAL-EFFICACY ARTERY-DISEASE THERAPY