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

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...

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Published in:Clinical pharmacology and therapeutics 2014-12, Vol.96 (6), p.713-722
Main Authors: Kristensen, K E, Zhu, H-J, Wang, X, Gislason, G H, Torp-Pedersen, C, Rasmussen, H B, Markowitz, J S, Hansen, P R
Format: Article
Language:English
Subjects:
Aged
Angiotensin-Converting Enzyme Inhibitors - pharmacology
Biotransformation
Carboxylic Ester Hydrolases - physiology
Drug Interactions
Female
Hemorrhage - chemically induced
Humans
Male
Middle Aged
Myocardial Infarction - drug therapy
Platelet Aggregation Inhibitors - pharmacokinetics
Risk
Ticlopidine - adverse effects
Ticlopidine - analogs & derivatives
Ticlopidine - pharmacokinetics
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Summary: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. Clinical Pharmacology & Therapeutics (2014); 96 6, 713–722. doi:10.1038/clpt.2014.183
ISSN:0009-9236
1532-6535
DOI:10.1038/clpt.2014.183