Kristensen, Karl E.4; Zhu, Hao-Jie4; Wang, Xinwen4; Gislason, Gunnar H.4; Torp-Pedersen, Christian1; Rasmussen, Henrik B.4; Markowitz, John S.4; Hansen, Peter R.4
1 Department of Health Science and Technology, The Faculty of Medicine, Aalborg University, VBN2 Public Health and Epidemiology Group, The Faculty of Medicine, Aalborg University, VBN3 The Faculty of Medicine, Aalborg University, VBN4 unknown
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 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 and Therapeutics, 2014, Vol 96, Issue 6, p. 713-722