TY - JOUR

T1 - Clopidogrel bioactivation and risk of bleeding in patients cotreated with angiotensin-converting enzyme inhibitors after myocardial infarction

T2 - a proof-of-concept study

AU - Kristensen, K E

AU - Zhu, H-J

AU - Wang, X

AU - Gislason, G H

AU - Torp-Pedersen, C

AU - Rasmussen, H B

AU - Markowitz, J S

AU - Hansen, Peter Riis

PY - 2014/12

Y1 - 2014/12

N2 - 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.

AB - 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.

KW - Aged

KW - Angiotensin-Converting Enzyme Inhibitors

KW - Biotransformation

KW - Carboxylic Ester Hydrolases

KW - Drug Interactions

KW - Female

KW - Hemorrhage

KW - Humans

KW - Male

KW - Middle Aged

KW - Myocardial Infarction

KW - Platelet Aggregation Inhibitors

KW - Risk

KW - Ticlopidine

U2 - 10.1038/clpt.2014.183

DO - 10.1038/clpt.2014.183

M3 - Journal article

C2 - 25222620

VL - 96

SP - 713

EP - 722

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

SN - 0009-9236

IS - 6

ER -