State-of-the-Art Paper
Clopidogrel–Drug Interactions

https://doi.org/10.1016/j.jacc.2010.11.024Get rights and content
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Multidrug therapy increases the risk for drug–drug interactions. Clopidogrel, a prodrug, requires hepatic cytochrome P450 (CYP) metabolic activation to produce the active metabolite that inhibits the platelet P2Y12 adenosine diphosphate (ADP) receptor, decreasing platelet activation and aggregation processes. Atorvastatin, omeprazole, and several other drugs have been shown in pharmacodynamic studies to competitively inhibit CYP activation of clopidogrel, reducing clopidogrel responsiveness. Conversely, other agents increase clopidogrel responsiveness by inducing CYP activity. The clinical implications of these pharmacodynamic interactions have raised concern because many of these drugs are coadministered to patients with coronary artery disease. There are multiple challenges in proving that a pharmacodynamic drug–drug interaction is clinically significant. To date, there is no consistent evidence that clopidogrel–drug interactions impact adverse cardiovascular events. Statins and proton pump inhibitors have been shown to decrease adverse clinical event rates and should not be withheld from patients with appropriate indications for therapy because of concern about potential clopidogrel–drug interactions. Clinicians concerned about clopidogrel–drug interactions have the option of prescribing either an alternative platelet P2Y12 receptor inhibitor without known drug interactions, or statin and gastro-protective agents that do not interfere with clopidogrel metabolism.

Key Words

atorvastatin
clopidogrel
drug interactions
omeprazole
proton pump inhibitors
statins

Abbreviations and Acronyms

ACS
acute coronary syndrome
cAMP
cyclic adenosine monophosphate
CYP
cytochrome P450
H2RA
histamine2 receptor antagonist
HMG-CoA
3-hydroxy-3-methylglutaryl coenzyme A
MI
myocardial infarction
PCI
percutaneous coronary intervention
PPI
proton pump inhibitor
VASP
vasodilator-stimulated phosphoprotein

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Dr. Bates has relationships with Daiichi Sankyo, Eli Lilly, Bristol-Myers Squibb, Sanofi-Aventis, Merck, GlaxoSmithKline, Takeda, and Dat. Dr. Lau was a consultant to and has received an educational grant for an investigator-initiated study from Eli Lilly. Dr. Angiolillo reports receiving honoraria for lectures from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly Co., Daiichi Sankyo, Inc.; consulting fees from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly Co., Daiichi Sankyo, Inc., The Medicines Company, Portola, Novartis, Medicure, Accumetrics, Arena Pharmaceuticals, AstraZeneca, Merck; and research grants from Bristol-Myers Squibb, Sanofi-Aventis, GlaxoSmithKline, Otsuka, Eli Lilly Co., Daiichi Sankyo, Inc., The Medicines Company, Portola, Accumetrics, Schering-Plough, AstraZeneca, and Eisai.