Clopidogrel–Drug Interactions

Abstract

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.

Patterns of antiplatelet drug use after a first myocardial infarction during a 10‐year period

“…In clopidogrel users, diabetes and hypercholesterolaemia were associated with a higher risk of antiplatelet drug nonpersistence. Although this was unexpected, it might be partly explained by the concern of a pharmacokinetic interaction between atorvastatin and clopidogrel in patients with hypercholesterolaemia 26, and diabetes was reported as a predictor of insufficient antiplatelet response to clopidogrel 27. Patients with previous CAD, who also have a higher risk for recurrent cardiovascular events, had a lower risk of clopidogrel nonpersistence but a higher risk of DAPT nonpersistence.…”

http://oatext.com/Dual-antiplatelet-therapy-after-coronary-artery-bypass-grafting-Do-we-have-a-consensus.php

“…Clopidogrel works by irreversibly inhibiting a receptor called P2Y12, an adenosine diphosphate (ADP) chemoreceptor on platelet cell membranes. Clopidogrel requires biotransformation into active metabolites and this step is dependent on genes encoding the cytochrome P40 system (specifically CYP2C19), which may suggest a degree of insensitivity or resistance, if it used as antiplatelet monotherapy following CABG [43,44]. The usual dose for clopidogrel is 75 mg daily.…”

Relationship Between Statin Type and Responsiveness to Clopidogrel in Patients Treated with Percutaneous Coronary Intervention: A Subgroup Analysis of the CILON-T Trial

“…All PCR analyses were performed in 384-well plates using a Dual 384-Well GeneAmp PCR System 9700 (ABI, Foster City, CA, USA), and the end point fluorescent readings were obtained using an ABI PRISM 7900HT Sequence Detection System (ABI, Foster City, CA, USA). Duplicate samples and negative controls were betes mellitus and a decreased renal function are associated with poor responsiveness to clopidogrel [4][5][6][7][8] .…”

“…The primary metabolic mediators are CYP2C19, CYP3A and CYP1A2 2) . A decreased function of CYPs as a result of drug interactions or genetic polymorphisms reduces the antiplatelet effects of clopidogrel, which is associated with poor outcomes after acute myocardial infarction and percutaneous coronary intervention (PCI) [2][3][4][5] . Previous studies have suggested that the CYP2C19 genotype, a female gender, an old age, dia-…”