Cytochrome P-450 Polymorphisms and Response to Clopidogrel

Abstract

Among persons treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers.

Antiplatelet Therapy Changes for Patients With Myocardial Infarction With Recurrent Ischemic Events: Insights Into Contemporary Practice From the TRANSLATE‐ACS (Treatment With ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) Study

“…Although high on‐clopidogrel platelet reactivity is prevalent and associated with a higher risk of recurrent ischemic events,28, 29, 30 and several studies have shown that switching between P2Y 12 inhibitors is safe and effectively reduces platelet reactivity in patients with high on‐clopidogrel platelet reactivity,31 no randomized controlled trial has demonstrated that intensifying P2Y 12 inhibition reduces clinical end points in patients with high on‐clopidogrel platelet reactivity 12, 13, 14, 15, 16. Platelet function testing is infrequently performed in current practice,15 and recurrent ischemic events while taking clopidogrel may not necessarily reflect inadequate platelet inhibition.…”

Platelet adenosine diphosphate receptor antagonists: ticlopidine to ticagrelor—a long continuing journey

“…11 The two-step activation process involving a series of cytochrome P-450 (CYP) isoenzymes, is susceptible to the interference of genetic polymorphisms and drug-drug interactions. 12,13 Proton pump inhibitors that inhibit CYP2C19, particularly omeprazole, decrease clopidogrel-induced platelet inhibition ex vivo, but there is currently no conclusive clinical evidence that co-administration of clopidogrel and proton pump inhibitors increases the risk of ischaemic events in addition, clopidogrel (and prasugrel) absorption is regulated by P-glycoprotein (encoded by ABCB1), which is an ATP-dependent efflux pump that transports various molecules across extracellular and intracellular membranes. It is expressed, among other places, on intestinal epithelial cells, where increased expression or function can affect the bioavailability of drugs that are substrates.…”

“…It is an orally active drug that binds reversibly to P2Y 12 , with a stronger and more rapid anti-platelet effect than clopidogrel. 21,22 The PLATO study showed that as compared to clopidogrel, ticagrelor was associated with a 16% relative risk reduction with regard to the primary end point-a composite of death from cardiovascular causes, myocardial infarction and stroke-but no significant increase in the overall risk of major bleeding.…”

“…Patients should be counseled on the need for and risks of DAPT before placement of intracoronary stents, especially DES, and alternative therapies should be pursued if patients are unwilling or unable to comply with the recommended duration of DAPT. The duration of P2Y 12 inhibitor therapy after stent implantation should generally be as follows: In patients receiving a stent (BMS or DES) during PCI for ACS, P2Y 12 inhibitor therapy should be given for at least 12 months. Options include: a. Clopidogrel 75 mg daily b. Prasugrel 10 mg daily c. Ticagrelor 90 mg twice daily.…”

“…The limited role of thromboxane A 2 in platelet activation explains why aspirin therapy, which effectively inhibits release of thromboxane A 2 by platelets is insufficient in high-risk conditions such as acute coronary syndromes (ACS) or percutaneous coronary intervention (PCI). The platelet P2Y 12 receptor, one of two adenosine diphosphate (ADP) receptors on platelets, plays a central and unique role in platelet activation through amplifying the effects of numerous platelet agonists. Platelet adenosine diphosphate receptor inhibitors are a class of agents that provide additional anti-aggregatory property to prevent initial platelet activation (Table 1).…”