Clopidogrel and Calcium-Channel Antagonists

Abstract

The medical management of patients with coronary artery disease is currently dominated by strategies to alter lipid levels and to inhibit platelet aggregation and activation. In fact, one can make a very strong argument that coronary artery stenting would never have achieved its current level of popularity and success had it not been for the pioneering work done by Colombo et al. (1) using the thienopyridine ticlopidine. Ticlopidine has been almost universally replaced by clopidogrel, a second-generation thienopyridine that is considerably better tolerated. Despite clopidogrel's success for patients receiving intracoronary stents and for patients with acute coronary syndromes, its use is hampered by the consistent finding that as many as 1 of 4 patients receiving clopidogrel have little evidence of antiplatelet response to the drug (2-4). The phenotype of clopidogrel "resistance" has been associated with an increased risk of cardiovascular events (3,5) and of stent thrombosis; several prospective investigations are being performed to verify these findings. See page 1557Clopidogrel is a pro-drug and is converted in the liver by the members of the cytochrome P450 (CYP) family (predominantly the 3A and 2C groups) to a series of metabolites, the last of which, the thiol metabolite, is an antagonist of the platelet purinergic receptor known as P2Y12 (6). As reviewed elsewhere, ligation of P2Y12 by the active metabolite of clopidogrel prevents adenoside diphosphate (ADP) from activating the receptor and prevents a chain of events that would otherwise lead to platelet shape change, secretion, and aggregation. Among the many tests that have been proposed to assess clopidogrel's biologic activity, a recent addition has been the development of assays for vasodilator stimulated phosphoprotein (VASP). The VASP assay developed by Schwarz et al. (7) appears to capture most of the activity of P2Y12 and has the advantage that, unlike functional assays such as platelet aggregation, it is pathwayspecific for P2Y12 activation. When ADP ligates P2Y12, G i protein signaling pathways reduce intracellular levels of cyclic adenosine monophosphate (cAMP), which in turn leads to decreased phosphorylation of VASP. Because phosphorylation inactivates VASP, high levels of dephosphorylated VASP reflect high levels of P2Y12 occupancy by ADP whereas high levels of phosphorylated VASP reflect blockade of P2Y12. The relationship is generally regarded as being linear. For clinical purposes, levels of VASP phosphorylation are indexed for maximal VASP phosphorylation (stimulated by prostaglandin E1) and are reported as the platelet reactivity index (PRI), or VASP phosphorylation index.In this issue of the Journal, Siller-Matula et al. (8) assessed whether calcium-channel antagonists, specifically verapamil and a number of dihydropyridines, altered the effect of clopidogrel on platelets in patients undergoing coronary arterial stenting. The interaction between calciumchannel antagonists and the metabolism of other drugs is well documented. Diltiazem ...

Clopidogrel pathway

“…The clinical implications of these findings are still under investigation [16,17]. Several clinical studies did not support the finding that atorvastatin can interfere with the effect of clopidogrel [18–20].…”