Aspirin and Clopidogrel Resistance

Abstract

Aspirin and clopidogrel provide significant clinical benefit in patients with cardiovascular disease. However, given the complexity of platelet activation, it is not surprising that aspirin or clopidogrel prevent a small proportion of cardiovascular events. Of late, the terms aspirin and clopidogrel "resistance" have entered the physicians' lexicon, and infer a lack of therapeutic response and a single underlying mechanism, which is misleading. The incidence of "resistance" detected in studies varies with the definition applied and assay used to measure response. Rather than true resistance, however, there is a variable response that reflects the unique pharmacology and pharmacokinetics of each drug, the clinical significance of which remains to be established. True "aspirin resistance" implies that cyclooxygenase-1 is less sensitive to inactivation by aspirin. Despite 95% inhibition of serum thromboxane B(2) by aspirin, residual platelet aggregation is detected in some cases, the clinical significance of which is unknown. Heritable factors directly and indirectly related to platelet cyclooxygenase may influence aspirin response. In contrast to aspirin, the response to clopidogrel is highly variable and reflects the bioavailability of the active metabolite and not "resistance" of the receptor to inhibition.

Diversity of platelet function and genetic polymorphism in clopidogrel-treated Chinese patients

“…Clopidogrel is an inactive prodrug that requires hepatic bioactivation via several cytochrome P450 enzymes, including CYP2C19, CYP1A2, CYP2B6, CYP2C19, CYP2C9, and CYP3A4/5 (Fitzgerald and Maree, 2007). The active metabolite irreversibly inhibits the platelet ADP receptor, P2Y12 (Fitzgerald and Maree, 2007).…”

“…The active metabolite irreversibly inhibits the platelet ADP receptor, P2Y12 (Fitzgerald and Maree, 2007). P2Y12 is polymorphic; the T744C variant is in linkage disequilibrium (Angiolillo et al, 2005).…”

Intracellular Erythrocyte Platelet-activating Factor Acetylhydrolase I Inactivates Aspirin in Blood

“…Erythrocyte Aspirin Hydrolysis Varies among IndividualsThe effectiveness of aspirin in inhibiting platelet function ex vivo varies among individuals and populations for unknown reasons (13,(42)(43)(44). We found that hydrolysis varied by over 2-fold when erythrocytes were prepared from 10 different donors (Fig.…”

Aspirin Hydrolysis in Plasma Is a Variable Function of Butyrylcholinesterase and Platelet-activating Factor Acetylhydrolase 1b2 (PAFAH1b2)

“…Not all individuals or members of groups appear to receive the benefits of aspirin administration (14 -17), but whether this phenomenon of "aspirin resistance" is a valid description or even identifiable given difficulties in clinical measurement of platelet function (17) is debated (14,15). Platelet resistance to aspirin inhibition is, however, present in ex vivo assays (42) in certain in vivo studies (15) and correlates with measures of type 2 diabetes (22,23).…”