Possible mechanisms of drug-induced aspirin and clopidogrel resistance

Abstract

Aspirin (ASA) and clopidogrel have been identified as standard of care in the prevention of major cardiovascular events. Aspirin irreversibly inhibits the cyclooxygenase-1 (COX-1) enzyme, whereas non-steroidal anti-inflammatory drugs (NSAIDs) reversibly inhibit the COX-1 enzyme. An analysis of the literature revealed a statistically significant decrease in clinical benefit of ASA with concomitant administration of ibuprofen. Another NSAID, diclofenac, showed minimal effect on the inhibition of platelet aggregation when administered with ASA. Furthermore, the selective COX-2 inhibitor, rofecoxib, was not shown to influence the effect of ASA. Clopidogrel is metabolized to an active thiol metabolite by the CYP 3A4 enzyme. Some HMG CoA reductase inhibitors have the ability to inhibit the CYP 3A4 enzyme, which can result in a possible interaction if administered concomitantly with clopidogrel. Studies have demonstrated clopidogrel's platelet inhibition being significantly attenuated by atorvastatin. However in a post-hoc analysis, it was demonstrated that there was no difference in clinical outcomes between patients taking clopidogrel and HMG-CoA reductase inhibitors metabolized by and not metabolized by CYP 3A4. Data suggest that the interaction observed involving clopidogrel and HMG-CoA reductase inhibitors appears to be significant in-vitro. Therefore, practitioners should advise patients receiving chronic aspirin therapy to limit the use of ibuprofen and may consider concomitant administration of clopidogrel with HMG-CoA reductase inhibitors without regard for the drug interaction. The intent of this paper is to review the literature discussing possible mechanisms of drug-induced aspirin and clopidogrel resistance and discuss whether the interactions translate into clinical effects.

Hemoptysis under Diclofenac and Antiplatelet Doses of Aspirin

“…COX I catalyzes the transformation of membrane-bound arachidonic acid to thromboxane 1, a platelet agonist. Recently, it has been suggested that co-administration of NSAIDs with aspirin may interfere with the irreversible antiplatelet function of aspirin resulting thus in competitive interaction and attenuation of the antiplatelet effect [7] . However, a recent paper indicates that in vitro concurrent administration of aspirin and diclofenac potentiates the inhibition of platelet aggregation [8] .…”

Effectiveness of Ticagrelor Compared to Clopidogrel in Reducing the Risk of Major Adverse Cardiovascular Events in Patients With Coronary Heart Disease After Percutaneous Coronary Intervention

“…Antiplatelet such as aspirin, clopidogrel, and ticagrelor are recommended to prevent thrombosis for patients with CHD with or without PCI. Clopidogrel is a pro-drug that requires metabolism primarily by CYP450 enzymes to become active metabolite [21,22]. The molecular target of the clopidogrel active metabolite is responsible for triggering platelet aggregation.…”

Hydrogen Sulfide and Platelets: A Possible Role in Thrombosis

“…In summary, inappropriate activation of platelets is a key driver of common cardiovascular diseases, and platelets are a major therapeutic target in the prevention and treatment of conditions such as myocardial infarction. Limitations in the efficacy of platelet-targeted antithrombotics are due to drug resistance in a high proportion of individuals and incidences of bleeding associated with use of antithrombotics (Schroeder et al 2006). …”