Resistance to clopidogrel: A review of the evidence

Abstract

Current available data show that about 4% to 30% of patients treated with conventional doses of clopidogrel do not display adequate antiplatelet response. Clopidogrel resistance is a widely used term that remains to be clearly defined. So far, it has been used to reflect failure of clopidogrel to achieve its antiaggregatory effect. The interpatient variability in clopidogrel response is multifactorial. It can be due to extrinsic or intrinsic mechanisms. Among extrinsic mechanisms are the possibility of clopidogrel underdosing in patients undergoing stenting or with acute coronary syndrome, and drug-drug interactions involving CYP3A4. Intrinsic mechanisms include genetic polymorphisms of the P2Y(12) receptor and of the CYP3As, accrued release of adenosine diphosphate, or up-regulation of other platelet activation pathways. Presently, there is no definite demonstration of an association between low responsiveness to clopidogrel and thrombotic events. The optimal level of clopidogrel-induced platelet inhibition, which will correlate quantitatively with clopidogrel's ability to prevent atherothrombotic events is still lacking. Furthermore, because there is no single and validated platelet function assay to measure clopidogrel's antiplatelet effect, it is not justified to routinely look for clopidogrel resistance in the clinical setting. This review discusses currently available evidence surrounding the variability in the antiplatelet response to clopidogrel.

Impact of Obstructive Sleep Apnea on Platelet Function Profiles in Patients With Acute Coronary Syndrome Taking Dual Antiplatelet Therapy

“…Suboptimal response to antiplatelet agents or HRPR, in fact, has been associated with an enhanced risk of major cardiovascular events and acute ischemic complications, especially with clopidogrel, where a high HRPR has been described in almost 30% of patients 18, 25, 26. In patients with ACS or undergoing PCI, HRPR is associated with ≈2‐ to 3‐fold greater risk of recurrent ischemic events and about 1.5‐fold greater risk of all‐cause mortality 27, 28, 29.…”

Associations of CYP3A4, NR1I2, CYP2C19 and P2RY12 polymorphisms with clopidogrel resistance in Chinese patients with ischemic stroke

“…platelet inhibition after clopidogrel therapy [4][5][6] , and this phenomenon is called clopidogrel resistance (CR). In fact, several clinical studies conducted in Chinese, Japanese and Korean patients reveal that the frequencies of clopidogrel resistance in Asians may vary from 20% to 65%, which highly exceeds the incidence reported in other ethnic groups [7,8] .…”

Brief review: Coronary drug-eluting stents and anesthesia

“…35 Causes of clopidogrel resistance include genetic polymorphisms of the P2Y12 receptor and of CYP3As, accrued release of ADP, and up-regulation of other platelet activation pathways. 36 The prevalence of clopidogrel non-response in patients is between 4% and 30% 24 hr after administration. [37][38][39][40][41][42][43] No single standard validated method is available to measure clopidogrel efficacy.…”

“…[37][38][39][40][41][42][43] No single standard validated method is available to measure clopidogrel efficacy. 36,44 Platelet function can be assessed by monitoring vasodilator-stimulated phosphoprotein, which directly measures the function of the clopidogrel target, the P2Y12 receptor, 44 or using platelet aggregometry, flow cytometry of P-selectin, impedance aggregation, and the platelet function analyzer. 34 Bleeding time is rarely used, as it is highly operator dependent and poorly reproducible.…”

“…The optimal level of clopidogrel-induced platelet inhibition, which will correlate quantitatively with clopidogrel's ability to prevent atherothrombotic events, is still lacking. 36 …”