Clopidogrel: A multifaceted affair

Abstract

Clopidogrel has been the therapy of choice, combined with aspirin, against platelet aggregation in patients at risk of suffering a vascular thrombotic event. Not all patients respond equally to clopidogrel, an observation that has led to searching for a test that, in the clinical setting, could predict patients' "resistance" to therapy. The evidence reveals a complex pharmacokinetic profile for clopidogrel, with multiple players involved, including cytochromes, characteristics of the target tissue, and accompanying clinical conditions. Despite FDA black box warnings recommending CYP2C19 genotyping before clopidogrel use, no robust evidence indicates that CYP2C19 function determines clinical response to the drug, either based on the presence of loss of function alleles or drug interactions with CYP2C19 inhibitors, like omeprazole. A tailored anti-aggregation treatment based on ex vivo platelet reactivity also seems unlikely due to the lack of robustness of most assays. The identification of clinical conditions that are at higher risk of new cardiovascular events, such as diabetes, obesity, coronary artery disease, or specific stenting procedures, seems to be a prudent approach to tailor anti-platelet therapy with more powerful drugs, accompanied by careful counseling to promote patient compliance. Keywords clopidogrel, response, pharmacogenetics, clinicalPlatelet anti-aggregation is the main therapeutic approach to prevent new cardiovascular complications in patients who have suffered a major acute cardiovascular event (MACE) and may have undergone a percutaneous coronary intervention (PCI). 1 A well-established treatment regime has been the combination of aspirin, that blocks thromboxane synthesis, and clopidogrel, a prodrug that, upon biotransformation, irreversibly blocks the binding of adenosine diphosphate (ADP) to its platelet P2Y 12 receptor (previously P2T), thus preventing the inactivation of adenylate cyclase (AC) and the subsequent activation of the glycoprotein GPIIb/IIIa complex, required for platelet aggregation. 2 The clinical benefit of adding clopidogrel to aspirin therapy has been demonstrated by several large, multicenter, randomized, controlled trials. The CAPRIE trial (clopidogrel vs. aspirin in patients at risk of ischemic events) was the first to prove the benefit of clopidogrel over aspirin, showing a relative risk reduction of 8.7% for the secondary prevention of cardiovascular events in 19,185 patients with clinical manifestations of atherosclerosis. 3 The CURE (clopidogrel in unstable angina to prevent recurrent events) study, performed in 12,562 patients with acute coronary syndrome (unstable angina or non-ST elevation myocardial infarction), demonstrated that a loading dose of 300 mg clopidogrel followed by a once daily treatment with 75 mg, in addition to aspirin (75-325 mg/day) significantly reduced the risk of the combined endpoint of cardiovascular death, myocardial infarction, and stroke (9.3% of the patients in the clopidogrel group vs. 11.4% of the patients in the p...

The correlation between recurrent risk and CYP2C19 gene polymorphisms in patients with ischemic stroke treated with clopidogrel for prevention

“…As a precursor, clopidogrel must pass through the liver cytochrome P450 enzyme to be metabolized into the active product and then play the role of antiplatelet aggregation, among which CYP2C19 plays the most important role. [ 3 ] Studies have demonstrated that the polymorphism of CYP2C19 gene is closely related to the degree of platelet inhibition of clopidogrel, and the extensive metabolizer (EM) type has a higher platelet inhibition rate than the intermediate metabolizer (IM) type and slow metabolizer. [ 4 ] Asians seem to have a higher probability of carrying a loss of function (LOF) CYP2C19 allele (e.g., CYP2C19∗2 or CYP2C19∗3) than persons of either African or Caucasian ethnicity.…”

CYP2C19 or CYP3A5 Genotyping Does Not Predict Clinical Response to Clopidogrel

“…After numerous studies, some of them supporting a black box warning by the US Food and Drug Administration (FDA), the value of CYP2C19 genotyping previous to clopidogrel administration is still a subject for debate, mostly because (1) ex vivo platelet aggregation assays do not accurately reflect the in vivo response to antiplatelet agents, and (2) there is great heterogeneity in the clinical studies performed to date, as expressed in recent reviews …”

“…Indeed, the pharmacokinetic and pharmacodynamic parameters of clopidogrel in healthy subjects both seem to be unpredictable based on a single factor, with clinical resistance likely dependent on multiple factors …”

“…19 After numerous studies, some of them supporting a black box warning by the US Food and Drug Administration (FDA), the value of CYP2C19 genotyping previous to clopidogrel administration is still a subject for debate, mostly because (1) ex vivo platelet aggregation assays do not accurately reflect the in vivo response to antiplatelet agents, 20 and (2) there is great heterogeneity in the clinical studies performed to date, as expressed in recent reviews. 19,[21][22][23] Indeed, the pharmacokinetic and pharmacodynamic parameters of clopidogrel in healthy subjects both seem to be unpredictable based on a single factor, 24 with clinical resistance likely dependent on multiple factors. 23 As there is still room to add knowledge in this field, we have followed a cohort of 368 subjects receiving combined antiaggregation therapy with aspirin and clopidogrel for 1 year and analyzed the influence in disease relapse of both CYP2C19 and CYP3A5 lossof-function alleles, as well as the effects of concomitant medication and the presence of known cardiovascular risk factors and comorbidity.…”

“…19,[21][22][23] Indeed, the pharmacokinetic and pharmacodynamic parameters of clopidogrel in healthy subjects both seem to be unpredictable based on a single factor, 24 with clinical resistance likely dependent on multiple factors. 23 As there is still room to add knowledge in this field, we have followed a cohort of 368 subjects receiving combined antiaggregation therapy with aspirin and clopidogrel for 1 year and analyzed the influence in disease relapse of both CYP2C19 and CYP3A5 lossof-function alleles, as well as the effects of concomitant medication and the presence of known cardiovascular risk factors and comorbidity.…”