Genotyping, Platelet Activation, and Cardiovascular Outcome in Patients after Percutaneous Coronary Intervention: Two Pieces of the Puzzle of Clopidogrel Resistance

Abstract

Objectives: Individual platelet responses to antiplatelet therapy depend on genetic, cellular, and clinical factors. CYP2C19 and P2Y12 receptor polymorphisms are implicated in platelet responses to antiplatelet treatment. We aimed to evaluate the impact of CYP2C19 and C34T P2Y12 genotyping on platelet reactivity and cardiovascular outcome in patients after percutaneous coronary intervention (PCI) on clopidogrel treatment. Methods: We enrolled 408 patients with stable coronary artery disease (CAD) receiving aspirin and clopidogrel (75 mg/day) 1 month after PCI. High on-treatment platelet reactivity was evaluated using the VerifyNow Assay in a subset of patients. CYP2C19*2 and C34T P2Y12 genotyping was performed by real-time polymerase chain reaction. The primary end point was the composite of death or hospitalization for cardiovascular causes, and patients were followed for a median time of 13 months. Results: In the total study population, 37% were carriers of at least 1 CYP2C19*2 loss-of-function allele, and 53% were carriers of at least 1 C34T loss-of-function allele. Interestingly, homozygotes of the CYP2C19*2 loss-of-function allele had significantly increased P2Y12 reaction units (PRU) (p = 0.007). However, PRU did not differ between carriers and noncarriers of the C34T loss-of-function allele (p = 0.41). Moreover, carriers of CYP2C19*2 had an increased hazard ratio (HR) for the occurrence of the primary end point (for carriers HR = 1.96, 95% CI 1.05-3.66, p = 0.03), whereas the C34T polymorphism had no impact on the cardiovascular outcome (p = 0.17). Finally, PRU was associated with cardiovascular outcome even after adjustment for the presence of any reduced function allele polymorphism. Conclusions: We documented a different effect of CYP2C19 and P2Y12 receptor polymorphisms on platelet reactivity and cardiovascular outcome in CAD patients after PCI on clopidogrel treatment. Importantly, increased platelet reactivity adversely affects the cardiovascular outcome independently of the studied polymorphisms.

The impact of smoking status on clopidogrel responsiveness in patients with coronary artery disease who undergo percutaneous coronary intervention

“…These findings were comparable to the findings of other studies. 7,8 Additionally, this study illustrated a significantly higher hemoglobin level among the smoking participants when compared to the non-smoking patients, although Yun Gi Kim and his team found evidence that the AUC measured by Multiplate Analyzer was not affected by hemoglobin level. 9 While there was a significantly lower AUC among the smoker participants as compared to the non-smoker in both study groups, these results are consistent with 5,10 and contrary to results by Kim et al, 2016.…”

Pharmacogenomic Impact of CYP2C19 Variation on Clopidogrel Therapy in Precision Cardiovascular Medicine

“…In some reports, HTPR in response to clopidogrel therapy affected up to 40% of treated individuals [ 9 , 94 , 95 ]. Of importance, the HTPR independently associated with larger intracoronary thrombus burden, worse post-PCI myocardial flow and perfusion, higher ischemic risk, and frequency of adverse cardiovascular outcomes such as stent thrombosis, myocardial infarction, stroke, and death in several studies on platelet aggregation, and therefore carries a poor prognosis in patients with ACS treated with clopidogrel after PCI [ 25 , 96 , 97 , 98 , 99 , 100 ]. HTPR can be partially overcome by assuring loading of clopidogrel prior to PCI, with administration of the higher dose (600 mg, compared to 300 mg) [ 101 , 102 ].…”

“…For example, a genome-wide association study followed by CYP2C*2 genotyping in patients undergoing PCI suggested a link between the CYP2C*2 genotype and both diminished platelet response to clopidogrel (accounting for 12% of interindividual variation) and cardiovascular ischemic events or death during 1 year of follow-up (hazard ratio 2.42, p = 0.02) [ 26 ]. In another study, individuals carrying the CYP2C19*2 variant allele exhibited a 3-fold increased risk for adverse ischemic cardiovascular events on clopidogrel therapy [ 32 , 100 ]. Notably, this association is more prominent during the first year after PCI, and thereafter decreases significantly [ 113 ].…”

“…The observation of genotype-phenotype discordance in some individuals can also imply differential regulation of the CYP2C19 gene leading to an acquired deficiency in enzyme activity [ 47 ]. Indeed, antiplatelet response to clopidogrel administration may depend on genetic, cellular, environmental, and clinical factors [ 100 ].…”

P2Y12 Polymorphisms and the Risk of Adverse Clinical Events in Patients Treated with Clopidogrel: A Meta-Analysis

“…Additionally, 434 articles (238 irrelevant studies, 119 reviews, 8 conference papers, 59 studies without adverse events, 4 animal trials, 4 case reports, and 2 non-English-language study) were excluded by title and abstract screening. Then, six studies [14][15][16][17][18] with incomplete data, one study [19] with incorrect data, one study [20] with a followup < 3 months and one study [21] without full-text were excluded respectively. Fifteen studies [8,9,[22][23][24][25][26][27][28][29][30][31][32][33][34] met the inclusion criteria.…”