Dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 receptor inhibitor currently represents the standard of care to mitigate the risk of stent-related and spontaneous ischemic events in patients undergoing percutaneous coronary intervention (PCI).1 For years, clopidogrel has been the most commonly prescribed P2Y12 inhibitor in patients treated with coronary stent implantation for acute or chronic coronary syndrome.1–3 In contemporary practice, this drug remains the P2Y12 inhibitor of choice in patients who are referred for elective PCI or on oral anticoagulation.2–5 Yet, platelet function studies have revealed substantial variability in the individual response to clopidogrel, such that approximately 20%–30% of patients are expected to have persistent, high on-treatment platelet reactivity.6–9 In these patients, the attenuated pharmacodynamics response to clopidogrel (a prodrug) is at least partly explained by genetic variants of CYP2C19, the gene responsible for encoding the CYP2C19 liver enzyme that metabolizes the drug to its active form.6,7 Loss-of-function (LOF) variants of CYP2C19 gene result in reduced activation of clopidogrel that can hamper its antiplatelet effect.6,7 Of note, available potent P2Y12 inhibitors (prasugrel and ticagrelor) do not require metabolic activation, and therefore, their efficacy is not affected by CYP2C19 function.1–3 These newer drugs have a faster and more consistent antiplatelet effect and have been proven, in the setting of randomized clinical trials and observational studies, to be more effective than clopidogrel in reducing the risk of ischemic events after acute coronary syndrome.1–4 Yet, previous studies also revealed an increased risk of bleeding complications when potent P2Y12 inhibitors are used instead of clopidogrel in combination with aspirin.1–4 Different LOF variants within CYP2C19 have been previously described, showing variegate effects on clopidogrel activity ranging from a functionally relevant reduction in drug metabolism to a complete absence of its enzymatic conversion.6,7 Differences in the drug metabolism can translate into a graded risk of coronary ischemic events during treatment.6,7
To address the issues related to the existence of genetic and biologic variability, several genotype- and phenotype-guided strategies have been proposed to optimize antiplatelet therapy after coronary stent implantation.6,7 In the past decade, randomized and observational studies have examined the potential of a clinical strategy relying on platelet function or genetic testing to guide the type of DAPT after PCI, offering controversial evidence.6,7
In the TAILOR-PCI trial,6 5302 patients undergoing urgent or elective PCI were randomized to conventional therapy (clopidogrel without initial genetic testing) or a genotype-guided therapy (clopidogrel vs. a potent P2Y12 inhibitor, ticagrelor or prasugrel, according to the CYP2C19 status). The aim of the TAILOR-PCI trial was to examine whether a clinical decision strategy relying on CYP2C19 genotyping to guide an antiplatelet drug was safe and effective in the post-PCI setting. At 12-month follow-up, among CYP2C19 LOF carriers, genotype-guided selection of an oral P2Y12 inhibitor resulted in no statistically significant reduction in the primary end point of cardiovascular events compared with conventional clopidogrel-based therapy of no point-of-care genotyping.6
Recently, an aggregate data meta-analysis has been conducted to summarize available evidence on guided antiplatelet therapy (with platelet function testing or genetic testing) versus standard therapy in patients undergoing PCI.7 Overall, 11 randomized controlled trials and 3 observational studies were included, composing a study population of 20,743 participants. In this comprehensive meta-analysis, guided selection of antiplatelet therapy was able to improve composite and individual clinical outcomes with a favorable safety profile compared with standard treatment strategies.7 In this context, the effect of CYP2C19 gene polymorphisms in patients with coronary artery disease undergoing stent implantation and subsequent DAPT remains relevant and worthy of investigation.
In this issue of the Journal of Cardiovascular Pharmacology, Zhang et al10 present the results of a retrospective single-center study, whose aim was to investigate the association between CYP2C19 gene polymorphisms and the risk of future cardiovascular events early and remotely after PCI during DAPT with clopidogrel. The study included 1341 patients who were recruited in the Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, between October 2015 and January 2017. According to the CYP2C19 genotype, patients were categorized as (1) non–loss-of-function metabolizers, (2) intermediate metabolizers, and (3) poor metabolizers, and the 3 study groups were compared for the 1-year occurrence of primary end point events (all-cause mortality, myocardial infarction, ischemic stroke, or stent thrombosis). From a total of 1341 participants, 161 patients (12.0%) presented with 2 LOF alleles and qualified as poor metabolizers, 621 (46.3%) had 1 LOF allele and qualified as intermediate metabolizers, and 559 (41.7%) had no LOF allele and qualified as non–loss-of-function metabolizers. At 90 days from index PCI, after adjusting for potential confounders, the risk of ischemic events was approximately 3-fold higher in poor metabolizers compared with non–loss-of-function metabolizers (adjusted hazard ratio: 2.94; P value = 0.020). These findings remained consistent when patients presenting with acute coronary syndrome were appraised separately (adjusted hazard ratio: 3.04; P value = 0.015). Of note, these differences in risks were not detected at landmark analysis considering events from 90 days to 1 year after the intervention. With respect to safety end points, no differences were observed among groups in bleeding complications during 1-year follow-up.10
The authors should be congratulated for reporting these interesting data from a large and well-conducted study, which adds to previous evidence that the risk of adverse events on clopidogrel among poor drug metabolizers might be higher early after PCI (ie, within 90 days) but not afterward (from 90 days to 1 year). Furthermore, this effect seemed consistent in the high-risk subgroup of patients presenting with acute coronary syndrome.10
For a proper interpretation of the study results, several considerations have to be made. First, carrying the LOF alleles does not necessarily indicate insufficient platelet inhibition on clopidogrel. The benefits and risks of DAPT depend on the intensity and duration of the treatment but also on patients' clinical status and risk profile.2,3 Second, recent advancements in procedural techniques and device technology have reduced the need for intensive antithrombotic strategies after PCI, particularly remotely after the intervention (ie, beyond the first 90 days).4,11,12 Third, although CYP2C19 polymorphisms have a crucial role in clopidogrel metabolism, other factors (ie, drug absorption, patient comorbidities, and treatment adherence) can affect the response to the drug and the occurrence of cardiovascular events after stent implantation.6,7
Evidence from the study by Zhang et al remarks on the importance of precision medicine in cardiology. The future of antithrombotic therapy is pointing toward personalized approaches, and genotype-guided strategies should be part of this scenario. In this regard, the true question remains “how much” the contemporary management of patients undergoing the implantation of a coronary stent should rely on these strategies. More studies are desirable to elucidate the intriguing topic of personalized antiplatelet therapy in patients with coronary artery disease and leave behind the still practiced one-size-fits-all approach in targeting atherothrombosis.
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