Routine Assessment of On-Clopidogrel Platelet Reactivity and Gene Polymorphisms in Predicting Clinical Outcome Following Drug-Eluting Stent Implantation in Patients With Stable Coronary Artery Disease

Anselmi, Chiara; Briguori, Carlo; Roncarati, Roberta; Papa, Laura; Visconti, Gabriella; Focaccio, Amelia; Micco, Francesca De; Latronico, Michael V.G.; Pagnotta, Paolo; Condorelli, Gianluigi

doi:10.1016/j.jcin.2013.06.010

Cited by 51 publications

(41 citation statements)

References 45 publications

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“…We also specifically analyzed the relationship between genetic polymorphisms with HTPR and MACEs, but could not demonstrate any association between the two. Our results are in disagreement with those reported by Viviani Anselmi, et al 39) which suggested that polymorphisms in the CYP2C19 gene were an independent predictor of MACEs after drug eluting stent (DES) implantation and can be used as a prognostic tool to determine the stability of CAD patients. Several possible reasons could explain the lack of association between HTPR and MACEs in our study.…”

Section: Discussioncontrasting

confidence: 99%

Genotype Frequencies of CYP2C19, P2Y<sub>12</sub> and GPIIIa Polymorphisms in Coronary Heart Disease Patients of Han Ethnicity, and Their Impact on Clopidogrel Responsiveness

et al. 2016

Int. Heart J.

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Section: Discussioncontrasting

confidence: 99%

Genotype Frequencies of CYP2C19, P2Y<sub>12</sub> and GPIIIa Polymorphisms in Coronary Heart Disease Patients of Han Ethnicity, and Their Impact on Clopidogrel Responsiveness

et al. 2016

Int. Heart J.

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“…Therefore, nearly half of patients with acute coronary syndromes who underwent percutaneous intervention are genotype carriers associated with increased risk of MACE while on standard doses of clopidogrel [20]. In short, there is a mutual agreement that genetic biomarkers may serve as an independent predictor of MACE after stenting in patients treated with clopidogrel [7][8][9][10].…”

Section: Discussionmentioning

confidence: 99%

“…Several mechanisms have been implicated to be responsible for interindividual differences such as drug absorption and variability in drug metabolism, and genetic polymorphisms (GP) of the P2Y12 receptor have been reported to increase ADP-induced platelet reactivity [4][5][6]. Since thienopyridines are metabolized by liver enzymes, there is a potential link between CYP2C19 GP and variability of antiplatelet potency in certain carriers [7][8][9][10]. However, while conventional clopidogrel is always a "prime suspect" of such shortcoming [11][12][13], prasugrel is mostly overprotected, claiming superiority or at least lack of impact due to fewer metabolization steps required than older thienopyridines.…”

Section: Introductionmentioning

confidence: 99%

Impact of CYP2C19 Polymorphism on Antiplatelet Potency of Prasugrel 5 and 10 mg Daily Maintenance

Kim

Guo

et al. 2018

Cardiology

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Background: Whether genetic polymorphisms (GP) impact residual platelet aggregation (RPA) following prasugrel is unclear, especially during maintenance phase. We assessed the influence of CYP2C19 GP carriers on RPA in the prospective observational cohort study. Methods and Results: All post-stent patients (n = 206) received prasugrel 60 mg loading and either 5 or 10 mg daily maintenance with aspirin100 mg. RPA levels by light transmission aggregometry (LTA), multiplate electrode aggregometry (MEA), and VerifyNow (P2Y12 reaction units, PRU) with CYP2C19 GP were measured simultaneously. Demographics and clinical characteristics were not useful for predicting response after prasugrel. GP carriers exhibited higher RPA (PRU: p = 0.001, LTA: p = 0.001, MEA: p = 0.023) than noncarriers. CYP2C19 carriers had higher RPA for 5 mg (n = 35; LTA: p = 0.043, MEA: p = 0.023) and reached significance for 10 mg (n = 27; LTA: p = 0.001, PRU: p = 0.001) prasugrel. When divided into extensive, intermediate, and poor metabolizers, all exhibited statistical differences among the 3 groups (LTA: 14.9 ± 12.3%, 22.6 ± 14.9%, 22.9 ± 15.6%, p = 0.002; PRU: 104.1 ± 70.8%, 141.8 ± 78.0%, 151.0 ± 84.8%, p = 0.003; MEA: 19.7 ± 8.9%, 24.4 ± 12.2%, 28.1 ± 14.7%, p = 0.002). Conclusion: CYP2C19 GP impacts RPA during maintenance phase prasugrel in Korean outpatients. This effect is consistent for both of the approved prasugrel doses potentially affecting long-term outcomes including bleeding risks. However, the clinical utility of these findings is still uncertain, and requires more evidence from larger randomized trials beyond East Asians.

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“…CYP1A2, CYP2B6, CYP2C9, CYP3A4 and CYP3A5) are also necessary for active clopidogrel metabolite formation, and all of these genes have known variant alleles. Some candidate gene studies identified significant effects on clopidogrel response (pharmacodynamic or clinical outcomes) with germline variants in CYP1A2 (with possible smoking interaction) [133, 134], CYP2C9 [68, 98, 135–137], CYP3A4 [138, 139], and CYP3A5 [140, 141]; however, the majority of clinical clopidogrel pharmacogenetic studies have not confirmed a significant independent role for these other CYP450 genes [61, 71, 72, 77, 80, 93, 142–145]. …”

Section: Clopidogrel Pharmacogeneticsmentioning

confidence: 99%

The pharmacogenetic control of antiplatelet response: candidate genes andCYP2C19

Yao¹,

Lewis²,

Hulot

et al. 2015

Expert Opinion on Drug Metabolism & Toxicology

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Introduction Aspirin, clopidogrel, prasugrel and ticagrelor are antiplatelet agents for the prevention of ischemic events in patients with acute coronary syndromes (ACS), percutaneous coronary intervention (PCI), and other indications. Variability in response is observed to different degrees with these agents, which can translate to increased risks for adverse cardiovascular events. As such, potential pharmacogenetic determinants of antiplatelet pharmacokinetics, pharmacodynamics and clinical outcomes have been actively studied. Areas covered This article provides an overview of the available antiplatelet pharmacogenetics literature. Evidence supporting the significance of candidate genes and their potential influence on antiplatelet response and clinical outcomes are summarized and evaluated. Additional focus is directed at CYP2C19 and clopidogrel response, including the availability of clinical testing and genotype-directed antiplatelet therapy. Expert opinion The reported aspirin response candidate genes have not been adequately replicated and few candidate genes have thus far been implicated in prasugrel or ticagrelor response. However, abundant data supports the clinical validity of CYP2C19 and clopidogrel response variability among ACS/PCI patients. Although limited prospective trial data are available to support the utility of routine CYP2C19 testing, the increased risks for reduced clopidogrel efficacy among ACS/PCI patients that carry CYP2C19 loss-of-function alleles should be considered when genotype results are available.

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Routine Assessment of On-Clopidogrel Platelet Reactivity and Gene Polymorphisms in Predicting Clinical Outcome Following Drug-Eluting Stent Implantation in Patients With Stable Coronary Artery Disease

Cited by 51 publications

References 45 publications

Genotype Frequencies of CYP2C19, P2Y<sub>12</sub> and GPIIIa Polymorphisms in Coronary Heart Disease Patients of Han Ethnicity, and Their Impact on Clopidogrel Responsiveness

Genotype Frequencies of CYP2C19, P2Y<sub>12</sub> and GPIIIa Polymorphisms in Coronary Heart Disease Patients of Han Ethnicity, and Their Impact on Clopidogrel Responsiveness

Impact of CYP2C19 Polymorphism on Antiplatelet Potency of Prasugrel 5 and 10 mg Daily Maintenance

The pharmacogenetic control of antiplatelet response: candidate genes andCYP2C19

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