Differential Impact of Clinical and Genetic Factors on High Platelet Reactivity in Patients with Coronary Artery Disease Treated with Clopidogrel and Prasugrel

Abstract

High platelet reactivity (HPR) is associated with increased risks of thrombotic events in patients with coronary artery disease. The recently developed ABCD-GENE score identified five clinical and genetic factors (age, body mass index, chronic kidney disease, diabetes, and the CYP2C19 loss-of-function allele) for HPR, although the significance of various stages of each factor is unclear.Methods: Four prospective studies were pooled, in which platelet reactivity was measured using the VerifyNow assay with clopidogrel and prasugrel; genotyping of CYP2C19 was also performed. Each component of the ABCD-GENE score was divided into three subcategories. VerifyNow P2Y12 reactivity units 208 were defined as HPR.Results: A total of 184 patients were included, of which 111 (60%) and 51 (28%) had HPR with clopidogrel and prasugrel. Chronic kidney disease had an impact on HPR on both clopidogrel and prasugrel, whereas the impact of diabetes was more evident in patients treated with prasugrel. Although the number of CYP2C19 lossof-function alleles was clearly associated with a likelihood of HPR with clopidogrel, P2Y12 reactivity units with prasugrel treatment were also significantly and progressively higher in patients with more CYP2C19 loss-offunction alleles.Conclusions: Clinical and genetic factors had a differential effect on a P2Y12 inhibitor reactivity with clopidogrel and prasugrel in patients with coronary artery disease. The severity of the factors also had a different impact on HPR.consisting of aspirin and a P2Y12 inhibitor, is the cornerstone of the antithrombotic regimen in patients undergoing PCI 2) . Currently, P2Y12 inhibitors of choice include clopidogrel, prasugrel, and ticagrelor 3) . Although clopidogrel is widely used in PCI, prasugrel and ticagrelor are the guideline-recommended P2Y12 inhibitors as a part of DAPT because of their potency Copyright©2021 Japan Atherosclerosis Society This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.

Derivation of a Novel Scoring System Predicting High Platelet Reactivity on Prasugrel in Patients with Coronary Artery Disease

“…In terms of genetics, although it has been believed that CYP2C19 variants do not affect inhibition of platelet aggregation in patients treated with prasugrel rather than clopidogrel 26) , some studies alluded that CYP2C19 genotypes may be associated with platelet inhibition even on prasugrel 27) . The present and our previous studies provide new data to this literature that CYP2C19 LOF alleles contributed to a higher likelihood of HPR on prasugrel, but the magnitude of genetic variant was smaller in prasugrel compared with that in clopidogrel 14) . Indeed, the addition of genetic factors into a model improved its diagnostic ability.…”

“…CKD is another well-known factor for HPR on clopidogrel, but among the patients with CKD, hemodialysis may have a different impact on P2Y12 inhibitor resistance. According to our previous report, clopidogrel reactivity was impacted by stage 3 CKD, whereas prasugrel was not 14) . However, even on prasugrel, hemodialysis was significantly associated with an increased risk of HPR.…”

“…We have conducted four prospective studies to investigate the effect of P2Y12 inhibitors (clopidogrel and prasugrel) in patients undergoing PCI at Chiba University Hospital (Supplementary Table 1) [9][10][11][12] . Individual patient data were pooled to create the dataset with which we previously validated the ABCD-GENE score in East Asian populations and evaluated the impact of severity of each factor of ABCD-GENE score on HPR on clopidogrel 13,14) . In this present analysis, factors associated with HPR on prasugrel were investigated to develop a novel scoring system.…”

“…In this present analysis, factors associated with HPR on prasugrel were investigated to develop a novel scoring system. Study details are described in previous reports 13,14) . In brief, all patients received aspirin (100 mg daily) as a part of DAPT, and there was no oral anticoagulant.…”

“…Patients were divided into extensive ( ＊ 1/ ＊ 1), intermediate ( ＊ 1/ ＊ 2 or ＊ 1/ ＊ 3), and poor ( ＊ 2/ ＊ 2, ＊ 2/ ＊ 3 or ＊ 3/ ＊ 3) metabolizer groups. The number of CYP2C19 LOS alleles was counted as 0, 1, and 2 in extensive, intermediate, and poor metabolizer, respectively 13,14) .…”