Impact of Implementing CYP2C19 Genotype-Guided Antiplatelet Therapy on P2Y12 Inhibitor Selection and Clinical Outcomes in Acute Coronary Syndrome Patients After Percutaneous Coronary Intervention: A Real-World Study in China

Abstract

Background: CYP2C19 loss-of-function (LOF) alleles reduce the effectiveness of clopidogrel in patients undergoing percutaneous coronary intervention for acute coronary syndrome. However, the clinical impact of implementing CYP2C19 gene-guided pharmacotherapy is unclear, especially among the Chinese population. The purpose of this study was to evaluate P2Y12 receptor inhibitor selection and clinical outcomes upon implementation of CYP2C19 genotype-guided pharmacotherapy in current clinical practice.Methods: This was a single-center observational cohort study. Adult percutaneous coronary intervention patients who received CYP2C19 genetic testing (*2, *3, *17 alleles) were included. Ticagrelor was recommended for patients with a LOF allele. Factors related to P2Y12 inhibitor selection were determined by logistic regression. The primary endpoint was major cardiac or cerebrovascular adverse events (MACCE) within 12 months. MACCE and clinically significant bleeding events (BARC ≥2) in the LOF-clopidogrel group, non-LOF-clopidogrel group, and non-LOF-ticagrelor group were compared with those in the LOF-ticagrelor group. The inverse probability of treatment weighting (IPTW) was adjusted in a Cox regression analysis to eliminate confounding factors.Results: Among 1,361 patients, 826 (60.7%) had a LOF allele. Patients with a LOF allele were more likely to be prescribed ticagrelor (multivariate-adjusted OR 1.349; 95% CI 1.040 to 1.751; p = 0.024). The MACCE rate was higher in the LOF-clopidogrel group than in the LOF-ticagrelor group (7.8 vs. 4.0%; log-rank p = 0.029; IPTW-adjusted HR 2.138; 95% CI 1.300–3.515). Compared with the LOF-ticagrelor group, the non-LOF-clopidogrel group showed no significant difference in MACCE rate (5.8 vs. 4.0%; log-rank p = 0.272; IPTW-adjusted HR 1.531; 95% CI 0.864–2.714). Among the patients treated with ticagrelor, there was no significant difference in the MACCE rate between the LOF group and non-LOF group (4.3 vs. 4.0%; log-rank p = 0.846; IPTW-adjusted HR 1.184; 95% CI 0.582–2.410). There was no significant difference in the incidence of clinically significant bleeding events among the four groups.Conclusion: This study confirms that efficiently returned CYP2C19 genotype results did partially guide cardiologists to prescribe ticagrelor for patients with a LOF allele, and that clopidogrel had a higher risk of MACCE than ticagrelor in these patients, which provides support for the implementation of CYP2C19 gene-guided antiplatelet therapy in clinical practice.

Clinical Outcomes after Percutaneous Coronary Intervention Over Time on the Basis of CYP2C19 Polymorphisms: Evidence from a Chinese Cohort

“…This implies that the superiority of new-generation drugs compared with clopidogrel might partially be explained by eliminating the interindividual variability of pharmacodynamic effects. On the other hand, in keeping with our conclusions, several studies have shown that patients who received clopidogrel had similar rates of bleeding events, irrespective of CYP2C19 genotypes [20,28]. In contrast, in a retrospective study focusing on patients with two LOF alleles, the risk of bleeding events was signi cantly higher in the ticagrelor group than in the clopidogrel group [39].…”

“…Patients were classi ed by predicted metabolic phenotype based on these genotype results. According to published scienti c information at the time of the study, the metabolic phenotypes of CYP2C19 were categorized into non-loss-of-function metabolizers (NLOFMs, including UM: ultrarapid metabolizer, *17/*17; RM: rapid metabolizer, *1/*17; NMs: normal metabolizer, *1/*1), intermediate metabolizers (IMs, *1/*2, *1/*3, *2/*17, or *3/*17) and poor metabolizers (PMs, *2/*2, *2/*3, or *3/*3) [20,21].…”

Clopidogrel versus Ticagrelor in CYP2C19 Loss-of-Function Allele Noncarriers: A Real-World Study in China

“…Lee et al's study 25 (involving 462 clopidogrel-treated patients and 143 ticagrelor-treated patients) and our previous study 12 (involving 397 clopidogrel-treated patients and 138 ticagrelor-treated patients). However, these studies, which were based on real-world data, were not sufficiently powered due to limited participants.…”

“…This study was a retrospective analysis of data from the PHARM-ACS registry (NCT04184583). 12 In PHARM-ACS, patients were recruited consecutively from April 2018 to December 2021 if they were diagnosed with ST-segment elevation myocardial infarction (STEMI), non-STEMI, or unstable angina, and were successfully indexed for PCI at Beijing Anzhen Hospital. Medical data, including baseline and follow-up data, were recorded in an electronic data capture system (EDCs) and were regularly monitored for data quality by specialized staff.…”

“…The processes of detection were published previously. 12 According to the Clinical Pharmacogenetics Implementation Consortium, 13 patients without CYP2C19 à 2 and à 3 alleles were defined as CYP2C19 LOF noncarriers.…”