Evaluation of the incremental prognostic value of the combination of CYP2C19 poor metabolizer status and ABCB1 3435 TT polymorphism over conventional risk factors for cardiovascular events after drug-eluting stent implantation in East Asians

Abstract

Original research article INTRODUCTIONThe identification of individuals at risk of future adverse cardiovascular outcomes is important after percutaneous coronary intervention (PCI). Thus, the use of novel risk markers such as genetic polymorphisms to augment standard risk algorithms, including conventional clinical risk factors, has attracted increasing attention in recent years.Dual antiplatelet therapy with aspirin and clopidogrel is the current standard of treatment after PCI with drug-eluting stent to reduce the rate of recurrent ischemic events. 1,2 However, considerable interindividual variability exists in response to clopidogrel, and those with high on-clopidogrel platelet reactivity are at increased risk of cardiovascular events. 3,4 Several clinical, genetic, and cellular factors have been suggested as mechanisms for clopidogrel response variability. 5 One of the common causes of individual variations in drug response is genetic polymorphism associated with drug absorption and metabolism. [6][7][8] Clopidogrel is a prodrug that requires active enteric absorption and conversion into an active metabolite in the liver. 9 A key protein involved in clopidogrel absorption is the intestinal efflux transporter P-glycoprotein which is encoded by the ABCB1 gene. Purpose: We evaluated the incremental prognostic value of combining the CYP2C19 poor metabolizer (PM) and ABCB1 3435 TT for adverse clinical outcomes over conventional risk factors in a percutaneous coronary intervention (PCI) cohort. Methods:We enrolled 2,188 patients. The primary end point was a composite of death from any cause, nonfatal myocardial infarction (MI), and stroke during 1-year follow-up. The population was stratified into the following four groups: CYP2C19 EM/IM+ABCB1 3435 CC/CT, CYP2C19 EM/IM+ABCB1 3435 TT, CYP2C19 PM+ABCB1 3435 CC/CT, and CYP2C19 PM+ABCB1 3435 TT. Results:A total of 87 (3.97%) primary end-point events occurred (64 deaths, 8 non-fatal MIs and 15 strokes). Multivariate Cox analysis indicated that CYP2C19 PM+ABCB1 3435 TT status was a significant predictor of the primary end point (hazard ratio = 4.51, 95% confidence interval (CI) = 1.92-10.58). However, addition of combined genetic status to the clinical risk model did not improve the model discrimination (C-statistic = 0.786 (95% CI = 0.734-0.837) to 0.785 (95% CI = 0.733-0.838)) or risk reclassification (categorical net reclassification improvement (0.040, P = 0.32), integrated discrimination improvement (0.021, P = 0.026)). Conclusions:In a real-world East Asian PCI population taking clopidogrel, although the concurrent presence of CYP2C19 PM and ABCB1 TT is a strong independent predictor of adverse outcomes, the combined status of two at-risk variants does not have an incremental prognostic value beyond that of the conventional clinical risk factors. Genet Med

The risk of clopidogrel resistance is associated with ABCB1 polymorphisms but not promoter methylation in a Chinese Han population

“…Searching the HAPMAP, the information showed that the frequency of the C allele in rs1045642 in Chinese patients was slightly higher than that of Caucasians. A recent study from east asians was indicated that CYP2C19 PM along with ABCB1 3435 TT status was a strong independent predictor of the primary end point (deaths, non-fatal MIs and strokes)[ 34 ]. Hence, the variance of the cardinal number in patients with three genotypes resulted in the inconsistent findings compared to the former study.…”

Multiple Mutations of CYP2C19, PON1 and ABCB1 Influence Platelet Response, Bleeding and Thrombosis Risk to Clopidogrel after Percutaneous Coronary Intervention: A Retrospective Study

“…A multicomponent guiding approach to personalize clopidogrel treatment is needed [26]. Some studies focus on the combined status of two at-risk variantsin PCI patients on clopidogrel [3,8,9,20].In the prior studies, both the CYP2C19 poor matebolism status and ABCB1 3435 TT genotype wasconsidered to in uence the clopidogrel metabolization and transportationandcontinuously elicited clopidogrel response [5]. The individuals carrying both at-risk variants showed the highest event rate compared to those with other combined genetic subsets.…”

“…patients with continuous drug prescription records; (4) patients who calculated the ADP dependent Platelet aggregation rate when clopidogrel treated for at least 7 days and stayed at a stable plasma concentration.The exclusion criteria: (1) patientswho experienced the major bleeding and thrombotic events in the last 6 months before PCI; (2)Patients who received anticoagulation drugs in the last 6 months before PCI; (3) patients received CYP2C19 or ABCB1inhibitors (such as Omeprazole or Clarithromycin)during 12 months after PCI; (3) patients who stopped or adjusted the dose of clopidogrel and aspirin during dual-antiplatelet therapy; (4) patients who switched to ticagrelor or prasugrel; (5)patients with severerenal and hepatic function failure. (6)patients with large surgery during the observation period.…”

Pharmacokinetic and Pharmacodynamic Responses to Clopidogrel: Evidences and Perspectives

“…Then Simon et al found that carriers of the ABCB1 3435 TT genotype had a higher rate of cardiovascular events than CC homozygotes in patients with acute myocardial infarction (AMI) [5]. Subsequent clinical studies and meta-analysis verified the association between ABCB1 3435TT genotype and impaired platelet response as well as the higher risk of major adverse cardiovascular events [6,7]. Several trials have shown that ABCB1 3435T was associated with lower levels of plasma clopidogrel and its active metabolite [8,9,10].…”