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Regular Article
Chronic kidney disease status modifies the association of CYP2C19polymorphism in predicting clinical outcomes following coronarystent implantation
Noriaki Tabata a, Seiji Hokimoto a,⁎, Tomonori Akasaka a, Yuichiro Arima a, Koichi Kaikita a, Naoki Kumagae b,Kazunori Morita b, Hiroko Miyazaki b, Kentaro Oniki b, Kazuko Nakagawa b, Kunihiko Matsui a, Hisao Ogawa a
a Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japanb Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto City, Japan
Introduction: There is some controversy regarding the effect of CYP2C19 polymorphism on clinical outcome in pa-tientswith dual antiplatelet therapy. Chronic kidney disease (CKD) is associatedwith increased risk of cardiovascu-lar event, but the association between the possession of CYP2C19 loss-of-function (LOF) alleles and clinical outcomeaccording to the presence of CKD is poorly understood. The aim of this studywas to investigatewhether CKD statusmodifies the association of CYP2C19 polymorphism in predicting outcomes in a prospective cohort study.Material and Methods:We enrolled 331 patients following coronary stent implantation. Patients were divided intotwo groups: CKD (n= 154) and non-CKD (n= 177). Platelet reactivity and CYP2C19 polymorphism were exam-ined. The subjectswere further divided into two groups according to the possession of CYP2C19 LOF alleles: carriersand non-carriers. Patients were followed up and clinical eventswere evaluated according to CKD and carrier status.Results: The proportion of high platelet reactivity was significantly higher in carriers than in non-carriers in bothCKD (42.4% versus 21.7%; P = 0.016) and non-CKD groups (34.3% versus 3.7%; P b 0.001). In the non-CKD group
alone, the incidence of cardiovascular events was significantly higher in carriers than in non-carriers (13.7% versus1.7%; P= 0.013). Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular events incarriers than in non-carriers in the non-CKD group (log-rank test: P = 0.013) and there was no significantdifference in the CKD group (log-rank test: P = 0.591). Multivariate analysis identified carriers as an independentpredictor of cardiovascular events only in the non-CKD group alone (hazard ratio: 8.048; 95% confidence interval:1.066 to 60.757; P= 0.043).Conclusions: CYP2C19 polymorphism significantly correlates with clinical outcome in non-CKD patients, and CKDstatus modifies the association of CYP2C19 polymorphism in predicting clinical outcomes following coronarystent implantation.
Dual antiplatelet therapy (DAPT) is currently recommended for theprevention of adverse cardiovascular events in patients undergoingpercutaneous coronary intervention (PCI) [1–3]. Clopidogrel is themainstay drug for DAPT; however, in some patients, an adequate anti-platelet effect is not achieved, and atherothrombotic events includingstent thrombosis are not completely prevented during DAPT includinglow-dose aspirin and clopidogrel [4,5]. The antiplatelet efficacy ofclopidogrel varies widely and high on-clopidogrel platelet reactivity isconsidered an independent risk factor for cardiovascular events in
arMedicine, Graduate School ofChuo-ku, Kumamoto City 860-6.moto).
onic kidney disease status mo(2014), http://dx.doi.org/10.
patients treated with stent implantation [6–8]. Thus, more intenseantiplatelet agents, such as prasugrel, ticagrelor and GPIIbIIIa inhibitor,have been developed and used in Western countries, although theyremain uncommon in Japan.
The mechanisms leading to high residual platelet reactivity areassociated with several demographic and clinical characteristics, suchas age, renal failure, obesity, diabetes mellitus, high plasma fibrinogen,genetic polymorphism and lack of adherence [9–12]. Of the genetic fac-tors, cytochrome P450 (CYP) polymorphism correlates with diminishedantiplatelet efficacy of clopidogrel and high risk for adverse cardiovas-cular events following stent implantation [8–10,13,14]. The incidenceof the CYP2C19 loss-of-function (LOF) genotype is higher in theJapanese population than in Caucasians [15], and we have demonstrat-ed the association of CYP2C19 genotypewithhigh residual platelet reac-tivity and increased risk of cardiovascular events in Japanese coronaryartery disease patients treated with stent placement [8,16]. Chronic
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kidney disease (CKD) is thought to be associated with cardiovascularevents, increased platelet activation and reduced platelet inhibition byDAPT [17]. At present, the association of the possession of CYP2C19LOF alleles with clinical outcome according to the presence of CKD ispoorly understood. Given that residual platelet reactivity and clinicaloutcome depend on the presence of CYP2C19 LOF alleles and CKD, it isimportant to determine the effect of CYP2C19 LOF alleles on clinicaloutcome according to the presence or absence of CKD. The aim of thepresent study was thus to investigate whether CKD status modifiesthe association of CYP2C19 polymorphism in predicting outcomes inJapanese patients undergoing coronary stent implantation.
Material and Methods
Study population
A total of 556 consecutive patients who underwent PCI from January2009 to November 2012 in our hospital were eligible for this study. Weexcluded patients who admitted for acute coronary syndrome, andpatients who had been treated with steroids, thrombolytic agents,sarpogrelate or cilostazol, andpatientswithdeepvein thrombosis, arterialfibrillation, collagen disease, liver dysfunction and malignant diseases.Thus, a total of 331 patients were enrolled in this study. CKDwas definedas estimated glomerular filtration rate (eGFR) b60 mL/min/1.73 m [2],and patients were divided into two groups: CKD (n = 154) and non-CKD (n = 177). All patients underwent cardiac catheterization and PCIduring hospitalization, and they received DAPT with maintenance dosesof 100 mg/day aspirin and 75 mg/day clopidogrel after a loading doseof 300 mg of clopidogrel. This is a prospective single-center study, witha mean follow-up of 890 days. The study protocol was approved by theethics committee of the institution and written informed consent wasobtained from each patient or their family.
Hypertension was defined as blood pressure of 140/90 mmHg orhigher, or the use of antihypertensive agents, and dyslipidemiaas low-density lipoprotein N140 mg/dl, high-density lipoproteinb40 mg/dl, or triglyceride N150 mg/dl. Diabetes was defined as a resulton the 2-hour glucose tolerance test of at least 200 mg/dl, a fastingglucose level of ≥126 mg/dl (≥7.0 mmol/l), HbA1c ≥6.5%, physician-diagnosed diabetes and/or use of diabetic medication.
Genotyping
Genomic DNA was extracted from whole blood using the DNA Ex-tractor WB kit (Wako Pure Chemical Industries, Ltd., Osaka, Japan)using themodified protocol described by Richards et al. [18] Polymerasechain reaction (PCR) restriction fragment length polymorphism (RELP)for CYP2C19*2 (681G N A) and CYP2C19*3 (636G N A)was performed asdescribed previously [19,20]. CYP2C19*2 and *3 are considered toaccount for N99% of alleles generating the null-activity enzyme proteinin the Japanese population [19]. Therefore, the subjects were dividedaccording to the CYP2C19 genotypes into two groups: carriers with atleast one CYP2C19 LOF allele (*1/*2, *1/*3, *2/*2, *3/*3 or *2/*3) andnon-carriers (*1/*1).
Measurement of platelet reactivity
Platelet reactivity was measured the day after clopidogrel loadingand administration of the maintenance dose for elective PCI. GPIIbIIIainhibitor, prasugrel, and ticagrelor were not available under theJapanese health care system. As reported previously [8], aggregation inplatelet-rich plasma induced by 20 μmol/L adenosine diphosphate(ADP; Chrono-Log) platelet reactivity wasmeasured using a light trans-mission aggregometer (MCM HEMA TRACER 313; PAM12C, LMS Inc.,Japan). Residual platelet reactivity was defined as the area under theplatelet aggregation curve, which was used to express the aggregationresponse over the measured time (aggregation units*min; AU*min).
Please cite this article as: Tabata N, et al, Chronic kidney disease status mooutcomes following coronary ..., Thromb Res (2014), http://dx.doi.org/10.
The area under the aggregation curve (AU*min) is probablymore sensi-tive and precise than maximal platelet aggregation calculated from thepercentage of inhibition [8,21]. Moreover, we previously reported asignificant positive correlation between residual platelet aggregationmeasured by 20 μmol/L ADP-induced platelet reactivity maximum ag-gregation and 20 μmol/L ADP-induced platelet reactivity area. [22]Thus, we used the area under the aggregation curve as a measure ofon-treatment platelet reactivity during antiplatelet therapy.Wedefinedhigh platelet reactivity as above 5000 AU*min. The threshold for highplatelet reactivity at this study was different from previous studies[23]. The incidence of cardiovascular events after acute coronary syn-drome or PCI is lower in Japanese patients compared with Caucasians,so it is difficult to determine the cut-off value of high platelet reactivityfor cardiovascular events following coronary stent implantation. In ourprevious study [22], Japanese cut-off levels of platelet reactivity byVerifyNow P2Y system that allowed discrimination of carriers of atleast one CYP2C19 loss-of-function allele from non-carriers were rela-tively higher than previous studies in Western countries (cut-offP2Y12 reaction units levels of 256 versus 230-240), and in our anotherstudy, CYP2C19 poor metabolizer platelet reactivity was 5088 ±1080 AU*min by light transmission aggregometer [8]. Based on thisbackground, we defined high platelet reactivity as above 5000 AU*minin this study.
Clinical outcomes
The endpoint was a composite of cardiovascular death, nonfatalmyocardial infarction, stroke, unstable angina, revascularization orintra-procedural thrombotic events (IPTE). Patients were followed upevery month after discharge in the outpatient department and we per-formed follow-up angiography at 6 to 9 months after the procedure.Then, the patients were followed every 6 months after the re-studyand contacted by phone (or their families were contacted) in theabsence of hospital visits. Cardiovascular death was defined as deathdue to myocardial infarction, congestive heart failure or documentedsudden cardiac death. We used the universal definition of myocardialinfarction in this study [24]. The diagnosis of stroke was based on clini-cal and radiological evidence of stroke. Revascularization therapy basedonly on angiographic data, including PCI-mediated restenosis, was notcounted as a cardiovascular event. Revascularization was defined as re-vascularization therapy for ischemic heart disease due to new lesions.An IPTEwasdefined as the development of newor increasing thrombus,abrupt vessel closure, no reflow or slow reflow, or distal embolizationoccurring at any time during the procedure [25,26]. For subjectsexperiencing more than two acute events, only the first event wasconsidered in the analysis.
Statistical analysis
Continuous variables are expressed as mean ± SD, and werecompared using unpaired t-test or Mann-Whitney, as appropriate.Categorical variables are expressed as numbers or percentages, andwere compared using chi-square test or Fisher’s exact test. The cumula-tive event-free probability was analyzed from the time of stent implan-tation to the first event according to the Kaplan-Meier method, andbetween-group differenceswere evaluated by the log-rank test. Univar-iate analysis was performed using clinical variables that are consideredto be associatedwith cardiovascular events (CYP2C19 LOF carrier status,sex, age, hypertension, dyslipidemia, diabetes, current smoking, leftventricular ejection fraction, high platelet reactivity, previousmyocardi-al infarction, previous stroke, peripheral artery disease and usage of onlydrug-eluting stent). Factors with a P value b1.0 were subsequentlyentered into multivariate analysis. Cox proportional hazard modelswere used to calculate hazard ratios (HRs) and to test for the interactionbetween CKD and the possession of CYP2C19 LOF alleles. The results ofthis analysis are expressed as HRs for comparison of risk with 95%
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confidence intervals (CI). A P value b0.05 was considered to denote thepresence of a statistically significant difference. SPSS version 22 soft-ware (IBM Institute Inc., USA) was used for all statistical analyses.
Results
Patient characteristics
Table 1 lists the clinical characteristics of CKD (n=154,male 70%) andnon-CKD groups (n = 177, male 74%). The mean eGFRs in CKD andnon-CKD groups were 41.9 ± 16.7 and 76.3 ± 13.2 mL/min/1.73 m [2],respectively (p b 0.01). CYP2C19 LOF genotypes distribution of *1/*1,*1/*2, *2/*2, *2/*3, *3/*3, and *1/*3, were 34.8%, 34.8%, 11.2%, 7.3%, 1.7%,and 9.6%, in the CKD group, and 33.1%, 33.1%, 12.3%, 5.8%, 1.3%, and14.3%, in the non-CKD group, respectively. Both groups were consistentwith Hardy Weinberg Equilibrium (P = 0.5493 and P = 0.6135, respec-tively). There was no significant difference in the proportion of carriersbetween the CKD and non-CKD groups, and no significant difference inclinical characteristics between carriers and non-carriers in both CKDandnon-CKDgroups. The proportion of highplatelet reactivitywas signif-icantly higher in the CKD group than in the non-CKD group (35.9% versus23.9%; P = 0.025), and was significantly higher in carriers than in non-carriers in both CKD (42.4% versus 21.7%; P = 0.016) and non-CKDgroups (34.3% versus 3.7%; P b 0.001).
Table 2Cardiovascular events encountered in the CKD and non-CKD groups according to carrier state.
Please cite this article as: Tabata N, et al, Chronic kidney disease status mooutcomes following coronary ..., Thromb Res (2014), http://dx.doi.org/10.
Incidence of cardiovascular events according to possession of CYP2C19 LOFalleles
A total of 40 patients suffered a cardiovascular event (Table 2). Therewas no significant difference in the clinical outcomes between CKD andnon-CKD groups (14.9% versus 10.1%; P = 0.241). The incidence ofcardiovascular events did not differ between carriers and non-carriersin the CKD group (15.5% versus 13.7%; P = 1.0). In contrast, a signifi-cantly higher ratio of cardiovascular events was noted in carriers thanin non-carriers in the non-CKD group (13.7% versus 1.7%, P = 0.013).Kaplan-Meier analysis demonstrated a significantly higher probabilityof cardiovascular events in carriers than in non-carriers in the non-CKD group (log-rank test: P = 0.013) and there was no significantdifference in the CKD group (log-rank test: P = 0.591) (Fig. 1).
Predictors of cardiovascular events
Univariate and multivariate Cox proportional hazard regressionanalyses for cardiovascular events were performed (Table 3). In theCKD group, ejection fraction of the left ventricle (HR: 0.959; 95%CI: 0.928 to 0.992; P= 0.014) was the only significant predictive factorin multivariate analysis. On the other hand, in the non-CKD group,multivariate analysis identified the possession of a CYP2C19 LOF allele(HR: 8.048; 95% CI: 1.066 to 60.757; P = 0.043) as an independent
Fig. 1.Kaplan-Meier curves for primary composite end points during the follow-up periodin CKD (A) and non-CKD groups (B). There was no difference in clinical outcome betweenCKD carriers and non-carriers of the CYP2C19 loss-of-function allele (log-rank P= 0.591).The incidence of cardiovascular events was higher in carriers than in non-carriers in thenon-CKD group (log-rank P = 0.013). Abbreviation: CKD, chronic kidney disease.
Table 3Predictors of outcome by Cox proportional hazard model for the CKD and non-CKD groups.
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Please cite this article as: Tabata N, et al, Chronic kidney disease status mooutcomes following coronary ..., Thromb Res (2014), http://dx.doi.org/10.
and significant predictor of cardiovascular events. The P value of the in-teraction between CKDand possession of a CYP2C19 LOF allelewas 0.09.
Discussion
This is the first study designed to clarify whether CKD statusmodifies the effects of CYP2C19 polymorphism on clinical outcome inpatients following coronary stent implantation. The findings of thepresent study are as follows: (1) Platelet reactivity was significantlyhigher in CKDpatients than in non-CKDpatients. (2) Carriers had signif-icantly higher platelet reactivity in both CKD and non-CKD patients.(3) There was no difference in the incidence of cardiovascular eventsbetween carriers and non-carriers in the CKD group and possession ofa CYP2C19 LOF allele was not an independent determinant of prognosisin stent-implanted CKD patients. On the other hand, in the non-CKDgroup, possession of a CYP2C19 LOF allelewas an independent predictorof cardiovascular events in patients treated with stent implantation. Inshort, the association of the possession of a CYP2C19 LOF allele withclinical outcome varies according to the presence of CKD.
It has been reported that the possession of a CYP2C19 LOF allele cor-relates with clinical outcome in patients undergoing PCI and DAPT [27].However, there is still some controversy regarding the effects of aCYP2C19 LOF allele on clinical outcome in patients with DAPT [28].Asians have a different genetic background from Caucasians [15], andthey exhibit different rates of cardiovascular events [29]. Taking thisinto account, we had clarified that possession of CYP2C19 LOF is associ-ated with adverse clinical events in Japanese patients, but evidence forthe association between CYP2C19 polymorphism and clinical outcomein patients with or without CKD was still insufficient. Against thisbackground, our study demonstrated that, without the factor of CKD,possession of a CYP2C19 LOF allele is an important and independent de-terminant of clinical outcome in patients undergoing PCI and DAPT.However, this study was performed in a single center, and comparedwith previous studies in Western countries, the number of patientswas small, so our study resulted in the HR with the larger interval of95% CI, which might make our findings less convincing. Further studieswith a large number of patients are needed in the future.
Because there are limited reports on this issue, it is unclear why thepossession of a CYP2C19 variant was associated with increased risk ofcardiovascular events in the non-CKD group, but not in the CKDgroup, in the present study. The presence of CKD is reported to be oneof the predictive factors of clinical outcome in patients with stentimplantation [30]; moreover, clinical studies have suggested that CKDitself contributes to high residual PR [17]. Thus, it is possible that thecontribution of CKD to adverse cardiovascular events may be consider-able and might outweigh the influence and impact of the CYP2C19genotype in CKD patients.
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It might seem a little strange that there were no significant differ-ences in the prevalence of adverse clinical events between the CKDand non-CKD groups in this study because it has been reported thatCKD increases the risk of cardiovascular diseases in patients takingclopidogrel after PCI [31,32]. In the present study, we defined CKD aseGFR b60 mL/min/1.73m [2], so patientswith relativelymild tomoder-ate CKD might also have been enrolled in the CKD group. Moreover,in our data, the prevalence of events was low in both groups, and revas-cularization therapy based only on angiographic data includingPCI-mediated restenosis was not counted as a cardiovascular event.These factorsmight have influenced our results. Further study is neededin the future to clarify our findings.
Conclusions
CYP2C19 polymorphism significantly correlates with clinicaloutcome in non-CKD patients, and CKD status modifies the associationof CYP2C19 polymorphism in predicting clinical outcomes followingcoronary stent implantation.
Limitations
One limitation of this study is that it was performed in a singlecenter. Compared with previous Western studies, the number ofpatients was also small, and the study may have been underpoweredto detect a difference in the clinical event rate. In addition, platelet reac-tivity was measured during hospitalization, but no data were availableregarding platelet reactivity at the time of occurrence of cardiovascularevents. In the present study, the level of platelet reactivity was notcalculated from the values of changes between before and after the ad-ministration of clopidogrel; therefore, we do not know if the underlyingplatelet hyperreactivity per se accounts for higher on-clopidogrel plate-let reactivity. We did not measure plasma concentrations of the activemetabolite of clopidogrel; thus, we cannot provide direct evidence ofthe reduced antiplatelet efficacy of clopidogrel in patients carrying atleast one CYP2C19 LOF allele. In addition, we cannot exclude the effectof other drug metabolism enzymes, such as CYP1A2, 2B6, 3A and 2C9,on clopidogrel response, in addition to CYP2C19. Further studies thatdeal with the above issues are thus needed.
Funding sources
This work was supported in part by Grants-in-Aid for ScientificResearch from the Ministry of Education, Culture, Sports, Science andTechnology, Japan.
Disclosures
None of the authors received any fees, honoraria, grants or consul-tancies that would constitute a conflict of interest with this study.
Acknowledgements
We wish to thank the medical technologist S. Iwashita, KumamotoUniversity Hospital, for measurement of platelet reactivity, and themedical secretaries A. Miyazaki, K. Watanabe, H. Koga and Y. Maeda,Kumamoto University, for collecting data.
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