British Journal of Clinical Pharmacology
DOI:10.1111/bcp.12794
The pharmacokinetic and pharmacodynamic interaction of clopidogrel and cilostazol in relation to CYP2C19 and CYP3A5 genotypes Ho-Sook Kim,1,2 Younghae Lim,1,2 Minkyung Oh,1,2 Jong-lyul Ghim,1,2 Eun-Young Kim,1,2 Dong-Hyun Kim1,2 & Jae-Gook Shin1,2 1
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine
and 2Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, South Korea
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • CYP2C19 loss-of-function alleles produce less clopidogrel active metabolite, causing less platelet aggregation inhibition, but more cilostazol active metabolite, leading to enhanced antiplatelet effects. • Cilostazol is a possible inhibitor of CYP3A enzymes that contribute to the formation of clopidogrel active metabolite. • There is a possibility of a clopidogrel– cilostazol drug interaction.
Correspondence Professor Jae-Gook Shin MD, PhD, Department of Pharmacology and Clinical Pharmacology, Inje University College of Medicine and Busan Paik Hospital, 633-165 Gaegum-dong, Jin-gu, Busan 614-735, South Korea. Tel.: +82 51 890 6709 Fax: +82 51 893 1232 E-mail:
[email protected] ----------------------------------------------------
Keywords cilostazol, clopidogrel, CYP2C19, CYP3A5, drug–drug interaction, pharmacogenomics ----------------------------------------------------
Received 27 February 2015
Accepted 27 September 2015
Accepted Article Published Online 1 October 2015
AIM The primary objective of the present study was to evaluate the pharmacokinetic and pharmacodynamic interactions between clopidogrel and cilostazol in relation to the CYP2C19 and CYP3A5 genotypes.
METHODS In a randomized, three-way crossover study, 27 healthy subjects were administered clopidogrel (300 mg), cilostazol (100 mg) or clopidogrel + cilostazol orally. Plasma concentrations of clopidogrel, cilostazol and their active metabolites (clopidogrel thiol metabolite, 3,4-dehydrocilostazol and 4″-trans-hydroxycilostazol), and adenosine diphosphate-induced platelet aggregation were measured for pharmacokinetic and pharmacodynamic assessment.
RESULTS
WHAT THIS STUDY ADDS • Cilostazol decreased the formation of clopidogrel active metabolite in CYP3A5*1/*3 but not in CYP3A5*3/*3 subjects. The antiplatelet effects of CYP2C19 EM, IM and PM after co-administration of clopidogrel and cilostazol were similar in CYP3A5*3/*3 genotypes. • Antiplatelet therapy which includes cilostazol might overcome the clopidogrel resistance caused by CYP2C19 PM in subjects with the CYP3A5*3/*3 genotype.
The area under the plasma concentration–time curve (AUC) of the active thiol metabolite of clopidogrel was highest in the CYP2C19 extensive metabolizers (EM) and lowest in the poor metabolizers (PM). Cilostazol decreased the thiol metabolite AUC by 29% in the CYP3A5*1/*3 genotype [geometric mean ratio (GMR) 0.71; 90% confidence interval (CI) 0.58, 0.86; P = 0.020] but not in the CYP3A5*3/*3 genotype (GMR 0.93; 90% CI 0.80, 1.10; P = 0.446). Known effects of the CYP2C19 and CYP3A5 genotypes on the exposure of cilostazol and its metabolites were observed but there was no significant difference in the AUC of cilostazol and 3,4-dehydrocilostazol between cilostazol and clopidogrel + cilostazol. The inhibition of platelet aggregation from 4 h to 24 h (IPA4–24) following the administration of clopidogrel alone was highest in the CYP2C19 EM genotype and lowest in the CYP2C19 PM genotype (59.05 ± 18.95 vs. 36.74 ± 13.26, P = 0.023). However, the IPA of the CYP2C19 PM following co-administration of clopidogrel and cilostazol was comparable with that of the CYP2C19 EM and intermediate metabolizers (IM) only in CYP3A5*3/*3 subjects.
CONCLUSIONS The additive antiplatelet effect of cilostazol plus clopidogrel is maximized in subjects with both the CYP2C19 PM and CYP3A5*3/*3 genotypes because of a lack of change of clopidogrel thiol metabolite exposure in CYP3A5*3/*3 as well as the highest cilostazol IPA in CYP2C19 PM and CYP3A5*3/*3 subjects. © 2015 The British Pharmacological Society
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Introduction Dual antiplatelet therapy with aspirin and thienopyridines such as clopidogrel is the currently recommended regimen for preventing atherothrombotic events in patients following acute myocardial infarction [1]. In spite of the benefits of dual antiplatelet therapy, the risk of a thrombotic event remains an important concern [2]. Triple therapy including cilostazol, clopidogrel and aspirin has been reported to reduce long-term cardiac events after percutaneous coronary intervention (PCI), especially for patients at high risk [3]. By contrast, a single study reported that triple therapy did not show any difference in reducing cardiovascular outcome compared with dual therapy [4]. To understand these controversies, an intensive study of the interaction between clopidogrel and cilostazol, based on their pharmacokinetics and pharmacodynamics, is needed, but no such report has been published to date. Clopidogrel is a thienopyridine antiplatelet agent that inhibits the P2Y12 receptor, an adenosine diphosphate (ADP) receptor subtype. Clopidogrel is an inactive prodrug that must be biotransformed into its active thiol metabolite to exert antiplatelet effects; this is accomplished by hepatic cytochrome P450 isoenzymes such as CYP2B6, CYP2C9, CYP3A4 and CYP3A5, especially CYP2C19 [5–7]. It is well known that carriers of the CYP2C19 loss-of-function (LOF) alleles (*2 and *3 alleles) form less of the active thiol metabolite, causing a lack of platelet aggregation inhibition, which translates into a higher rate of subsequent cardiovascular events than in noncarriers [8–10]. It has been reported that cilostazol might ameliorate platelet responsiveness to clopidogrel in patients who have undergone primary PCI [11]. Furthermore, some studies have shown that the administration of cilostazol after PCI can significantly lower the incidence of in-stent restenosis [12–15]. Cilostazol is a potent inhibitor of type III phosphodiesterase and suppresses the degradation of cyclic adenosine monophosphate (cAMP), resulting in an increase in cAMP both in platelets and vascular smooth muscle cells [16–18]. Cilostazol is metabolized via CYP enzymes into two major metabolites, 3,4-dehydrocilostazol (4–7-fold increased activity compared with cilostazol) and 4″-trans-hydroxycilostazol (with one-fifth of the activity of cilostazol). 3,4-Dehydrocilostazol is produced by CYP3A4, and 4″-trans-hydroxycilostazol is produced mainly by CYP3A5 and CYP2C19 [19]. It was reported that the single oral-dose pharmacokinetics of cilostazol in healthy subjects was affected by CYP2C19 and CYP3A5 polymorphisms [20]. Several studies have reported that addition of cilostazol to the dual antiplatelet therapy of aspirin and clopidogrel might improve nonresponsiveness in patients with CYP2C19 LOF alleles who are taking clopidogrel [21, 22]. 302
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Although combination therapy with clopidogrel and cilostazol is widely used in clinical situations, especially in East Asia [23], no studies have been conducted on the pharmacokinetic and pharmacodynamic interaction between clopidogrel and cilostazol, or the relationship between genetic polymorphisms and the interaction between clopidogrel and cilostazol. To address these issues, we explored the potential pharmacokinetic and pharmacodynamic interactions between clopidogrel and cilostazol in relation to the CYP2C19 or CYP3A5 genotypes in healthy Korean subjects.
Method Study subjects Healthy Korean males, aged 20–45 years, without clinically significant abnormalities in medical history, physical examinations, ECGs or clinical laboratory measurements, were eligible for inclusion. Subjects were excluded if they had a history or evidence of hepatic, renal, gastrointestinal or haematological abnormalities, any other acute or chronic disease, any drug allergies, or if they were taking any medication that induces or inhibits drug-metabolizing enzymes. No medications, herbal medicines, alcohol, citrus juice, grapefruit juice or beverages containing caffeine were permitted for 10 days prior to the study and for the duration thereof. All subjects were advised of the risks and benefits of participation in the study and submitted written, signed and dated informed consent voluntarily prior to clinical trial participation. The study was conducted in compliance with the principles outlined in the Declaration of Helsinki, and the study protocol and all amendments were approved by the Institutional Review Board of Inje University Busan Paik Hospital (IRB approval number: 10–105).
Study design The present study had a randomized, open-label, singledose, three-treatment, three-sequence crossover design with a two-week washout period (Supplemental Figure S1). Subjects were allocated to one of three groups in a 1 : 1 : 1 ratio according to a predesigned randomization table generated using SAS software (version 9.3; SAS Institute Inc., Cary, NC, USA). Twenty-seven subjects, pregenotyped for CYP2C19 and CYP3A5, were administered a single oral dose of 100 mg cilostazol (Otsuka Pharmaceutical Co. Ltd, Tokyo, Japan) alone, 300 mg clopidogrel (Sanofi-Aventis, Paris, France) alone or 100 mg cilostazol plus 300 mg clopidogrel. The dosing of cilostazol and clopidogrel was selected based on the approved maximal single dose [24, 25]. All subjects were admitted to the clinical trial centre one day prior to drug administration. Subjects fasted
Genotype-based clopidogrel–cilostazol interaction
overnight and continued fasting until a standardized lunch was served 4 h after drug administration on day 7. Blood samples for pharmacokinetic assessments were obtained at 0, 0.33, 0.66, 1, 1.5, 2, 3, 4, 5, 12 and 24 h for clopidogrel and its active metabolite and 0, 1, 2, 3, 4, 6, 8, 12 and 24 h for cilostazol and its active metabolites. For measurement of clopidogrel and its active metabolite, 4 ml of whole blood was collected in an Ethylenediaminetetraacetic acid (EDTA) tube pretreated with 25 μl 500 mM 2-bromo-3′-methoxyacetophenone. For measurement of cilostazol and its active metabolites, 3 ml of whole blood were collected in an EDTA tube. Plasma samples were transferred immediately to eppendorf tubes and stored at 80 °C until analysis. Blood samples were also collected to measure ADP-induced platelet aggregation. The platelet aggregation tests were performed at day 1 and 0, 1, 2, 4, 6, 12 and 24 h after drug administration.
Genotyping The CYP2C19 and CYP3A5 genotypes were determined using the single-base extension method. Analytical validation for the Korean population has been previously established and published by the PharmacoGenomics Research Center (PGRC, Inje University College of Medicine, Busan, Korea) [26]. Genomic DNA was used to genotype for the presence of major Korean alleles, including CYP2C19*2 (rs4244285), CYP2C19*3 (rs4986893), CYP2C19*17 (rs12248560) and CYP3A5*3 (rs776746) using an ABI PRISM® genetic analyzer and its mounted GeneMapper® software according to the protocol of SNaPshot® Multiplex kit from Applied Biosystems (Foster City, CA, USA). No significant deviations from Hardy– Weinberg equilibrium were observed for any of the single nucleotide polymorphisms tested.
Drug analysis Plasma concentrations of clopidogrel, cilostazol and their active metabolites (3,4-dehydrocilostazol and 4″-transhydroxycilostazol) were analysed using a modified liquid chromatography–tandem mass spectrometry (LC-MS/MS) method as reported previously [27–29]. Briefly, for clopidogrel and its thiol active metabolite, plasma samples (50 μl) were precipitated by adding 100 μl acetonitrile containing the internal standard (clopidogrel-d4). After centrifugation, a 5 μl aliquot of the supernatant was injected into an Agilent 1200 series high-performance liquid chromatography (HPLC) system (Agilent, Wilmington, DE, USA) coupled to a QTRAP 5500 triple quadrupole mass spectrometer (AB Sciex, Foster City, CA, USA) equipped with electrospray ionization. Chromatographic separation of the compounds was achieved using a Luna C18 column (particle size 3 μm, 100 × 2 mm2, i.d.; Phenomenex, Torrance, CA, USA) with a mobile phase consisting of 50% acetonitrile in water containing 0.1% formic acid. The flow rate was
0.2 ml min1 and the retention times for clopidogrel and its thiol metabolite were 7.9 min and 8.6 min, respectively. The mass spectrometer was run in positive mode and m/z 326.2 → 216.0 for clopidogrel-d4, m/z 322.1 → 212.0 for clopidogrel and m/z 504.3 → 353.9 for the thiol metabolite derivative were monitored. Calibration curves in the range of 0.02–20 ng ml1 for clopidogrel (r = 0.9991) and 0.5–200 ng ml1 for the thiol metabolite derivative (r = 0.9993) were established. The intraday and interday coefficients of variation were less than 11.8%. The coefficient of variation for the assay precision was 95.9%. For analysis of plasma concentrations of cilostazol, 3,4-dehydrocilostazol and 4″-trans-hydroxycilostazol, a 0.3 ml aliquot of plasma was spiked with an internal standard (propyphenazone 5 μg ml1) and extracted with 3 ml methyl tert-butyl ether. After vortex mixing for 5 min and centrifugation at 1910 g for 10 min, the organic layer was separated and evaporated to dryness. The residue was reconstituted with 150 μl 50% methanol. A 2 μl aliquot was injected into the LC-MS/MS system. Chromatographic separation was performed on a Luna C18 column (particle size 3 μm, 100 × 2 mm2, i.d.; Phenomenex, Torrance, CA, USA). The mobile phases were as follows: mobile phase A, 1 mM ammonium acetate (pH 4.5); mobile phase B, acetonitrile containing 0.1% formic acid. A gradient program was used for the HPLC separation, with a flow rate of 0.2 ml min1. The initial composition of solvent B was 25%, increased to 60% after 8 min and then maintained for 4 min, followed by re-equilibriation to the initial condition for 6 min. Quantification was performed using a mass spectrometer in Multiple-Reaction Monitoring (MRM) with positive electrospray ionization at m/z 370.2 → 288.3 for cilostazol, m/z 368.3 → 286.2 for 3,4-dehydrocilostazol, m/z 386.2 → 288.3 for 4″-trans-hydroxycilostazol and m/z 231.2 → 189.1 for the internal standard, respectively. Calibration curves in the range of 2–3000 ng ml1 for cilostazol (r2 = 0.9976) and 2–1000 ng ml1 for 3,4-dehydrocilostazol and 4″-trans-hydroxycilostazol) (r2 = 0.9992 and 0.9995, respectively) were established. The coefficient of variation for the assay precision was 92.5%. No relevant crosstalk and matrix effect were observed.
Measurement of platelet aggregation Platelet aggregation was measured using a Chrono-log Lumi Aggregometer (model 700-4DR; Chrono-log Corp., Havertown, PA, USA) equipped with the AggroLink software package, and using a turbidometric method, as described previously [9, 29].
Pharmacokinetic and pharmacodynamic data analysis The pharmacokinetic parameters of clopidogrel, cilostazol and their metabolites were calculated using Br J Clin Pharmacol
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WinNonlin® version 6.1 (Pharsight Co., Mountain View, CA, USA). The maximum concentration (Cmax) and the time to Cmax (Tmax) were obtained from concentration– time curves. The area under the concentration–time curve from zero to the last observation (AUCt) was calculated using the linear trapezoidal rule. AUCt molar ratios of metabolite to parent drug were estimated, to evaluate metabolic status. For the pharmacodynamic evaluation, platelet reactivity [absolute value of the observed maximal platelet aggregation (MPA)] was used and the inhibition of platelet aggregation (IPA) value was calculated from the observed MPA as follows: IPA ð%inhibitionÞ ¼
MPA0 MPAt 100% MPA0
where MPA0 is the average value of the platelet aggregation response at baseline (on day 1 and 0 h before treatment on day 1), and MPAt is MPA at each scheduled time t after each treatment. The maximum effect of IPA (IPAmax) was obtained from IPA–time curves. The area under the effect–time curve from 0 h to 24 h (AUEC) was calculated using the linear trapezoidal rule. The average value of the IPA from 4 h to 24 h after dosing (IPA4–24) was estimated.
Statistical analysis Continuous variables were expressed as means ± standard deviation. Geometric mean ratios (GMRs) of natural log-transformed AUCt and Cmax, and arithmetic mean ratios of Tmax for clopidogrel, cilostazol and their metabolites were calculated in order to evaluate the magnitude of the drug interaction between clopidogrel and cilostazol, along with estimated 90% confidence intervals (CIs). Log-transformed AUCt and Cmax, other pharmacokinetic and pharmacodynamic parameters of clopidogrel and cilostazol, alone and co-administered were analysed using a mixed-model analysis of variance with fixed effects for sequence, period and treatment, and a random effect for subject within sequence. The pharmacokinetic and pharmacodynamic parameters among the various CYP2C19 genotype groups and between different CYP3A5 genotype groups were compared using the Kruskal–Wallis or Wilcoxon rank-sum tests after testing for normality. Values of P < 0.05 were considered to indicate statistical significance. All statistical analyses were performed using SAS version 9.2 (SAS institute Inc.).
Results Subjects Twenty-seven healthy male subjects were enrolled in and completed the study. All subjects were classified into 304
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three genotype groups according to the number of LOF alleles of the CYP2C19 genotypes: CYP2C19 extensive metabolizers (CYP2C19 EM; CYP2C19*1/*1; n = 9), CYP2C19 intermediate metabolizers (CYP2C19 IM; CYP2C19*1/*2 or CYP2C19*1/*3; n = 9), and CYP2C19 poor metabolizers (CYP2C19 PM; CYP2C19*2/*2, CYP2C19*2/*3 or CYP2C19*3/*3; n = 9). In addition, two genotype groups, CYP3A5*1/*3 (n = 10) and CYP3A5*3/*3 (n = 17), were compared to evaluate the effect of the CYP3A5 genotype on the pharmacokinetics and pharmacodynamics of clopidogrel and cilostazol. No subjects with the CYP2C19*17 allele or CYP3A5*1/*1 genotype were identified in the present study. The average age, weight and height of all subjects were 24.9 (±2.4) years , 68.0 (±7.2) kg and 174.5 (±5.0) cm, respectively. There was no significant difference in age, weight or height among the CYP2C19 EM, IM and PM genotypes or between CYP3A5*1/*3 and CYP3A5*3/*3.
Pharmacokinetic results of clopidogrel and its active thiol metabolite There was no significant difference in the AUCt or Cmax of clopidogrel between administration of clopidogrel with and without cilostazol (Table 1 and Figure 1A). The Tmax of clopidogrel was delayed from 0.66 h to 1 h. after the co-administration of clopidogrel and cilostazol. However, the Tmax of the thiol metabolite was no different between administration of clopidogrel with and without cilostazol. The AUCt and Cmax of the thiol metabolite were significantly decreased after co-administration of clopidogrel and cilostazol compared with administration of clopidogrel alone (GMR 0.82; P = 0.015 and GMR 0.84; P = 0.028, respectively; Table 1 and Figure 1B). The pharmacokinetic parameters of the thiol metabolite were further compared between clopidogrel with and without cilostazol, stratified into CYP2C19 or CYP3A5 genotype groups (Table 2). The AUCt and Cmax of the thiol metabolite were significantly highest in the CYP2C19 EM genotype, and lowest in the CYP2C19 PM genotype group after administration of clopidogrel alone (51.83 ± 18.00 vs. 15.91 ± 7.94 for AUCt, P < 0.001; 39.43 ± 12.00 vs. 15.92 ± 7.59 for Cmax, P = 0.001). Differences in thiol metabolite pharmacokinetic parameters among the CYP2C19 genotype group were also observed after co-administration of clopidogrel and cilostazol. However, these parameters of the thiol metabolite were not statistically different between administration of clopidogrel with and without cilostazol in any CYP2C19 genotype groups. Unlike the CYP2C19 genotypes, no significant difference was observed in the pharmacokinetic parameters of the thiol metabolite between subjects with the CYP3A5*1/*3 and CYP3A5*3/*3 genotypes after administration of clopidogrel with and without cilostazol. However, the AUCt and Cmax of the thiol metabolite were
Genotype-based clopidogrel–cilostazol interaction
Table 1 Pharmacokinetic parameters of clopidogrel and its thiol metabolite in healthy subjects after a single oral administration of clopidogrel alone or co-administration of clopidogrel and cilostazol
Clopidogrel
Clopidogrel + cilostazol
P value
GMR (90% CI)
Clopidogrel AUCt (ng h ml Cmax (ng ml
1
1
)
)
Tmax (h)
6.80 ± 6.09
7.28 ± 5.46
1.11* (0.99 ~ 1.26)
0.139
3.76 ± 3.81
4.12 ± 4.22
1.07* (0.93 ~ 1.23)
0.435
0.66 (0.33 ~ 2)
1.00 (0.66 ~ 3)
1.35 (1.19 ~ 1.52)
0.028
33.00 ± 18.84
28.10 ± 15.78
0.82* (0.72 ~ 0.93)
0.015
27.83 ± 13.95
23.41 ± 12.13
0.84* (0.74 ~ 0.95)
0.028
1.00 (0.33 ~ 2)
1.00 (0.33 ~ 3)
1.15 (0.98 ~ 1.31)
0.374
4.82 ± 3.92
3.73 ± 3.71
0.87 (0.69 ~ 1.04)
0.070
Thiol metabolite AUCt (ng h ml Cmax (ng ml
1
1
)
)
Tmax (h) AUCthiol/AUCclopidogrel†
Data represent as arithmetic mean ± standard deviation, except for data for Tmax, which represent the median (range). AUC, area under the concentration–time curve; AUCt, area under the concentration–time curve from zero to the last observation; CI, confidence interval; Cmax, maximum concentration; Tmax, time to Cmax. *GMR, geometric mean ratio of clopidogrel + cilostazol vs. clopidogrel. †AUCthiol/AUCclopidogrel, AUC molar ratio of thiol metabolite vs. clopidogrel.
significantly decreased in subjects with the CYP3A5*1/*3 but not CYP3A5*3/*3 genotype after co-administration of clopidogrel and cilostazol compared with clopidogrel alone (GMR 0.71 and 0.69 for CYP3A5*1/*3 vs. GMR 0.90 and 0.93 for CYP3A5*3/*3; Table 2).
Pharmacokinetic results of cilostazol and its active metabolites
Figure 1 Mean concentration–time profiles of clopidogrel (A) and its thiol metabolite (B) after a single oral administration of 300 mg clopidogrel alone and co-administration of 300 mg clopidogrel and 100 mg cilostazol, and comparison of the thiol metabolite area under the plasma concentration– clopidogrel, time curve stratified by CYP2C19 and CYP3A5 genotypes. clopidogrel+cilostazol
The AUCt of cilostazol and 3,4-dehydro cilostazol (which is 4–7 times more potent than cilostazol) was not significantly different between the administration of clopidogrel with and without cilostazol, although a small decrease in Cmax was observed after co-administration of clopidogrel and cilostazol (Table 3, and Figure 2A,B). The AUCt and Cmax of 4″-trans-hydroxycilostazol, which has one-fifth the activity of cilostazol, were decreased after co-administration of clopidogrel and cilostazol compared with cilostazol alone (Table 3 and Figure 2C). A small decrease in the AUCt molar ratio of 4″-trans-hydroxycilostazol vs. cilostazol was observed (GMR 0.91, P = 0.005). The AUCt of cilostazol and 3,4-dehydro cilostazol was highest in the CYP2C19 PM genotype after administration of cilostazol both with and without clopidogrel, and that of 4″-trans-hydroxycilostazol was lowest for the CYP2C19 PM genotype (Table 4). No significant differences in the AUCt of cilostazol or 3,4-dehydro cilostazol were observed in any of the CYP2C19 genotype groups between cilostazol with and without clopidogrel, whereas the AUCt of 4″-trans-hydroxycilostazol was decreased after coadministration of cilostrazol and clopidogrel. Similar to the CYP2C19 genotype, the AUC t values of cilostazol and 3,4-dehydro cilostazol were higher in the CYP3A5*3/*3 than in the CYP3A5*1/*3 genotype group after administration of cilostazol both with and without clopidogrel (Table 4). The AUCt of 4″-trans-hydroxycilostazol was lower in the CYP3A5*3/*3 Br J Clin Pharmacol
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Table 2 The pharmacokinetic parameters of clopidogrel thiol metabolite according to CYP2C19 or CYP3A5 genotypes in healthy subjects after a single oral administration of clopidogrel alone or co-administration of clopidogrel and 100 mg cilostazol
Clopidogrel AUCt (ng h ml
CYP2C19†
1
GMR* (90% CI)
P value
0.330
)
EM
51.83 ± 18.00
46.33 ± 8.89
0.93 (0.81 ~ 1.06)
IM
31.27 ± 5.92
24.65 ± 6.17
0.78 (0.63 ~ 0.96)
0.057
PM
15.91 ± 7.94
13.31 ± 7.69
0.77 (0.52 ~ 1.13)
0.229
