Heart Vessels DOI 10.1007/s00380-014-0516-5
ORIGINAL ARTICLE
Lack of association between peri-procedural myocardial damage and CYP2C19 gene variant in elective percutaneous coronary intervention Hiromi Yoshimura • Koichi Kaikita • Takamichi Ono • Satomi Iwashita • Naoki Nakayama • Koji Sato • Eiji Horio • Kenichi Tsujita • Sunao Kojima Shinji Tayama • Seiji Hokimoto • Hisao Ogawa
•
Received: 26 December 2013 / Accepted: 11 April 2014 Ó Springer Japan 2014
Abstract Peri-procedural myocardial damage (MD) is associated with increased risk of major in-hospital complications and adverse clinical events. The aim of this study was to evaluate the effects of on-clopidogrel platelet aggregation and CYP2C19-reduced-function gene variants on elective percutaneous coronary intervention (PCI)related MD. We measured changes in serum high-sensitive troponin T (hs-TnT) levels, CYP2C19 genotype, and onclopidogrel platelet aggregation (PA) using VerifyNowÒ P2Y12 system in 91 patients who received stent implantation (stent group). The control group comprised 30 patients who did not receive PCI. Blood samples were obtained before and 24 h after PCI or coronary angiography (CAG). Patients of the stent group were divided into high and low MD groups based on the median value of hsTnT level at 24 h after PCI. Serum hs-TnT levels were significantly higher 24 h after PCI (86.8 ± 121.5 pg/ml) compared with before PCI (9.4 ± 5.3, p \ 0.001), whereas the levels were identical before and 24 h after CAG in the control group. Simple logistic regression analysis demonstrated that MD correlated with age (p = 0.014), estimated GFR (p = 0.003), hemoglobin A1c (p = 0.015), baseline serum hs-TnT (p = 0.049), and stent length (p \ 0.001). Multiple logistic regression analysis identified old age, high hemoglobin A1c level, and long stent, but not CYP2C19 reduced-function allele or high on-clopidogrel PA, as independent predictors of elective PCI-related MD.
H. Yoshimura K. Kaikita (&) T. Ono S. Iwashita N. Nakayama K. Sato E. Horio K. Tsujita S. Kojima S. Tayama S. Hokimoto H. Ogawa Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan e-mail: [email protected]
The present study demonstrated no significant relation between peri-procedural MD and high on-clopidgrel PA associated with CYP2C19 reduced-function allele in patients undergoing elective PCI. Keywords Angina pectoris Coronary artery disease Blood coagulation Platelets Thrombosis
Introduction Dual antiplatelet therapy with aspirin and clopidogrel regulates activated platelets in disrupted coronary plaques and reduces atherothrombotic complications, including stent thrombosis, in patients with acute coronary syndrome (ACS) who undergo percutaneous coronary intervention (PCI) [1–8]. Clopidogrel is a prodrug that requires biotransformation to an active metabolite by cytochrome P450 (CYP) enzymes. Recently, it has been reported that carriers of at least one reduced-function CYP2C19 allele have low levels of the active metabolites of clopidogrel, diminished platelet inhibition and a higher rate of major adverse cardiovascular events among ACS patients undergoing PCI [9–14]. Especially, the reported frequency of CYP2C19 reduced-function allele in Japanese population is approximately twice that in Caucasians, indicating that regulation of platelet aggregation can be inadequate in Japanese patients undergoing PCI [15]. On the other hand, myocardial damage (MD) during PCI is reported to be associated with increased risk of major inhospital complications and major adverse clinical events [16–19]. During PCI, myocardial necrosis may result from one or more peri-procedural events, such as side-branch occlusion, disruption of collateral flow, distal embolization, coronary dissection, slow flow or no-reflow phenomenon,
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and microvascular plugging, which can be detected by coronary angiography [20]. The recent ESC guidelines define peri-procedural myocardial infarction during PCI as elevation of cardiac biomarkers [21]. A recent study demonstrated that Asian patients carriers of CYP2C19 reduced-function alleles with non-ST elevation acute coronary syndrome, often exhibit high platelet reactivity, which is associated with increased risk for periprocedural myocardial infarction [22]. However, little is known about the effect of CYP2C19 reduced-function gene polymorphism on the incidence of peri-procedural MD in patients with stable coronary artery disease (CAD) undergoing elective PCI. The aim of the present study was to evaluate the relation between CYP2C19 loss-of-function gene polymorphism and the incidence of peri-procedural MD in stable CAD patients undergoing elective PCI.
Methods Study population and study protocol The study subjects were 138 patients with stable CAD and angiographic evidence of C75 % organic coronary stenosis, who were admitted to our institution between September 2008 and October 2010 (Fig. 1). All patients were scheduled for elective PCI based on the presence of cardiac ischemia on stress thallium-201 single-photon emission computed tomography or treadmill test, and were treated with dual-antiplatelet therapy of both aspirin (100 mg/day) and clopidogrel (loading dose of 300 mg followed by 75 mg/day). Of the 138 patients, PCI was conducted in 108 patients with stable exertional angina. Following PCI, we excluded from the analysis 17 patients for the following reasons: only balloon angioplasty (n = 2), incomplete sampling (n = 11), and high-sensitive troponin T (hs-TnT) level at baseline of [0.030 ng/ml (n = 4). Thus, the stent group comprised 91 patients. The other 30 patients who did not receive PCI were included as the control group. The stent group was subsequently divided into high and low MD groups based on the median value of serum hs-TnT levels. The study did not include patients treated with warfarin, steroids, thrombolytic agents, ticlopidine, sarpogrelate or cilostazol, and those with deep vein thrombosis, atrial fibrillation, collagen disease, infection, hepatic dysfunction (serum aspartate aminotransferase or alanine aminotransferase levels C twice the upper limit of normal), renal dysfunction (serum creatinine C2.0 mg/dl or on dialysis), and malignant diseases. We also excluded patients with ACS, defined as either acute myocardial infarction (with or without ECG evidence of ST-segment elevation) or those with unstable angina (class II or III of Braunwald’s classification).
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Fig. 1 Flow chart of the study recruitment process. CAG Coronary angiography, hs-TnT high-sensitive troponin T
The study protocol was approved by the Human Ethics Review Committee of Kumamoto University Graduate School of Medicine, and an informed signed consent form was obtained from each subject. Measurement of cardiac biomarker Venous blood samples were obtained before, immediately after, 1, 2, and 28 days after elective PCI, or before and 24 h after coronary angiography (CAG) in the control group. At the time of blood sampling, the first 3 ml of blood was used for biochemical assessment, while the subsequent 4.5 ml of venous blood was collected into a Vacutainer tube containing 0.5 ml of sodium citrate solution (0.13 mol/l, pH 7.5). All blood samples were centrifuged immediately at 1,7009g for 10 min at 4 °C, and aliquots of samples were stored at -80 °C until analysis. Serum hs-TnT levels were measured by Elecsys 2010 analyzer (Roche Diagnostics, Mannheim, Germany) as described previously [23]. The detection limit of serum hsTnT in the method was 0.005 ng/ml. Determination of CYP2C19 genotype and phenotype Genomic DNA was extracted from whole blood using the DNA Extractor WB kit (Wako Pure Chemical Industries, Osaka, Japan) and the modified protocol of Richards et al. [24]. PCR restriction fragment length polymorphisms
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(RFLPs) for CYP2C19*2 (681G [ A) and CYP2C19*3 (636G [ A) were performed as described previously [25]. The CYP2C19 genotype was classified into three phenotypes: extensive metabolizer (EM) carrying normal function alleles (CYP2C19*1/*1), intermediate metabolizer (IM) carrying one loss-of-function allele (*1/*2, *1/*3), and poor metabolizer (PM) carrying two loss-of-function alleles (*2/*2, *2/*3, *3/*3). Assessment of clinical outcome
Table 1 Clinical characteristics of the control and stent groups at baseline Control group n = 30
Stent group n = 91
p value
Age, (years)
71.7 ± 9.2
68.8 ± 9.6
0.256
Female sex, n (%)
9 (30.0)
23 (25.3)
0.523
Body mass index (per kg/m2)
26.0 ± 2.3
25.3 ± 3.4
0.289
Current smokers, n (%)
3 (10.0)
22 (24.1)
0.116
Diabetes mellitus, n (%)
12 (40.0)
23 (25.3)
0.093
Hypertension, n (%)
25 (83.3)
77 (84.6)
0.309
After laboratory sampling and elective PCI, all patients received standard medical therapy and were followed for a maximum of 6 months or by visits until occurrence of the clinical endpoint. The clinical endpoint was a major cardiac or cerebrovascular event, such as cardiac death, nonfatal myocardial infarction, unstable angina pectoris, or ischemic stroke.
Dyslipidemia, n (%)
23 (76.7)
63 (69.2)
0.286
Total cholesterol, (mg/dl)
160.8 ± 31.7
168.0 ± 32.3
0.422
LDL-C, (mg/dl)
90.8 ± 34.0
96.0 ± 25.7
0.524
HDL-C, (mg/dl) Triglyceride, (mg/dl)
50.9 ± 18.2 146.7 ± 53.7
48.0 ± 13.2 147.3 ± 100.2
0.721 0.454
Hemoglobin A1c, (%)
6.22 ± 1.12
5.92 ± 1.01
0.158
Statistical analysis
Baseline serum hs-TnT, (pg/ml)
12.0 ± 13.4
9.4 ± 5.3
0.156
eGFR, (ml/min/1.73 m2)
68.8 ± 31.0
68.0 ± 17.3
0.902
Data are expressed as mean ± standard deviation. Categorical data are presented by frequencies and percentages. Differences between carriers and noncarriers were tested with the v2 test (and Fisher exact test) for categorical variables. Differences in continuous variables were analyzed by the unpaired t test and Mann–Whitney U test. The statistical significance of changes in the time course of platelet function tests and biomarkers between carriers and noncarriers were evaluated by one-way analysis of variance for repeated measures. Associations between the presence of carriers of at least one reduced-function CYP2C19 allele and other significant parameters that have been shown to alter platelet function in recent studies [26–30] were analyzed by multiple logistic regression analysis with the forced entry method. The Hosmer–Lemeshow statistic was applied to assess model calibration. A p value of \0.05 denoted statistical significance. All statistical analyses were performed using The Statistical Package for Social Sciences version 18 (SPSS Inc., Tokyo).
CYP2C19 genotype *1/*1, n (%)
13 (43.3)
32 (35.1)
0.422
*1/*2, n (%)
9 (30.0)
36 (39.6)
0.346
*1/*3, n (%)
4 (13.3)
12 (12.2)
0.772
*2/*2, n (%)
2 (6.7)
7 (7.7)
0.829
*2/*3, n (%)
2 (6.7)
2 (2.2)
0.943
*3/*3, n (%) Carriers, n (%)
0 (0) 17 (56.7)
2 (2.2) 59 (64.8)
0.995 0.422
Use of b-blockers, n (%)
12 (40.0)
43 (47.3)
0.489
Use of ISDNs, n (%)
4 (13.3)
29 (31.9)
0.082
Use of CCBs, n (%)
12 (40.0)
52 (57.1)
0.103
Use of ACE-Is or ARBs, n (%)
20 (66.7)
54 (59.3)
0.475
Use of Statins, n (%)
19 (63.3)
69 (75.8)
0.183
Use of PPIs, n (%)
6 (20.0)
30 (33.0)
0.178
Data are mean ± SD or n (%) LDL-C Low-density lipoprotein cholesterol, HDL-C high-density lipoprotein cholesterol, hs-TnT high-sensitivity troponin T, eGFR estimated glomerular filtration rate, ISDN isosorbide dinitrates, CCB calcium-channel blocker, ACE-I angiotensin-converting enzyme antagonist, ARB angiotensin II receptor antagonist, PPI proton pump inhibitor
Results Frequency of CYP2C19 phenotypes and patient characteristics The distributions of the CYP2C19 genotype in the 121 patients are listed in Table 1. 59 cases (64.8 %) were carriers of at least one CYP2C19 reduced-function allele, and 32 cases (35.2 %) were noncarriers (EM) in the Stent group. Of the 30 patients who underwent CAG and were
treated with aspirin and clopidogrel, 17 cases (56.7 %) were carriers, and 13 cases (43.3 %) were noncarriers. The clinical features of patients of the control and the stent groups are listed in Table 1. There were no significant differences between the two groups in baseline characteristics known to be associated with platelet aggregation. Table 1 also lists the medication history in each group at the time of baseline blood sampling. The proportions of patients on isosorbide dinitrates, calcium channel blockers,
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Heart Vessels Fig. 2 Serum hs-TnT levels before and 24 h after PCI (PCI group, n = 91) or CAG (Control group, n = 30). Data of individual patients and the mean ± SD for each group
angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, b-blockers, statins, and proton pump inhibitors were identical in the two groups. Changes in serum hs-TnT levels before and 24 h after PCI or CAG, and clinical outcome in carriers and noncarriers Serum hs-TnT levels increased significantly 24 h after PCI (baseline: 9.4 ± 5.3, Post-PCI: 86.8 ± 121.5 pg/ml, p \ 0.001, Fig. 2), whereas the levels did not change 24 h after CAG in the control group (baseline: 12.0 ± 13.4, Post-CAG: 17.9 ± 14.5 pg/ml, p = 0.249). We underwent coronary stenting with BMS in 16 patients (17.6 %) and with DES in 75 patients (82.4 %). There was no significant difference in serum hs-TnT levels at baseline (8.6 ± 2.7 vs 8.5 ± 3.8 pg/ml, p = 0.865) and 24 h after PCI (58 ± 72 vs 93 ± 144 pg/ ml, p = 0.144) between BMS and DES groups. During the follow-up period, only 1 carrier developed epidural hematoma caused by trauma, while no major cardiac or cerebrovascular events were encountered in the noncarriers of the stent group. Patient characteristics and angiographic morphology based on ACC/AHA lesion classification in high and low peri-procedural MD groups Table 2 lists the clinical features of patients of the stent group divided into low and high MD groups. Age, serum hemoglobin A1c level, and baseline serum hs-TnT levels
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were significantly higher in the high peri-procedural MD than the low peri-procedural MD group. On the other hand, the frequencies of dyslipidemia and estimated glomerular filtration rate (eGFR) were significantly lower in the high peri-procedural MD than the other group. Furthermore, PCI involving the left anterior descending (LAD) lesions were more common in low MD than high MD patients (Table 3). The ACC/AHA lesion class was identical between the two groups. There was no significant difference in the number of patients implanted DES between Low MD and High MD groups (Table 3). The stent diameter was significantly smaller, and the total stent length was significantly longer in the high MD than low MD group. Simple and multiple logistic regression analyses for prediction of peri-procedural MD Finally, we used logistic regression analysis to determine predictors of high peri-procedural MD in the stent group. Simple logistic regression analysis demonstrated that high peri-procedural MD was significantly associated with age, eGFR, serum HbA1c level, serum hs-TnT level before PCI, and total stent length (Table 4). Multiple logistic regression analysis identified old age ([75 years), high serum HbA1c level ([6.1 %), and long stent ([3.0 mm long), but not presence of CYP2C19 reduced-function allele or on-clopidgrel PA, as significant predictors of high peri-procedural MD (Table 4). Hosmer–Lemeshow goodness of fit v2 was 1.603 with a p value of 0.979.
Heart Vessels Table 2 Clinical characteristics of patients of the stent group with low and high myocardial damage
Table 3 Angiographic morphology of the stent group Low MD n = 45
High MD n = 46
Left main, n (%)
3 (6.7)
2 (4.3)
Left anterior descending (%)
26 (57.8)
17 (37.0)
0.046
Left circumflex, n (%)
4 (8.9)
8 (17.4)
0.354
Right, n (%)
12 (26.7)
19 (41.3)
0.141
A, n (%) B1, n (%)
11 (24.4) 16 (35.6)
5 (10.9) 16 (34.8)
0.105 0.938
0.096 0.119
Simple Lesion (A/B1) (%)
26 (57.8)
19 (41.3)
0.116
B2 (%)
13 (28.9)
14 (30.4)
0.871
C (%)
7 (15.6)
13 (28.3)
0.226
Low MD n = 45
High MD n = 46
p value
Age, (years)
67.0 ± 8.77
70.3 ± 10.8
0.038
Female sex, n (%)
8 (17.8)
15 (32.6)
0.165
Body mass index (per kg/m2)
25.0 ± 2.9
25.6 ± 3.8
0.540
Current smokers, n (%)
13 (28.9)
9 (19.6)
0.427
Diabetes mellitus, n (%)
11 (24.4)
12 (26.1)
0.865
Hypertension, n (%) Dyslipidemia, n (%)
33 (73.3) 34 (75.6)
35 (76.1) 29 (63.0)
p value
Target lesion coronary artery
ACC/AHA lesion class
Total cholesterol, (mg/dl)
166.7 ± 36.4
171.5 ± 27.2
0.560
LDL-C, (mg/dl)
93.0 ± 28.8
97.7 ± 22.7
0.307
HDL-C, (mg/dl)
48.8 ± 13.5
48.1 ± 13.0
0.735
Stent diameter, (mm)
Triglyceride, (mg/dl)
162.9 ± 117.9
134.1 ± 81.7
0.273
Total stent length per patients (mm)
Hemoglobin A1c, (%)
5.67 ± 0.83
6.19 ± 1.14
0.015
Baseline serum hs-TnT, (pg/ml)
7.6 ± 3.8
10.9 ± 5.9
0.002
eGFR, (ml/min/ 1.73 m2)
72.5 ± 14.9
63.5 ± 18.3
0.003
20 lmol/L ADP-PR max (%)
52.9 ± 11.9
51.3 ± 12.5
0.549
20 lmol/L ADP-PR area (AU*min)
3560.3 ± 1692.2
3485.0 ± 1594.9
0.880
P2Y12 reaction unit
245.4 ± 88.3
238.4 ± 85.8
0.723
% Inhibition (%)
26.8 ± 22.7
26.9 ± 21.4
0.911
*1/*1, n (%)
16 (35.6)
16 (34.8)
0.938
*1/*2, n (%)
16 (35.6)
20 (43.5)
0.440
*1/*3, n (%)
6 (13.3)
6 (13.0)
0.788
*2/*2, n (%) *2/*3, n (%)
5 (11.1) 1 (2.2)
2 (4.3) 1 (2.2)
0.414 0.484
*3/*3, n (%)
1 (2.2)
1 (2.2)
0.484
Complex lesion (B2/C) (%)
CYP2C19 genotype
Carriers, n (%)
29 (64.4)
30 (65.2)
0.938
Use of b-blockers, n (%)
23 (51.1)
20 (43.5)
0.465
Use of ISDNs, n (%)
12 (26.7)
17 (37.0)
0.292
Use of CCBs, n (%)
23 (51.1)
29 (63.0)
0.250
Use of ACE-Is or ARBs, n (%)
23 (51.1)
31 (67.4)
0.114
Use of Statins, n (%)
38 (84.4)
31 (67.4)
0.098
Use of PPIs, n (%)
17 (37.8)
13 (28.3)
0.671
Data are mean ± SD or n (%) Abbreviation as in Table 1. MD myocardial damage, ADP-PR max adenosine diphosphate induced platelet reactivity maximum aggregation
0.677
Use of DES
20 (44.4)
27 (58.7)
0.174
10 (22.2)
8 (17.4)
0.563
3.08 ± 0.47
2.86 ± 0.37
0.033
22.5 ± 10.8
35.8 ± 15.8 \0.001
Data are mean ± SD or n (%) DES Drug-eluting stent
Discussion The present study demonstrated that high peri-procedural MD correlated closely with old age, high serum hemoglobin A1c levels, and long stent, but not the presence of CYP2C19 reduced-function allele or high on-clopidogrel PA activity, in stable CAD patients undergoing elective PCI. This is the first report describing the lack of association between peri-procedural MD and CYP2C19 reducedfunction polymorphism in stable CAD patients undergoing elective PCI. Carriers of at least one reduced-function CYP2C19 allele are reported to have weak platelet inhibition and are at high risk of major adverse cardiovascular events among ACS patients undergoing PCI [13, 31]. Another report also described a high incidence of peri-procedural MD in patients with high post-treatment platelet reactivity and non-ST elevation acute coronary syndrome [22]. However, our study demonstrated that peri-procedural MD is not necessarily influenced by the presence of CYP2C19 reduced-function allele or high on-clopidogrel PA in stable CAD patients undergoing elective PCI. In this regard, the GRAVITAS trial did not recommend a treatment strategy of high-dose clopidogrel in low-risk patients with high residual reactivity identified by a single platelet function test after elective PCI [32]. The ARCTIC study also demonstrated no significant improvement in clinical outcome by platelet function monitoring and adjustment of treatment before elective PCI, compared to standard antiplatelet therapy without monitoring [33].
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Heart Vessels Table 4 Results of simple and multiple regression analyses for determinants of high hs-TnT levels
Data are mean ± SD or n (%) a Data of these parameters were divided into two groups based on the following criteria; age [75 years, body mass index [25 kg/m2, total cholesterol [167 mg/dl, LDLC [100 mg/dl, HDLC \40 mg/dl, TG [150 mg/dl, HbA1c [6.1 % (JDS), PRU [230 b
Data of these parameters were divided into two groups based on the median value. Abbreviations as in Tables 1, 2 and 3
Simple regression analysis
Multiple regression analysis
OR
95 % CI
p value
OR
95 % CI
p value
Age, (years)a
3.36
1.32–8.54
0.014
2.05
1.67–36.3
0.009
Male sex, n (%)
2.24
0.83–5.97
0.148
Body mass index (per kg/m2)a
0.82
0.35–1.91
0.674
Current Smokers, n (%)
0.60
0.20–1.58
0.336
Hypertension, n (%)
2.42
0.82–7.16
0.121
Dyslipidemia, n (%)
0.46
0.18–1.13
0.119
Total cholesterol, (mg/dl)a
1.15
0.50–2.66
0.832
LDL-C, (mg/dl)a
1.99
0.85–4.64
0.137
HDL-C, (mg/dl)a
1.20
0.46–3.10
0.810
Triglyceride, (mg/dl)a
0.51
021–1.25
0.183
Platelet count, (103/ll)b Hemoglobin A1c, (%)a
0.91 3.86
0.40–2.09 1.38–10.71
0.837 0.015
1.49
1.06–18.6
0.041
eGFR, (ml/min/1.73 m2)b
4.24
1.62–11.05
0.003
1.01
0.73–10.3
0.137
ADP-PRmax (%)b
0.55
0.23–1.27
0.202
1.25
0.55–2.84
0.677
P2Y12 reaction unit
1.01
0.43–2.38
1.000
CYP2C19 carrier
1.04
0.44–2.42
1.000
Baseline hs-TnT (pg/ml)b
2.55
1.05–6.18
0.049
1.02
0.81–9.44
0.103
Previous myocardial infarction
3.22
0.94–11.02
0.088
Previous PCI
2.34
1.01–5.43
0.060 2.29
2.29–42.7
0.002
ADP-PR area (AU*min)b a
Use of DES
1.36
0.48–3.83
0.563
Total stent length, (mm)b
8.44
3.11–23.0
\0.001
Stent diameter, (mm)b
0.55
0.23–1.27
0.202
Complex lesion (Type B2, C)
1.78
0.77–4.08
0.211
Peri-PCI MD could be caused by one or more of the following events: side-branch occlusion, disruption of collateral flow, distal embolization, coronary dissection, slow flow or no-reflow phenomenon, and microvascular plugging, which can be demonstrated on CAG [20, 23]. Several clinical studies indicated that the development of peri-procedural MD correlated with the presence of lowdensity coronary atherosclerotic plaques on computed tomography, positive remodeling and spotty calcification of coronary plaques on intravascular ultrasonography, yellowish coronary plaque on vascular endoscopy, and implantation of long stent [16, 34, 35]. The present results suggested that modification of PCI strategy or reduction of coronary risk, rather than anti-platelet therapy for high onclopidgrel PA, may be more important in reducing periprocedural MD in patients with stable CAD undergoing elective PCI. Peri- PCI procedural myocardial infarction is defined as high cardiac troponin (cTn) level [[5 9 99th percentile of upper reference limit (URL)] in patients with normal baseline values (B99th percentile of URL), or high cTn levels (by [20 %) in patients with high stable or falling baseline levels [21]. However, it is possible that the
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diagnosis of the peri-procedural myocardial infarction might fluctuate by the kind of cardiac biomarkers used because the sensitivity and normal baseline values are different among each cardiac biomarker. In the present study, we used a highly sensitive assay system of serum TnT to assess the peri-procedural MD and divided the stent group into high and low MD groups based on the median value of serum hs-TnT levels. In the present study, none of the patients developed major cardiac or cerebrovascular events during the followup period, with the exception of peri-procedural MD. Carriers of CYP2C19 reduced-function allele constituted 65 % of the patients in the present study, while the remaining 35 % were noncarriers for the allele. In a recent study of healthy Caucasians, the prevalence of the CYP2C19 reduced-function allele was only 30 % among the total study population [13]. Previous studies indicated that adverse cardiovascular events, including stent thrombosis after primary or elective PCI, are lower in Japanese than Caucasians [36–38], although the frequency of carriers of at least one CYP2C19 reduced-function allele is higher in the Japanese than Caucasians. The reason for the low frequency of adverse cardiovascular events in Japan
Heart Vessels
remains unknown; however, it is possible that other factors, such as the PCI procedure, the characteristics of the culprit coronary plaques, and coronary risk factors, rather than high on-clopidogrel PA caused by the CYP2C19 reducedfunction allele, may influence the clinical outcome of CAD patients undergoing elective PCI. In conclusion, the present study demonstrated no significant relation between peri-procedural MD and clopidogrel resistance in patients undergoing elective PCI. The frequency of peri-procedural MD did not correlate with high on-clopidogrel PA in stable CAD patients undergoing elective PCI. The results emphasize the need for an effective interventional strategy for elderly diabetic patients, rather than adjustment of strategy for high onclopidgrel PA associated with CYP2C19 reduced-function allele, to reduce the incidence of peri-procedural MD in elective PCI. Acknowledgments We are grateful to Megumi Nagahiro and Saeko Tokunaga from the Department of Cardiology, Kumamoto University, for the skillful technical assistance. This study was supported in part by Grants-in-Aid for Scientific Research C24591062 from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Conflict of interest
The authors declare no conflict of interest.
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ORIGINAL ARTICLE
Lack of association between peri-procedural myocardial damage and CYP2C19 gene variant in elective percutaneous coronary intervention Hiromi Yoshimura • Koichi Kaikita • Takamichi Ono • Satomi Iwashita • Naoki Nakayama • Koji Sato • Eiji Horio • Kenichi Tsujita • Sunao Kojima Shinji Tayama • Seiji Hokimoto • Hisao Ogawa
•
Received: 26 December 2013 / Accepted: 11 April 2014 Ó Springer Japan 2014
Abstract Peri-procedural myocardial damage (MD) is associated with increased risk of major in-hospital complications and adverse clinical events. The aim of this study was to evaluate the effects of on-clopidogrel platelet aggregation and CYP2C19-reduced-function gene variants on elective percutaneous coronary intervention (PCI)related MD. We measured changes in serum high-sensitive troponin T (hs-TnT) levels, CYP2C19 genotype, and onclopidogrel platelet aggregation (PA) using VerifyNowÒ P2Y12 system in 91 patients who received stent implantation (stent group). The control group comprised 30 patients who did not receive PCI. Blood samples were obtained before and 24 h after PCI or coronary angiography (CAG). Patients of the stent group were divided into high and low MD groups based on the median value of hsTnT level at 24 h after PCI. Serum hs-TnT levels were significantly higher 24 h after PCI (86.8 ± 121.5 pg/ml) compared with before PCI (9.4 ± 5.3, p \ 0.001), whereas the levels were identical before and 24 h after CAG in the control group. Simple logistic regression analysis demonstrated that MD correlated with age (p = 0.014), estimated GFR (p = 0.003), hemoglobin A1c (p = 0.015), baseline serum hs-TnT (p = 0.049), and stent length (p \ 0.001). Multiple logistic regression analysis identified old age, high hemoglobin A1c level, and long stent, but not CYP2C19 reduced-function allele or high on-clopidogrel PA, as independent predictors of elective PCI-related MD.
H. Yoshimura K. Kaikita (&) T. Ono S. Iwashita N. Nakayama K. Sato E. Horio K. Tsujita S. Kojima S. Tayama S. Hokimoto H. Ogawa Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan e-mail: [email protected]
The present study demonstrated no significant relation between peri-procedural MD and high on-clopidgrel PA associated with CYP2C19 reduced-function allele in patients undergoing elective PCI. Keywords Angina pectoris Coronary artery disease Blood coagulation Platelets Thrombosis
Introduction Dual antiplatelet therapy with aspirin and clopidogrel regulates activated platelets in disrupted coronary plaques and reduces atherothrombotic complications, including stent thrombosis, in patients with acute coronary syndrome (ACS) who undergo percutaneous coronary intervention (PCI) [1–8]. Clopidogrel is a prodrug that requires biotransformation to an active metabolite by cytochrome P450 (CYP) enzymes. Recently, it has been reported that carriers of at least one reduced-function CYP2C19 allele have low levels of the active metabolites of clopidogrel, diminished platelet inhibition and a higher rate of major adverse cardiovascular events among ACS patients undergoing PCI [9–14]. Especially, the reported frequency of CYP2C19 reduced-function allele in Japanese population is approximately twice that in Caucasians, indicating that regulation of platelet aggregation can be inadequate in Japanese patients undergoing PCI [15]. On the other hand, myocardial damage (MD) during PCI is reported to be associated with increased risk of major inhospital complications and major adverse clinical events [16–19]. During PCI, myocardial necrosis may result from one or more peri-procedural events, such as side-branch occlusion, disruption of collateral flow, distal embolization, coronary dissection, slow flow or no-reflow phenomenon,
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and microvascular plugging, which can be detected by coronary angiography [20]. The recent ESC guidelines define peri-procedural myocardial infarction during PCI as elevation of cardiac biomarkers [21]. A recent study demonstrated that Asian patients carriers of CYP2C19 reduced-function alleles with non-ST elevation acute coronary syndrome, often exhibit high platelet reactivity, which is associated with increased risk for periprocedural myocardial infarction [22]. However, little is known about the effect of CYP2C19 reduced-function gene polymorphism on the incidence of peri-procedural MD in patients with stable coronary artery disease (CAD) undergoing elective PCI. The aim of the present study was to evaluate the relation between CYP2C19 loss-of-function gene polymorphism and the incidence of peri-procedural MD in stable CAD patients undergoing elective PCI.
Methods Study population and study protocol The study subjects were 138 patients with stable CAD and angiographic evidence of C75 % organic coronary stenosis, who were admitted to our institution between September 2008 and October 2010 (Fig. 1). All patients were scheduled for elective PCI based on the presence of cardiac ischemia on stress thallium-201 single-photon emission computed tomography or treadmill test, and were treated with dual-antiplatelet therapy of both aspirin (100 mg/day) and clopidogrel (loading dose of 300 mg followed by 75 mg/day). Of the 138 patients, PCI was conducted in 108 patients with stable exertional angina. Following PCI, we excluded from the analysis 17 patients for the following reasons: only balloon angioplasty (n = 2), incomplete sampling (n = 11), and high-sensitive troponin T (hs-TnT) level at baseline of [0.030 ng/ml (n = 4). Thus, the stent group comprised 91 patients. The other 30 patients who did not receive PCI were included as the control group. The stent group was subsequently divided into high and low MD groups based on the median value of serum hs-TnT levels. The study did not include patients treated with warfarin, steroids, thrombolytic agents, ticlopidine, sarpogrelate or cilostazol, and those with deep vein thrombosis, atrial fibrillation, collagen disease, infection, hepatic dysfunction (serum aspartate aminotransferase or alanine aminotransferase levels C twice the upper limit of normal), renal dysfunction (serum creatinine C2.0 mg/dl or on dialysis), and malignant diseases. We also excluded patients with ACS, defined as either acute myocardial infarction (with or without ECG evidence of ST-segment elevation) or those with unstable angina (class II or III of Braunwald’s classification).
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Fig. 1 Flow chart of the study recruitment process. CAG Coronary angiography, hs-TnT high-sensitive troponin T
The study protocol was approved by the Human Ethics Review Committee of Kumamoto University Graduate School of Medicine, and an informed signed consent form was obtained from each subject. Measurement of cardiac biomarker Venous blood samples were obtained before, immediately after, 1, 2, and 28 days after elective PCI, or before and 24 h after coronary angiography (CAG) in the control group. At the time of blood sampling, the first 3 ml of blood was used for biochemical assessment, while the subsequent 4.5 ml of venous blood was collected into a Vacutainer tube containing 0.5 ml of sodium citrate solution (0.13 mol/l, pH 7.5). All blood samples were centrifuged immediately at 1,7009g for 10 min at 4 °C, and aliquots of samples were stored at -80 °C until analysis. Serum hs-TnT levels were measured by Elecsys 2010 analyzer (Roche Diagnostics, Mannheim, Germany) as described previously [23]. The detection limit of serum hsTnT in the method was 0.005 ng/ml. Determination of CYP2C19 genotype and phenotype Genomic DNA was extracted from whole blood using the DNA Extractor WB kit (Wako Pure Chemical Industries, Osaka, Japan) and the modified protocol of Richards et al. [24]. PCR restriction fragment length polymorphisms
Heart Vessels
(RFLPs) for CYP2C19*2 (681G [ A) and CYP2C19*3 (636G [ A) were performed as described previously [25]. The CYP2C19 genotype was classified into three phenotypes: extensive metabolizer (EM) carrying normal function alleles (CYP2C19*1/*1), intermediate metabolizer (IM) carrying one loss-of-function allele (*1/*2, *1/*3), and poor metabolizer (PM) carrying two loss-of-function alleles (*2/*2, *2/*3, *3/*3). Assessment of clinical outcome
Table 1 Clinical characteristics of the control and stent groups at baseline Control group n = 30
Stent group n = 91
p value
Age, (years)
71.7 ± 9.2
68.8 ± 9.6
0.256
Female sex, n (%)
9 (30.0)
23 (25.3)
0.523
Body mass index (per kg/m2)
26.0 ± 2.3
25.3 ± 3.4
0.289
Current smokers, n (%)
3 (10.0)
22 (24.1)
0.116
Diabetes mellitus, n (%)
12 (40.0)
23 (25.3)
0.093
Hypertension, n (%)
25 (83.3)
77 (84.6)
0.309
After laboratory sampling and elective PCI, all patients received standard medical therapy and were followed for a maximum of 6 months or by visits until occurrence of the clinical endpoint. The clinical endpoint was a major cardiac or cerebrovascular event, such as cardiac death, nonfatal myocardial infarction, unstable angina pectoris, or ischemic stroke.
Dyslipidemia, n (%)
23 (76.7)
63 (69.2)
0.286
Total cholesterol, (mg/dl)
160.8 ± 31.7
168.0 ± 32.3
0.422
LDL-C, (mg/dl)
90.8 ± 34.0
96.0 ± 25.7
0.524
HDL-C, (mg/dl) Triglyceride, (mg/dl)
50.9 ± 18.2 146.7 ± 53.7
48.0 ± 13.2 147.3 ± 100.2
0.721 0.454
Hemoglobin A1c, (%)
6.22 ± 1.12
5.92 ± 1.01
0.158
Statistical analysis
Baseline serum hs-TnT, (pg/ml)
12.0 ± 13.4
9.4 ± 5.3
0.156
eGFR, (ml/min/1.73 m2)
68.8 ± 31.0
68.0 ± 17.3
0.902
Data are expressed as mean ± standard deviation. Categorical data are presented by frequencies and percentages. Differences between carriers and noncarriers were tested with the v2 test (and Fisher exact test) for categorical variables. Differences in continuous variables were analyzed by the unpaired t test and Mann–Whitney U test. The statistical significance of changes in the time course of platelet function tests and biomarkers between carriers and noncarriers were evaluated by one-way analysis of variance for repeated measures. Associations between the presence of carriers of at least one reduced-function CYP2C19 allele and other significant parameters that have been shown to alter platelet function in recent studies [26–30] were analyzed by multiple logistic regression analysis with the forced entry method. The Hosmer–Lemeshow statistic was applied to assess model calibration. A p value of \0.05 denoted statistical significance. All statistical analyses were performed using The Statistical Package for Social Sciences version 18 (SPSS Inc., Tokyo).
CYP2C19 genotype *1/*1, n (%)
13 (43.3)
32 (35.1)
0.422
*1/*2, n (%)
9 (30.0)
36 (39.6)
0.346
*1/*3, n (%)
4 (13.3)
12 (12.2)
0.772
*2/*2, n (%)
2 (6.7)
7 (7.7)
0.829
*2/*3, n (%)
2 (6.7)
2 (2.2)
0.943
*3/*3, n (%) Carriers, n (%)
0 (0) 17 (56.7)
2 (2.2) 59 (64.8)
0.995 0.422
Use of b-blockers, n (%)
12 (40.0)
43 (47.3)
0.489
Use of ISDNs, n (%)
4 (13.3)
29 (31.9)
0.082
Use of CCBs, n (%)
12 (40.0)
52 (57.1)
0.103
Use of ACE-Is or ARBs, n (%)
20 (66.7)
54 (59.3)
0.475
Use of Statins, n (%)
19 (63.3)
69 (75.8)
0.183
Use of PPIs, n (%)
6 (20.0)
30 (33.0)
0.178
Data are mean ± SD or n (%) LDL-C Low-density lipoprotein cholesterol, HDL-C high-density lipoprotein cholesterol, hs-TnT high-sensitivity troponin T, eGFR estimated glomerular filtration rate, ISDN isosorbide dinitrates, CCB calcium-channel blocker, ACE-I angiotensin-converting enzyme antagonist, ARB angiotensin II receptor antagonist, PPI proton pump inhibitor
Results Frequency of CYP2C19 phenotypes and patient characteristics The distributions of the CYP2C19 genotype in the 121 patients are listed in Table 1. 59 cases (64.8 %) were carriers of at least one CYP2C19 reduced-function allele, and 32 cases (35.2 %) were noncarriers (EM) in the Stent group. Of the 30 patients who underwent CAG and were
treated with aspirin and clopidogrel, 17 cases (56.7 %) were carriers, and 13 cases (43.3 %) were noncarriers. The clinical features of patients of the control and the stent groups are listed in Table 1. There were no significant differences between the two groups in baseline characteristics known to be associated with platelet aggregation. Table 1 also lists the medication history in each group at the time of baseline blood sampling. The proportions of patients on isosorbide dinitrates, calcium channel blockers,
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Heart Vessels Fig. 2 Serum hs-TnT levels before and 24 h after PCI (PCI group, n = 91) or CAG (Control group, n = 30). Data of individual patients and the mean ± SD for each group
angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, b-blockers, statins, and proton pump inhibitors were identical in the two groups. Changes in serum hs-TnT levels before and 24 h after PCI or CAG, and clinical outcome in carriers and noncarriers Serum hs-TnT levels increased significantly 24 h after PCI (baseline: 9.4 ± 5.3, Post-PCI: 86.8 ± 121.5 pg/ml, p \ 0.001, Fig. 2), whereas the levels did not change 24 h after CAG in the control group (baseline: 12.0 ± 13.4, Post-CAG: 17.9 ± 14.5 pg/ml, p = 0.249). We underwent coronary stenting with BMS in 16 patients (17.6 %) and with DES in 75 patients (82.4 %). There was no significant difference in serum hs-TnT levels at baseline (8.6 ± 2.7 vs 8.5 ± 3.8 pg/ml, p = 0.865) and 24 h after PCI (58 ± 72 vs 93 ± 144 pg/ ml, p = 0.144) between BMS and DES groups. During the follow-up period, only 1 carrier developed epidural hematoma caused by trauma, while no major cardiac or cerebrovascular events were encountered in the noncarriers of the stent group. Patient characteristics and angiographic morphology based on ACC/AHA lesion classification in high and low peri-procedural MD groups Table 2 lists the clinical features of patients of the stent group divided into low and high MD groups. Age, serum hemoglobin A1c level, and baseline serum hs-TnT levels
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were significantly higher in the high peri-procedural MD than the low peri-procedural MD group. On the other hand, the frequencies of dyslipidemia and estimated glomerular filtration rate (eGFR) were significantly lower in the high peri-procedural MD than the other group. Furthermore, PCI involving the left anterior descending (LAD) lesions were more common in low MD than high MD patients (Table 3). The ACC/AHA lesion class was identical between the two groups. There was no significant difference in the number of patients implanted DES between Low MD and High MD groups (Table 3). The stent diameter was significantly smaller, and the total stent length was significantly longer in the high MD than low MD group. Simple and multiple logistic regression analyses for prediction of peri-procedural MD Finally, we used logistic regression analysis to determine predictors of high peri-procedural MD in the stent group. Simple logistic regression analysis demonstrated that high peri-procedural MD was significantly associated with age, eGFR, serum HbA1c level, serum hs-TnT level before PCI, and total stent length (Table 4). Multiple logistic regression analysis identified old age ([75 years), high serum HbA1c level ([6.1 %), and long stent ([3.0 mm long), but not presence of CYP2C19 reduced-function allele or on-clopidgrel PA, as significant predictors of high peri-procedural MD (Table 4). Hosmer–Lemeshow goodness of fit v2 was 1.603 with a p value of 0.979.
Heart Vessels Table 2 Clinical characteristics of patients of the stent group with low and high myocardial damage
Table 3 Angiographic morphology of the stent group Low MD n = 45
High MD n = 46
Left main, n (%)
3 (6.7)
2 (4.3)
Left anterior descending (%)
26 (57.8)
17 (37.0)
0.046
Left circumflex, n (%)
4 (8.9)
8 (17.4)
0.354
Right, n (%)
12 (26.7)
19 (41.3)
0.141
A, n (%) B1, n (%)
11 (24.4) 16 (35.6)
5 (10.9) 16 (34.8)
0.105 0.938
0.096 0.119
Simple Lesion (A/B1) (%)
26 (57.8)
19 (41.3)
0.116
B2 (%)
13 (28.9)
14 (30.4)
0.871
C (%)
7 (15.6)
13 (28.3)
0.226
Low MD n = 45
High MD n = 46
p value
Age, (years)
67.0 ± 8.77
70.3 ± 10.8
0.038
Female sex, n (%)
8 (17.8)
15 (32.6)
0.165
Body mass index (per kg/m2)
25.0 ± 2.9
25.6 ± 3.8
0.540
Current smokers, n (%)
13 (28.9)
9 (19.6)
0.427
Diabetes mellitus, n (%)
11 (24.4)
12 (26.1)
0.865
Hypertension, n (%) Dyslipidemia, n (%)
33 (73.3) 34 (75.6)
35 (76.1) 29 (63.0)
p value
Target lesion coronary artery
ACC/AHA lesion class
Total cholesterol, (mg/dl)
166.7 ± 36.4
171.5 ± 27.2
0.560
LDL-C, (mg/dl)
93.0 ± 28.8
97.7 ± 22.7
0.307
HDL-C, (mg/dl)
48.8 ± 13.5
48.1 ± 13.0
0.735
Stent diameter, (mm)
Triglyceride, (mg/dl)
162.9 ± 117.9
134.1 ± 81.7
0.273
Total stent length per patients (mm)
Hemoglobin A1c, (%)
5.67 ± 0.83
6.19 ± 1.14
0.015
Baseline serum hs-TnT, (pg/ml)
7.6 ± 3.8
10.9 ± 5.9
0.002
eGFR, (ml/min/ 1.73 m2)
72.5 ± 14.9
63.5 ± 18.3
0.003
20 lmol/L ADP-PR max (%)
52.9 ± 11.9
51.3 ± 12.5
0.549
20 lmol/L ADP-PR area (AU*min)
3560.3 ± 1692.2
3485.0 ± 1594.9
0.880
P2Y12 reaction unit
245.4 ± 88.3
238.4 ± 85.8
0.723
% Inhibition (%)
26.8 ± 22.7
26.9 ± 21.4
0.911
*1/*1, n (%)
16 (35.6)
16 (34.8)
0.938
*1/*2, n (%)
16 (35.6)
20 (43.5)
0.440
*1/*3, n (%)
6 (13.3)
6 (13.0)
0.788
*2/*2, n (%) *2/*3, n (%)
5 (11.1) 1 (2.2)
2 (4.3) 1 (2.2)
0.414 0.484
*3/*3, n (%)
1 (2.2)
1 (2.2)
0.484
Complex lesion (B2/C) (%)
CYP2C19 genotype
Carriers, n (%)
29 (64.4)
30 (65.2)
0.938
Use of b-blockers, n (%)
23 (51.1)
20 (43.5)
0.465
Use of ISDNs, n (%)
12 (26.7)
17 (37.0)
0.292
Use of CCBs, n (%)
23 (51.1)
29 (63.0)
0.250
Use of ACE-Is or ARBs, n (%)
23 (51.1)
31 (67.4)
0.114
Use of Statins, n (%)
38 (84.4)
31 (67.4)
0.098
Use of PPIs, n (%)
17 (37.8)
13 (28.3)
0.671
Data are mean ± SD or n (%) Abbreviation as in Table 1. MD myocardial damage, ADP-PR max adenosine diphosphate induced platelet reactivity maximum aggregation
0.677
Use of DES
20 (44.4)
27 (58.7)
0.174
10 (22.2)
8 (17.4)
0.563
3.08 ± 0.47
2.86 ± 0.37
0.033
22.5 ± 10.8
35.8 ± 15.8 \0.001
Data are mean ± SD or n (%) DES Drug-eluting stent
Discussion The present study demonstrated that high peri-procedural MD correlated closely with old age, high serum hemoglobin A1c levels, and long stent, but not the presence of CYP2C19 reduced-function allele or high on-clopidogrel PA activity, in stable CAD patients undergoing elective PCI. This is the first report describing the lack of association between peri-procedural MD and CYP2C19 reducedfunction polymorphism in stable CAD patients undergoing elective PCI. Carriers of at least one reduced-function CYP2C19 allele are reported to have weak platelet inhibition and are at high risk of major adverse cardiovascular events among ACS patients undergoing PCI [13, 31]. Another report also described a high incidence of peri-procedural MD in patients with high post-treatment platelet reactivity and non-ST elevation acute coronary syndrome [22]. However, our study demonstrated that peri-procedural MD is not necessarily influenced by the presence of CYP2C19 reduced-function allele or high on-clopidogrel PA in stable CAD patients undergoing elective PCI. In this regard, the GRAVITAS trial did not recommend a treatment strategy of high-dose clopidogrel in low-risk patients with high residual reactivity identified by a single platelet function test after elective PCI [32]. The ARCTIC study also demonstrated no significant improvement in clinical outcome by platelet function monitoring and adjustment of treatment before elective PCI, compared to standard antiplatelet therapy without monitoring [33].
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Heart Vessels Table 4 Results of simple and multiple regression analyses for determinants of high hs-TnT levels
Data are mean ± SD or n (%) a Data of these parameters were divided into two groups based on the following criteria; age [75 years, body mass index [25 kg/m2, total cholesterol [167 mg/dl, LDLC [100 mg/dl, HDLC \40 mg/dl, TG [150 mg/dl, HbA1c [6.1 % (JDS), PRU [230 b
Data of these parameters were divided into two groups based on the median value. Abbreviations as in Tables 1, 2 and 3
Simple regression analysis
Multiple regression analysis
OR
95 % CI
p value
OR
95 % CI
p value
Age, (years)a
3.36
1.32–8.54
0.014
2.05
1.67–36.3
0.009
Male sex, n (%)
2.24
0.83–5.97
0.148
Body mass index (per kg/m2)a
0.82
0.35–1.91
0.674
Current Smokers, n (%)
0.60
0.20–1.58
0.336
Hypertension, n (%)
2.42
0.82–7.16
0.121
Dyslipidemia, n (%)
0.46
0.18–1.13
0.119
Total cholesterol, (mg/dl)a
1.15
0.50–2.66
0.832
LDL-C, (mg/dl)a
1.99
0.85–4.64
0.137
HDL-C, (mg/dl)a
1.20
0.46–3.10
0.810
Triglyceride, (mg/dl)a
0.51
021–1.25
0.183
Platelet count, (103/ll)b Hemoglobin A1c, (%)a
0.91 3.86
0.40–2.09 1.38–10.71
0.837 0.015
1.49
1.06–18.6
0.041
eGFR, (ml/min/1.73 m2)b
4.24
1.62–11.05
0.003
1.01
0.73–10.3
0.137
ADP-PRmax (%)b
0.55
0.23–1.27
0.202
1.25
0.55–2.84
0.677
P2Y12 reaction unit
1.01
0.43–2.38
1.000
CYP2C19 carrier
1.04
0.44–2.42
1.000
Baseline hs-TnT (pg/ml)b
2.55
1.05–6.18
0.049
1.02
0.81–9.44
0.103
Previous myocardial infarction
3.22
0.94–11.02
0.088
Previous PCI
2.34
1.01–5.43
0.060 2.29
2.29–42.7
0.002
ADP-PR area (AU*min)b a
Use of DES
1.36
0.48–3.83
0.563
Total stent length, (mm)b
8.44
3.11–23.0
\0.001
Stent diameter, (mm)b
0.55
0.23–1.27
0.202
Complex lesion (Type B2, C)
1.78
0.77–4.08
0.211
Peri-PCI MD could be caused by one or more of the following events: side-branch occlusion, disruption of collateral flow, distal embolization, coronary dissection, slow flow or no-reflow phenomenon, and microvascular plugging, which can be demonstrated on CAG [20, 23]. Several clinical studies indicated that the development of peri-procedural MD correlated with the presence of lowdensity coronary atherosclerotic plaques on computed tomography, positive remodeling and spotty calcification of coronary plaques on intravascular ultrasonography, yellowish coronary plaque on vascular endoscopy, and implantation of long stent [16, 34, 35]. The present results suggested that modification of PCI strategy or reduction of coronary risk, rather than anti-platelet therapy for high onclopidgrel PA, may be more important in reducing periprocedural MD in patients with stable CAD undergoing elective PCI. Peri- PCI procedural myocardial infarction is defined as high cardiac troponin (cTn) level [[5 9 99th percentile of upper reference limit (URL)] in patients with normal baseline values (B99th percentile of URL), or high cTn levels (by [20 %) in patients with high stable or falling baseline levels [21]. However, it is possible that the
123
diagnosis of the peri-procedural myocardial infarction might fluctuate by the kind of cardiac biomarkers used because the sensitivity and normal baseline values are different among each cardiac biomarker. In the present study, we used a highly sensitive assay system of serum TnT to assess the peri-procedural MD and divided the stent group into high and low MD groups based on the median value of serum hs-TnT levels. In the present study, none of the patients developed major cardiac or cerebrovascular events during the followup period, with the exception of peri-procedural MD. Carriers of CYP2C19 reduced-function allele constituted 65 % of the patients in the present study, while the remaining 35 % were noncarriers for the allele. In a recent study of healthy Caucasians, the prevalence of the CYP2C19 reduced-function allele was only 30 % among the total study population [13]. Previous studies indicated that adverse cardiovascular events, including stent thrombosis after primary or elective PCI, are lower in Japanese than Caucasians [36–38], although the frequency of carriers of at least one CYP2C19 reduced-function allele is higher in the Japanese than Caucasians. The reason for the low frequency of adverse cardiovascular events in Japan
Heart Vessels
remains unknown; however, it is possible that other factors, such as the PCI procedure, the characteristics of the culprit coronary plaques, and coronary risk factors, rather than high on-clopidogrel PA caused by the CYP2C19 reducedfunction allele, may influence the clinical outcome of CAD patients undergoing elective PCI. In conclusion, the present study demonstrated no significant relation between peri-procedural MD and clopidogrel resistance in patients undergoing elective PCI. The frequency of peri-procedural MD did not correlate with high on-clopidogrel PA in stable CAD patients undergoing elective PCI. The results emphasize the need for an effective interventional strategy for elderly diabetic patients, rather than adjustment of strategy for high onclopidgrel PA associated with CYP2C19 reduced-function allele, to reduce the incidence of peri-procedural MD in elective PCI. Acknowledgments We are grateful to Megumi Nagahiro and Saeko Tokunaga from the Department of Cardiology, Kumamoto University, for the skillful technical assistance. This study was supported in part by Grants-in-Aid for Scientific Research C24591062 from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Conflict of interest
The authors declare no conflict of interest.
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