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It remains unknown whether the time course of the antiplatelet effects of clopidogrel differs according to cytochrome P450 (CYP) 2C19 phenotype in Japanese patients with acute coronary syndromes (ACS).
Methods and results
Platelet reactivity was serially assessed by VerifyNow-P2Y12 assay (Accumetrics, San Diego, CA, USA). Results were expressed as P2Y12-reaction-units (PRU) in 177 patients with ACS who underwent stent implantation and received aspirin plus a 300-mg loading dose of clopidogrel followed by 75 mg/day. High on-clopidogrel treatment platelet reactivity (HTPR) was defined as PRU > 235. On the basis of the CYP2C19*2 and *3 alleles, 46 patients (26.0%) were classified as extensive metabolizers (EM), 103 (58.2%) as intermediate metabolizers (IM), and 28 (15.8%) as poor metabolizers (PM). At <7 days, the PRU level (232 ± 102 vs. 279 ± 70, 308 ± 67, p < 0.001) and the incidence of HTPR (49% vs. 74%, 86%, p = 0.001) was lower in EM than in IM and PM. At 14–28 days the effects of CYP2C19 polymorphisms on PRU levels increased in a stepwise fashion (168 ± 99 vs. 213 ± 77 vs. 278 ± 69, p < 0.001), and EM and IM had lower percentages of HTPR than PM (28%, 37% vs. 73%, p < 0.001). There was no significant difference in the cumulative frequency of 12-month adverse cardiovascular events among 3 phenotypes (16.5%, 14.1%, 9.2%; p = 0.67).
Conclusion
About three quarters of Japanese patients with ACS carried CYP2C19 variant alleles. The majority of IM and PM had increased platelet reactivity during the early phase of ACS. Although HTPR was frequently observed even 14–28 days after standard maintenance doses of clopidogrel in PM, the incidence of adverse outcomes did not differ, irrespective of CYP2C19 genotype.
Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel has been a cornerstone of medical treatment for patients who have acute coronary syndromes (ACS) or undergo percutaneous coronary intervention (PCI) [
], and high on-clopidogrel treatment platelet reactivity (HTPR) is associated with adverse cardiovascular events, including stent thrombosis after implantation [
Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate?.
]. Clopidogrel is a prodrug that must be metabolized by the cytochrome P (CYP) 450 enzyme system to generate active metabolites. Metabolic activation by CYP2C19 is crucial for generation of such metabolites. Several gene variants are associated with reduced or enhanced CYP2C19 activity, however, CYP2C19*2 and CYP2C19*3 are the major mutant alleles of CYP2C19 that account for >99% of loss-of-function (LOF) alleles in Asian populations [
]. Carriers of the CYP2C19*2 and/or CYP2C19*3 LOF alleles have a reduced pharmacodynamic response to clopidogrel and worse clinical outcomes as compared with noncarriers in Asian countries [
Effect of CYP2C19*2 and *3 loss-of-function alleles on platelet reactivity and adverse clinical events in east Asian acute myocardial infarction survivors treated with clopidogrel and aspirin.
]. However, it is unknown whether the time course of the antiplatelet effects of clopidogrel differs according to CYP2C19 phenotype in Japanese patients with ACS. We serially assessed platelet reactivity in the early and late phases of ACS according to CYP2C19 phenotypes in Japanese patients who underwent coronary stent implantation.
Methods
Study population
We conducted a prospective, multicenter study designed to assess platelet function serially according to CYP2C19 genotype in ACS patients who were scheduled to undergo coronary stent implantation treated with DAPT. A total of 300 consecutive patients were assessed for eligibility. Patients who met the inclusion criteria were registered to randomized study to assess the impacts of omeprazole and famotidine on the antiplatelet effects of clopidogrel (n = 180). Patients excluded from the randomized study were registered to cohort study (n = 88). Finally, 177 patients were analyzed in the present study in whom platelet reactivity was serially assessed by VerifyNow-P2Y12 (Accumetrics, San Diego, CA, USA) assay and CYP2C19 phenotype was determined (Fig. 1).
The inclusion criteria for patients with ST-segment elevation myocardial infarction (STEMI) were ischemic symptoms that lasted for 20 min or more, ST-segment elevation of ≥1 mm in ≥2 continuous precordial leads or in ≥2 limb leads, elevated levels of a cardiac biomarker of necrosis, and undergoing primary PCI within 12 h after onset of symptoms. ACS patients without persistent ST-segment elevation had to have ischemic symptoms lasting ≥10 min and occurring within 72 h before the study entry, and either ST-segment deviation of ≥1 mm or elevated levels of a cardiac biomarker of necrosis.
Exclusion criteria included major bleeding events within 7 days before enrollment, a serum hemoglobin level of <11 g/dl or >17 g/dl, a platelet count of <120,000/mm3 or >500,000/mm3, hematologic or malignant disease, a serum creatinine level of >2.0 mg/dl, severe liver dysfunction, or the use of oral anticoagulant agents, thienopyridine derivatives, cilostazol, glycoprotein IIb/IIIa inhibitors, or fibrinolytic agents within 7 days before enrollment. Patients were also excluded if they did not receive stent implantation within 14 days after symptom onset, if they underwent coronary artery bypass grafting (CABG), or if they received oral anticoagulant agents during the study period.
Antiplatelet therapy and PCI procedure
All patients were required to receive aspirin 100 mg/day indefinitely and a 300-mg loading dose of clopidogrel followed by 75 mg/day for at least 12 months. A 200-mg loading dose of aspirin was administered only in aspirin-naïve patients. Primary PCI was performed immediately after a loading dose of clopidogrel was administered. Planned PCI was performed at least 6 h after patients received the loading dose of clopidogrel. PCI was performed in a standard manner. The choice of vessels treated, devices used (including stent type), and adjunctive medication administered to support PCI was left to the discretion of the treating physicians. At the time of the study, glycoprotein IIb/IIIa inhibitors and intravenous anticoagulants other than unfractionated heparin were not approved for use in patients with ACS or stent implants (or both) in Japan. Intravascular ultrasound (IVUS) examination was performed at the end of PCI procedure in all study patients. Intracoronary isosorbide dinitrate (2 mg) was administered before IVUS examination to prevent coronary spasm. All coronary angiograms and IVUS findings were evaluated by a single cardiologist who was blinded to all other clinical data.
Platelet function tests and genotyping
Platelet function tests were serially performed with the use of the VerifyNow P2Y12/aspirin assays before clopidogrel loading (baseline), within 7 days after clopidogrel loading (early phase), and at 14–28 days (late phase). If platelet function test was performed after stent implantation, it was required that the time from PCI to blood sampling was >96 h in order to avoid the influence of heightened platelet reactivity induced by PCI procedure. Thus, the second platelet function test was done 5–7 days after clopidogrel loading in patients with primary PCI. Medical treatment was not changed according to the results of VerifyNow P2Y12/aspirin assays. CYP2C19 genotypes were determined. The attending physician was blinded to the results of CYP2C19 genotype. The institutional review boards of all participating centers approved the study protocol, and all patients provided written informed consent and agreed to CYP2C19 genotyping.
VerifyNow P2Y12/aspirin assays
Whole blood was collected from peripheral venous sites using a 21-gauge or larger needle into a Greiner blood collection tube (GP-CD018) containing 3.2% sodium citrate, after first discarding the initial approximately 2 mL collected. The VerifyNow system® is a rapid point-of-care platelet function test system. The VerifyNow P2Y12 test measures ADP-induced platelet aggregation and reports results as P2Y12 Reaction Units (PRU). A second channel in the test device activates platelets through the thrombin receptor pathway, which is P2Y12-receptor-independent and provides a simultaneous estimate of baseline total platelet function, which is reported as “Base PRU.” The percent inhibition of ADP-induced platelet aggregation is calculated from the PRU and Base PRU values. Because it has been reported that a cutoff of HTPR is determined as 230–240 PRU based on receiver-operating characteristic curve analysis in Western populations [
Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up.
Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention results of the ARMYDA-PRO (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity Predicts Outcome) study.
Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation.
Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data.
], HTPR was defined as PRU > 235 in the present study, despite a lack of consensus on the cutoff value associated with clinical outcomes in Japanese patients with ACS [
]. In a similar manner, the VerifyNow Aspirin test contains arachidonic acid to activate the platelets and measure the antiplatelet effect of aspirin. Results from the VerifyNow Aspirin test are reported as aspirin reaction units (ARU). Aspirin resistance was defined as ARU > 550 [
CYP2C19 genotypes were determined by Invader assay. Genotyping was performed for CYP2C19*2 (rs4244285, c.681G>A) and CYP2C19*3 (rs4986893, c.636G>A) variants. Genomic DNA was extracted from whole blood using a commercially available QIAamp DNA Blood Mini kit (Qiagen, Venlo, The Netherlands). Previous studies have reported that the CYP2C19*2 and CYP2C19*3 alleles are frequent, whereas the CYP2C19*17 allele is rare in Asians [
]. Patients were classified into categories of metabolizer phenotypes with the use of established common-consensus star allele nomenclature. Thus, patients without a *2 or *3 allele (non-carriers) were classified as “extensive metabolizers (EM),” those with one *2 or *3 allele were classified as “intermediate metabolizers (IM),” and those with two *2 or *3 alleles were classified as “poor metabolizers (PM).” Carriers of at least 1 CYP2C19 LOF allele were classified as “CYP2C19 LOF allele carriers.”
Clinical outcomes
Follow-up visits were conducted at participating centers for at least 12 months. Patients who became unable or were unwilling to come to the hospital were contacted by telephone. Adverse cardiovascular events were defined as death from cardiovascular causes, spontaneous myocardial infarction, stent thrombosis, ischemic stroke, target vessel revascularization, or non-target vessel revascularization. Myocardial infarction was defined according to the universal definition proposed in 2007 [
]. Non-target vessel revascularization was defined as the procedure to newly diagnosed stenosis (≥75%) or occlusion on the coronary angiogram. All the procedures were carried out at the discretion of the operator. Planned PCI for residual stenotic lesion was not considered an adverse event. Similar to trials such as REPLACE-2 [
], non-CABG-related major bleeding was defined as symptomatic intracranial, intraocular, or retroperitoneal hemorrhage, clinically overt blood loss including gastrointestinal bleeding resulting in a decrease in hemoglobin by >3 g/dl, or bleeding requiring transfusion of ≥2 units of red blood cells. The study was designed and conducted by the authors. The sponsor had no role in the design or conduct of the study, in the analysis of the results, or in the decision to publish the paper.
Statistical analysis
Categorical variables are expressed as percentages and were compared by the chi-square test. Allele frequencies were calculated, and departure from Hardy–Weinberg equilibrium was tested by the chi-square test. Continuous variables were compared by one-factor analysis of variance and are reported as means ± SDs. Potential predictors which were demographic, clinical, and angiographic variables (shown in Table 1, Table 2) with p-values of <0.20 on univariate analysis were included in multivariate logistic regression analysis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. Event-free rates from the time of clopidogrel loading were estimated by the Kaplan–Meier method and compared with the use of the log-rank test. Values of p < 0.05 were considered to indicate statistical significance. Data were analyzed with SPSS 19 (SPSS, Inc., Chicago, IL, USA).
Table 1Patient characteristics and angiographic findings.
Platelet reactivity was serially assessed and CYP2C19 genotypes were determined in 177 patients with ACS who underwent stent implantation and received aspirin and clopidogrel. There was no significant difference in the baseline characteristics between 126 patients in the randomized study and 51 patients in the cohort study, except for the rates of medical history of proton pump inhibitors (0% vs. 29%, p < 0.001) and H2 receptor antagonists (0% vs. 14%, p < 0.001) (data not shown). The numbers of patients carrying the CYP2C19*1/*1, *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3 genotypes were 46 (26.0%), 75 (42.4%), 28 (15.8%), 14 (7.9%), 13 (7.3%), and 1 (0.6%), respectively. The proportions of patients with the CYP2C19*1, CYP2C19*2, and CYP2C19*3 polymorphisms were 55.1%, 32.8%, and 12.1%, respectively. Genotype frequency results were consistent with Hardy–Weinberg equilibrium (p > 0.05). The distribution of CYP2C19 phenotype was as follows: 26.0% in EM, 58.2% in IM, and 15.8% in PM. The proportion of CYP2C19 LOF allele carriers was extremely high (74.0%).
There were no significant differences in patient characteristics and angiographic findings among 3 phenotypes, except for the proportion of current smokers (Table 1). Significant difference was not observed in medication among 3 phenotypes. Omeprazole (73%) was frequently prescribed among proton pump inhibitor-treated patients (n = 86), whereas the rate of taking omeprazole was similar among 3 phenotypes (Table 2). PRU levels at baseline were similar among the 3 phenotypes. Time course of PRU levels from baseline to the late phase among the 3 phenotypes is shown in Fig. 2. At <7 days (an average of 3.6 days), the PRU level (232 ± 102 vs. 279 ± 70, 308 ± 67, p < 0.001) and the incidence of HTPR (PRU > 235) (49% vs. 74%, 86%, p = 0.001) were lower in EM than in IM or PM. At 14–28 days (an average of 19.9 days), the effects of CYP2C19 polymorphisms on PRU levels increased in a stepwise fashion (168 ± 99 vs. 213 ± 77 vs. 278 ± 69, p < 0.001), and the rates of HTPR were lower in EM and IM than that in PM (28%, 37% vs. 73%, p < 0.001). Whereas there was no significant difference in PRU value at <7 days between IM and PM (p = 0.19), IM had significantly lower PRU level at 14–28 days compared with PM (p < 0.01). The rates of aspirin resistance were low at <7 days and at 14–28 days in all 3 phenotypes (Table 3). On multivariate logistic regression analysis, IM (OR: 2.86, CI: 1.25–6.53, p = 0.01) and PM (OR: 5.65, CI: 1.51–21.03, p = 0.01) were both independent predictors of HTPR at <7 days, as were an age of >70 years (OR: 5.07, CI: 2.05–12.53), diabetes mellitus (OR: 2.62, CI: 1.01–6.75), and current smoker (OR: 0.41, CI: 0.18–0.93) (Table 4a). In contrast, PM (OR: 6.59, CI: 2.13–20.31, p = 0.001) and an age of >70 years (OR: 2.18, CI: 1.05–4.50) were independent predictors of HTPR at 14–28 days, whereas IM was not (OR: 1.39, CI: 0.61–3.13, p = 0.42) (Table 4b). There was no significant difference in the cumulative frequency of adverse cardiovascular events at 12 months among 3 phenotypes (16.5%, 14.1%, 9.2%; p = 0.67) (Fig. 3). The most common adverse event was target or non-target vessel revascularization. Only 2 patients in IM had myocardial infarction or ischemic stroke, and stent thrombosis did not occur.
Fig. 2Time course of P2Y12 reaction units (PRU) measured by VerifyNow P2Y12 assay. The mean PRU level significantly decreased from baseline to the late phase in course of time in EM and IM, although it remained unchanged during the study period in PM. Data are expressed as mean and standard deviations. EM, extensive metabolizers; IM, intermediate metabolizers; PM, poor metabolizers.
Obesity was defined as body mass index>25 (kg/m2).
1.65 (0.77–3.48)
0.19
Potential predictors, which were demographic, clinical, and angiographic variables with p-values of <0.20 on univariate analysis, were included in a multivariate logistic regression analysis. HTPR, high on-treatment platelet reactivity; OR, odds ratio; CI, confidence interval; EM, extensive metabolizers; IM, intermediate metabolizers; PM, poor metabolizers. HTPR was defined as P2Y12 reaction units > 235.
a Obesity was defined as body mass index > 25 (kg/m2).
Fig. 3Event-free rates from the time of clopidogrel loading according to CYP2C19 phenotype. Adverse cardiovascular events were defined as death from cardiovascular causes, spontaneous myocardial infarction, stent thrombosis, ischemic stroke, target vessel revascularization, or non-target vessel revascularization. CYP, cytochrome P450; EM, extensive metabolizers; IM, intermediate metabolizers; PM, poor metabolizers.
In our study, the prevalence of CYP2C19 LOF allele carriers was extremely high (74.0%) among Japanese patients with ACS. The presence of even 1 CYP2C19 LOF allele was an independent predictor of HTPR within 7 days after clopidogrel loading (early phase of ACS). In contrast, only the presence of 2 CYP2C19 LOF alleles was an independent predictor of HTPR at 14–28 days (late phase of ACS). Although HTPR was frequently observed even 14–28 days after standard maintenance doses of clopidogrel in PM, the incidence of adverse outcomes did not differ, irrespective of CYP2C19 genotype.
The addition of clopidogrel to aspirin reduces ischemic events during and after ACS and PCI. However, recurrent ischemic events including stent thrombosis, remain a major concern even in patients who receive DAPT. Several studies have demonstrated a relation between HTPR and adverse cardiovascular events [
Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate?.
]. Variable and poor responses to clopidogrel can be explained in part by single nucleotide polymorphisms of genes encoding CYP2C19 isoenzymes with different activities [
]. A meta-analysis demonstrated that the presence of even 1 reduced-function CYP2C19 allele was associated with a significantly increased risk of adverse cardiovascular events (particularly stent thrombosis) in patients who receive clopidogrel [
Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.
]. Most episodes of stent thrombosis occurred within the first 30 days (especially within the first 7 days) after stent implantation. The results of recent clinical trials suggest that intensive platelet inhibition is prerequisite to preventing cardiovascular events, including early stent thrombosis, in patients with ACS who receive early invasive treatment [
Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial.
Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial.
]. However, there are few reports serially assessing the antiplatelet effects of clopidogrel according to CYP2C19 phenotype in patients with ACS. The present study showed that carriers of at least 1 CYP2C19 LOF allele (IM or PM), older age, and diabetes mellitus were associated with HTPR in the early phase of ACS. These results suggest that platelet reactivity in the early phase is influenced not only by CYP2C19 polymorphisms, but also by non-genetic factors, which are known to predict baseline platelet reactivity. HTPR is more frequent in patients with diabetes mellitus treated with DAPT compared with nondiabetic patients [
]. Cigarette smoking induces CYP1A2, which converts clopidogrel into its active metabolite and leads to the beneficial effect of clopidogrel on clinical outcomes [
]. In the early phase of ACS, both IM and PM had higher platelet reactivity compared with EM, although platelet function was moderately inhibited in IM who received extended treatment with clopidogrel beyond 7 days. IM still have 1 functional copy of the allele, and platelet reactivity might gradually decrease until the late phase, suggesting that a higher dose of clopidogrel or the addition of cilostazol to DAPT may be effective [
Cilostazol attenuates on-treatment platelet reactivity in patients with CYP2C19 loss of function alleles receiving dual antiplatelet therapy: a genetic substudy of the CILON-T randomised controlled trial.
Usefulness of high clopidogrel maintenance dose according to CYP2C19 genotypes in clopidogrel low responders undergoing coronary stenting for non ST elevation acute coronary syndrome.
Current status and prospects of antiplatelet therapy in percutaneous coronary intervention in Japan: focus on adenosine diphosphate receptor inhibitors.
]. Large randomized trials have failed to confirm clinical efficacy of tailoring antiplatelet therapy according to results of platelet function tests [
A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study.
]. A recent trial showed no significant improvement in ischemic outcomes and no better safety outcomes with a strategy of monitoring and drug adjustment as compared with a conventional treatment strategy. However, primary PCI for STEMI was excluded and only 27% of patients presenting with ACS without ST-segment elevation were included in the study [
]. There is the possibility of a benefit of platelet function testing in a higher-risk population.
The prevalence of the CYP2C19*2 allele is higher in Asians (30%) than in Westerners (about 15%), whereas the CYP2C19*3 allele is found in an appreciable proportion of Asians (10–20%), but is rare in Caucasians (0.04%) [
Effect of CYP2C19*2 and *3 loss-of-function alleles on platelet reactivity and adverse clinical events in east Asian acute myocardial infarction survivors treated with clopidogrel and aspirin.
Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.
]. The present study showed that PM and older age were independent predictors of HTPR in the late phase of ACS, consistent with the results of the Korean trial [
Effect of CYP2C19*2 and *3 loss-of-function alleles on platelet reactivity and adverse clinical events in east Asian acute myocardial infarction survivors treated with clopidogrel and aspirin.
]. There are considerable ethnic differences in the distribution of CYP2C19 polymorphisms and the magnitude of response to clopidogrel, and CYP2C19 genotype is significantly associated with HTPR in Asian patients. Despite this association, however, data from local registries indicate that the incidence of stent thrombosis is lower in Japanese patients (0.3% at 30 days, 0.26%/year) than in Caucasian patients [
Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study.
]. It is difficult to explain the apparent contradiction between the high prevalence of HTPR and the low incidence of thrombotic events after stent implantation among Asians. One possible explanation is that Asians have a favorable endogenous thrombolytic profile, whereas Westerners are in a prothrombotic state [
First direct comparison of platelet reactivity and thrombolytic status between Japanese and Western volunteers: possible relationship to the “Japanese paradox”.
]. Modest platelet inhibition may be enough to avoid thrombotic events in Japanese patients. Another explanation is that aspirin may have an important role in thrombotic events. Among Japanese patients with stent thrombosis, the interval from discontinuation of DAPT to onset of stent thrombosis was short (13 days), however, the interval from discontinuation of thienopyridine alone to onset of stent thrombosis was long (314 days) [
Comparisons of baseline demographics, clinical presentation, and long-term outcome among patients with early, late, and very late stent thrombosis of sirolimus-eluting stents: observations from the Registry of Stent Thrombosis for Review and Reevaluation (RESTART).
]. The low rate of aspirin resistance in the present study might be related to the low incidence of thrombotic events in Japanese patients. Other genetic and environmental factors, including angiographic and procedural characteristics, may play an important role in recurrent ischemic events in patients with ACS who undergo stent implantation.
Limitations
Our study had several limitations. First, the sample size was too small to evaluate clinical outcomes. However, our results suggested that the incidence of thrombotic events was low in Japanese ACS patients treated with DAPT who underwent stent implantation, despite the high prevalence of CYP2C19 polymorphisms and HTPR. In addition, the PRU threshold was defined as PRU > 235 in the present study. Recent studies in Korean populations have suggested a higher cutoff of HTPR (252–274) compared with Western studies [
Multicenter randomized trial evaluating the efficacy of cilostazol on ischemic vascular complications after drug-eluting stent implantation for coronary heart disease: results of the CILON-T (influence of CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stenT implantation) trial.
Different prognostic significance of high on-treatment platelet reactivity as assessed by the VerifyNow P2Y12 assay after coronary stenting in patients with and without acute myocardial infarction.
]. A threshold value of on-treatment platelet reactivity might depend on the subset of patients studied, clopidogrel loading dose, and timing of blood sampling. Further studies are needed to determine the optimal cutoff of HTPR based on receiver-operating characteristic curve analysis in Japanese patients. Moreover, the endpoint of our study was a surrogate marker, PRU value. Whether HTPR is a modifiable risk factor or simply a marker of risk remains a matter of debate [
High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI.
]. Furthermore, the time window of platelet function testing of the acute phase was wide. We performed the second platelet function test between 6 h and 7 days after clopidogrel loading, however, there was no difference in the time to measurement among 3 phenotypes. Finally, we did not evaluate active metabolites of clopidogrel, markers of platelet activation, or other genetic variants.
Acknowledgment
The work was supported by a grant from Daiichi Sankyo Co., Ltd.
References
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Zhao F.
Mehta S.R.
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Tognoni G.
Fox K.K.
Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate?.
Effect of CYP2C19*2 and *3 loss-of-function alleles on platelet reactivity and adverse clinical events in east Asian acute myocardial infarction survivors treated with clopidogrel and aspirin.
Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up.
Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention results of the ARMYDA-PRO (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity Predicts Outcome) study.
Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation.
Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data.
Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.
Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial.
Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial.
Cilostazol attenuates on-treatment platelet reactivity in patients with CYP2C19 loss of function alleles receiving dual antiplatelet therapy: a genetic substudy of the CILON-T randomised controlled trial.
Usefulness of high clopidogrel maintenance dose according to CYP2C19 genotypes in clopidogrel low responders undergoing coronary stenting for non ST elevation acute coronary syndrome.
Current status and prospects of antiplatelet therapy in percutaneous coronary intervention in Japan: focus on adenosine diphosphate receptor inhibitors.
A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study.
Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study.
First direct comparison of platelet reactivity and thrombolytic status between Japanese and Western volunteers: possible relationship to the “Japanese paradox”.
Comparisons of baseline demographics, clinical presentation, and long-term outcome among patients with early, late, and very late stent thrombosis of sirolimus-eluting stents: observations from the Registry of Stent Thrombosis for Review and Reevaluation (RESTART).
Multicenter randomized trial evaluating the efficacy of cilostazol on ischemic vascular complications after drug-eluting stent implantation for coronary heart disease: results of the CILON-T (influence of CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stenT implantation) trial.
Different prognostic significance of high on-treatment platelet reactivity as assessed by the VerifyNow P2Y12 assay after coronary stenting in patients with and without acute myocardial infarction.
High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI.
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