Jin-Sin Koh

Carriage of Cytochrome 2C19 Polymorphism Is Associated With Risk of High Post-Treatment Platelet Reactivity on High Maintenance-Dose Clopidogrel of 150 mg/day: Results of the ACCEL-DOUBLE (Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene Polymorphism) Study

OBJECTIVES This study sought to determine the impact of gene polymorphisms on platelet reactivity (PR) after clopidogrel 150 mg/day in patients treated with percutaneous coronary intervention (PCI). BACKGROUND Although high maintenance-dose (MD) clopidogrel reduces PR, it is unknown whether gene polymorphisms are related with the risk of high post-treatment PR (HPPR) after high-MD clopidogrel. METHODS We included mostly patients receiving high-MD clopidogrel after PCI from previously registered Gyeongsang National University Hospital data. A total of 126 PCI-treated patients receiving high-MD clopidogrel were enrolled. Platelet reactivity was assessed with conventional aggregometry and VerifyNow (Accumetrics Inc., San Diego, California) after receiving clopidogrel 150 mg/day for at least 1 month. CYP3A5, CYP2C19, and ABCB1 genotyping was performed. We defined HPPR as 5 micromol/l adenosine diphosphate (ADP)-induced maximal PR (PR(max)) >50%. RESULTS CYP3A5 and ABCB1 polymorphisms did not influence PR. Carriers of CYP2C19 variant (*2 or *3) (n = 80) had significantly higher 5 and 20 micromol/l ADP-induced PR(max) than did noncarriers (n = 46) (40.7 +/- 16.8% vs. 30.3 +/- 12.6%, p < 0.001; 54.2 +/- 16.2% vs. 40.5 +/- 15.8%, p < 0.001, respectively). Late PR and VerifyNow results indicated consistently greater measures in carriers versus noncarriers of CYP2C19 variant. All platelet measures proportionally increased according to the number of CYP2C19 variant alleles. Twenty-seven (21.4%) patients met the criteria for HPPR. Prevalence of HPPR was 8.7%, 21.7%, and 50.0% in carriers of 0, 1, and 2 CYP2C19 variant alleles, respectively (p < 0.001). By multivariate analysis, carriage of CYP2C19 variant was a significant predictor of HPPR (odds ratio: 5.525, 95% confidence interval: 1.333 to 23.256, p = 0.018). CONCLUSIONS Among PCI-treated patients receiving high-MD clopidogrel, carriage of CYP2C19 variant relates to increased PR and predicts risk of HPPR. (Adjunctive Cilostazol Versus High Maintenance-dose ClopidogrEL in Acute Myocardial Infarction [AMI] Patients According to CYP2C19 Polymorphism [ACCELAMI2C19]; NCT00915733; and Comparison of Platelet Inhibition With Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel According to Hepatic Cytochrome 2C19 Allele (CYP2C19) Polymorphism [ACCEL2C19]; NCT00891670).

The cytochrome 2C19*2 and *3 alleles attenuate response to clopidogrel similarly in East Asian patients undergoing elective percutaneous coronary intervention

INTRODUCTION Carriage of CYP2C19*2 allele is associated with diminished platelet response to clopidogrel. However, the loss-of-function impact of CYP2C19*3 allele on antiplatelet effect of clopidogrel has not been definitely verified. We conducted this study to compare decreased response to clopidogrel according to carriage of CYP2C19*2 vs. *3 allele. MATERIALS AND METHODS The study included 190 consecutive Korean patients undergoing elective percutaneous coronary intervention. Light transmittance aggregometry and the VerifyNow P2Y(12) assay were used to assess platelet reactivity (PR) at least 12 hours after 300-mg loading of clopidogrel. The cutoff of high on-treatment PR (HPR) was defined as 5 μmol/L ADP-induced PR >50%. CYP2C19 genotype was analyzed by the SNaPshot method. RESULTS Carriers of at least one CYP2C19 variant allele were 115 patients (60.5%), and allelic frequency of CYP2C19*2 and *3 was 30.3% and 6.8%, respectively. PR and the rate of HPR increased proportionally according to the number of CYP2C19 variant allele. Carriage of CYP2C19 variant allele was an only independent predictor of HPR in multivariate analysis. When we compare the effect of allelic carriage, there were no significant differences in platelet measures and the rate of HPR between carriers of CYP2C19*2 and/or *3 allele(s) whether they were intermediate or poor metabolizers. CONCLUSION Carriage of CYP2C19*3 allele is associated with diminished antiplatelet effect of clopidogrel, which may be as potent as the loss-of-function effect of CYP2C19*2 allele.

Risk Stratification Using Computed Tomography Coronary Angiography in Patients Undergoing Intermediate-Risk Noncardiac Surgery

OBJECTIVES This study evaluated whether coronary artery calcium scores (CACS) and the degree of stenosis that were measured with computed tomography coronary angiography (CTCA) predicted post-operative cardiovascular events in patients who were undergoing intermediate-risk noncardiac surgery. BACKGROUND Cardiovascular complications are important causes of mortality and morbidity in patients undergoing major noncardiac surgeries. METHODS A total of 239 patients underwent CTCA before intermediate-risk noncardiac surgeries. We measured CACS and the degree of stenosis with CTCA and assessed clinical risk factors according to the revised cardiac risk index (RCRI) scores. Post-operative cardiovascular events were defined as cardiac death, acute coronary syndrome, pulmonary edema, ventricular arrhythmia with hemodynamic compromise, and complete heart block. RESULTS Nineteen patients (8%) had post-operative cardiac events. The variables that correlated with the occurrence of cardiac events were RCRI (p < 0.001), CACS (p < 0.001), the presence of significant coronary artery stenosis (diameter stenosis ≥50%) (p = 0.01), and multivessel coronary artery disease (p < 0.001). In the receiver-operating characteristic (ROC) curve analysis of CACS for prediction of cardiac events, the cutoff value was 113 (sensitivity, 0.79; specificity, 0.61; area under the curve, 0.762). When comparing ROC curves of the combination models of RCRI, high CACS (≥113), and the presence of multivessel disease, RCRI plus high CACS, RCRI plus multivessel disease, and RCRI plus high CACS plus multivessel disease were significantly more predictable of post-operative cardiovascular events than RCRI alone. CONCLUSIONS In the pre-operative risk stratification of patients who were undergoing intermediate-risk noncardiac surgeries, CTCA evaluations showed additive value to RCRI.

The Impact of Generic Clopidogrel Bisulfate on Platelet Inhibition in Patients with Coronary Artery Stents: Results of the ACCEL-GENERIC Study

Background/Aims In patients with coronary artery stents, the cost of clopidogrel has been cited as a factor in the premature discontinuation of therapy. Thus, the introduction of lower-cost generic clopidogrel may increase patient compliance. However, platelet inhibition by generic clopidogrel has not been compared to the original clopidogrel formulation in patients with coronary artery stents. Methods We prospectively enrolled 20 patients receiving chronic therapy with the original clopidogrel bisulfate (Plavix®). After assessing patient compliance with Plavix®, maintenance therapy was switched to generic clopidogrel bisulfate (Plavitor®). Platelet reactivity was assessed at baseline and 30-day after the switch using conventional aggregometry and the VerifyNow P2Y12 assay. Results All patients completed maintenance therapy with Plavitor®. Before and after switching therapy maximal (36.5 ± 7.9% vs. 39.8 ± 16.2%, p = 0.280) and late platelet aggregation (23.5 ± 10.9% vs. 29.1 ± 18.3%, p = 0.156) with 5 µmol/L adenosine diphosphate (ADP) stimulus did not differ. Likewise, 20 µmol/L ADP-induced platelet aggregation and P2Y12 reaction unit in patients on Plavitor® therapy was comparable to that in patients on Plavix® therapy. However, Bland-Altman analysis showed wide limits of agreement between measured platelet reactivity on Plavix® vs. Plavitor® therapies. Conclusions Among patients on Plavix® maintenance therapy with coronary stents, replacement with Plavitor® shows a comparable inhibition of ADP-induced platelet aggregation. However, due to poor inter-therapy agreement, between two regimens, physicians may be cautious when introducing generic clopidogrel bisulfate.

Smoking at least 10 cigarettes per day increases platelet inhibition by clopidogrel in patients with ST-segment-elevation myocardial infarction.

BACKGROUND Recent data suggest that cigarette smoking (CS) might decrease the risk of cardiovascular events in patients with ST-segment-elevation myocardial infarction (STEMI) or established cardiovascular disease. Although it may be related to the effect of CS on the metabolism of clopidogrel, the association between the extent of CS and clopidogrel-induced platelet inhibition has not been well defined. PATIENTS AND METHODS We tested the association between smoking status and inhibition of platelet aggregation (IPA) in response to a clopidogrel loading of 600-mg in 20 healthy subjects. We then enrolled 138 consecutive STEMI patients treated with primary coronary stenting. On-clopidogrel platelet reactivity (PR) was assessed with conventional aggregometry and the VerifyNow P2Y(12) assay, according to smoking status. RESULTS After 6 hours post-loading in healthy subjects, CS patients on ≥10 cigarettes/day showed a significantly higher value of 5 μmol/L ADP-stimulated IPA (P=0.006), and had a trend toward a greater value of 20 μmol/L ADP-stimulated IPA (P=0.093) compared with non-smokers. In STEMI patients, there was no difference in PR between non-smokers (n=66) and CS patients<10 cigarettes/day (n=16). CS patients on ≥10 cigarettes/day (n=56) demonstrated lower PR with 5 and 20 μmol/L ADP (40.9±16.1% versus 46.6±11.7%, P=0.028, and 53.8±16.6% versus 59.2±12.2%, P=0.040, respectively) and lower P2Y(12) reaction units (204±85 versus 270±69, P<0.001) than non-smokers. On multivariate analyses, CS≥10 cigarettes/day was the only predictor of low on-clopidogrel PR (≤33%; the lowest quartile of 5 μmol/L ADP-induced PR; odds ratio 4.651, 95% confidence interval 1.181-18.519, P=0.028). CONCLUSION CS seems to increase antiplatelet response to clopidogrel in healthy volunteers and STEMI patients. Smoking 10 or more cigarettes/day can significantly decrease on-clopidogrel platelet reactivity in these populations.

The Impact of Smoking on Post-Clopidogrel Platelet Reactivity in Patients With Acute Myocardial Infarction

Background and Objectives Smoking increases inhibition of clopidogrel-induced platelet reactivity in patients undergoing elective coronary stenting. However, an association between pre-admission smoking (PS) and post-clopidogrel platelet reactivity in patients with acute myocardial infarction (AMI) has not been determined. Subjects and Methods Study cohorts were recruited from a pool of patients at our hospital who were undergoing coronary stenting for AMI (n=134). Immediately after arrival at the emergency room (ER), all patients received a 600 mg loading dose of clopidogrel followed by a maintenance dose of 75 mg/day. Platelet aggregation was measured with light transmittance aggregometry (LTA) after addition of 5 or 20 µmol/L adenosine diphosphate (ADP). Results Maximal platelet aggregation (Aggmax) was lower in PS patients after 5 µmol/L ADP (43.6±15.7% vs. 48.4±12.5%, p=0.096) and 20 µmol/L ADP stimuli (56.2±15.6% vs. 61.3±11.6%, p=0.073) compared with non-smoking (NS) patients. However, there were no differences in 5 µmol/L (42.6±16.3% vs. 43.8±15.6%, p=0.776) and 20 µmol/L ADP-induced Aggmax (54.8±14.3% vs. 56.5±15.9%, p=0.692) between PS patients <0.5 pack/day and ≥0.5 pack/day. Although more PS patients met the criteria for low post-clopidogrel platelet reactivity (LPPR) (≤37%; the lowest quartile of 5 µmol/L ADP-induced Aggmax) than NS patients (30.9% vs. 13.5%, p=0.048), advancing age was the only independent predictor of LPPR {odds ratio (OR) 0.960, 95% confidence interval (CI) 0.929 to 0.993, p=0.019}. Conclusion PS is significantly not associated with decreased residual platelet reactivity in AMI patients.

Influence of CYP2C19*2 and *3 loss-of-function alleles on the pharmacodynamic effects of standard- and high-dose clopidogrel in East Asians undergoing percutaneous coronary intervention: the results of the ACCEL-DOUBLE-2N3 study.

Y . -H . J EONG,*† 1 K . A . ABADILLA ,†‡ 1 U . S . TANTRY ,† Y . PARK ,* J . S . KOH,* C . H . KWAK,* J . -Y . HWANG* and P . A . GURBEL† *Department of Internal Medicine, Gyeongsang National University Hospital and Gyeongsang National University School of Medicine, Jinju, Korea; †Sinai Center for Thrombosis Research; and ‡Department of Internal Medicine, Sinai Hospital of Baltimore, Baltimore, MD, USA

Effects of Peroxisome Proliferator-Activated Receptor-δ Agonist on Cardiac Healing after Myocardial Infarction

Peroxisome proliferator-activated receptor-delta (PPAR-δ)-dependent signaling is associated with rapid wound healing in the skin. Here, we investigated the therapeutic effects of PPAR-δ-agonist treatment on cardiac healing in post-myocardial infarction (MI) rats. Animals were assigned to the following groups: sham-operated control group, left anterior descending coronary artery ligation (MI) group, or MI with administration of the PPAR-δ agonist GW610742 group. GW610742 (1 mg/kg) was administrated intraperitoneally after the operation and repeated every 3 days. Echocardiographic data showed no differences between the two groups in terms of cardiac function and remodeling until 4 weeks. However, the degrees of angiogenesis and fibrosis after MI were significantly higher in the GW610742-treated rats than in the untreated MI rats at 1 week following MI, which changes were not different at 2 weeks after MI. Naturally, PPAR-δ expression in infarcted myocardium was highest increased in 3 day after MI and then disappeared in 14 day after MI. GW610742 increased myofibroblast differentiation and transforming growth factor-beta 2 expression in the infarct zone at 7 days after MI. GW610742 also increased bone marrow-derived mesenchymal stem cell (MSC) recruitment in whole myocardium, and increased serum platelet-derived growth factor B, stromal-derived factor-1 alpha, and matrix metallopeptidase 9 levels at day 3 after MI. PPAR-δ agonists treatment have the temporal effect on early fibrosis of infarcted myocardium, which might not sustain the functional and structural beneficial effect.

Pharmacodynamic effect of clopidogrel therapy and switching to cilostazol in patients with the CYP2C19 loss-of-function allele (ACCEL-SWITCH) study.

Restenosis and stent thrombosis (ST) are catastrophic events that can occur in stented patients. In spite of the development of the drug-eluting stent (DES) platform, selected DES-treated patients still suffer from these clinical events [1]. Early events (within post-stent 30 days) are more likely as a result of mechanical issues, inadequate platelet inhibition or the prothrombotic profile, whereas late events may be attributed to biological issues such as delayed re-endothelialization, inflammation, and impaired vascular function and remodeling [2]. In addition to use of new generation DES, optimal pharmacologic regimens may reduce DES-related complications [2]. Adjunctive medications such as statin and thiazolidinedione may reduce the risk of restenosis through stem cell homing balancing the re-endothelialization and neointimal proliferation, whereas antiplatelet therapy may decrease the risk of DES-mediated ST. Cilostazol is a reversible dual inhibitor of adenosine uptake and phosphodiesterase 3 (PDE3) [3]. In addition to its antiplatelet effect, cilostazol has pleotropic effects influencing stem cell homing, re-endothelialization, vascular repair and inflammation process [3,4]. In DES-treated patients, compared with aspirin and clopidogrel treatment, adjunctive cilostazol therapy not only decreased the risk of restenosis by 40% [5] but also reduced the prevalence of 1year ST (hazard ratio, 0.14; P = 0.004) without increasing the risk of bleeding [6]. Furthermore, treatment with cilostazol and aspirin in diabetic patients showed similar efficacy in decreasing post-DES ischemic events and lessened the risk of restenosis compared with treatment with clopidogrel and aspirin [7]. About two-third of East Asians have the CYP2C19 lossof-function (LoF) allele, which is associated with increased on-treatment platelet aggregation (PA) during clopidogrel treatment [8], but the rate of ischemic events appeared to be similar to Caucasians [8,9]. Because East Asians may have a different thrombogenic property and platelet reactivity threshold for adverse event occurrences, the concept of tailored antiplatelet therapy balancing clinical efficacy and safety is more important during the post-percutaneous coronary intervention (PCI) late phase. Cilostazol therapy with its low bleeding risk and pleiotropic effects [3] may be another alternative option for this population, but a previous report showing the lower pharmacodynamic effect of cilostazol compared with clopidogrel [10] may be a limitation of its clinical application. However, the pharmacodynamic effects of clopidogrel and cilostazol are significantly related to the CYP2C19 LoF variant [3,8]. We thus performed the present study to compare the effect of clopidogrel and switching to cilostazol in DES-treated patients with the CYP2C19 LoF allele. Between January 2010 and December 2010, in this prospective, observational study, 20 CYP2C19*1 homozygotes and 27 carriers of the CYP2C19 LoF allele receiving clopidogrel (75 mg daily) and aspirin for at least 6 months after DES implantation (Fig. 1A) were recruited. In CYP2C19 LoF allele carriers, clopidogrel was switched to cilostazol (100 mg twice daily). CYP2C19*1 homozygotes were used as the control group to evaluate variability in clopidogrel responsiveness over time. At 14 ± 3 days follow-up, compliance and adverse events were assessed based on interview, pill counting, a questionnaire and laboratory evaluation. Blood sampling was conducted at 2–6 h after the last-dose ingestion, and the data were enrolled for the analysis if patients showed 100% compliance. Genotyping and the platelet function assay (conventional aggregometry and the VerifyNow P2Y12 assay Correspondence: Young-Hoon Jeong, Division of Cardiology, Department of Internal Medicine, Gyeongsang National University Hospital, 90 Chiram-dong, Jinju, Gyeongsangnam-do 660-702, South Korea. Tel.: +8 255 750 8873; fax: +8 255 758 9122. E-mail: goodoctor@naver.com

Risk Factors and Effects on Long-Term Outcomes of Cardiac Troponin I Elevation After Drug-Eluting Stent Implantation in Patients With Stable Coronary Artery Disease

This study evaluated the risk factors of postprocedure cardiac troponin I (cTnI) increase and its effects on repeat revascularization and on overall clinical outcomes in patients with angina and normal preprocedural cTnI levels who underwent successful drug-eluting stent implantation. Postprocedure cTnI increase (≥0.5 ng/ml) was observed in 207 of 802 patients (25.8%). Patients with cTnI increase had more extensive coronary disease than patients without cTnI increase, which necessitated for the cTnI group more multilesion interventions and a longer total stent length. In multivariate analysis, total stent length (odds ratio 1.02, 1.01 to 1.03, p = 0.001) and use of glycoprotein IIb/IIIa inhibitors (3.07, 1.54 to 6.11, p <0.001) were identified as independent predictors of cTnI increase. During a median follow-up of 42 months, however, there were no significant between-group differences in Kaplan-Meier estimates of any repeat revascularization (24.8% vs 18.4%, hazard ratio 1.085, 0.723 to 1.627, p = 0.694) and major adverse cardiovascular events (27.0% vs 22.4%, 1.022, 0.703 to 1.485, p = 0.911). In conclusion, patients with postprocedure cTnI increase had more severe baseline coronary disease and received more complex interventional procedures. However, cTnI increase after successful drug-eluting stent implantation was not associated with an increased risk of repeat revascularization or of other adverse events.