Jin-Yong Hwang

Adding Cilostazol to Dual Antiplatelet Therapy Achieves Greater Platelet Inhibition than High Maintenance Dose Clopidogrel in Patients With Acute Myocardial Infarction Results of the Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With AMI (ACCEL-AMI) Study

Background—Optimal platelet inhibition is an important therapeutic adjunct in patients acute myocardial infarction (AMI) undergoing coronary stenting. Whether adjunctive cilostazol to dual antiplatelet therapy (triple antiplatelet therapy) can inhibit enhanced platelet reactivity in patients with AMI yet has not been determined. The aim of this study was to assess the degree of platelet inhibition by triple antiplatelet therapy in patients with AMI. Methods and Results—Immediately after emergency room arrival, patients with AMI received clopidogrel (600-mg loading dose, followed by 75 mg daily) and aspirin (300-mg loading dose and 200 mg daily throughout the study period). After patients underwent coronary stenting (n=90), they were randomly assigned to 1 of 3 groups before discharge: standard group, clopidogrel of 75 mg daily (n=30); high maintenance dose (MD) group, clopidogrel of 150 mg daily (n=30); and triple group, adjunctive cilostazol of 100 mg twice daily to clopidogrel of 75 mg daily (n=30). Platelet reactivity was assessed at predischarge and 30-day follow-up by conventional aggregometry and the VerifyNow P2Y12 assay. Predischarge platelet reactivities were similar in the 3 groups. At 30-day follow-up, inhibition of maximal aggregation with 20 &mgr;M ADP stimuli was 6.0% in the standard group, 19.1% in the high-MD group, and 42.4% in the triple group (P<0.001), whereas inhibition of late aggregation with 20&mgr;M ADP stimuli was 10.8%, 38.1%, and 66.4%, respectively (P<0.001). Similar results were demonstrated when 5 &mgr;M ADP was used. Furthermore, percent changes of P2Y12 reaction unit were significantly different among regimens (10.6% in the standard group, 30.7% in the high-MD group, and 43.0% in the triple group; P<0.001). With respect to high-postclopidogrel platelet reactivity (prespecified as 20 &mgr;M ADP-induced maximal aggregation >50% of light transmission), fewer patients in the triple group (13.3%) met the criteria as compared with those in the standard (76.7%) and high-MD groups (56.7%) at 30-day follow-up (P<0.001). In the triple group, there were more potent and consistent platelet inhibitions by all parameters as compared with the high-MD group except for percent changes of P2Y12 reaction unit (P=0.071). Conclusions—Among patients with AMI undergoing coronary stenting, triple antiplatelet therapy results in a greater antiplatelet effect at 30 days as compared with a high-MD clopidogrel or standard dual antiplatelet therapy.

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).

Adding Cilostazol to Dual Antiplatelet Therapy Achieves Greater Platelet Inhibition than High Maintenance Dose Clopidogrel in Patients With Acute Myocardial Infarction

Background—Optimal platelet inhibition is an important therapeutic adjunct in patients acute myocardial infarction (AMI) undergoing coronary stenting. Whether adjunctive cilostazol to dual antiplatelet therapy (triple antiplatelet therapy) can inhibit enhanced platelet reactivity in patients with AMI yet has not been determined. The aim of this study was to assess the degree of platelet inhibition by triple antiplatelet therapy in patients with AMI. Methods and Results—Immediately after emergency room arrival, patients with AMI received clopidogrel (600-mg loading dose, followed by 75 mg daily) and aspirin (300-mg loading dose and 200 mg daily throughout the study period). After patients underwent coronary stenting (n=90), they were randomly assigned to 1 of 3 groups before discharge: standard group, clopidogrel of 75 mg daily (n=30); high maintenance dose (MD) group, clopidogrel of 150 mg daily (n=30); and triple group, adjunctive cilostazol of 100 mg twice daily to clopidogrel of 75 mg daily (n=30). Platelet reactivity was assessed at predischarge and 30-day follow-up by conventional aggregometry and the VerifyNow P2Y12 assay. Predischarge platelet reactivities were similar in the 3 groups. At 30-day follow-up, inhibition of maximal aggregation with 20 &mgr;M ADP stimuli was 6.0% in the standard group, 19.1% in the high-MD group, and 42.4% in the triple group (P<0.001), whereas inhibition of late aggregation with 20&mgr;M ADP stimuli was 10.8%, 38.1%, and 66.4%, respectively (P<0.001). Similar results were demonstrated when 5 &mgr;M ADP was used. Furthermore, percent changes of P2Y12 reaction unit were significantly different among regimens (10.6% in the standard group, 30.7% in the high-MD group, and 43.0% in the triple group; P<0.001). With respect to high-postclopidogrel platelet reactivity (prespecified as 20 &mgr;M ADP-induced maximal aggregation >50% of light transmission), fewer patients in the triple group (13.3%) met the criteria as compared with those in the standard (76.7%) and high-MD groups (56.7%) at 30-day follow-up (P<0.001). In the triple group, there were more potent and consistent platelet inhibitions by all parameters as compared with the high-MD group except for percent changes of P2Y12 reaction unit (P=0.071). Conclusions—Among patients with AMI undergoing coronary stenting, triple antiplatelet therapy results in a greater antiplatelet effect at 30 days as compared with a high-MD clopidogrel or standard dual antiplatelet therapy.

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.

Platelet Inhibition by Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel in Patients With Acute Myocardial Infarction According to Cytochrome P450 2C19 Genotype

OBJECTIVES The aim of this study was to assess the degree of platelet inhibition by adjunctive cilostazol in patients with acute myocardial infarction (AMI) according to hepatic cytochrome P450 2C19 (CYP2C19) genotype. BACKGROUND Although adjunctive cilostazol intensifies platelet inhibition in AMI patients, it is not established whether this regimen can be free from the effect of CYP2C19 loss-of-function variants (*2/*3). METHODS We randomly assigned 126 AMI patients with available CYP2C19 genotyping to receive adjunctive cilostazol (triple group; n = 64) or high maintenance-dose (MD) clopidogrel of 150 mg/day (high-MD group; n = 62). Using conventional aggregometry and VerifyNow (Accumetrics Inc., San Diego, California), platelet reactivity was measured at pre-discharge and 30-day follow-up. Primary endpoint was change in maximal platelet aggregation (ΔAgg(max)) between pre-discharge and 30-day follow-up. High on-treatment platelet reactivity (HPR) was defined as 20 μmol/l adenosine diphosphate-induced maximal platelet aggregation (Agg(max)) >59%. RESULTS In noncarriers, despite numerically greater inhibition by adjunctive cilostazol, changes in platelet measures and the rate of HPR did not significantly differ between the 2 groups. In carriers, ΔAgg(max) after 5 and 20 μmol/l adenosine diphosphate stimuli was significantly higher in the triple (n = 39) versus high-MD group (n = 38) (21.8 ± 13.9% vs. 9.0 ± 13.3%, p < 0.001, and 24.2 ± 17.2% vs. 7.7 ± 15.5%, p < 0.001, respectively). Likewise, changes in late platelet aggregation and P2Y12 reaction unit were consistently greater in the triple versus high-MD group. Fewer patients in the triple group met the criteria of HPR at 30-day follow-up than in the high-MD group (15.4% vs. 44.7%, p = 0.005). CONCLUSIONS Compared with high-MD clopidogrel, adjunctive cilostazol significantly enhances platelet inhibition and reduces the rate of HPR, especially in AMI patients with CYP2C19 loss-of-function variants. (Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel in Acute Myocardial Infarction (AMI) Patients According to CYP2C19 Polymorphism [ACCELAMI2C19]; NCT00915733).

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.

The optimal threshold of high post-treatment platelet reactivity could be defined by a point-of-care VerifyNow P2Y12 assay

We read with great interest the study by Price et al. ,1 which verifies that high post-treatment platelet reactivity (HPPR) measured with a point-of-care VerifyNow assay (Accumetrics Inc., San Diego, CA, USA) is associated with post-discharge events after percutaneous coronary intervention (PCI) with drug-eluting stent (DES), including stent thrombosis. To the best of our knowledge, this is the first study to identify a threshold of HPPR of VerifyNow based on the clinical outcomes. Recently, a number of studies have demonstrated that clopidogrel non-responsiveness proven in the laboratory testing, i.e. HPPR, has been associated with an increased risk for cardiovascular events.2 Light transmittance aggregometry …

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 concordance and correlation of measurements by multiple electrode and light transmittance aggregometries based on the pre-defined cutoffs of high and low on-treatment platelet reactivity.

The consensus document suggested the definition of high on-treatment platelet reactivity (HPR) and future directions. Although multiple platelet function assays have developed based on different mechanisms, inter-assay concordance of HPR identification may be an important pressing need. This study was performed to correlate between the cutoffs of HPR suggested by multiple electrode (MEA) and light transmittance aggregometries (LTA). We enrolled 246 consecutive patients undergoing non-emergent percutaneous coronary intervention after dual antiplatelet therapy. On the basis of consensus document, the cutoffs of HPR to adenosine diphosphate (ADP) were defined as ADPtest ≥ 47 U, and 5 and 20 µM ADP-induced maximal platelet aggregation (MPA) ≥ 46% and 59%, respectively. In addition, the cutoff of low PR (LPR) for major bleeding was selected as ADPtest ≤ 19 U. ADPtest showed moderate correlations with ADP-based LTA data (0.663 ≤ r ≤ 0.710). In the receiver-operating characteristics (ROC) curve analysis, ADPtest ≥ 47 U was corresponded to 5 and 20 µM ADP-induced MPAs ≥ 46.4% and ≥56.8%, respectively. Good agreements were observed between ADPtest ≥ 47 U, and 5 µM ADP-induced MPA ≥ 46% (κ = 0.537, 80.5% of concordance rate) and 20 µM ADP-induced MPA ≥ 59% (κ = 0.564, 81.7% of concordance rate). In the ROC curve analysis for the cutoff of LPR (ADPtest ≤ 19 U), 5 and 20 µM ADP-induced MPAs ≤ 26.6% and ≤35.3%, respectively, were suggested as the hypothetical threshold for major bleeding. On the basis of consensus document, the cutoffs of MEA- and LTA-based HPR are well matched. However, the agreement of HPR between assays is moderate, which may implicate the limitation of risk stratification by platelet function testing.