High Post-treatment Platelet Reactivity Research Articles

An Observational Study of the Relationship Between Outcome and Platelet Reactivity in Chinese Patients Undergoing PCI Loading with 600 mg Clopidogrel

Objectives: We sought to determine whether high posttreatment platelet reactivity (HPPR) to a 600 mg loading dose of clopidogrel affects outcomes in Chinese patients with acute coronary syndrome (ACS) following percutaneous coronary intervention (PCI) and to investigate whether there is a relationship between the number of platelet reactivity units (PRUs) and the characteristics of the patients. Background: Although impaired platelet response to clopidogrel is a strong predictor of unfavorable outcome after PCI, the impact of HPPR to a 600 mg loading dose of clopidogrel in Chinese patients with ACS undergoing PCI is still unknown. Methods: We performed observational research on 134 unselected patients with ACS undergoing urgent or planned PCI with a 600 mg loading dose of clopidogrel. Platelet activation was expressed as the PRU value measured by the VerifyNow assay. Results: Among the 134 patients (mean age 60.62 years [standard deviation 9.13 years], 60.4% male), there were 46 patients with HPPR (34.3%) and 88 patients without HPPR (65.7%). At a mean follow-up of 6 months (standard deviation 1 month), the rates of cardiac death, unstable angina, and rehospitalization for target lesion revascularization were higher in the HPPR group (19.6% vs. 6.8%, P=0.029). Multivariate analysis identified hemoglobin level and sex as independent predictors of the PRU value (y=456.355−1.736x 1−31.880x 2, P<0.05). On receiver operating characteristic curve analysis, PRU values could significantly discriminate between patients with and patients without cardiac death, unstable angina, and rehospitalization for target lesion revascularization (area under the curve 0.758, 95% confidence interval 0.62–0.85, P=0.001, P<0.05). Conclusion: In patients with ACS, HPPR to a 600 mg loading dose of clopidogrel is associated with worse outcomes after PCI. There is some relationship between the PRU value and the hemoglobin level and sex. PRU values can predict the prognosis.

Monitoring the Antiplatelet Effect of Cilostazol with Light Transmission Aggregometer: Two Cases of Possible Cilostazol Resistance

eISSN 2093-6338 let-derived growth factors and thicken the intima of vessel walls, worsening symptoms [1]. It is important to prescribe antiplatelet agents to prevent thrombus formation in patients with a stent insertion. Aspirin and clopidogrel are the major antiplatelet agents used. Aspirin is a cyclooxygenase (COX) inhibitor and prevents platelet aggregation by inhibiting the formation of thromboxane A2. Clopidogrel is a 5 -adenosine diphosphate (ADP) receptor blocker and inhibits platelet aggregation by increasing the amount of cyclic adenosine monophosphate (cAMP) in platelets. Recently, patients showing high post treatment platelet reactivity (HPPR) after taking antiplatelet agents have been reported to show worse prognoses. The frequency of HPPR is reported to be 5-45% in patients taking aspirin [2] and 4-30% in patients taking clopidogrel [3]. Methods for monitoring the effects of these medications have been deINTRODUCTION

Antiplatelet Effect of Clopidogrel Can Be Reduced by Calcium-Channel Blockers

PurposeClopidogrel is metabolized by the hepatic cytochrome P450 (CYP) system into its active thiol metabolite. CYP3A4 is involved in the metabolism of both clopidogrel and dihydropyridine calcium channel blockers (CCBs). A few reports have suggested an inhibitory interaction between CCBs and clopidogrel. Accordingly, the aim of this study was to determine the effect of CCBs on the antiplatelet activity of clopidogrel by serial P2Y12 reaction unit (PRU) measurements.Materials and MethodsWe assessed changes in antiplatelet activity in patients receiving both clopidogrel and CCBs for at least 2 months prior to enrollment in the study. The antiplatelet activity of clopidogrel was measured by VerifyNow P2Y12 assay in the same patient while medicated with CCBs and at 8 weeks after discontinuation of CCBs. After discontinuation of the CCBs, angiotensin receptor blockers were newly administered to the patients or dosed up for control of blood pressure.ResultsThirty patients finished this study. PRU significantly decreased after discontinuation of CCBs (238.1±74.1 vs. 215.0±69.3; p=0.001). Of the 11 patients with high post-treatment platelet reactivity to clopidogrel (PRU≥275), PRU decreased in nine patients, decreasing below the cut-off value in seven of these nine patients after 8 weeks. Decrease in PRU was not related to CYP2C19 genotype.ConclusionCCBs inhibit the antiplatelet activity of clopidogrel.

Impact of Obesity and the Metabolic Syndrome on Response to Clopidogrel or Prasugrel and Bleeding Risk in Patients Treated After Coronary Stenting

This study aimed to analyze the impact of body mass index (BMI) and the metabolic syndrome (MS) on responses to clopidogrel or prasugrel and bleeding risk after acute coronary syndrome. The study included 1,542 consecutive patients who underwent coronary stenting (287 clopidogrel 75 mg, 868 clopidogrel 150 mg, and 387 prasugrel 10 mg). Platelet reactivity was assessed 1 month after discharge using platelet reactivity index vasodilator stimulated phosphoprotein (PRI VASP). Three hundred thirty-six patients (21.8%) were obese (BMI ≥30), and we observed higher platelet reactivity associated with higher BMI across thienopyridine regimens. Incidence of high on-treatment platelet reactivity (PRI VASP >50%) was higher in obese than nonobese patients (p <0.05 for all regimens). Conversely, incidence of low on-treatment platelet reactivity with prasugrel therapy (PRI VASP <20%) was lower in obese than nonobese patients: 13% (12 of 93) versus 33% (97 of 294); odds ratio 0.30, 95% confidence interval 0.16 to 0.58; p <0.001. Accordingly, incidence of Bleeding Academic Research Consortium bleeding complications was higher in nonobese than in obese patients: 10% (119 of 1,206) versus 6% (20 of 336); odds ratio 1.7, 95% confidence interval 1.1 to 2.8; p = 0.03. This impaired response was only observed in obese patients with the MS, and obese with the MS had significantly higher platelet reactivity than other obese patients with all regimens (p <0.01). Obese patients without the MS had no significant difference in platelet reactivity compared with nonobese patients. In conclusion, the present study confirmed that BMI has a strong impact on response to clopidogrel and prasugrel with higher incidence of high on-treatment platelet reactivity, lower incidence of low on-treatment platelet reactivity, and lower bleeding complication in obese patients. However, among obese patients, the presence of the MS strongly affects response to antiplatelet agents, indicating that the metabolic status might be a better predictor of platelet inhibition than BMI.

First experience of a bioresorbable vascular scaffold implantation in left main stenosis

[1] Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability in individual responsiveness to clopidogrel clinical implications, management, and future perspectives. J Am Coll Cardiol 2007;49:1505–16. [2] Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109:3171–5. [3] Cuisset T, Frere C, Quilici J, et al. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thromb Haemost 2006;4:542–9. [4] Buonamici P, Marcucci R, Migliorini A, et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007;49:2312–7. [5] Cuisset T, Cayla G, Frere C, et al. Predictive value of post-treatment platelet reactivity for occurrence of post-discharge bleeding after non-ST elevation acute coronary syndrome. Shifting from antiplatelet resistance to bleeding risk assessment? EuroIntervention 2009;5:325–9. [6] Sibbing D, Schulz S, Braun S, et al. Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost 2010;8:250–6. [7] Campo G, Parrinello G, Ferraresi P, et al. Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome. J Am Coll Cardiol 2011;57:2474–83. [8] Cuisset T, Quilici J, LoosveldM, et al. Comparison between initial and chronic response to clopidogrel therapy after coronary stenting for acute coronary syndrome and influence on clinical outcomes. Am Heart J 2012;164(3):327–33. [9] Alexopoulos D, Dimitropoulos G, Davlouros P, et al. Prasugrel overcomes high onclopidogrel platelet reactivity post-stentingmore effectively than high-dose (150-mg) clopidogrel: the importance of CYP2C19*2 genotyping. JACC Cardiovasc Interv 2011;4:403–10.

Chronic kidney disease — Is it a true risk factor of reduced clopidogrel efficacy in elderly patients with stable coronary artery disease?

BackgroundChronic kidney disease (CKD) is an established predictor of recurrent ischemic events in patients with coronary artery disease (CAD). This association has been partially ascribed to high post-treatment platelet reactivity (HPPR) according to platelet function testing. However, the influencing factors of HPPR are assay-dependent, and the relevant data of elderly patients with stable CAD are absent. Patients and Methods310 elderly patients (>80years of age) with stable CAD taking prolonged maintenance clopidogrel (75mg/day) were studied. Maximal platelet aggregation rate (MPA%) with light transmittance aggregometry and Platelet Reactive Units (PRU) with VerifyNow (VN) P2Y12 system were obtained. Markers of platelet activation, including PAC-1 and CD62P, were also determined. ResultsPatients on different stages of CKD presented similar MPA% and expression of PAC-1 and CD62P. Although severe CKD patients were more likely to present HPPR identified by VNP2Y12 (odds ratio: 1.85, p=0.038), multiple logistic regression diminished this effect (adjusted odds ratio: 1.19, p=0.642), and revealed anemia as a possible predictor of HPPR (adjusted odds ratio: 5.92, p=0.001). However, in a parallel way, hemoglobin correlated with baseline PRU values as well as with post-treatment values (r=−0.624 and r=−0.463, respectively, p<0.001). Association between hemoglobin and PRU inhibition rate was not found. Moreover, hemoglobin exerted no influence on MPA% at all. ConclusionCKD is not necessarily associated with reduced antiplatelet effects of clopidogrel in elderly patients with stable CAD taking prolonged maintenance clopidogrel, and the seemingly influence of CKD on HPPR assessed by VNP2Y12 assay may be due to the artifactual effect of hemoglobin on VNP2Y12.

048 Antiplatelet therapy monitoring in elderly patients with unstable coronary artery disease: Discordance between high post-treatment platelet reactivity, adequate response to clopidogrel and impaired Cl

048 Antiplatelet therapy monitoring in elderly patients with unstable coronary artery disease: Discordance between high post-treatment platelet reactivity, adequate response to clopidogrel and impaired Cl

Loading Effect of 200 mg Cilostazol on Platelet Inhibition in Patients Undergoing Percutaneous Coronary Intervention

To date, most studies conducted on cilostazol have examined its effects as an agent of maintenance-dose therapy, but its loading effects on platelet inhibition have never been reported. This study aimed to determine the loading effects of 200 mg cilostazol in addition to aspirin and clopidogrel on platelet inhibition in patients undergoing percutaneous coronary intervention.Sixty consecutive patients undergoing coronary intervention were enrolled and assigned to receive 300 mg of aspirin and clopidogrel with or without 200 mg of cilostazol. All loading doses were given at least 3 hours before percutaneous coronary intervention and followed by dual or triple maintenance-dose therapy. Platelet function tests were performed just before and at 24 hours and 30 days after percutaneous coronary intervention by light transmittance aggregometry and VerifyNow® P2Y12 assay.There were no significant differences in baseline or angiographic characteristics between the 2 groups. The results of platelet function tests revealed that the adjunctive loading dose of 200 mg of cilostazol induced more potent platelet inhibition compared to a dual regimen at each time point. Cilostazol reduced the incidence of high post-treatment platelet reactivity (HPPR).Adjunctive 200 mg cilostazol can improve platelet responsiveness to clopidogrel in the pre- and postprocedural phases, reducing the prevalence of HPPR.

Comparison of Platelet Reactivity and Clopidogrel Response in Patients ≤75 Years Versus >75 Years Undergoing Percutaneous Coronary Intervention for Non–ST-Segment Elevation Acute Coronary Syndrome

Specific data about the clopidogrel response in elderly patients are lacking. The present study was performed to compare the platelet reactivity and clopidogrel response between patients aged > 75 years and < 75 years undergoing percutaneous coronary intervention for non-ST-segment elevation acute coronary syndrome. A total of 689 patients were enrolled, including 162 patients aged > 75 years and 527 younger patients. All patients received a loading dose of 600 mg clopidogrel followed by 150 mg/day. Post-treatment platelet reactivity was assessed by adenosine diphosphate 10 μmol/L-induced platelet aggregation and the specific pharmacologic response to clopidogrel by the platelet reactivity index vasoactive stimulated phosphoprotein. High post-treatment platelet reactivity was defined as adenosine diphosphate 10 μmol/L-induced platelet aggregation >70%. Clinical events were recorded during 1 month of follow-up. The patients > 75 years old had a greater rate of both ischemic and bleeding complications (p = 0.04 and p = 0.03, respectively). The post-treatment platelet reactivity in response to both the loading and the maintenance clopidogrel dose was greater in patients > 75 years old than in the younger patients: 50 ± 17% versus 45 ± 17% (p = 0.002) and 57 ± 15% versus 53 ± 16% (p = 0.0005), respectively. The rate of high post-treatment platelet reactivity was significantly greater in patients aged > 75 years after 600 mg and 150 mg clopidogrel: 14% versus 9% (p = 0.04) and 23% versus 15% (p = 0.02), respectively. In contrast, the pharmacologic response to clopidogrel was not impaired in patients > 75 years after loading and maintenance doses: 43 ± 21% versus 46 ± 21% (p = 0.17) and 38 ± 18% versus 39 ± 18% (p = 0.55), respectively. In conclusion, patients aged > 75 years have an impaired prognosis after acute coronary syndrome. They display greater post-treatment platelet reactivity. However, this greater platelet reactivity does not seem to be related to an impaired specific response to clopidogrel.

Clinical Predictors of High Posttreatment Platelet Reactivity to Clopidogrel in Koreans

High posttreatment platelet reactivity to clopidogrel (HPPR) is associated with major adverse cardiac events. However, the clinical predictors of HPPR in Asians have not been studied previously. We sought to determine clinical predictors of HPPR in Koreans. We measured platelet reactivity with the VerifyNow P2Y12 assay in 1431 consecutive patients undergoing coronary angiography. We used the cut-off value of greater than 275 P2Y12 Reaction Unit (PRU) to define patients with HPPR. The clinical characteristics were compared between patients with HPPR (36.3%) and those without HPPR (63.7%). The mean age (65.4 ± 9.1 vs. 62.2 ± 9.7 years) was higher, hypertension (68.5% vs. 62.0%), diabetes mellitus (35.4% vs. 28.5%), chronic kidney disease (36.3% vs. 22.5%), renal replacement treatment (1.2% vs. 0.2%), and congestive heart failure (1.3% vs. 0.3%) were more common among patients with HPPR, while male gender (72.6% vs. 54.8%) and smoking (19.9% vs. 13.1%) were more common among non-HPPR patients. Mean glomerular filtration rate (63.5 ± 18.6 vs. 69.7 ± 16.1 mL/min/1.73 m(3) ) was lower and C-reactive protein (hs-CRP) (6.6 ± 20.5 mg/L vs. 4.2 ± 12.1 mg/L) level was higher among those with HPPR. Independent predictors of HPPR were female gender (OR 1.90, P≤ 0.001), chronic kidney disease (OR 1.51, 0 = 0.004), diabetes mellitus (OR 1.35, P= 0.024), hs-CRP ≥ 2.0 mg/L (OR 1.31, P= 0.005), and age increase in decades (OR 1.21, P= 0.002), while smoking was negative risk factor (OR 0.63, P= 0.015). The number of risk factors was linearly associated with the risk of HPPR, with most patients having one or two predictors. In Korean population, independent clinical predictors of HPPR included diabetes mellitus, increased age, female gender, chronic kidney disease, and hs-CRP ≥ 2.0 mg/L, while cigarette smoking was associated with better responsiveness. Mean platelet reactivity and HPPR prevalence steadily increased with the number of clinical predictors.

The Assessment of High Post-Clopidogrel Platelet Reactivity Using the Vasodilator-Stimulated Phosphoprotein Phosphorylation Index – Comparison with Light Transmittance Aggregometry.

AbstractAbstract 1093 BackgroundFlow cytometric analysis of platelet reactivity index of vasodilator-stimulated phosphoprotein-phosphorylation (VASP-P) is a suitable test to evaluate the “high post-treatment platelet reactivity (HPPR)”. A reliable cut-off of VASP-P index is needed to identify the HPPR. However, an ideal cut-off identifying HPPR using the VASP-P index remains undetermined. We aimed to show the comparison between light transmittance aggregometry (LTA) and flow cytometric analysis of VASP-P index and assess the cut-offs of identifying HPPR using VASP-P index. MethodsWe enrolled consecutively patients undergoing percutaneous coronary intervention (PCI) in real clinical practice (n = 516). They all received clopidogrel and aspirin, performed LTA (5 and 20 μmol/l ADP-induced, and 1.6 nmol/l arachidonic acid (AA)-induced PR) and flow cytometric analysis of VASP-P index simultaneously and compared the different platelet measures. Based on previously suggested cut-offs, 5 μmol/l ADP-induced maximal platelet reactivity (PRmax) > 42.9%, 5 μmol/l ADP-induced PRmax > 50%, 20 μmol/l ADP-induced PRmax > 62%, 20 μmol/l ADP-induced PRmax > 64.5%, and 1.6 mmol/l AA-induced PRmax > 20%, the cut-offs of identifying HPPR using flow cytometric analysis of VASP-P were determined by receiver-operating characteristics (ROC) curve analysis. ResultsExcellent correlations were observed between LTA with ADP-induced PRmax and flow cytometric analysis of VASP-P according to the ROC curve analyses. The ROC curve analyses demonstrated that 5 μmol/l ADP-induced PRmax > 42.9% could distinguish between patients with and without VASP-P index > 54.9% (area under curve [AUC] 0.926, 95% confidence interval (CI) 0.903–0.949, sensitivity 82.8%, and specificity 88.5%, p < 0.001) and 5 μmol/l ADP-induced PRmax > 50% could distinguish between patients with and without VASP-P index > 57.4% (AUC 0.937, 95% CI 0.914–0.961, sensitivity 91.5%, and specificity 85.2%, p < 0.001). ROC curve analysis demonstrated 20 μmol/l ADP-induced PRmax > 62% could distinguish between patients with and without VASP-P index > 55.2% (AUC 0.948, 95% CI 0.927–0.969, sensitivity 95.7%, and specificity 87.3%, p < 0.001) and 20 μmol/l ADP-induced PRmax > 64.5% could distinguish between patients with and without VASP-P index > 55.9% (AUC 0.925, 95% CI 0.900–0.951, sensitivity 88.3%, and specificity 83.0%, p < 0.001), respectively. However, fair correlation was observed between AA-induced PRmax and VASP-P index and 1.6 nmol/l AA-induced PRmax > 20% could distinguish between patients with and without VASP-P index > 52.4% (AUC 0.761, 95% CI 0.719–0.802, sensitivity 68.5%, and specificity 72.7%, p < 0.001). We defined the ideal threshold of VASP-P index > 56%. The VASP-P index > 56% showed a substantial agreement with 5 μmol/l and 20 μmol/l ADP-induced PRmax (Table 1). However, VASP-P index > 56% showed a moderate agreement with 1.6 nmol/l AA)-induced PRmax > 20% (Table 1). ConclusionThere are significant correlations between the suggested cut-offs of HPPR. Because VASP-P index > 56 is well matched with 5 μmol/l ADP-induced PRmax > 42.9%, 5 μmol/l ADP-induced PRmax > 50%, 20 μmol/l ADP-induced PRmax > 62%, and 20 μmol/l ADP-induced PRmax > 64.5%., it might suggest that VASP-P index > 56 has a practical implication for stratification of high-risk ischemic events.Table 1Concordance among cut-off points of high post-treatment platelet reactivity based on VASP indexCriteriaComparative parameterk statisticpConcordanceSensitivitySpecificityPositive predictive valueNegative predictive valueVASP-P index > 56%5 μmol/l ADP-PRmax > 42.9%0.686<0.00185.7%81.5%87.9%78.0%90.0%5μmol/l ADP-PRmax > 50%0.623<0.00184.1%62.9%95.3%87.5%83.0%20μmol/l ADP-PRmax > 62%0.763<0.00189.8%76.4%96.7%92.5%88.6%20μmol/l ADP-PRmax > 64.5%0.631<0.00184.7%60.7%97.3%92.3%82.5%1.6 nM AA-PRmax > 20%0.360<0.00170.3%62.4%74.6%56.3%79.0% Disclosures:No relevant conflicts of interest to declare.

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

AbstractAbstract 3322 ObjectivesThe aim of this study was to assess the degree of platelet inhibition by adjunctive cilostazol in patients with acute myocardial infarction (AMI) according to CYP2C19 genotype. BackgroundAlthough adjunctive cilostazol intensifies platelet inhibition in AMI patients, it is not established whether this regimen can overcome the loss-of-function effect of CYP2C19 variants. MethodsWe 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, platelet reactivity was measured at pre-discharge and 30-day follow-up. Primary endpoint was change in maximal platelet aggregation (Aggmax). High post-treatment platelet reactivity (HPPR) was defined as 5 μmol/l ADP-induced Aggmax > 50%. ResultsIn non-carriers, the two groups did not differ with respect to changes in platelet measures, and could achieve fewer rates of HPPR at 30-day follow-up (< 5%). In carriers, changes in 5 and 20 μmol/l ADP-induced Aggmax were 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 vs. high-MD group. Fewer patients in the triple group met the criteria of HPPR at 30-day follow-up compared with the high-MD group (2.6% vs. 21.1%, p = 0.014). ConclusionsAmong AMI patients with CYP2C19 variants, adjunctive cilostazol enhances platelet inhibition and reduces the rate of HPPR, as compared with high-MD clopidogrel. (Adjunctive Cilostazol Versus High-MD ClopidogrEL in Patients With Acute Myocardial Infarction According to CYP2C19 genotype [ACCEL-AMI-CYP2C19]; NCT00915733). Disclosures:No relevant conflicts of interest to declare.

Effect of cilostazol on optimized standard antiplatelet therapy in a patient with a cytochrome P450 2C19 *2/*2 genotype

A 54-year-old man with acute coronary syndrome underwent primary percutaneous coronary intervention (PCI) to implant a bare metal stent. Three weeks later, a subclinical in-stent thrombus was found at staged PCI despite dual antiplatelet therapy with aspirin and clopidogrel. Platelet function tests revealed high post-treatment platelet reactivity, indicating an inadequate response to clopidogrel. The patient's cytochrome P450 2C19 genotype was *2/*2. Cilostazol at 200mg/day was initiated in addition. Three months later, platelet inhibition was enhanced, and no thrombus was detectable by coronary angiography. Our experience suggests that triple antiplatelet therapy with cilostazol as well as aspirin and clopidogrel could prevent stent thrombosis with improved clopidogrel responsiveness.

Cytochrome 2C19 Polymorphism and Response to Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention

Among patients treated with clopidogrel, carriers of the cytochrome P450 (CYP) 2C19 loss-of-function allele have shown increased platelet reactivity and higher rates of ischemic events. Although adjunctive cilostazol to dual antiplatelet therapy (or "triple antiplatelet therapy") intensifies platelet inhibition, it remains unknown whether triple antiplatelet therapy after percutaneous coronary intervention can achieve adequate platelet inhibition in patients with the CYP2C19 mutant allele. CYP2C19 genotyping for *1, *2, and *3 was performed in 134 high-risk patients undergoing elective percutaneous coronary intervention. After measurement of preprocedural platelet reactivity, patients were randomly assigned to receive either adjunctive cilostazol 100 mg twice daily (triple group; n=69) or high maintenance-dose (MD) clopidogrel of 150 mg daily (high-MD group; n=65). Using light transmittance aggregometry and the VerifyNow P2Y(12) assay, platelet reactivity was assessed before the index procedure and at 30-day follow-up. The primary end point was absolute change in maximal platelet aggregation (ΔAgg(max)) according to CYP2C19 genotyping. High posttreatment platelet reactivity was defined as 5 μmol/L ADP-induced maximal platelet aggregation >50%. In noncarriers of the CYP2C19*2/*3 mutant allele, ΔAgg(max) values after 5 and 20 μmol/L ADP stimuli did not differ significantly between the triple (n=22) versus the high-MD group (n=22) (23.6±21.6% versus 16.6±15.4%, P=0.224 and 26.4±22.2% versus 18.6±14.9%, P=0.174, respectively). Absolute changes in late platelet aggregation and P2Y(12) reaction unit were not different between the groups. The rate of high posttreatment platelet reactivity at 30-day follow-up also was comparable between the triple versus the high-MD group (4.5% versus 13.6%, P=0.607). In carriers of at least 1 CYP2C19*2/*3 mutant allele, the triple group (n=47) showed greater values of ΔAgg(max) after addition of 5 μmol/L (25.8±16.8% versus 11.1±19.8%, P<0.001) and 20 μmol/L ADP (26.3±16.0% versus 11.5±16.3%, P<0.001) compared with the high-MD group (n=43). Likewise, absolute changes in late platelet aggregation and P2Y(12) reaction unit were consistently greater in the triple versus the high-MD group. Fewer patients in the triple group met the criteria of high posttreatment platelet reactivity at 30-day follow-up compared with the high-MD group (6.4% versus 37.2%, P<0.001). Among high-risk patients undergoing elective percutaneous coronary intervention, adjunctive cilostazol can achieve consistently intensified platelet inhibition and reduce the risk of high posttreatment platelet reactivity irrespective of CYP2C19 genotyping. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01012193.

Individual Variability of Response to Antiplatelet Therapy is an Important Determinant of Adverse Clinical Outcome

Dual antiplatelet therapy with aspirin (acetylsalicylic acid) and clopidogrel is widely used in order to prevent recurrent ischaemic events in patients undergoing percutaneous coronary intervention. The goal is to achieve an optimal platelet inhibition, providing clear clinical benefit in most patients. However, a wide inter-individual variability exists in the response to antiplatelet drugs. Several factors, such as genetic, cellular and clinical factors, may contribute to determine fluctuation in platelet reactivity even within the individual patient. Patients with high post-treatment platelet reactivity are at higher risk of ischaemic events in both the short term (during or shortly after percutaneous coronary intervention) and the long term. Several methodologies and devices have been developed to monitor individual response to antiplatelet treatment assessing different pathways of platelet activation and aggregation. In these patients, more aggressive antithrombotic strategies and new generation drugs may be beneficial in order to reduce ischaemic complications after percutaneous coronary intervention.

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

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). 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. 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%. 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). 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).

Residual Platelet Reactivity: Predicting Short- and Long-Term Clinical Outcome in Patients Undergoing Percutaneous Coronary Revascularization

Adequate platelet inhibition is mandatory in patients undergoing percutaneous coronary intervention in order to prevent recurrent thrombotic events. Dual antiplatelet therapy with aspirin and thienopyridine (e.g., clopidogrel) is the treatment of choice in this setting, providing clear clinical benefit in most of the patients. However, a wide interindividual variability exists in the response to antiplatelet drugs and several factors may contribute to determine fluctuation in platelet reactivity, even within the individual patient. Several methodologies and devices have been developed to monitor individual response to antiplatelet treatment, assessing different pathways of platelet activation and aggregation. Studies performed with the use of these methodologies have clearly demonstrated that patients with high post-treatment residual platelet reactivity present a higher risk of ischemic events both at short (during or soon after percutaneous coronary intervention) and long term. In these patients, more aggressive antithrombotic strategies, based on the results of platelet function tests, may be beneficial in order to reduce ischemic complications after percutaneous coronary intervention.

Correlation of high post-treatment platelet reactivity assessed by light transmittance aggregometry and the VerifyNow P2Y12 assay

In vitro "high post-treatment platelet reactivity" (HPPR) measured with light transmittance aggregometry (LTA) and the VerifyNow P2Y(12) assay has been associated with an increased risk of ischemic events after percutaneous coronary intervention (PCI). However, there are many criteria for HPPR according to the methods used for assessment, and correlations among suggested criteria have not been evaluated. To this end, we enrolled 1,058 unselected patients undergoing PCI in real clinical practice, simultaneously assessed platelet measures with LTA (both 5 and 20μmol/l ADP-induced) and the VerifyNow P2Y(12) assay, and based on previous studies, evaluated the following criteria for HPPR: 5 or 20μmol/l ADP-induced maximal platelet reactivity (PR(max)) ≥50%; 5μmol/l ADP-induced late PR (PR(late)) >14%; 20μmol/l ADP-induced PR(max) ≥62%; and P2Y(12) reaction unit (PRU) ≥240. Receiver-operating characteristics (ROC) curve analysis demonstrated that PRU (cut-off=241) distinguished between patients with and without 5μmol/l ADP-induced PR(max) ≥50% (area under curve [AUC] 0.822, sensitivity 83.0%, specificity 66.0%, P<0.001), and 20μmol/l ADP-induced PR(max) ≥62% (AUC 0.840, sensitivity 80.7%, specificity 71.4%, P<0.001), respectively. PRU ≥240 showed a moderate agreement with 5μmol/l ADP-induced PR(max) ≥50% (κ=0.438, concordant rate 71.6%, P<0.001) and 20μmol/l ADP-induced PR(max) ≥62% (κ=0.505, concordant rate 75.1%, P<0.001). Cut-offs matched for 20μmol/l ADP-induced PR(max) ≥50% (PRU=195) and 5μmol/l ADP-induced PR(late) >14 (PRU=194) also were similar. The presence of significant correlations between the suggested criteria for HPPR has practical implications on the possible use of the VerifyNow P2Y(12) assay for risk stratification in PCI-treated patients.

Determinants to optimize response to clopidogrel in acute coronary syndrome

The inhibition of platelet function by antiplatelet therapy determines the improvement of the survival of patients with clinically evident cardiovascular disease. Clopidogrel in combination with aspirin is the recommended standard of care for reducing the occurrence of cardiovascular events in patients with acute coronary syndromes undergoing percutaneous coronary intervention. However, major adverse cardiovascular events including stent thrombosis occur in patients taking clopidogrel and aspirin. A growing body of evidence demonstrates that high post-treatment platelet reactivity on antiplatelet treatment is associated with increased risk of adverse clinical events. Clopidogrel requires conversion to active metabolite by cytochrome P450 isoenzymes. The active metabolite inhibits ADP-stimulated platelet activation by irreversibly binding to P2Y(12) receptors. Recently, the loss-of-function CYP2C19*2 allele has been associated with decreased metabolization of clopidogrel, poor antiaggregant effect, and increased cardiovascular events. In high risk vascular patients, the CYP2C19*2 polymorphism is a strong predictor of adverse cardiovascular events and particularly of stent thrombosis. Prospective studies evaluating if an antiplatelet treatment tailored on individual characteristics of patients, CYP2C19*2 genotypes, platelet phenotype, drug-drug interaction, as well as traditional and procedural risk factors, are now urgently needed for the identification of therapeutic strategies providing the best benefit for the single subject.

AS-252: The Impact of Non-Cytochrome 3A4 Metabolized Statin in Patients with High Post-Clopidogrel Platelet Reactivity: The Results of the ACCEL-SWITCH Study

Clopidogrel is an inactive prodrug that is converted into the active metabolites by the cytochrome P-450 (CYP) system. The impact of coadministration of statin and clopidogrel on platelet inhibition is controversial, which may result from assessment during early period statin use, differences in assays used, and the selection of high posttreatment platelet reactivity (HPPR) and normal responders to clopidogrel. During chronic phase of coadministration of statin and clopidogrel, the influence of CYP3A4 vs non-CYP3A4 metabolized statin on platelet inhibition has not been evaluated.