Evaluation of platelet activity by multiple electrode impedance aggregometry in acute coronary syndromes: pilot study in a Brazilian tertiary-care public hospital

There is no definite recommendation for testing platelet aggregation (PA) in acute coronary syndromes (ACS) due to inconclusive evidence on the usefulness of platelet function tests to guide therapy and improve clinical outcomes. The evaluation of PA with multiple electrode impedance platelet aggregometry (MEA) may be useful to manage antiplatelet therapy and possibly influence patient outcome. The primary aim of this study was to measure PA with MEA in Brazilian patients with ACS and evaluate the association between PA and adverse clinical outcomes. Forty-seven consecutive patients admitted with ACS to a Brazilian tertiary-care public hospital were studied and PA was evaluated using MEA. Patients were followed for six months for the occurrence of all-cause death, acute myocardial infarction, or stroke. Suboptimal inhibition of PA was found in 7 patients (14.9%); 5 (10.6%) in response to ASA (acetylsalicylic acid), 2 (5.0%) to clopidogrel, and none to ticagrelor. Inadequate PA inhibition in response to ASA was significantly associated with the composite end point, but there was no significant association for insufficient PA inhibition in response to clopidogrel. This study suggested that the evaluation of PA in ACS using MEA may identify non-responders to ASA. Larger studies are necessary to define, in a public health scenario, the value of MEA in the management of ACS.

Comparison of the Infarct Size between the Loading of Ticagrelor and Clopidogrel in Patients with Acute Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

BACKGROUND AND OBJECTIVES: Ticagrelor is considered a potent antiplatelet agent compared to clopidogrel. However, there are no studies regarding the effect of ticagrelor loading on infarct size in patients with ST-segment elevation myocardial infarction (STEMI) in a primary percutaneous coronary intervention (PCI) setting. SUBJECTS AND METHODS: In this single-center, randomized, open-label study, 188 patients who underwent primary PCI for STEMI were enrolled (92 patients in the clopidogrel group and 96 in the ticagrelor group) and compared the infarct size by technetium-99m (Tc-99m) tetrofosmin single-photon emission computed tomography (SPECT) and serial cardiac biomarker levels between the groups. SPECT was performed at a median of 2 days after PCI. RESULTS: Baseline clinical and procedural characteristics were similar between the groups. Infarct size on SPECT, was similar between the 2 groups (28.1%±34.5% vs. 32.8%±29.2%; p=0.169). At all time-points after PCI (8, 24, and 48 hours), the peak levels of creatine kinase-myocardial band (CK-MB) and troponin T were lower in the clopidogrel group. The clopidogrel group showed lower cumulative troponin T levels than the ticagrelor group (12.59±10.66 vs. 17.67±19.51 ng/mL; p=0.029). CONCLUSION: Ticagrelor loading before primary PCI was not associated with reduced myocardial infarct size during the first 48 hours, compared to clopidogrel loading.

Head to Head Comparison of Two Point-of-care Platelet Function Tests Used for Assessment of On-clopidogrel Platelet Reactivity in Chinese Acute Myocardial Infarction Patients Undergoing Percutaneous Coronary Intervention / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Platelet function tests are widely used in clinical practice to guide personalized antiplatelet therapy. In China, the thromboelastography (TEG) test has been well accepted in clinics, whereas VerifyNow, mainly used for scientific research, has not been used in routine clinical practice. The aim of the current study was to compare these two point-of-care platelet function tests and to analyze the consistency between the two tests for evaluating on-clopidogrel platelet reactivity in Chinese acute myocardial infarction patients undergoing percutaneous coronary intervention (PCI).</p><p><b>METHODS</b>A total of 184 patients admitted to Fuwai Hospital between August 2014 and May 2015 were enrolled in the study. On-clopidogrel platelet reactivity was assessed 3 days after PCI by TEG and VerifyNow using adenosine diphosphate as an agonist. Based on the previous reports, an inhibition of platelet aggregation (IPA) <30% for TEG or a P2Y12 reaction unit (PRU) >230 for VerifyNow was defined as high on-clopidogrel platelet reactivity (HPR). An IPA >70% or a PRU <178 was defined as low on-clopidogrel platelet reactivity (LPR). Correlation and agreement between the two methods were analyzed using the Spearman correlation coefficient (r) and kappa value (κ), respectively.</p><p><b>RESULTS</b>Our results showed that VerifyNow and TEG had a moderate but significant correlation in evaluating platelet reactivity (r = -0.511). A significant although poor agreement (κ = 0.225) in identifying HPR and a significantly moderate agreement in identifying LPR (κ = 0.412) were observed between TEG and VerifyNow. By using TEG as the reference for comparison, the cutoff values of VerifyNow for the Chinese patients in this study were identified as PRU >205 for HPR and PRU <169 for LPR.</p><p><b>CONCLUSIONS</b>By comparing VerifyNow to TEG which has been widely used in clinics, VerifyNow could be an attractive alternative to TEG for monitoring on-clopidogrel platelet reactivity in Chinese patients.</p>

A pharmacodynamic study of the optimal P2Y12 inhibitor regimen for East Asian patients with acute coronary syndrome

BACKGROUND/AIMS: Newer P2Y12 inhibitors, such as prasugrel and ticagrelor, have greater antiplatelet efficacy but may increase the risk of bleeding. In this study, we compared the pharmacodynamic efficacy of prasugrel and ticagrelor in East Asian patients with acute coronary syndrome (ACS). METHODS: We selected 83 ACS patients undergoing percutaneous coronary intervention who were discharged with 90 mg ticagrelor twice daily (n = 24), 10 mg prasugrel daily (n = 39) or 5 mg prasugrel daily (n = 20). After 2 to 4 weeks, on-treatment platelet reactivity (OPR) was assessed in terms of P2Y12 reaction units (PRUs) using the VerifyNow P2Y12 assay (Accumetrics). We compared East Asian (85 < PRU < or = 275) and Caucasian (85 < PRU < or = 208) criteria for assessing the therapeutic window of OPR. RESULTS: OPR was lowest in the ticagrelor group, followed by the 10 mg prasugrel and 5 mg prasugrel groups (49.1 ± 29.9 vs. 83.7 ± 57.1 vs. 168.5 ± 60.8, respectively; p < 0.001). The 5 mg prasugrel group had the highest proportion of patients with OPR values within the therapeutic window, followed by the 10 mg prasugrel and ticagrelor groups (90.0% vs. 46.2% vs. 12.5%, respectively; p < 0.001 for East Asian criteria; 60.0% vs. 43.6% vs. 12.5%, respectively; p < 0.001 for Caucasian criteria). CONCLUSIONS: Short-term administration of 5 mg prasugrel facilitated maintenance within the therapeutic window of OPR compared with the 10 mg prasugrel and ticagrelor groups. Thus, 5 mg prasugrel daily may be the optimal antiplatelet regimen for stabilized East Asian ACS patients.

Association between clopidogrel resistance and polymorphism of platelet adenosine diphosphate receptor in patients with coronary atherosclerotic disease / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the relation of clopidogrel resistance to polymorphism of adenosine diphosphate receptor (P2Y12).</p><p><b>METHODS</b>Three hundred and seventy patients with coronary atherosclerotic heart disease, who were admitted in hospital from May 2011 to November 2012 and underwent percutaneous coronary intervention, were enrolled in the study. All patients received antiplatelet therapy (oral aspirin 100 mg per night and clopidogrel 75 mg per day for >7 d). The gene polymorphisms of C34T and G52T P2Y12 receptor were detected by using DNA sequencing technique. The relationship of gene polymorphism with the incidence of clopidogrel resistance and clinical outcomes were analyzed.</p><p><b>RESULTS</b>Among 370 patients, clopidogrel resistance developed in 100 cases, including 36 males (36%) and 64 females (64%). In the C34T locus, 212 cases were of CC genotype and 158 were of CT+TT genotype; the incidence of clopidogrel resistance in CC genotype was significantly lower than that in CT+TT genotype (P<0.05). In the G52T locus, 218 cases were of GG genotype and 152 cases were of GT+TT genotype; the incidence of clopidogrel resistance in GT+TT genotype were significantly higher than that in GG genotype (P<0.05). After 1-year follow-up, patients with CC genotype had lower incidence of angina recurrence than patients with CT+TT genotype did (13.2% vs 19.6%, Χ2=4.956, P<0.05), and patients with GG genotype had lower incidence of emergency revascularization, angina, and cardiovascular composite endpoint events than patients with GT+TT genotype did (Χ2=4.135,6.823,5.916, Ps<0.05).</p><p><b>CONCLUSION</b>T-34, -52 mutations on P2Y12 receptor gene may be a risk factor for clopidogrel resistance and adverse cardiovascular events.</p>

Effects of coexisting polymorphisms of CYP2C19 and P2Y12 on clopidogrel responsiveness and clinical outcome in patients with acute coronary syndromes undergoing stent-based coronary intervention / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The CYP2C19 G681A single polymorphism has been proven to affect clopidogrel responsiveness. However, the effect of coexisting polymorphisms of other genes has not yet been reported in the Chinese population. This study investigated the effect of coexisting polymorphisms of CYP2C19 and P2Y12 on clopidogrel responsiveness and adverse clinical events in Chinese patients.</p><p><b>METHODS</b>In 577 Han Chinese patients undergoing stent placement because of acute coronary syndrome had platelet reactivity assessed by thromboelastography, and the CYP2C19 G681A and P2Y12 C34T polymorphisms were detected by the ligase detection reaction. Primary clinical endpoints included cardiovascular death, nonfatal myocardial infarction, target vessel revascularization, and stent thrombosis. The secondary clinical endpoints were thrombolysis in myocardial infarction bleeding. The follow-up period was 12 months.</p><p><b>RESULTS</b>Genotyping revealed 194 carriers of the wild type GG genotype of CYP2C19 and the wild type CC genotype of P2Y12 (group 1), 102 carriers of the wild type GG genotype of CYP2C19 and the mutational T allele of P2Y12 (group 2), 163 carriers of the mutational A allele of CYP2C19 and the wild type CC genotype of P2Y12 (group 3), and 118 carriers of the mutational A allele of CYP2C19 and the mutational T allele of P2Y12 (group 4). Group 4 had the lowest ADP-inhibition (49.74 ± 32.61) and the highest prevalence of clopidogrel low response (29.7%) of the four groups. The rate of the composite of primary clinical endpoints increased more in group 4 (8.5%) than in the other three groups; the rate of composite primary endpoints in group 2 (2.9%) and group 3 (3.7%) were not significantly different than that of group 1 (1.5%).</p><p><b>CONCLUSION</b>Coexisting polymorphisms of different genes affected clopidogrel responsiveness and clinical outcome more than single polymorphism in Chinese patients with acute coronary syndrome undergoing percutaneous coronary intervention.</p>

Adjunctive Cilostazol versus High Maintenance Dose of Clopidogrel in Patients with Hyporesponsiveness to Chronic Clopidogrel Therapy

PURPOSE: Whether addition of cilostazol is superior to increasing dose of clopidogrel in patients with hyporesponsiveness to chronic clopidogrel therapy is unknown. MATERIALS AND METHODS: We studied 73 patients with hyporesponsiveness to clopidogrel on standard dual antiplatelet therapy for more than 2 weeks. Clopidogrel hyporesponsiveness was defined as percent inhibition of P2Y12 reaction units (PRU) <30% on VerifyNow P2Y12 assay. Patients were randomly assigned to increased dose of clopidogrel (aspirin 100 mg+clopidogrel 150 mg daily: group A, n=38) or to receiving additional cilostazol (aspirin 100 mg+clopidogrel 75 mg+cilostazol 100 mg bid daily: group B, n=35). RESULTS: Baseline percent inhibition of PRU and PRU was similar between 2 groups (13.0+/-10.2% versus 11.8+/-9.7%, p=0.61, and 286.3+/-54.7 versus 295.7+/-53.7, p=0.44, respectively). At follow-up, percent inhibition of PRU was higher and PRU was lower significantly in group B than in group A (38.5+/-17.9% versus 28.3+/-16.6%, p=0.02, and 207.3+/-68.2 versus 241.3+/-76.7, p=0.050, respectively). Among those still showing hyporesponsiveness to clopidogrel at follow-up (21 patients in group A, 10 patients in group B), 12 patients completed further crossover study. Compared to the baseline, magnitude of change in percent inhibition of PRU and PRU showed an improved tendency after the crossover (from 2.7+/-8.7% to 15.8+/-18.4%, p=0.08, and from -18.6+/-58.0 to -61.9+/-84.3, p=0.08). CONCLUSION: Adjunctive cilostazol improved clopidogrel responsiveness better than the higher maintenance dose of clopidogrel in hyporesponsive patients with chronic clopidogrel therapy.

Clinical application of VerifyNow-P2Y12 assay in evaluation of platelet inhibition efficacy of clopidogrel / 中华心血管病杂志

<p><b>OBJECTIVE</b>To evaluate the platelet inhibition efficacy in patients under regular maintenance dose of clopidogrel by VerifyNow-P2Y12 assay and explore the clinical characteristics of clopidogrel non-responders and related predicting factors.</p><p><b>METHODS</b>A total of 99 patients underwent percutaneous coronary intervention procedure and receiving clopidogrel in regular maintenance dose for at least 1 week were enrolled. Platelet reactivity, including baseline, P2Y12 reaction unit (PRU), and platelet inhibition rate were measured with VeifyNow-P2Y12 assay. The dosage of anti-platelet drugs, combination with any other drugs, clinical characters in baseline of all enrolled patients were analyzed. PRU ≤ 240 was used as cut-off to identify clopidogrel responder and clopidogrel non-responder. In the non-responder group, patients were further separated into 3 sub-groups (types) according to the baseline and platelet inhibition rate: type I with high baseline, high inhibition rate, representing false non-responder; type II with low inhibition rate, representing true non-responder and type III mixed type.</p><p><b>RESULTS</b>In this study, 48 of 99 patients were found to be clopidogrel non-responder (48.5%). The ratio of type I, type II and type III in the non-responder group was 9.1% (n = 9), 27.3% (n = 27), and 12.1% (n = 12), respectively. Baseline platelet value in female patients was significantly higher than in males (P < 0.01), number of females with high PRU also is higher than males (P < 0.01), female gender was a predict factor for type I non-responder (OR = 6.5, 95%CI 2.295 - 18.407, P < 0.01). BMI > 24 kg/m(2) was a risk factor for clopidogrel non-responder (P < 0.05), and may be regarded as a predict factor for type II non-responder (OR = 3.207, 95%CI 1.375 - 7.485, P < 0.01). Age, hypertension, diabetics, smoking, hyperlipidemia, CRP and pantoprazole use do not show significant correlation with baseline and platelet inhibition rate.</p><p><b>CONCLUSIONS</b>Clopidogrel responses could be reliably detected by VerifyNow-P2Y12 assay. Female gender and high body weight are independent risk factors for clopidogrel non-responses.</p>

Determination of the Prevalence of Aspirin and Clopidogrel Resistances in Patients with Coronary Artery Disease by using Various Platelet-function Tests / 대한진단검사의학회지

BACKGROUND: Dual therapy with aspirin and clopidogrel has emerged as the gold standard therapy for patients treated with drug-eluting stents (DES). However, there is variability in patients' responses to this antiplatelet therapy, and some patients continue to show ischemic recurrences after therapy. The purpose of the study was to compare the simultaneously obtained results of various platelet-function tests for assessing the prevalence of antiplatelet resistance in coronary artery disease patients undergoing DES therapy. METHODS: A total of 66 patients were administered a loading dose of aspirin, clopidogrel, and cilostazol at least 12 hr before stenting. The results of VerifyNow (Accumetrics, USA), multiplate analyzer (Dynabyte Medical, Germany), and vasodilator-stimulated phosphoprotein/P2Y12 (Biocytex, France) assays were compared with those of light transmission aggregometry (LTA) analysis. RESULTS: The P2Y12 reaction units and P2Y12% inhibition values obtained using the VerifyNow assay showed strong correlation (r) with the results of the LTA analysis. All tests results showed low concordance in defining the antiplatelet resistance in patients, and the degrees of agreement were as follows: 0 for aspirin reaction units; 0.25, P2Y12% inhibition; 0, aspirin-sensitive patients' identification test; 0.21, ADPtest; and 0.14, platelet reactivity index, expressed as the kappa statistics. The prevalence of aspirin and clopidogrel resistances in patients resulted in remarkable variations, from 0% to 22.7% and from 9.1% to 48.5%, respectively. CONCLUSIONS: The clinical usefulness of the different assays for the correct classification of patients in terms of antiplatelet resistance remains unclear. Further studies are required to determine the best method for correlating the occurrences of adverse ischemic events.