Maintenance Dose Of Clopidogrel Research Articles

Association of serum PCSK9 levels with platelet function in patients with acute coronary syndromes.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein (LDL) homeostasis and plays a key role in acute coronary syndrome (ACS). The cardioprotective effect of PCSK9 inhibition extends beyond LDL cholesterol reduction, involving regulation of platelet function by not yet unraveled mechanisms. Oxidized-LDL (ox-LDL) is increased during ACS and induces platelet activation via binding to platelet surface. We will evaluate serum PCSK9 and its correlation with platelet reactivity and platelet-ox-LDL binding in Chinese ACS patients. In this pilot cross-sectional study, we will enroll 115 Chinese participants aged 30 to 75 years with ACS. Blood sample will be obtained after the first maintenance dose of aspirin and clopidogrel during morning time. Serum PCSK9 will be measured by an enzyme-linked immunoadsorbent assay. Platelet reactivity will be assessed by; Platelet activation (P-selectin and GPIIbIIIa expression using flow cytometry) and; Platelet aggregation using light transmission aggregometry in response to various stimuli. On-treatment platelet reactivity is measured by adenosine diphosphate-induced platelet aggregation. Binding of ox-LDL to platelet will be evaluated by flow cytometry. Spearman correlations will be used to determine association of serum PCSK9 with platelet functional parameters and platelet-ox-LDL binding. Additionally, continuous PCSK9 levels will be categorized into tertiles of equal size to investigate its association with on-treatment platelet reactivity. This study will reveal possible relationship between serum PCSK9 and platelet reactivity in the setting of ACS which may shed light on therapeutic potential in platelet inhibition by targeting PCSK9. The study will also explore the association of serum PCSK9 and platelet-ox-LDL binding, an important mechanism for platelet-LDL interplay, to provide mechanistic insight into PCSK9-mediated regulation of platelet reactivity.

Correlation between CYP2C19 Polymorphisms and recurrent risk in Patients with Ischemic Stroke treated with Clopidogrel in Kurdistan region-Iraq

Clopidogrel is a prodrug that must be transformed into an active metabolite by hepatic cytochrome P450 (CYP) isoenzymes to prevent platelet clotting. Polymorphisms of the CYP2C19 gene can cause a reduction or complete loss of CYP2C19 enzyme activity resulting in inhibiting clopidogrel metabolism, effectiveness and increase stroke recurrence risk in ischemic stroke patients. This study aims to investigate the correlation between genetic polymorphisms in CYP2C19*2 and*3 and recurrent risk in patients with ischemic stroke taking clopidogrel 75mg in Kurdistan region –Iraq. This retrospective case-control study was carried out at Kurdistan, Erbil, Medicina medical center, and Rizgary general hospital from January 2021 to August 2021. The blood sample was taken from the participants and tested for genotyping. The collection of data was taken from patients' medical charts in the hospital and patients’ electronic medical records from the neurology clinic. Sixty patients participated, (34) were male and (26) were female, with age range (38-96) years, diagnosed from not more than two years with ischemic stroke and taking 75 mg clopidogrel maintenance dose. Genotyping analysis showed 61.7 % were homozygotes for wild allele *1, the heterozygotes divided into 26.7% (*1/*2) and 6.7 % (*1/*3) genotype, while the homozygotes for mutant alleles CYP2C19*2,*3 distributed in 3.3 %(*2/*2) and 1.7 %(*3/*3). The (*2/*3) was not detected in the study population. A significant relation was found between risk of stroke recurrence with carrying the variant allele CYP2C19 *2, reduced CYP2C19 enzyme metabolic activity, and ACEIs/ARBs usage (P = 0.024, P = 0.039, P=0.24 respectively). On the other hand, there was no significant relationship between the risk of stroke recurrence and carrying the variant allele CYP2C19 *3 (P = 1.000). Ischemic stroke patients treated with clopidogrel and carrying a CYP2C19*2 allele had a higher risk of recurrent stroke as it is associated with reduced the metabolic activity of CYP2C19 enzyme leading to reduction of clopidogrel effect.

High triglyceride is an independent predictor of high on-treatment platelet reactivity in ischemic stroke patients

BackgroundPrevious studies have shown high triglyceride (TG) is associated with platelet hyperactivation in metabolic syndrome patients. However, limited information is available regarding this relationship on dual anti-platelet therapy (DAPT) in ischemic stroke (IS). In this study, we attempted to evaluate the association between TG and high on-treatment platelet reactivity (HTPR) in IS patients. MethodsIschemic stroke patients who received maintenance doses of clopidogrel and aspirin were categorized and analyzed retrospectively in this research. The platelet reactivity was assessed by Thromboelastography (TEG). If ADP-induced platelet inhibition rate (ADPi)<30%, it was defined as HTPR, else, it would be defined as normal on-treatment platelet reactivity (NTPR). Patients were divided into high-TG-level and lower-TG-level based on a TG level of 1.7mmol/L, the cutoff point of hypertriglyceridemia. A logistic regression model was applied to calculate the odds ratio (OR) and 95% confidence interval (CI). ResultsA total of 123 patients were included in this study and 24 (19.51%) patients were identified as HTPR. HTPR was observed in 36.2% of the patients in high-TG-level (TG≥1.7mmol/L) group while only 9.2% of the patients in the low-TG-level group (TG<1.7mmol/L) were HTPR (P<0.001 ). According to multivariate analysis, TG≥1.7mmol/L was independently associated with HTPR (OR=14.715, 2.445-88.549,P=0.003). ConclusionsHigh TG is an independent predictor of HTPR in IS patients. For IS patients with high TG level undergoing DAPT, platelet reactivity should be monitored to identify HTPR, which may proactively help to optimize the anti-platelet therapy.

Comparative evaluation of standard maintenance-dose clopidogrel versus low-dose prasugrel in patients with stable coronary artery disease after percutaneous coronary intervention

BackgroundTreatment with low-dose prasugrel might be more beneficial even in chronic stable coronary artery disease (CAD) patients treated with clopidogrel. We compared platelet reactivity between standard maintenance-dose and low-dose prasugrel in stable CAD patients. MethodsThis multicenter study enrolled 164 stable CAD patients receiving dual antiplatelet therapy with aspirin and clopidogrel. Patients were randomly assigned to continue treatment with 75-mg clopidogrel daily (n = 80) or switch to 3.75-mg prasugrel daily (n = 84). Platelet reactivity was evaluated by measuring P2Y12 reaction unit (PRU) before randomization and at 5 and 30 days thereafter using the VerifyNow® assay. Patients were classified into three groups according to CYP2C19-clopidogrel metabolic phenotype: extensive (without a *2 or *3 allele), intermediate (one *2 or *3 alleles), or poor (two *2 or *3 alleles) metabolizers. ResultsThe PRU level was comparable between the two groups at baseline but was significantly lower in the prasugrel group than in the clopidogrel group on days 5 (133.0 vs. 156.8 PRU, P = 0.005) and 30 (124.3 vs. 158.0 PRU, P < 0.001). On day 30, the PRU level was lower in the prasugrel group among patients categorized as poor and intermediate metabolizers but not among extensive metabolizers. ConclusionsLow-dose prasugrel achieves more consistent antiplatelet effects than clopidogrel irrespective of the metabolic phenotype in Japanese patients with stable CAD. Low-dose prasugrel might be also beneficial in the chronic phase without increasing the bleeding risk among stable CAD patients in other countries.

Prognostic implication of systemic inflammatory state on antiplatelet effect in patients after percutaneous coronary intervention for ST-elevation myocardial infarction: A retrospective cohort study.

Patients with ST-elevation myocardial infarction (STEMI) show an inflammatory response. The level of systemic inflammation is known to affect platelet aggregation function and antiplatelet therapy, which leads to different clinical prognosis. This study aims to evaluate the prognostic implication of systemic inflammatory state in patients with STEMI undergoing percutaneous coronary intervention.In this study, 203 patients with STEMI who underwent primary percutaneous coronary intervention were included. The patients were divided into 3 groups based on the inflammation levels assessed by tertiles of high-sensitivity C-reactive protein (hs-CRP) level on admission. Platelet aggregation evaluation was performed by residual platelet reactivity, which was assessed by the value of residual ADP-induced light transmittance aggregometry after clopidogrel maintenance dose therapy and in follow-up. Major adverse cardiac events (MACEs) were defined to include all-cause mortality, cardiovascular mortality, reinfarction, target vessel revascularization (TVR), cardiopulmonary resuscitation, advanced heart failure, ventricular fibrillation or ventricular tachycardia, and atrioventricular block.Levels of white blood cell was observed to be significantly higher at high tertile levels. Residual ADP-induced platelet aggregation was significantly higher at high tertile levels after clopidogrel maintenance dose therapy and in follow-up. Multivariate analysis identified that reperfusion time, alanine aminotransferase, platelet count, ADP-induced light transmittance aggregometry in follow-up and hs-CRP was independent predictors of MACEs. Platelet inhibition function of clopidogrel decreases progressively at different inflammation levels. The different levels of hs-CRP were demonstrated to be associated with MACEs at follow-up assessments.The presence of hs-CRP was not only significantly associated with platelet inhibition function, but was also a prognostic marker in STEMI.

Clinical validation of AggreGuide A-100 ADP, a novel assay for assessing the antiplatelet effect of oral P2Y12 antagonists

In this prospective, 3-arm, repeated-measure multicenter investigation in 280 patients with cardiovascular risk factors, platelet aggregation was measured with the novel AggreGuide A-100 ADP (A-100 ADP) and VerifyNow (VN)-PRU assays at baseline, and after United States Food and Drug Administration approved loading and 7days maintenance doses of clopidogrel (n = 94), prasugrel (n = 43) or ticagrelor, (n = 143). Based on the predetermined cutoff values of < 4.7 platelet activity index with A-100 ADP assay to indicate antiplatelet response, more than 91% of patients met the criteria following loading and maintenance doses of prasugrel and more than 84% patients met the criteria following loading and maintenance doses of ticagrelor whereas only 32% and 51% of patients met the criteria following loading and maintenance doses of clopidogrel, respectively. The total percent agreement between the A-100 ADP and VN-PRU assays was 89%. The A-100 ADP assay, which includes whole blood in motion, performs comparably to the VN-PRU assay in a study of patients with cardiovascular risk factors treated with P2Y12 inhibitors possessing known differences in antiplatelet potencies. Trial registration ClinicalTrials.gov Identifier: NCT3111420.

Risk Factors for Bleeding and Clinical Ineffectiveness Associated With Clopidogrel Therapy: A Comprehensive Meta-Analysis.

Although clopidogrel is a frequently used antiplatelet medication to treat and prevent atherothrombotic disease, clinicians must balance its clinical effectiveness with the potential side effect of bleeding. However, many previous studies have evaluated beneficial and adverse factors separately. The objective of our study was to perform a comprehensive meta‐analysis of studies of clopidogrel’s clinical effectiveness and/or risk of bleeding in order to identify and assess all reported risk factors, thus helping clinicians to balance patient safety with drug efficacy. We analyzed randomized controlled trials (RCTs) of maintenance use in four stages: search for relevant primary articles; abstract and full article screening; quality assessment and data extraction; and synthesis and data analysis. Screening of 7,109 articles yielded 52 RCTs that met the inclusion criteria. Twenty‐seven risk factors were identified. “Definite risk factors” were defined as those with aggregated odds ratios (ORs) > 1 and confidence intervals (CIs) > 1 if analyzed in more than one study. Definite risk factors for major bleeding were concomitant aspirin use (OR 2.83, 95% CI 2.04–3.94) and long duration of clopidogrel therapy (> 6 months) (OR 1.74, 95% CI 1.21–2.50). Dual antiplatelet therapy, extended clopidogrel therapy, and high maintenance dose (150 mg/day) of clopidogrel were definite risk factors for any bleeding. Reduced renal function, both mild and severe, was the only definite risk factor for clinical ineffectiveness. These findings can help clinicians predict the risks and effectiveness of clopidogrel use for their patients and be used in clinical decision support tools.

Association of FMO3 rs1736557 polymorphism with clopidogrel response in Chinese patients with coronary artery disease

Dual antiplatelet therapy with aspirin and clopidogrel is commonly used for coronary artery disease (CAD) patients undergoing percutaneous coronary intervention to prevent stent thrombosis and ischemic events. However, some patients show high on-treatment platelet reactivity (HTPR) during clopidogrel therapy. Genetic factors such as loss-of-function variants of CYP2C19 are validated to increase the risk of HTPR. Flavin-containing monooxygenase 3 (FMO3) is reported to be associated with potency of platelet responsiveness and thrombosis. This study aimed to explore the association between FMO3 rs1736557 polymorphism and clopidogrel response. Five hundred twenty-two Chinese CAD patients treated with dual antiplatelet therapy were recruited from Xiangya Hospital. After oral administration of 300mg loading dose (LD) clopidogrel for 12-24h or 75mg daily maintenance dose (MD) clopidogrel for at least 5days, the platelet reaction index (PRI) was determined by vasodilator-stimulated phosphoprotein-phosphorylation assay. FMO3 rs1736557, CYP2C19*2, and CYP2C19*3 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Mean PRI value was significantly higher in CYP2C19 poor metabolizers (PMs) and intermediate metabolizers (IMs) than the extensive metabolizers (EMs) (p < 0.001). In addition, FMO3 rs1736557 AA homozygotes showed significantly lower PRI as compared with carriers of the major rs1736557 G allele in the entire cohort and in the MD cohort (p = 0.011, p = 0.008, respectively). The risk of HTPR was decreased significantly in carriers of the rs1736557 A allele (AA vs GG: OR = 0.316, 95% CI: 0.137-0.726, p = 0.005; AA vs GA: OR = 0.249, 95% CI: 0.104-0.597, p = 0.001; AA vs GG+GA: OR = 0.294, 95% CI: 0.129-0.669, p = 0.002), and the association was observed mainly in patients carrying the CYP2C19 LOF allele and in those administered with MD. The FMO3 rs1736557 AA genotype was related to an increased the antiplatelet potency of clopidogrel in Chinese CAD patients. Additional studies are required to verify this finding.

High glycated albumin is an independent predictor of low response to clopidogrel in ACS patients: a cross-sectional study

BackgroundGlycated albumin (GA) is a marker of short-term glycemic control and is strongly associated with the occurrence of diabetes. Previous studies have shown an association between GA and the effect of clopidogrel therapy on ischemic stroke. However, limited information is available regarding this relationship in acute coronary syndrome (ACS) patients. In this study, we evaluated the effect of GA on platelet P2Y12 inhibition by clopidogrel in patients with ACS.MethodsConsecutive Chinese patients with ACS who received loading or maintenance doses of clopidogrel in addition to aspirin were recruited. At least 12 h after the patient had taken the clopidogrel dose, thromboelastography (TEG) and light transmittance aggregometry (LTA) were used to calculate the quantitative platelet inhibition rate to determine clopidogrel-induced antiplatelet reactivity. A prespecified cutoff of the maximum amplitude of adenosine diphosphate (ADP)-induced platelet-fibrin clot strength > 47 mm plus an ADP-induced platelet inhibition rate < 50% assessed by TEG or ADP-induced platelet aggregation > 40% assessed by LTA to indicate low responsiveness to clopidogrel were applied for evaluation. Patients were categorized into two groups based on a GA level of 15.5%, the cutoff point indicating the development of early-phase diabetes. Multivariate linear regression analysis was used to assess the interaction of GA with clopidogrel antiplatelet therapy.ResultsA total of 1021 participants were evaluated, and 28.3% of patients (289 of 1021) had low responsiveness to clopidogrel assessed by TEG. In patients with elevated GA levels, low responsiveness to clopidogrel assessed by TEG was observed in 33.7% (139 of 412) of patients, which was a significantly higher rate than that in the lower-GA-level group (24.6%, P = 0.002). According to multivariate linear regression analysis, a GA level > 15.5% was independently associated with low responsiveness to clopidogrel after adjustment for age, sex and other conventional confounding factors. This interaction was not mediated by a history of diabetes mellitus. A GA level ≤ 15.5% was associated with a high positive value [75.4%, 95% CI 73.0–77.6%] for predicting a normal responsiveness to clopidogrel.ConclusionsGA could be a potential biomarker to predict the effects of clopidogrel antiplatelet therapy in ACS patients and might be a clinical biomarker to guide DAPT de-escalation.

Dose adjustment of clopidogrel in hyper-responder patients with unruptured intracranial aneurysms treated with stents

BackgroundThe management of clopidogrel in hyper-responders has not been well described. We report the treatment and dose adjustment individualization with clopidogrel oral solution (COS) in hyper-responder patients with an unruptured...

Pharmacodynamic changes of platelet reactivity status in patients with chronic kidney disease after coronary artery stenting

ObjectivesThis study was to evaluate platelet reactivity over time among patients with chronic kidney disease (CKD) receiving standard dose of clopidogrel after percutaneous coronary intervention (PCI). The effect of CYP2C19 loss-of-function genotypes on platelet reactivity was also determined. MethodsPatients with CKD (n = 138) on maintenance dose of clopidogrel after PCI were enrolled. Platelet reactivity was assessed by measuring P2Y12 reaction units (PRU) with VerifyNow P2Y12 assay, and platelet reactivity index (PRI) with flow cytometric using vasodilator-stimulated phosphoprotein (VASP) at baseline and 2 weeks later, respectively. The genotypes of CYP2C19 were also measured concurrently. ResultsThe proportion of patients with high platelet reactivity (HPR) ranged from 23.2% to 59.4%, and almost 1 in 5 patients had a dual conversion between HPR and non-HPR status. Patients carrying CYP2C19 loss-of-function genotypes showed a higher platelet reactivity than non-carriers, but with an undetermined HPR status between the first and second visits. The individual switch of HPR to non-HPR status existed in both loss-of-function genotype carriers and non-carriers. ConclusionsHPR conversions occur in a significant proportion of CKD patients with maintenance doses of clopidogrel treatment post-PCI, and this conversion was not confined to CYP2C19 loss-of-function genotype carriers. Risk stratification for treatment adjustment in personalized antiplatelet therapy should be investigated in future research.

Association of N6AMT1 rs2254638 Polymorphism With Clopidogrel Response in Chinese Patients With Coronary Artery Disease.

Dual antiplatelet treatment with aspirin and clopidogrel is the standard therapy for patients undergoing percutaneous coronary intervention (PCI). However, a portion of patients suffer from clopidogrel resistance (CR) and consequently with recurrence of cardiovascular events. Genetic factors such as loss-of-function variants of CYP2C19 contribute a lot to CR. Recently, the N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) rs2254638 polymorphism is reported to be associated with clopidogrel response. To validate the association between N6AMT1 rs2254638 polymorphism and clopidogrel response, 435 Chinese CAD patients receiving aspirin and clopidogrel were recruited. N6AMT1 rs2254638 and CYP2C19*2/*3 polymorphisms were genotyped. Platelet reaction index (PRI) was measured by VASP-phosphorylation assay after treated with a 300 mg loading dose (LD) clopidogrel or 75 mg daily maintenance dose (MD) clopidogrel for at least 5 days. There was a significant difference in PRI between LD cohort and MD cohort. Carriers of CYP2C19*2 allele showed significantly increased PRI in the entire cohort and in respective of the MD and LD cohorts (p < 0.001, p = 0.003, p < 0.001, respectively). However, carriers of CYP2C19*3 allele exhibited significantly higher PRI only in the entire cohort and LD cohort (p = 0.023, p = 0.023 respectively). PRI value was significantly higher in CYP2C19 PM genotyped patients as compared with those carrying the IM genotypes and EM genotype (p < 0.001). Besides, carriers of the rs2254638 C allele showed significantly higher PRI in entire cohort and in the LD cohort (p = 0.023, p = 0.008, respectively). When the patients were grouped into clopidogrel resistance (CR) and non-clopidogrel resistance (non-CR) groups, CYP2C19*2 was associated with increased risk of CR in the entire cohort, the LD cohort and the MD cohort (p < 0.001, p < 0.001, and p = 0.019, respectively). Carriers of the rs2254638 C allele also showed increased risk of CR in the entire cohort and the LD cohort (p = 0.024, and p = 0.028, respectively). N6AMT1 rs2254638 remained as a strong predictor for CR (TC vs. TT: OR = 1.880, 95% CI = 1.099–3.216,p = 0.021; CC vs. TT: OR = 1.930, 95% CI = 1.056-3.527, p = 0.032; TC + CC vs. TT: OR = 1.846, 95%CI = 1.126–3.026, p = 0.015) after adjustment for confounding factors. Our study confirmed the influence of CYP2C19*2 and rs2254638 polymorphisms on clopidogrel resistance in Chinese CAD patients. Both CYP2C19*2 and N6AMT1 rs2254638 polymorphism may serve as independent biomarkers to predict CR.

Vasodilator-stimulated phosphoprotein-guided Clopidogrel maintenance therapy reduces cardiovascular events in atrial fibrillation patients requiring anticoagulation therapy and scheduled for percutaneous coronary intervention: a prospective cohort study

BackgroundIn a previous study, we found that titrating clopidogrel maintenance doses (MDs) according to vasodilator-stimulated phosphoprotein (VASP) monitoring minimised the rate of major adverse cardiovascular and cerebral events (MACCE) after percutaneous coronary intervention (PCI) without increasing bleeding in patients with high on-treatment platelet reaction to clopidogrel. This study aimed to investigate whether VASP-guided clopidogrel MD could reduce thromboembolism and bleeding in atrial fibrillation (AF) patients requiring anticoagulation and scheduled for PCI.MethodsAF patients scheduled for PCI were recruited between July 2014 and July 2016. These patients were allocated into VASP-guided (n = 250) and control (n = 253) groups depending on the clopidogrel MD profile. In the VASP-guided group, clopidogrel MD was titrated by the platelet reactivity index (PRI), whereas in the control group, clopidogrel MD was fixed at 75 mg per day. The primary endpoint was MACCE and secondary endpoints were thrombolysis in myocardial infarction (TIMI) major and minor bleeding 1 year after PCI.ResultsFive hundred and three patients were included in the present study, with 1-year data available for 95.6% patients. The average CHA2DS2-VASc score of the whole population was 3.7 ± 0.7 and the average HAS-BLED score was 3.2 ± 0.4. MACCE was less in the VASP-guided group than in the control group (2.5% vs. 5.0%, P = 0.02). The incidence of major bleeding was comparable between both groups (3.0% vs. 2.8%, P = 0.72) and minor bleeding was higher in the VASP-guided group than in the control group (15.3% vs. 9.7%, P = 0.03). Kaplan-Meier analysis indicated that there was no difference in survival between both groups (log-rank test, P = 0.68).ConclusionsIn AF patients requiring anticoagulation and scheduled for PCI, VASP-guided antiplatelet therapy reduced major cardiovascular and cerebral adverse events, accompanied by increased minor bleeding events.Trial registrationThe present study was retrospectively registered in the Chinese Clinical Trial Registry, A Primary Registry of the International Clinical Trial Registry Platform, World Health Organisation (Registration no: ChiCTR-IOR-17013854). The registered date was December 11, 2117.

Twenty-four-hour time dependency of clopidogrel effects in patients with acute coronary syndromes: The CiCAD-Study

Long-term evidence shows an increased risk of cardiovascular events in the morning hours and recent studies in aspirin-treated patients have shown increased platelet reactivity at the end of the dosing interval. Similar pharmacodynamic analyses of adenosine-diphosphate (ADP) receptor inhibitors are scarce. We therefore investigated changes in clopidogrel-dependent platelet function and activation over 24 h and whether enhanced platelet turnover might explain diurnal variability of platelet function and activation.Twenty-one patients after acute coronary syndromes (ACS) on maintenance doses of clopidogrel (75 mg) and aspirin (100 mg) Once per day (OD) were included. Blood was collected at five time points in 24 h. Platelet function and activation was analyzed by vasodilator-stimulated phosphoprotein-phosphorylation (VASP-P), Verify Now, multiple electrode aggregometry (MEA), and platelet PAC-1 and P-selectin (P-sel) expression. Additionally, platelet count, mean platelet volume (MPV), and reticulated platelet fraction (RPF) were analyzed.There was significant diurnal variability of clopidogrel effects as documented with VASP-P, Verify Now, and PAC-1 and P-sel (all p < 0.05), whereas MEA did not differ over 24 h. Neither MPV nor RPF varied significantly over 24 h. In patients with high RPF, platelet function and activation was significantly higher in all assays, compared to patients with low RPF (all p < 0.05). However, the changes over time in low versus high RPF groups were similar.ADP-dependent platelet function and activation recovers significantly at the end of the 24-h dosing interval in patients with ACS on a maintenance dose of clopidogrel and aspirin. Although platelet function and activation is increased in patients with higher RPF, platelet turnover might not explain the observed diurnal variability.

Pharmacogenetic association study on clopidogrel response in Puerto Rican Hispanics with cardiovascular disease: a novel characterization of a Caribbean population.

IntroductionHigh on-treatment platelet reactivity (HTPR) to clopidogrel imparts an increased risk for ischemic events in adults with coronary artery disease. Platelet reactivity varies with ethnicity and is influenced by both clinical and genetic variables; however, no clopidogrel pharmacogenetic studies with Puerto Rican patients have been reported. Therefore, we sought to identify clinical and genetic determinants of on-treatment platelet reactivity in a cohort of Puerto Rican patients with cardiovascular disease.MethodsWe performed a retrospective study of 111 patients on 75 mg/day maintenance dose of clopidogrel. Patients were allocated into 2 groups: Group I, without HTPR; and Group II, with HTPR. Platelet function was measured ex vivo using the VerifyNow® P2Y12 assay and HTPR was defined as P2Y12 reaction units (PRU) ≥230. Genotyping testing was performed using Taqman® Genotyping Assays.ResultsThe mean PRU across the cohort was 203±61 PRU (range 8–324), and 42 (38%) patients had HTPR. Multiple logistic regression showed that 27% of the total variation in PRU was explained by a history of diabetes mellitus, hematocrit, CYP2C19*2, and PON1 p.Q192R. Body mass index (odds ratio [OR]=1.15; 95% CI: 1.03–1.27), diabetes mellitus (OR=3.46; 95% CI: 1.05–11.43), hematocrit (OR=0.75; 95% CI: 0.65–0.87), and CYP2C19*2 (OR=4.44; 95% CI: 1.21–16.20) were the only independent predictors of HTPR.ConclusionMoreover, we propose a predictive model to determine PRU values as measured by VerifyNow P2Y12 assay for the Puerto Rican Hispanic population. This model has the potential to identify Hispanic patients at higher risk for adverse events on clopidogrel.

2042 CYP2C19*2 and PON1 Q192R polymorphisms are associated with platelet reactivity to clopidogrel in Puerto Rican Hispanics with cardiovascular disease

OBJECTIVES/SPECIFIC AIMS: High on-treatment platelet reactivity (HTPR) with clopidogrel imparts an increased risk for ischemic events in adults with coronary artery disease. Although more potent antiplatelet agents are available, clopidogrel remains the most commonly used P2Y12 inhibitor in Puerto Rico. Platelet reactivity varies with ethnicity and is influenced by both clinical and genetic variables; however, no clopidogrel pharmacogenetic studies with Puerto Rican patients have been reported. Therefore, we sought to identify clinical and genetic determinants of on-treatment platelet reactivity in a cohort of Puerto Rican patients with cardiovascular disease. METHODS/STUDY POPULATION: We performed a retrospective study of 111 Puerto Rican patients on 75 mg/day maintenance dose of clopidogrel. Patients were allocated into 2 groups: Group I, without HTPR; and Group II, with HTPR. Clinical data was obtained from the medical record. Platelet function was measured ex vivo using the VerifyNow® P2Y12 assay and HTPR was defined as P2Y12 reaction units (PRU)≥230. Genotyping of CYP2C19, ABCB1, PON1, PY2R12, B4GALT2, CES1, and PEAR1 was performed using Taqman® Genotyping Assays. RESULTS/ANTICIPATED RESULTS: The mean PRU across the cohort was 203±61 PRU (range, 8–324), and 42 (38%) patients had HTPR. One in four individuals carried at least 1 copy of the CYP2C19*2 variant allele. Hematocrit and PON1 p.Q192R variant were inversely correlated with platelet reactivity (p&lt;0.05). Multiple logistic regression showed that 27% of the total variation in PRU was explained by a history of diabetes mellitus, hematocrit, CYP2C19*2, and PON1 p.Q192R. Body mass index (OR=1.15; CI: 1.03–1.27), diabetes mellitus (OR=3.46; CI: 1.05–11.43), hematocrit (OR=0.75; CI: 0.65–0.87), and CYP2C19*2 (OR=4.44; CI: 1.21–16.20) were the only independent predictors of HTPR. DISCUSSION/SIGNIFICANCE OF IMPACT: In a representative sample of Puerto Rican patients with cardiovascular disease, diabetes mellitus, hematocrit, CYP2C19*2, and PON1 p.Q192R were associated with on-treatment platelet reactivity. These factors may identify a subset of patients at higher risk for adverse events on clopidogrel in the Hispanic population.

Effect of cytochrome P450 2C19 polymorphism on adverse cardiovascular events after drug-eluting stent implantation in a large Hakka population with acute coronary syndrome receiving clopidogrel in southern China.

The objective of this study is to evaluate the effects of cytochrome P450 2C19 (CYP2C19) polymorphism on adverse cardiovascular events (MACE) in Hakka patients with acute coronary syndrome (ACS) receiving clopidogrel who had undergone coronary drug-eluting stent placement after percutaneous coronary intervention (PCI) in southern China. Genotyping of CYP2C19 and MACE of 934 ACS patients with PCI on clopidogrel maintenance therapy were analyzed. Patients who carried loss-of-function CYP2C19 were treated with a 150-mg maintenance dose of clopidogrel or 90mg of ticagrelor antiplatelet therapy, and patients who were non-carriers received clopidogrel therapy daily at a maintenance dose of 75mg and the patients were followed-up for at least 12months. The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, and target vessel revascularization and stroke. The allelic frequency of CYP2C19*2 and CYP2C19*3 of Hakka patients in the current study was 31.64 and 5.19%, respectively. The CYP2C19 wild-type homozygotes (*1/*1) were the most predominant among the patients (40.36%), followed by the CYP2C19*2 heterozygotes (*1/*2) (40.26%). The distribution of CYP2C19 phenotypes was divided into extensive metabolizers (EM; 40.36%), intermediate metabolizers (IM; 45.61%), and poor metabolizers (PM; 14.03%). Based on the genotype-guided antiplatelet therapy, there was no significant association between the carrier status and the clinical outcome at 1, 6, and 12months. In addition, no significant difference in the rates of bleeding was found among the three groups. After logistic regression analysis, hypertension was the only independent predictor of cardiovascular events (relative risk, 1.501; 95% CI, 1.011 to 2.229; P = 0.044). Our results shed new light on the important benefit of testing CYP2C19 polymorphisms before prescribing clopidogrel in patients treated with drug-eluting stent implantation after PCI. The testing may help to optimize pharmacotherapy effectiveness by providing individualized treatment to the Chinese population. Our findings mandate further studies aimed at initiating genome-based personalized antiplatelet therapy in a Hakka population in southern China.

Recent Evolution of the Treatment of Coronary Artery Disease in China: A Conversation With Ya-Ling Han, MD, PhD.

Ya-Ling Han, MD, PhD, was born in Wuhan, Hubei province, in 1953. She graduated from Haebin Medical University in 1978. She received her doctorate in 1994 from Shanghai Second Military Medical University. She was a visiting scholar at the National Heart Center, Singapore. She is currently a professor and the director of the Department of Cardiology, General Hospital of Shenyang Military Region; the director of the Cardiovascular Research Institute; and the director of the Key Laboratory of Acute Severe Cardiovascular Treatment Research of the Chinese People’s Liberation Army. She is the president of the Chinese College of Cardiovascular Physicians and Chairperson-elect of the Chinese Society of Cardiology. Dr Rutherford asks: Could you describe the scope of clinical cardiac care provided in the Department of Cardiology at the General Hospital of Shenyang Military Region? Dr Ya-L ing Han replies : The Department of Cardiology at the General Hospital of Shenyang Military Region, together with the departments of congenital heart disease and cardiovascular surgery, constitute the cardiovascular institute of the People’s Liberation Army, which is among the top 5 centers in China providing comprehensive care for CVD. Our center is located in Northeast China, an area with the highest prevalence of CAD, so the treatment and prevention of CAD is our major focus. We are a busy center: we perform ≈7000 PCIs, 1400 radiofrequency ablations, 550 pacemaker implantations, 900 congenital heart disease interventions, and ≈2500 cardiovascular surgeries annually, with an overall in-hospital mortality rate of <1%. We have pioneered many facets of CVD treatment in China, including PCI for complicated coronary lesions, CTO of coronary arteries, left main coronary disease, treatment of high-risk patients with AMI, novel antithrombotic strategies for coronary patients, and surgical and percutaneous treatment of complicated congenital heart disease. Over the past 2 decades, you and your team have …

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OBJECTIVES/SPECIFIC AIMS: To determine the association between clinical characteristics and platelet reactivity in Hispanic patients on clopidogrel therapy. METHODS/STUDY POPULATION: A cross-sectional pilot study was performed in 58 Puerto Rican patients diagnosed with any type of vascular disease and actively receiving a maintenance dose of clopidogrel for at least 7 days. The study population was divided into 2 groups: Group I with non-high on-treatment platelet reactivity (TPR); Group II with high TPR. To determine the platelet function, P2Y12 reaction units (PRU) were obtained by VerifyNow® P2Y12 assay (Accumetrics, USA). RESULTS/ANTICIPATED RESULTS: We studied a heterogeneous cohort of patients with coronary artery disease (57%), peripheral artery disease (30%), carotid artery stenosis (7%), cerebral artery aneurysm (3%), and stroke (3%) on clopidogrel therapy for secondary prevention of thromboembolic events. The mean TPR was 205±49 PRU (range: 61–304), with a prevalence of 28% patients with high TPR (PRU≥230). No significant clinical differences were found between the non-high TPR and high-TPR groups (p&gt;0.05). However, multivariable logistic regression analysis showed that both diabetes mellitus (OR=7.5; CI: 1.01–51.9) and proton-pump inhibitors (OR=13.6; CI: 1.3–142.0) were independently correlated with high TPR (p&lt;0.05) after adjusting for other clinical variables. DISCUSSION/SIGNIFICANCE OF IMPACT: These results provide new insight into the importance of clinical characteristics on platelet reactivity in this Caribbean population. Further studies are warranted to determine whether important clopidogrel pharmacogenes are related with platelet function in Hispanics, as well as the role of TPR in guiding antiplatelet therapy and predicting future adverse cardiovascular events in this population.

Clopidogrel loading dose versus maintenance dose to treat patients with acute ischaemic stroke in China (CLASS-China): results from a prospective double-blind randomised clinical trial

AimThe role of clopidogrel in treating patients with acute ischaemic stroke is unclear. We have conducted the clinical trial in order to evaluate the efficacy and safety of clopidogrel with...