Abstract 2041: Low P2Y 12 -Specific Platelet Inhibition in Clopidogrel-Treated Patients with Coronary Artery Disease is Common and not Reliably Detected by Conventional Aggregation Tests

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Andreas Schaefer ◽  
Sarah Weinberger ◽  
Martin Eigenthaler ◽  
Georg Ertl ◽  
Johann Bauersachs
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Real World ◽  
Platelet Reactivity ◽  
Reactivity Index ◽  
Individual Response ◽  
Specific Assay ◽  
Cardiovascular Morbidity And Mortality ◽  
Increased Risk ◽  
Artery Disease

Background: Incomplete inhibition of P2Y 12 -mediated platelet activation during clopidogrel treatment has been associated with increased cardiovascular morbidity and mortality after percutaneous coronary intervention. This study aimed to investigate the incidence of impaired individual clopidogrel-responsiveness using a P2Y 12 -specific and pre-treatment-independent assay in a real world situation. Methods: 100 consecutive patients with coronary artery disease on clopidogrel treatment (> 5 days including a loading dose of at least 300 mg) were screened for response to ADP-induced platelet signalling. We assessed the vasodilator-stimulated phosphoprotein-based platelet reactivity index (PRI) as the only P2Y 12 -specific assay to determine clopidogrel responsiveness. Insufficient inhibition of P2Y 12 by clopidogrel was defined as a PRI >50% based on previous studies indicating increased risk of stent thrombosis under this condition. The results were compared with conventional assays to assess ADP-induced P-selectin surface-expression and conventional turbinometric platelet aggregation to several concentrations of ADP. Results: Clopidogrel significantly lowered functional platelet reactivity in patients with coronary artery disease compared to untreated patients. However, insufficient individual response to treatment predisposing for adverse events and therefore previously described as “non-response” was diagnosed in 69% of clopidogrel-treated patients using PRI. Conventional aggregation failed to detect insufficient P2Y 12 -inhibition in 1/3of patients with a PRI>50%. Conclusion: Using the PRI as the only P2Y 12 -specific assay to evaluate the treatment effect of clopidogrel in patients with coronary artery disease, insufficient P2Y 12 -inhibition was present in the majority of patients in a real-world scenario. Insufficient P2Y12-inhibition could not be reliably detected by conventional aggregation More prospective studies are needed to evaluate the influence of the high prevalence of incomplete clopidogrel responsiveness to major adverse cardiac events.

ADP-induced platelet aggregation frequently fails to detect impaired clopidogrel-responsiveness in patients with coronary artery disease compared to a P2Y12-specific assay

2008 ◽  
Vol 100 (10) ◽  
pp. 618-625 ◽  
Author(s):  
Sarah Weinberger ◽  
Ulrike Flierl ◽  
Martin Eigenthaler ◽  
Stefan Störk ◽  
Ulrich Walter ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Platelet Aggregation ◽  
Real World ◽  
Platelet Reactivity ◽  
Reactivity Index ◽  
Individual Response ◽  
Specific Assay ◽  
Artery Disease ◽  
Impaired Individual

SummaryIncomplete P2Y12-inhibition during clopidogrel treatment is associated with increased cardiovascular events and mortality after coronary intervention. We investigated the incidence of impaired individual clopidogrel-responsiveness using a P2Y12-specific and pre-treatment-independent assay in a real world situation. One hundred consecutive patients with coronary artery disease (CAD) on combined acetylsalicylic acid and clopidogrel treatment (75 mg/d) and 33 patients on aspirin only were screened for platelet ADP-induced signalling by conventional aggregometry, platelet P-selectin expression and the platelet reactivity index (PRI). Impaired P2Y12-specific inhibition by clopidogrel was defined as a PRI>50%. Functional platelet reactivity was significantly lower in clopidogrel-treated patients compared to controls. Impaired individual response to treatment was diagnosed in 69% of clopidogrel-treated patients. Conventional assessment of maximum ADP-induced platelet aggregation failed to detect impaired P2Y12 inhibition in 36% of patients identified by PRI to have an impaired clopidogrel response. Impaired clopidogrel response was associated with lower HDL levels and a history of hyperlipidaemia. In conclusion, PRI as a P2Y12-specific assay to evaluate the treatment effect of clopidogrel in patients with CAD revealed insufficient P2Y12-inhibition in two thirds of patients in a real-world scenario indicating a markedly higher incidence than previously assumed. PRI detected significantly more patients with impaired response than conventional platelet aggregation.

scholarly journals Association of the coronary artery disease risk gene GUCY1A3 with ischaemic events after coronary intervention

2019 ◽  
Vol 115 (10) ◽  
pp. 1512-1518 ◽  
Author(s):  
Thorsten Kessler ◽  
Bernhard Wolf ◽  
Niclas Eriksson ◽  
Daniel Kofink ◽  
Bakhtawar K Mahmoodi ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Stent Thrombosis ◽  
Risk Allele ◽  
Platelet Reactivity ◽  
Coronary Intervention ◽  
Cardiovascular Death ◽  
Impedance Aggregometry ◽  
Increased Risk ◽  
Artery Disease

AbstractAimA common genetic variant at the GUCY1A3 coronary artery disease locus has been shown to influence platelet aggregation. The risk of ischaemic events including stent thrombosis varies with the efficacy of aspirin to inhibit platelet reactivity. This study sought to investigate whether homozygous GUCY1A3 (rs7692387) risk allele carriers display higher on-aspirin platelet reactivity and risk of ischaemic events early after coronary intervention.Methods and resultsThe association of GUCY1A3 genotype and on-aspirin platelet reactivity was analysed in the genetics substudy of the ISAR-ASPI registry (n = 1678) using impedance aggregometry. The clinical outcome cardiovascular death or stent thrombosis within 30 days after stenting was investigated in a meta-analysis of substudies of the ISAR-ASPI registry, the PLATO trial (n = 3236), and the Utrecht Coronary Biobank (n = 1003) comprising a total 5917 patients. Homozygous GUCY1A3 risk allele carriers (GG) displayed increased on-aspirin platelet reactivity compared with non-risk allele (AA/AG) carriers [150 (interquartile range 91–209) vs. 134 (85–194) AU⋅min, P < 0.01]. More homozygous risk allele carriers, compared with non-risk allele carriers, were assigned to the high-risk group for ischaemic events (>203 AU⋅min; 29.5 vs. 24.2%, P = 0.02). Homozygous risk allele carriers were also at higher risk for cardiovascular death or stent thrombosis (hazard ratio 1.70, 95% confidence interval 1.08–2.68; P = 0.02). Bleeding risk was not altered.ConclusionWe conclude that homozygous GUCY1A3 risk allele carriers are at increased risk of cardiovascular death or stent thrombosis within 30 days after coronary stenting, likely due to higher on-aspirin platelet reactivity. Whether GUCY1A3 genotype helps to tailor antiplatelet treatment remains to be investigated.

Pharmacodynamic effects of standard dose prasugrel versus high dose clopidogrel in non-diabetic obese patients with coronary artery disease

2014 ◽  
Vol 111 (02) ◽  
pp. 258-265 ◽  
Author(s):  
Andrew Darlington ◽  
Antonio Tello-Montoliu ◽  
Fabiana Rollini ◽  
Masafumi Ueno ◽  
José Luis Ferreiro ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Platelet Reactivity ◽  
Standard Dose ◽  
Statistical Significance ◽  
Reactivity Index ◽  
High Dose ◽  
Obese Patients ◽  
Size Estimation ◽  
Artery Disease

SummaryIncreased body weight is independently associated with impaired clopidogrel pharmacodynamic (PD) response. Prasugrel has more potent PD effects compared with clopidogrel, although its PD effects in obese patients are unknown. The aim of this prospective, randomised, study was to compare the PD effects of standard-dose prasugrel [60 mg loading dose (LD)/10 mg daily maintenance dose (MD)] with highdose clopidogrel (900 mg LD/150 mg daily MD) in non-diabetic obese [body mass index (BMI) ≥30 kg/m2] patients, with coronary artery disease (CAD) on aspirin therapy. PD assessments (baseline, 2 hours post-LD and 6 ± 2 days after MD) were conducted using four platelet function assays, and the platelet reactivity index (PRI) assessed by VASP was used for sample size estimation. A total of 42 patients with a BMI of 36.42 ± 5.6 kg/m2 completed the study. There were no differences in baseline PD measures between groups. At 2 hours post-LD, prasugrel was associated with lower PRI compared with clopidogrel (24.3 ± 5.5 vs 58.7 ± 5.7, p≤0.001), with consistent findings for all assays. At one-week, PRI values on prasugrel MD were lower than clopidogrel MD without reaching statistical significance (34.7 ± 5.8 vs 42.9 ± 5.8, p=0.32), with consistent findings for all assays. Accordingly, rates of high on-treatment platelet reactivity were markedly reduced after prasugrel LD, but not after MD. In conclusion, in non-diabetic obese patients with CAD, standard prasugrel dosing achieved more potent PD effects than high-dose clopidogrel in the acute phase of treatment, but this was not sustained during maintenance phase treatment. Whether an intensified prasugrel regimen is required in obese patients warrants investigation.

scholarly journals Women with Stable Angina Pectoris and No Obstructive Coronary Artery Disease: Closer to a Diagnosis

2017 ◽  
Vol 12 (1) ◽  
pp. 14 ◽  
Author(s):  
Marie Mide Michelsen ◽  
Naja Dam Mygind ◽  
Daria Frestad ◽  
Eva Prescott ◽  
◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Obstructive Coronary Artery Disease ◽  
Microvascular Dysfunction ◽  
Coronary Microvascular Dysfunction ◽  
Stable Angina Pectoris ◽  
Cardiovascular Morbidity And Mortality ◽  
Increased Risk ◽  
Artery Disease ◽  
Diagnostic Modalities

A large proportion of women with chest pain have no obstructive coronary artery disease. Recent studies have demonstrated that these women continue to have symptoms and are at increased risk of cardiovascular morbidity and mortality. Coronary microvascular dysfunction (CMD) leads to an impairment of blood flow regulation to the myocardium and possible transient ischaemia. CMD is a disease entity with several pathophysiologic aspects and diagnostic modalities continue to be developed. However, due to the complexity of the disease, it remains elusive whether CMD is the explanation for the symptoms and the poor prognosis in women with angina and no obstructive coronary artery disease.

scholarly journals Influence of GAS5 /MicroRNA‐223‐3p/P2Y12 Axis on Clopidogrel Response in Coronary Artery Disease

2021 ◽  
Author(s):  
Yan‐Ling Liu ◽  
Xiao‐Lei Hu ◽  
Pei‐Yuan Song ◽  
He Li ◽  
Mu‐Peng Li ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Cell Line ◽  
Antiplatelet Therapy ◽  
Dual Antiplatelet Therapy ◽  
Platelet Reactivity ◽  
T Antigen ◽  
Luciferase Reporter ◽  
Reactivity Index ◽  
Artery Disease

Background Dual antiplatelet therapy based on aspirin and P2Y12 receptor antagonists such as clopidogrel is currently the primary treatment for coronary artery disease (CAD). However, a percentage of patients exhibit clopidogrel resistance, in which genetic factors play vital roles. This study aimed to investigate the roles of GAS5 (growth arrest‐specific 5) and its rs55829688 polymorphism in clopidogrel response in patients with CAD. Methods and Results A total of 444 patients with CAD receiving dual antiplatelet therapy from 2017 to 2018 were enrolled to evaluate the effect of GAS5 single nucleotide polymorphism rs55829688 on platelet reactivity index. Platelets from 37 patients of these patients were purified with microbeads to detect GAS5 and microRNA‐223‐3p (miR‐223‐3p) expression. Platelet‐rich plasma was isolated from another 17 healthy volunteers and 46 newly diagnosed patients with CAD to detect GAS5 and miR‐223‐3p expression. A dual‐luciferase reporter assay was performed to explore the interaction between miR‐223‐3p and GAS5 or P2Y12 3′‐UTR in (human embryonic kidney 293 cell line that expresses a mutant version of the SV40 large T antigen) HEK 293T and (megakaryoblastic cell line derived in 1983 from the bone marrow of a chronic myeloid leukemia patient with megakaryoblastic crisis) MEG‐01 cells. Loss‐of‐function and gain‐of‐function experiments were performed to reveal the regulation of GAS5 toward P2Y12 via miR‐223‐3p in MEG‐01 cells. We observed that rs55829688 CC homozygotes showed significantly decreased platelet reactivity index than TT homozygotes in CYP2C19 poor metabolizers. Platelet GAS5 expression correlated positively with both platelet reactivity index and P2Y12 mRNA expressions, whereas platelet miR‐223‐3p expression negatively correlated with platelet reactivity index. Meanwhile, a negative correlation between GAS5 and miR‐223‐3p expressions was observed in platelets. MiR‐223‐3p mimic reduced while the miR‐223‐3p inhibitor increased the expression of GAS5 and P2Y12 in MEG‐01 cells. Knockdown of GAS5 by siRNA increased miR‐223‐3p expression and decreased P2Y12 expression, which could be reversed by the miR‐223‐3p inhibitor. Meanwhile, overexpression of GAS5 reduced miR‐223‐3p expression and increased P2Y12 expression, which could be reversed by miR‐223‐3p mimic. Conclusions GAS5 rs55829688 polymorphism might affect clopidogrel response in patients with CAD with the CYP2C19 poor metabolizer genotypes, and GAS5 regulates P2Y12 expression and clopidogrel response by acting as a competitive endogenous RNA for miR‐223‐3p.

Antiplatelet for Coronary Artery Disease in Specific Condition “No Size Fits All”

2018 ◽  
Vol 24 (4) ◽  
pp. 478-495
Author(s):  
Benny M. Setiadi ◽  
Beny Hartono ◽  
Adhitia B. Prakoso ◽  
Anggia C. Lubis ◽  
Reza M. Munandar ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Platelet Reactivity ◽  
Antiplatelet Agent ◽  
Current Evidence ◽  
Efficacy And Safety ◽  
Current Recommendation ◽  
Risk Of Bleeding ◽  
Increased Risk ◽  
Artery Disease

Antiplatelet is the cornerstone therapy for patient with coronary artery disease. Several comorbidities can influence the efficacy and safety of antiplatelet agent. Diabetes mellitus is characterized by increased platelet reactivity and reduced response to antiplatelet. Elderly patients have both reduced response to antiplatelet and increased risk of bleeding. Patients with renal dysfunction also had decreased efficacy of antiplatelet accompanied with increased risk of bleeding. In patients with atrial fibrillation, the concomitant use of anticoagulant with antiplatelet poses an increased risk of bleeding. In patients with these comorbidities, caution should be stressed in selecting the best regimen of antiplatelet which translates the most optimal efficacy while minimizing the risk of adverse events. In this review, we will discuss the platelet changes in these comorbidities, current evidence of antiplatelet usage in these group of patients and current recommendation.

scholarly journals The effect of CYP2C19 gene polymorphisms on the pharmacokinetics and pharmacodynamics of prasugrel 5-mg, prasugrel 10-mg and clopidogrel 75-mg in patients with coronary artery disease

2014 ◽  
Vol 112 (09) ◽  
pp. 589-597 ◽  
Author(s):  
Thomas Bergmeijer ◽  
Udaya Tantry ◽  
Jurrien ten Berg ◽  
Dominick Angiolillo ◽  
Stefan James ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Active Metabolite ◽  
Light Transmission ◽  
Platelet Reactivity ◽  
Stable Coronary Artery Disease ◽  
Geometric Mean ◽  
Reactivity Index ◽  
Cyp2c19 Genotype ◽  
Artery Disease

Summary CYP2C19 genotype has been shown to impact response to clopidogrel 75-mg but not prasugrel 10-mg. Here, we assessed effects of CYP2C19 metaboliser status on pharmacokinetics (PK) and pharmacodynamic (PD) responses to prasugrel 5-mg and 10-mg and clopidogrel 75-mg using data from two PK/PD studies in stable coronary artery disease (CAD) patients (GENERATIONS and FEATHER). Active metabolite concentrations (area under the curve, AUC[0-tlast]), maximum platelet aggregation (MPA) measured by light transmission aggregometry, vasodilator- stimulated phosphoprotein platelet reactivity index, and VerifyNow P2Y12-platelet reaction units (VN-PRU) were analysed by CYP2C19-predicted phenotype (extensive metaboliser [EM; N=154], *2-*8 non-carriers, vs reduced metaboliser [RM; N=41],*2-*8 carriers/* 17 non-carriers). AUC(0-tlast) was unaffected by metaboliser status for prasugrel 5-mg and 10-mg (geometric mean EM/RM ratios 1.00, 95% confidence interval [CI]: 0.86,1.17, p>0.99; and 0.97, 95% CI:0.85,1.12, p=0.71, respectively), but was lower among RMs receiving clopidogrel 75-mg (1.37, 95% CI:1.14,1.65, p<0.001). Platelet reactivity was not significantly affected by CYP2C19 metaboliser status for prasugrel 5-mg, or for prasugrel 10-mg by MPA and VNPRU, but for clopidogrel 75-mg was significantly higher in reduced metabolisers (all measures p<0.01). Prasugrel 10-mg showed greater antiplatelet effects vs clopidogrel 75-mg (all comparisons p<0.001). Prasugrel 5-mg showed greater antiplatelet effects vs clopidogrel 75-mg in RMs (all p<0.001), and comparable effects in EMs (all p≥0.37). In contrast to clopidogrel, prasugrel active metabolite PK was not influenced by CYP2C19 genotype. Antiplatelet effect for prasugrel 10-mg was greater irrespective of metaboliser status and for prasugrel 5-mg was greater for RMs and comparable for EMs as compared to clopidogrel 75-mg.

The additive antiplatelet action of clopidogrel in patients with coronary artery disease treated with aspirin

2007 ◽  
Vol 98 (07) ◽  
pp. 201-209 ◽  
Author(s):  
Jerzy Dropinski ◽  
Bogdan Jakiela ◽  
Marek Sanak ◽  
Wojciech Wegrzyn ◽  
Marta Biernat ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Healthy Subjects ◽  
Platelet Reactivity ◽  
Flow Cytometric Analysis ◽  
Aspirin Resistance ◽  
Reactivity Index ◽  
Activation Markers ◽  
Artery Disease ◽  
Sensitive Group

SummaryWe searched for additional anti-platelet effects of clopidogrel in coronary artery disease (CAD) patients treated with aspirin. Response to clopidogrel was also stratified according to aspirin resistance. Out of 76 screened aspirin-treated CAD male patients, five were aspirin-resistant based on arachidonic acid (AA) and ADP aggregometry.These five patients and 15 aspirin-sensitive patients entered the proper study. Platelet function was assessed at baseline and after one week of additional clopidogrel treatment using aggregometry, flow cytometry (ADP, TRAP-6) and platelet reactivity index (PRI) based on VASP (vasodilatorstimulated phosphoprotein) expression.We evaluated the same markers in 15 healthy men after aspirin treatment. In healthy subjects aspirin did not affect resting or ADP-induced activated GPIIb/IIIa and P-selectin expression. The P-selectin expression on ADP-activated platelets was increased (p<0.01) in aspirin treated ASA-resistant CAD patients as compared to ASA-sensitive group or aspirin-treated healthy subjects. Clopidogrel significantly decreased ADP and AA-induced platelet aggregation and overcame aspirin resistance in four of five patients. Expression of ADP-induced activation markers was significantly lowered after clopidogrel in all patients.Out of 20 patients,five did not respond to clopidogrel (<10% inhibition of ADP aggregation), and this group showed no change in expression of ADPinduced activation markers after clopidogrel. Clopidogrel treatment significantly reduced PRI only in the clopidogrel-sensitive group. In conclusion, the addition of clopidogrel to aspirin provides greater inhibition of platelets and can overcome aspirin resistance. Flow cytometric analysis of platelets is useful for monitoring of clopidogrel therapy.

Molecular Evaluation of MicroRNA-146 Gene Variability (rs2910164 C> G) and its Association with Increased Susceptibility to Coronary Artery Disease

MicroRNA ◽  
2020 ◽  
Vol 09 ◽  
Author(s):  
Rashid Mir ◽  
Imadeldin Elfaki ◽  
Chandan k Jha ◽  
Jamsheed Javid ◽  
Suriya Rehman ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Genetic Factors ◽  
Mirna Gene ◽  
Amplification Refractory Mutation System ◽  
Coronary Artery Diseases ◽  
Increased Risk ◽  
Inheritance Model ◽  
Artery Disease ◽  
Increased Susceptibility

Aim: Apart from the modifiable risk factors, genetic factors are believed to also influence the outcome of the coronary artery diseases (CAD). Under the genetic factors, miRNA polymorphisms, namely Hsa-miR-146a-5p (rs2910164) have become an important tool to study the mechanism that underlies the pathogenesis of this disease. Therefore, we investigated the association of miR-146a gene variations with susceptibility of coronary artery diseases. Methodology: This study was conducted on 100 CAD patients and 117 matched healthy individuals. Genotyping of the Hsa-miR-146a-5p C>G gene variation was performed by using amplification refractory mutation system PCR method (ARMS-PCR). Results: The distribution of Hsa-miR-146a-5p rs2910164 C>G genotypes observed between patients and controls was significantly different (P=0.048). Moreover, the frequency of G allele (fG) was found to be significantly higher among patients than in controls (0.36 vs. 0.25). Our findings showed that the Hsa-miR-146a-5p C>G variant was associated with an increased risk of CAD in codominant inheritance model CC vs. CG genotype (OR = 1.84, 95 % CI, 1.02-3.31; p=0.040) and (OR = 3.18, 95 % CI, 1.02-9.9; p=0.045) for CC vs. GG genotype in dominant inheritance model. Whereas the G allele significantly increased the risk of coronary artery disease (OR =1,81, 95 % CI, 1.18-2.78; p=0.006) compared to C allele. Taken together, these results demonstrated that miR-146a/rs2910164 is associated with susceptibility to coronary artery disease, providing novel insights into the genetic etiology and underlying biology of coronary artery disease. Conclusion: Our findings indicated that Hsa-miR-146a-5p rs2910164 GG genotype and G allele are associated with an increased susceptibility to Coronary Artery Disease. A larger sample size can be the key to progress in establishing the genetic co-relation of miRNA gene polymorphisms and cardiovascular diseases.

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