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.

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.

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 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.

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.

Abstract 1716: Calcium Channel Blockers Reduce the Antiplatelet Effect of Clopidogrel

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Jolanta Siller-Matula ◽  
Irene Lang ◽  
Guenter Christ ◽  
Bernd Jilma
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Platelet Aggregation ◽  
Calcium Channel ◽  
Calcium Channel Blocker ◽  
Calcium Channel Blockers ◽  
Channel Blocker ◽  
Platelet Reactivity ◽  
Channel Blockers ◽  
Artery Disease

Due to the known CYP3A4 inhibition by calcium channel blockers, we hypothesized that there might be a pharmacodynamic interaction between clopidogrel and dihydropyridines in patients with coronary artery disease (CAD). Clopidogrel is activated by CYP3A4 which also metabolizes calcium channel blockers of the dihydropyridine class. Methods: Responsiveness to clopidogrel was assessed by the vasodilator stimulated phosphoprotein (VASP) phosphorylation assay and aggregometry in 200 patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). The platelet reactivity index (PRI in the VASP assay, normal range 69–100%) was higher in patients on both clopidogrel and calcium channel blockers (61%) as compared to patients on clopidogrel without calcium channel blockers (48%). The absolute difference was 13% (95%CI: 6 –20%; p = 0.001) and the relative difference approached 21%. A high post-treatment platelet reactivity (PRI > 69%) was seen in 40% of patients with concomitant calcium channel blocker treatment compared to 20% without (X2-test: p = 0.008). Intake of calcium channel blocker remained an independent predictor of high platelet reactivity after adjustment for cardiovascular risk factors. This corresponded to an increased platelet aggregation of similar magnitude (p < 0.05). In vitro incubation with calcium channel blockers (nimodipine, verapamil, amlodipine and diltiazem) did not alter the PRI or the ADP-induced platelet aggregation of patients on clopidogrel, indicating that the interaction occurs in vivo, conceivably at the level of the CYP3A4 cytochrome. Co-administration of calcium channel blockers is associated with a decreased platelet inhibition by clopidogrel.

Thrombopoietin and platelet aggregation in patients with stable coronary artery disease

Platelets ◽  
2017 ◽  
Vol 28 (8) ◽  
pp. 822-824
Author(s):  
Sanne Bøjet Larsen ◽  
Erik Lerkevang Grove ◽  
Søs Neergaard-Petersen ◽  
Morten Würtz ◽  
Anne-Mette Hvas ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Platelet Aggregation ◽  
Stable Coronary Artery Disease ◽  
Artery Disease

scholarly journals Effects of Monotherapy with Clopidogrel vs. Aspirin on Vascular Function and Hemostatic Measurements in Patients with Coronary Artery Disease: The Prospective, Crossover I-LOVE-MONO Trial

2021 ◽  
Vol 10 (12) ◽  
pp. 2720
Author(s):  
Hyun-Woong Park ◽  
Min-Gyu Kang ◽  
Jong-Hwa Ahn ◽  
Jae-Seok Bae ◽  
Udaya S. Tantry ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Endothelial Function ◽  
Vascular Function ◽  
Platelet Reactivity ◽  
Reactive Hyperemia ◽  
Open Label ◽  
Peripheral Arterial Tonometry ◽  
Coagulation Activity ◽  
Artery Disease

To evaluate the effect of clopidogrel vs. aspirin monotherapy on vascular function and hemostatic measurement. Background: Monotherapy with P2Y12 receptor inhibitor vs. aspirin can be a useful alterative to optimize clinical efficacy and safety in high-risk patients with coronary artery disease (CAD). Methods: We performed a randomized, open-label, two-period crossover study in stented patients receiving at least 6-month of dual antiplatelet therapy (DAPT). Thirty CAD patients with moderate-to-high ischemic risk were randomly assigned to receive either 75 mg of clopidogrel or 100 mg of aspirin daily for 4 weeks, and were crossed over to the other strategy for 4 weeks. Vascular function was evaluated with reactive hyperemia-peripheral arterial tonometry (RH-PAT) and brachial-ankle pulse wave velocity (baPWV). Hemostatic profiles were measured with VerifyNow and thromboelastography (TEG). The primary endpoint was the reactive hyperemia index (RHI) during clopidogrel or aspirin monotherapy. Results: Clopidogrel vs. aspirin monotherapy was associated with better endothelial function (RHI: 2.11 ± 0.77% vs. 1.87 ± 0.72%, p = 0.045), lower platelet reactivity (130 ± 64 vs. 214 ± 50 P2Y12 reaction unit [PRU], p < 0.001) and prolonged reaction time (TEG R: 5.5 ± 1.2 vs. 5.1 ± 1.1 min, p = 0.037). In multivariate analysis, normal endothelial function (RHI ≥ 2.1) was significantly associated with clot kinetics (TEG angle ≤ 68 degree) and ‘PRU ≤ 132’. ‘PRU ≤ 132’ was achieved in 46.2% vs. 3.8% during clopidogrel administration vs. aspirin monotherapy (odds ratio 21.4, 95% confidence interval 2.7 to 170.1, p < 0.001). Conclusions: In CAD patients, clopidogrel vs. aspirin monotherapy was associated with better endothelial function, greater platelet inhibition and lower coagulation activity, suggesting pleiotropic effects of clopidogrel on endothelial function and hemostatic profiles.

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