Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection.

Small studies have indicated that drug-drug interactions and such clinical characteristics as diabetes mellitus may increase residual platelet reactivity in patients on clopidogrel therapy. The independent contribution of these variables to high residual platelet reactivity (HRPR) is not well studied. Residual platelet reactivity was assessed using the VerifyNow P2Y12 assay (Accumetrics Inc., San Diego, California) in 377 patients with stable coronary artery disease on maintenance clopidogrel therapy. HRPR was defined using a threshold previously shown to predict adverse clinical outcomes. Residual platelet reactivity was significantly higher in women (220 ± 82 vs 200 ± 77 P2Y12 reaction units [PRU]; p = 0.041), non-Caucasians (229 ± 79 vs 202 ± 78 PRU; p = 0.047), patients with diabetes mellitus (220 ± 73 vs 196 ± 80 PRU; p = 0.005), and those treated with nitrates (233 ± 70 vs 200 ± 80 PRU; p = 0.018) or proton-pump inhibitors (218 ± 79 vs 198 ± 78 PRU; p = 0.02), whereas residual platelet reactivity was significantly lower in active smokers (168 ± 82 vs 208 ± 77 PRU; p = 0.006). Independent predictors of HRPR were female gender (odds ratio [OR] 1.91, 95% confidence interval [CI] 1.14 to 3.19, p = 0.014), non-Caucasian ethnicity (OR 3.05, 95% CI 1.49 to 6.28, p = 0.002), use of proton-pump inhibitors (OR 1.64, 95% CI 1.03 to 2.59, p = 0.035), and active smoking (OR 0.37, 95% CI 0.14 to 0.94, p = 0.037). HRPR was associated with increased 6-month mortality rates (3.0% vs 0%; p = 0.016). In conclusion, our findings support the hypothesis that clopidogrel nonresponsiveness is primarily the result of genetic mechanisms and factors that may influence activity of the cytochrome P-450 system.

Predictors of heightened platelet reactivity despite dual-antiplatelet therapy in patients undergoing percutaneous coronary intervention.

Dual antiplatelet therapy with aspirin and a thienopyridine is a cornerstone of treatment for patients with coronary artery disease. Compared with aspirin alone, the combination of aspirin and a thienopyridine significantly improves outcomes in patients with ST-elevation myocardial infarction (MI) and non–ST-elevation acute coronary syndrome (ACS),1,2 in stable patients after percutaneous coronary intervention (PCI),3,4 and, by subgroup analysis, in stable patients with established atherosclerosis.5 The marked association between premature discontinuation of dual antiplatelet therapy and stent thrombosis further underscores the importance of prolonged treatment with aspirin and a thienopyridine in patients receiving drug-eluting stents (DES).6 The pharmacodynamic effect of the thienopyridine clopidogrel varies substantially between individuals despite a clinical benefit across a range of disease states. Furthermore, a growing body of data supports an association between a lack of pharmacodynamic effect and ischemic events. These observations have spurred interest in the use of point-of-care platelet function assays to identify and treat at-risk patients. This review discusses the evidence that supports platelet function screening, describes the currently available assay devices, and outlines the future developments necessary for the adoption of routine platelet function testing in clinical practice.

The molecular target of the thienopyridines is the platelet P2Y12 receptor. Binding of the P2Y12 receptor by its agonist, ADP, activates the G-protein inhibitor secondary messenger system, which, through a complex series of events, mediates the completion and amplification of the aggregatory response.7 Ticlopidine and clopidogrel are prodrugs that are converted to an active metabolite through a 2-step process mediated by the hepatic cytochrome P450 (CYP) system. The active metabolite achieves its antiaggregatory effect by irreversibly binding and antagonizing the P2Y12 receptor for the life of the platelet.8 This antiaggregatory effect can be measured ex vivo by light transmittance aggregometry (LTA). First described by Born …

Bedside evaluation of thienopyridine antiplatelet therapy

http://news.medlive.cn/uploadfile/20140326/13958187976444.pdf

Evaluation of individualized clopidogrel therapy after drug-eluting stent implantation in patients with high residual platelet reactivity: design and rationale of the GRAVITAS trial.

Effectiveness of in-laboratory high-dose clopidogrel loading versus routine pre-load in patients undergoing percutaneous coronary intervention: results of the ARMYDA-5 PRELOAD (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) randomized trial.

Despite common use of clopidogrel in patients with vascular disease, monitoring of platelet inhibition is still not conventional in clinical practice. Considering substantial response variability, when some patients may experience inadequate protection, and/or increased risk of bleeding, simple and reliable methods to control adequate antiplatelet regimen is mandatory. We validated a new VerifyNow-P2Y12 assay to measure inhibition of the P2Y12 platelet receptors by clopidogrel by evaluating its receptor specificity, precision, and potential interference with platelet count, hematocrit, age, cholesterol, triglycerides, and other antiplatelet agents. Platelet aggregation induced by ADP or ADP + prostaglandin E1 (ADP + PGE1) in the presence of specific P2Y12 inhibitor 2-methylthio-AMP (2MeSAMP) for the assessment of assay specificity was performed in 10 volunteers. Seventeen medications were used for the VerifyNow-P2Y12 interference testing, and assay interplay with blood constituents was evaluated in a clinical setting in 131 patients with coronary artery disease. In the presence of 2MeSAMP, the average residual aggregation level across the 10 donors was 27% for ADP and 5% for ADP + PGE1. There also was a strong agreement between ADP + PGE1 aggregometry and VerifyNow-P2Y12 assay (93% vs. 95% average inhibition across all donors). The coefficient of variation for the test precision was less than 8%. The VerifyNow-P2Y12 readings were not influenced by age, platelet count, hematocrit, fibrinogen, cholesterol, or triglycerides level. There was an interference with abciximab before P2Y12 inhibition; however, after platelet suppression with cilostazol, the interference with all tested substances was minimal. VerifyNow-P2Y12 is a reliable, simple, and sensitive device suitable for monitoring of P2Y12 platelet receptor inhibitors in the clinical arena.

Validation of a VerifyNow-P2Y12 cartridge for monitoring platelet inhibition with clopidogrel.

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Validation of a VerifyNow-P2Y12 cartridge for monitoring platelet inhibition with clopidogrel.