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Harmsze A.M.,St Antonius Center For Platelet Function Research
Pharmacogenetics and genomics

To investigate the impact of genotypes on the basis of the loss-of-function variant CYP2C19*2 and the gain-of-function variant CYP2C19*17 on on-treatment platelet reactivity and on the occurrence of Thrombolysis in Myocardial Infarction (TIMI) major bleedings in 820 clopidogrel-treated patients who underwent elective coronary stenting. On-treatment platelet reactivity was quantified using ADP-induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay. Postdischarge TIMI major bleedings within 1 year after enrollment were recorded. In total, 25 major bleedings (3.0% of the study population) were observed. Patients with the CYP2C19*1/*17 and *17/*17 diplotypes exhibited a lower magnitude of platelet reactivity as compared with patients with the CYP2C19*1/*1 diplotype (for the light transmittance aggregometry-adjusted mean difference: -5.8%, 95% confidence interval: -9.6 to -2.1, P=0.002). Patients with the *1/*17 and *17/*17 genotype had a 2.7-fold increased risk in the occurrence of major bleedings [adjusted hazard ratio: 2.7, 95% confidence interval: 1.1-7.0, P=0.039]. The diplotypes *2/*17, *1/*2, and *2/*2 exhibited higher on-treatment platelet reactivity as compared with the wild type (P<0.0001). However, this was not translated into an altered risk on major bleedings as compared with the wild type [hazard ratio: 1.3 (0.45-4.0), P=0.60]. Results have not been adjusted for multiple testing. Patients with the CYP2C19*1/*17 and *17/*17 diplotype have a lower magnitude of on-treatment platelet reactivity and are at a 2.7-fold increased risk of postdischarge TIMI major bleeding events after coronary stenting than patients with the *1/*1 genotype. The diplotypes *2/*17, *1/*2, and *2/*2 are associated with increased on-treatment platelet reactivity; however, this is not translated into a lower risk of bleeding events. Source

Bouman H.J.,St. Antonius Hospital Nieuwegein | Bouman H.J.,St Antonius Center For Platelet Function Research | Bouman H.J.,Maastricht University | Schomig E.,University of Cologne | And 10 more authors.
Nature Medicine

Clinical efficacy of the antiplatelet drug clopidogrel is hampered by its variable biotransformation into the active metabolite. The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors, but the specific genes and mechanisms underlying clopidogrel bioactivation remain unclear. Using in vitro metabolomic profiling techniques, we identified paraoxonase-1 (PON1) as the crucial enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite formation. We tested the clinical relevance of the PON1 Q192R genotype in a population of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy. PON1 QQ192 homozygous individuals showed a considerably higher risk than RR192 homozygous individuals of stent thrombosis, lower PON1 plasma activity, lower plasma concentrations of active metabolite and lower platelet inhibition. Thus, we identified PON1 as a key factor for the bioactivation and clinical activity of clopidogrel. These findings have therapeutic implications and may be exploited to prospectively assess the clinical efficacy of clopidogrel. © 2011 Nature America, Inc. All rights reserved. Source

Janssen P.W.A.,St Antonius Center For Platelet Function Research | ten Berg J.M.,St Antonius Center For Platelet Function Research | Hackeng C.M.,St Antonius Center For Platelet Function Research
Blood Reviews

Antiplatelet drugs are widely used in the treatment of patients with coronary artery disease. Dual anti-platelet therapy with acetylsalicylic acid (ASA) and a P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) is the recommended strategy for patients undergoing a percutaneous coronary intervention (PCI), while patients that undergo coronary artery bypass grafting (CABG) are treated with ASA monotherapy. However, the response to these drugs as assessed with platelet function tests varies between patients. Despite these drugs, many patients still exhibit high on-treatment platelet reactivity (HPR), while platelet reactivity seems to be excessively inhibited in other patients. This review will discuss the use of platelet function testing in the prediction of atherothrombotic and bleeding events in patients undergoing PCI or CABG. Furthermore, options for tailoring based on platelet function testing in these patients are described. © 2014 Elsevier Ltd. Source

Jhagroe D.A.,St Antonius Center For Platelet Function Research | Janssen P.W.A.,St Antonius Center For Platelet Function Research | Ten Berg J.M.,St Antonius Center For Platelet Function Research
Current Opinion in Cardiology

Purpose of review Despite being the subject of extensive research, the optimal antithrombotic therapy for patients on chronic oral anticoagulation (OAC) undergoing percutaneous coronary intervention (PCI) with stent implantation is still unknown. This review presents the latest data regarding this much-debated topic. Recent findings Dual therapy, with clopidogrel (a P2Y12 inhibitor) and OAC, may be an alternative to triple therapy, which usually consists of aspirin and clopidogrel in addition to OAC, in terms of improving clinical outcomes in patients on chronic OAC following PCI with stent implantation. With the arrival of new, safer nonvitamin K antagonists oral anticoagulants (NOACs), the combination of NOAC and clopidogrel may also be an option for replacing triple therapy. In contrast to clopidogrel, combining the more potent P2Y12 inhibitors (prasugrel and ticagrelor) with OAC may only be considered in certain specific circumstances. Summary Patients on chronic OAC undergoing PCI with stent implantation require triple therapy. However, triple therapy is controversial, because it increases the risk of bleeding. With the introduction of prasugrel, ticagrelor and NOACs, the question arises which P2Y12 inhibitor to choose as part of the triple therapy regime and how NOACs combine with antiplatelet agents when treating patients undergoing PCI. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source

Harmsze A.M.,St. Antonius Hospital | Harmsze A.M.,St Antonius Center For Platelet Function Research | Harmsze A.M.,University Utrecht | Van Werkum J.W.,St Antonius Center For Platelet Function Research | And 11 more authors.
European Heart Journal

Aims Despite treatment with clopidogrel on top of aspirin, stent thrombosis (ST) still occurs being the most serious complication after percutaneous coronary interventions (PCIs). In this study, we aimed to determine the effect of variations in genes involved in the absorption (ABCB1 C1236T, G2677T/A, C3435T), metabolism (CYP2C19*2 and *3, CYP2C9*2 and *3, CYP3A4*1B and CYP3A5*3), and pharmacodynamics (P2Y1 A1622G) of clopidogrel on the occurrence of ST. Methods and results The selected genetic variants were assessed in 176 subjects who developed ST while on dual antiplatelet therapy with aspirin and clopidogrel and in 420 control subjects who did not develop adverse cardiovascular events, including ST, within 1 year after stenting. The timing of the definite ST was acute in 66, subacute in 87, and late in 23 cases. The presence of the CYP2C19*2 and CYP2C9*3 variant alleles was significantly associated with ST (ORadj: 1.7, 95 CI: 1.0-2.6, P = 0.018 and ORadj: 2.4, 95 CI: 1.0-5.5, P = 0.043, respectively). The influence of CYP2C19*2 (ORadj: 2.5, 95 CI: 1.1-5.5, P = 0.026) and CYP2C9*3 (ORadj: 3.3, 95 CI: 1.1-9.9, P = 0.031) was most strongly associated with subacute ST. No significant associations of the other genetic variations and the occurrence of ST were found. Conclusion Carriage of the loss-of-function alleles CYP2C19*2 and CYP2C9*3 increases the risk on ST after PCI. © 2010 The Author. Source

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