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Assessment of P2Y(12) inhibition with the point-of-care device VerifyNow P2Y12 in patients treated with prasugrel or clopidogrel coadministered with aspirin
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (UCR)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (UCR)
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2009 (English)In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 157, no 3, 562.e1-9 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Variability in response to thienopyridines has led to the development of point-of-care devices to assess adenosine diphosphate (ADP)-induced platelet aggregation. These tests need to be evaluated in comparison to reference measurements of P2Y(12) function during different thienopyridine treatments. METHODS: After a run-in on 75 mg aspirin, 110 subjects were randomized to double-blind treatment with clopidogrel 600 mg loading dose (LD)/75 mg maintenance dose (MD) or prasugrel 60 mg LD/10 mg MD. Antiplatelet effects were evaluated by VerifyNow P2Y12 (VN-P2Y12) device (Accumetrics, San Diego, CA), vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay, and light transmission aggregometry (LTA). Prasugrel's and clopidogrel's active metabolite concentration were also determined. RESULTS: Dose- and time-dependent inhibition of P2Y(12) was evident with VN-P2Y12. There was strong correlation with VN-P2Y12 and VASP or LTA for all treatments through a wide range of P2Y(12) function. At high levels of P2Y(12) inhibition, platelet function measured by VN-P2Y12 was maximally inhibited and could not reflect further changes seen with VASP or LTA methods. Correlation was also observed between exposure to clopidogrel's active metabolite and VN-P2Y12 during MD and LD, whereas it was observed only with prasugrel MD. CONCLUSION: The VN-P2Y12 correlated strongly with inhibition of P2Y(12) function, as measured with either VASP or LTA. VN-P2Y12 also correlated to exposure to the active metabolite of prasugrel and clopidogrel up to levels associated with assumed saturation of the P2Y(12) receptor.

Place, publisher, year, edition, pages
2009. Vol. 157, no 3, 562.e1-9 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-123195DOI: 10.1016/j.ahj.2008.11.021ISI: 000264214700024PubMedID: 19249429OAI: oai:DiVA.org:uu-123195DiVA: diva2:313152
Available from: 2010-04-26 Created: 2010-04-26 Last updated: 2012-07-12Bibliographically approved
In thesis
1. Platelet Inhibition in Coronary Artery Disease – Mechanisms and Clinical Importance: Studies with Focus on P2Y12 Inhibition
Open this publication in new window or tab >>Platelet Inhibition in Coronary Artery Disease – Mechanisms and Clinical Importance: Studies with Focus on P2Y12 Inhibition
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Despite the currently recommended dual antiplatelet treatment (DAT) with aspirin and P2Y12 inhibition in patients with coronary artery disease (CAD) there is a risk of adverse clinical outcome. Pharmacodynamic (PD) poor response to clopidogrel occurs in ~ 30% of clopidogrel-treated patients and is associated with an increased risk of recurrent thrombotic events.

The aims of this thesis were to compare the PD and pharmacokinetic effects of clopidogrel 600 mg loading dose (LD)/ 75 mg standard maintenance dose (MD) with the novel P2Y12 inhibitor prasugrel 60 mg LD/10 mg MD, in 110 patients with CAD. The mechanisms behind clopidogrel poor response were investigated by assessing the pharmacodynamics after adding clopidogrel active metabolite (AM) and genotyping for variation in CYP-genes involved in thienopyridine metabolism. In another study, we compared the on-clopidogrel platelet reactivity of patients with stent thrombosis (ST) (n=48) or myocardial infarction (MI) (n=30) while on DAT and their matched controls (n=50 + 28).

Prasugrel achieved a faster and greater P2Y12-mediated platelet inhibition than clopidogrel measured with light transmission aggregometry, VASP and VerifyNow® P2Y12. Prasugrel’s greater platelet inhibition was associated with higher exposure of AM. The addition of clopidogrel AM led to maximal platelet inhibition in all subjects, suggesting that prasugrel’s greater antiplatelet effect was related to more efficient AM generation compared to that of clopidogrel. Lower levels of AM as well as less platelet inhibition were seen in clopidogrel-treated patients with reduced-metabolizer genotype CYP2C19 compared to those with normal genotype. Patients with ST while on DAT showed higher on-clopidogrel platelet reactivity compared to matched stented controls. Patients with spontaneous MI after stenting did not.

In conclusion, these results showed a high rate PD poor response to a high bolus dose of clopidogrel because of a partly genetically caused lower generation of AM which could be overcome by prasugrel treatment. In patients after coronary stenting, clopidogrel poor response was related to ST but not to spontaneous MI, illustrating difficulties in optimizing treatment with clopidogrel based on platelet function or genetic testing in individual patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 77 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 605
coronary artery disease, myocardial infarction, acute coronary syndromes, stent thrombosis, P2Y12 inhibitors, thienopyridines, clopidogrel poor response, clopidogrel, prasugrel
National Category
Cardiac and Cardiovascular Systems
Research subject
urn:nbn:se:uu:diva-131154 (URN)978-91-554-7914-5 (ISBN)
Public defence
2010-11-26, Ebba Enghoffsalen, Ingång 50, bv. Akademiska Sjukhuset, Uppsala, 13:00 (Swedish)
Available from: 2010-11-04 Created: 2010-09-25 Last updated: 2011-01-13Bibliographically approved

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Varenhorst, ChristophJames, StefanWallentin, LarsSiegbahn, Agneta
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