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Relationship between Clopidogrel-Induced Platelet P2Y12 Inhibition and Stent Thrombosis or Myocardial Infarction after Percutaneous Coronary Intervention: A Case-Control Study
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. (Cardiology)
Department of Cardiology, Lund University.
Department of Cardiology, Lund University.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. (Cardiology)
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2011 (English)In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 162, no 2, 363-371 p.Article in journal (Refereed) Published
Abstract [en]

Aims: Platelet inhibition levels were investigated in patients with previous angiographically confirmed stent thrombosis (ST), myocardial infarction (MI) and controls.

Methods and Results: Using The Swedish Coronary Angiography and Angioplasty Registry we identified patients with angiographically confirmed ST (n=48) or MI (n=30) while on dual antiplatelet therapy within 6 months of percutaneous coronary intervention (PCI) and matched control patients (n=78) with none of these events in the same setting. On-clopidogrel platelet reactivity was measured with VerifyNow™ P2Y12 and vasodilator stimulated phosphoprotein phosphorylation (VASP-P) assay.

The mean P2Y12 reaction units (PRU) was higher (246.8 ± 75.9 vs. 200.0 ± 82.7, p=0.001) in ST patients compared to controls. The optimal cut-off for ST was ≥222 PRU (area under the curve 0.69, p<0.0001) in a receiver operating characteristics (ROC) analysis, which was identical to the cut-off level defined as the proportion of controls below the 30th percentile of P2Y12 inhibition distribution in patients with ST.  The cut-off level resulted in 70.2% sensitivity and 67.3% specificity. There was no significant difference in mean PRU but a higher device-reported % inhibition (45.1 ± 23.8 vs 32.1 ± 23.2, p=0.04) in patients with MI compared to controls. Results with the VASP-P assay were not related to the occurrence of ST or MI.

Conclusion: Stent thrombosis was associated with high on-clopidogrel platelet reactivity measured with VerifyNow™. Spontaneous MI in stented patients on clopidogrel treatment was not. There was, however, a substantial overlap in clopidogrel platelet reactivity response between patients with and without on-treatment ST.

Place, publisher, year, edition, pages
2011. Vol. 162, no 2, 363-371 p.
Keyword [en]
clopidogrel, acute coronary syndromes, coronary artery disease, stent thrombosis, VerifyNow™, VASP, clopidogrel poor response
Keyword [sv]
klopidogrel, akuta koronara syndrom, hjärtinfarkt, stenttrombos
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
URN: urn:nbn:se:uu:diva-131953DOI: 10.1016/j.ahj.2011.06.003ISI: 000293729400021OAI: oai:DiVA.org:uu-131953DiVA: diva2:356241
Available from: 2010-10-11 Created: 2010-10-11 Last updated: 2017-12-12Bibliographically 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 605
Keyword
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
Cardiology
Identifiers
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)
Opponent
Supervisors
Available from: 2010-11-04 Created: 2010-09-25 Last updated: 2011-01-13Bibliographically approved

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Varenhorst, ChristophLagerqvist, BoSiegbahn, AgnetaWallentin, LarsJames, Stefan

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