PON1 Q192R genetic variant and response to clopidogrel and prasugrel: pharmacokinetics, pharmacodynamics, and a meta-analysis of clinical outcomes
Autor: | Jean-Sébastien Hulot, Dirk Sibbing, Jean-Philippe Collet, Guillaume Paré, Stephen D. Wiviott, Tabassome Simon, Sandra L Close, Matthew J. Price, Jessica T. Delaney, Elliott M. Antman, Scott S. Sundseth, Michael Man, Jessica L. Mega, Marc S. Sabatine, Suman Duvvuru, Dietmar Trenk, Joseph R. Walker, Sabina A. Murphy |
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Přispěvatelé: | BRUNEL, Nadège, Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
Jazyk: | angličtina |
Rok vydání: | 2016 |
Předmět: |
Male
medicine.medical_specialty Acute coronary syndrome Ticlopidine Prasugrel [SDV]Life Sciences [q-bio] Mutation Missense 030204 cardiovascular system & hematology Pharmacology Gastroenterology 03 medical and health sciences Percutaneous Coronary Intervention 0302 clinical medicine Internal medicine medicine Humans cardiovascular diseases 030212 general & internal medicine Acute Coronary Syndrome Stroke ComputingMilieux_MISCELLANEOUS Aged Randomized Controlled Trials as Topic Prasugrel Hydrochloride Aryldialkylphosphatase business.industry Hematology Middle Aged medicine.disease Clopidogrel 3. Good health [SDV] Life Sciences [q-bio] Amino Acid Substitution Pharmacodynamics Female Cardiology and Cardiovascular Medicine business Mace medicine.drug |
Zdroj: | Journal of Thrombosis and Thrombolysis Journal of Thrombosis and Thrombolysis, Springer Verlag (Germany), 2016 Journal of Thrombosis and Thrombolysis, 2016 |
ISSN: | 0929-5305 1573-742X |
Popis: | Clopidogrel and prasugrel are antiplatelet therapies commonly used to treat patients with cardiovascular disease. They are both pro-drugs requiring biotransformation into active metabolites. It has been proposed that a genetic variant Q192R (rs662 A>G) in PON1 significantly alters the biotransformation of clopidogrel and affects clinical outcomes; however, this assertion has limited support. The relationship between this variant and clinical outcomes with prasugrel has not been studied. We genotyped PON1 Q192R in 275 healthy subjects treated with clopidogrel or prasugrel and 2922 patients with an ACS undergoing PCI randomized to treatment with clopidogrel or prasugrel in the TRITON-TIMI 38 trial. A meta-analysis was performed including 13 studies and 16,760 clopidogrel-treated patients. Among clopidogrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.62) or change in platelet aggregation (P = 0.51). Consistent with these results, in clopidogrel-treated patients in TRITON-TIMI 38, there was no association between Q192R and the rates of CV death, myocardial infarction, or stroke (RR 11.2 %, QR 8.6 %, and QQ 9.3 %; P = 0.66) or stent thrombosis (RR 2.4 %, QR 0.7 %, and QQ 1.6 %, P = 0.30), with patients with the putative at-risk Q variant having numerically lower event rates. Likewise, among prasugrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.88), change in platelet aggregation (P = 0.97), or clinical outcomes (P = 0.72). In a meta-analysis, the Q variant was not significantly associated with MACE (QQ vs. RR 1.22, 95 % CI 0.84-1.76) or stent thrombosis (QQ vs. RR OR 1.36, 95 % CI 0.77-2.38). Furthermore, when restricted to the validation studies, the OR (95 % CI) for MACE and stent thrombosis were 0.99 (0.77-1.27) and 1.23 (0.74-2.03), respectively. In the present study, the Q192R genetic variant in PON1 was not associated with the pharmacologic or clinical response to clopidogrel, nor was it associated with the response to prasugrel. The meta-analysis reinforced a lack of a significant association between Q192R and cardiovascular outcomes in clopidogrel-treated patients. |
Databáze: | OpenAIRE |
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