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Journal of Thrombosis and Thrombolysis

, Volume 41, Issue 3, pp 374–383 | Cite as

PON1 Q192R genetic variant and response to clopidogrel and prasugrel: pharmacokinetics, pharmacodynamics, and a meta-analysis of clinical outcomes

  • Jessica L. MegaEmail author
  • Sandra L. Close
  • Stephen D. Wiviott
  • Michael Man
  • Suman Duvvuru
  • Joseph R. Walker
  • Scott S. Sundseth
  • Jean-Philippe Collet
  • Jessica T. Delaney
  • Jean-Sebastien Hulot
  • Sabina A. Murphy
  • Guillaume Paré
  • Matthew J. Price
  • Dirk Sibbing
  • Tabassome Simon
  • Dietmar Trenk
  • Elliott M. Antman
  • Marc S. SabatineEmail author
Article

Abstract

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.

Keywords

Clopidogrel Prasugrel Genetics PON1 

Notes

Acknowledgments

Supported by research grants from Daiichi Sankyo and Eli Lilly.

Compliance with ethical standards

Conflict of interest

Drs. Close, Delaney, Sibbing do not have conflicts to disclose.

Disclosures

Dr. Mega: employee of Google Life Sciences; grant support from AstraZeneca, Bayer Healthcare, Bristol-Myers Squibb, Daiichi/Eli Lilly, Johnson & Johnson, Sanofi-Aventis, Nanosphere, Accumetrics; consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, Portola. Dr. Wiviott: grant support from Daiichi Sankyo, Eli Lilly, Sanofi-Aventis; consulting fees from Astra-Zeneca and Sanofi-Aventis; lecture fees from Daiichi-Sankyo, Eli Lilly, and AstraZeneca. Drs. Man and Duvvuru: employees of Eli Lilly with an equity interest or stock options in the company. Dr. Walker: employee of Daiichi Sankyo with an equity interest or stock options in the company during the study and now an employee of Celgene. Dr. Sundeth: consulting fees from Eli Lilly. Dr. Collet: grant support from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, Medtronic, Boston Scientific, Cordis, Stago, Fondation de France, INSERM, Nanospheres, Fédération Française de Cardiologie and SociétéFrançaise de Cardiologie; consulting fees from Sanofi-Aventis, Eli Lilly, and Bristol-Myers Squibb; lecture fees from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, and AstraZeneca. Dr. Hulot: grant support from Biotronik, Medco Research Institute; honoraria from Biotronik, Medco Health Solutions. Ms. Murphy: consulting fees from Amarin Pharmaceuticals. Dr. Paré: consulting fees from Sanofi-Aventis, Bristol-Myers Squibb. Dr. Price: consulting fees from AstraZeneca, Daiichi Sankyo/Eli Lilly, Accumetrics, The Medicines Company, Merck, Medicure, Janssen Pharmaceuticals, Boston Scientific; speakers honoraria from AstraZeneca and Daiichi Sankyo/Eli Lilly; equity interest (modest) from Iverson Genetics. Dr. Simon: grant support Astra-Zeneca, Daiichi-Sankyo, Eli Lilly, Glaxo-Smith-Kline, MSD, Novartis, Pfizer, Sanofi-aventis, Servier; speaker, advisory Board and consulting fees from AstraZeneca, Bayer-Schering, Eli-Lilly, Sanofi-Aventis. Dr. Trenk: consulting fees from Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly; lecture fees from AstraZeneca, Bayer Vital, Daiichi Sankyo, Eli Lilly, MSD; grant support Eli Lilly. Dr. Antman: grant support from Daiichi Sankyo, Eli Lilly, consulting fees from Sanofi-Aventis; lecture fees from Eli Lilly, Sanofi-Aventis. Dr. Sabatine: research grant support through Brigham and Women’s Hospital from Abbott Laboratories, Amgen, AstraZeneca, Bristol-Myers Squibb, Critical Diagnostics, Daiichi-Sankyo, Eisai, Genzyme, GlaxoSmithKline, Intarcia, Merck, Roche Diagnostics, Sanofi-aventis, Takeda; consulting fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Cubist, CVS Caremark, Merck, MyoKardia, Quest Diagnostics, Zeus Scientific. JLM and MSS had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Supplementary material

11239_2015_1264_MOESM1_ESM.docx (27 kb)
Supplementary material 1 (DOCX 26 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Jessica L. Mega
    • 1
    Email author
  • Sandra L. Close
    • 2
  • Stephen D. Wiviott
    • 1
  • Michael Man
    • 3
  • Suman Duvvuru
    • 3
  • Joseph R. Walker
    • 4
  • Scott S. Sundseth
    • 5
  • Jean-Philippe Collet
    • 6
  • Jessica T. Delaney
    • 7
  • Jean-Sebastien Hulot
    • 8
    • 9
  • Sabina A. Murphy
    • 1
  • Guillaume Paré
    • 10
  • Matthew J. Price
    • 11
  • Dirk Sibbing
    • 12
  • Tabassome Simon
    • 13
  • Dietmar Trenk
    • 14
  • Elliott M. Antman
    • 1
  • Marc S. Sabatine
    • 1
    Email author
  1. 1.Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  2. 2.Division of Clinical PharmacologyIndiana University School of MedicineIndianapolisUSA
  3. 3.Eli Lilly and CompanyIndianapolisUSA
  4. 4.Celgene CorporationSummitUSA
  5. 5.Cabernet PharmaceuticalsDurhamUSA
  6. 6.Institut de Cardiologie, INSERM U 937, Groupe Hospitalier Pitié-SalpêtrièreParisFrance
  7. 7.Division of Cardiovascular MedicineVanderbilt University Medical CenterNashvilleUSA
  8. 8.Cardiovascular Research CenterMount Sinai School of MedicineNew YorkUSA
  9. 9.Pharmacology Department, INSERM UMR S 956, Université Pierre et Marie Curie-Paris 6Pitié-Salpêtrière University HospitalParisFrance
  10. 10.Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac Vascular and Stroke Research InstituteMcMaster UniversityHamiltonCanada
  11. 11.Scripps Clinic and Scripps Translational Science InstituteLa JollaUSA
  12. 12.I. Medizinische Klinik und PoliklinikLudwig-Maximilians-UniversitätMunichGermany
  13. 13.Department of Clinical Pharmacology, AP-HP, Hôpital Saint AntoineINSERM U-698ParisFrance
  14. 14.Klinik für Kardiologie und Angiologie IIUniversitaets-Herzzentrum Freiburg-Bad KrozingenBad KrozingenGermany

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