European Journal of Clinical Pharmacology

, Volume 71, Issue 11, pp 1315–1324 | Cite as

Genetic and platelet function testing of antiplatelet therapy for percutaneous coronary intervention: the ARCTIC-GENE study

  • Jean-Philippe Collet
  • Jean-Sébastien Hulot
  • Thomas Cuisset
  • Grégoire Rangé
  • Guillaume Cayla
  • Eric Van Belle
  • Simon Elhadad
  • Hélène Rousseau
  • Pierre Sabouret
  • Stephen A. O’Connor
  • Jérémie Abtan
  • Mathieu Kerneis
  • Christophe Saint-Etienne
  • Olivier Barthélémy
  • Farzin Beygui
  • Johanne Silvain
  • Eric Vicaut
  • Gilles Montalescot
  • for the ARCTIC investigators
Pharmacodynamics

Abstract

Background

The ARCTIC study randomized 2440 patients scheduled for stent implantation to a strategy of platelet function monitoring with drug adjustment in patients who had a poor response to antiplatelet therapy or to a conventional strategy without monitoring and drug adjustment. No significant improvement in clinical outcomes with platelet function monitoring was observed.

Objective

The purpose of this study is to assess the relationships between CYP2C19 genotypes, clopidogrel pharmacodynamic response, and clinical outcome.

Methods and results

In the ARCTIC-GENE study, 1394 patients were genotyped for loss- and gain-of-function CYP2C19 alleles. Randomization of treatment strategy was well balanced. Slow metabolizers identified as carriers of at least one loss-of-function allele CYP2C19*2 (n = 459) were more likely poor responders at randomization (41.6 vs. 31.6 %, p = 0.0112) and 14 days later (23.8 vs. 10.4 %, p < 0.0001) and more frequently on prasugrel (11.5 vs. 8.1 %, p = 0.039) as compared with rapid metabolizers (n = 935). Intensification of antiplatelet treatment did not differ between slow and rapid metabolizers according to the study algorithm based on platelet function only. The primary study outcome defined as the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization 1 year after stent implantation did not differ between slow and rapid metabolizers (HR 0.988, 95 % CI [0.812;1.202], p = 0.90). Likewise, the primary safety outcome did not differ between rapid and slow metabolizer phenotype.

Conclusions

The genetic clopidogrel profile was a good marker of platelet function response on clopidogrel but was not related to clinical outcome suggesting that the genetic added little to the pharmacodynamic information used in the study to adjust antiplatelet therapy.

ClinicalTrials.gov: NCT00827411.

Keywords

Antiplatelet therapy Stent thrombosis Pharmacogenetic Platelet reactivity Clopidogrel 

Supplementary material

228_2015_1917_MOESM1_ESM.docx (29 kb)
ESM 1(DOCX 603 kb)
228_2015_1917_MOESM2_ESM.docx (68 kb)
ESM 2(DOCX 602 kb)

References

  1. 1.
    Authors/Task Force members, Windecker S, Kolh P, et al. (2014) 2014 ESC/EACTS guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 35(37):2541–2619CrossRefGoogle Scholar
  2. 2.
    Angiolillo DA, Fernandez-Ortiz A, Bernardo E, et al. (2007) Variability in individual responsiveness to clopidogrel clinical implications, management, and future perspectives. J Am Coll Cardiol 49:1505–1516CrossRefPubMedGoogle Scholar
  3. 3.
    Kazui M, Nishiya Y, Ishizuka T, et al. (2009) Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos 38(1):92–99CrossRefGoogle Scholar
  4. 4.
    Cayla G, Hulot J-S, O’Connor SA, et al. (2011) Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis. JAMA J. Am. Med. Assoc. 306(16):1765–1774CrossRefGoogle Scholar
  5. 5.
    Collet JP, Hulot JS, Montalescot G (2009) Cytochrome P450 2C19 polymorphism and clopidogrel after MI. Lancet 373:1172–1173CrossRefGoogle Scholar
  6. 6.
    Mega JL, Simon T, Collet J-P, et al. (2010) Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA J. Am. Med. Assoc. 304(16):1821–1830CrossRefGoogle Scholar
  7. 7.
    Collet J-P, Cuisset T, Rangé G, et al. (2012) Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 367(22):2100–2109CrossRefPubMedGoogle Scholar
  8. 8.
    Price MJ, Berger PB, Teirstein PS, et al. (2011) Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 305(11):1097–1105CrossRefPubMedGoogle Scholar
  9. 9.
    Trenk D, Stone GW, Gawaz M, et al. (2012) A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol 59(24):2159–2164CrossRefPubMedGoogle Scholar
  10. 10.
    Campo G, Parrinello G, Ferraresi P, et al. (2011) Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention. J Am Coll Cardiol 57:2474–2483CrossRefPubMedGoogle Scholar
  11. 11.
    Stone GW, Witzenbichler B, Weisz G, et al. (2013) Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet 382(9892):614–623CrossRefPubMedGoogle Scholar
  12. 12.
    Aradi D, Storey RF, Komocsi A, et al. (2013) Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention. Eur Heart J 62(24):2261–2273Google Scholar
  13. 13.
    Collet JP, Cayla G, Cuisset T, et al. (2011) Randomized comparison of platelet function monitoring to adjust antiplatelet therapy versus standard of care: rationale and design of the assessment with a double randomization of (1) a fixed dose versus a monitoring-guided dose of aspirin and clopidogrel after DES implantation, and (2) treatment interruption versus continuation, 1 year after stenting (ARCTIC) study. Am Heart J 161(1):5–12 e5CrossRefPubMedGoogle Scholar
  14. 14.
    Montalescot G, Rangé G, Silvain J, et al. (2014) High on-treatment platelet reactivity as a risk factor for secondary prevention after coronary stent revascularization: a landmark analysis of the ARCTIC study. Circulation 129(21):2136–2143CrossRefPubMedGoogle Scholar
  15. 15.
    Montalescot G, Sechtem U, Achenbach S, et al. (2013) 2013 ESC guidelines on the management of stable coronary artery disease: the task force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 34(38):2949–3003CrossRefPubMedGoogle Scholar
  16. 16.
    Collet JP, Hulot JS, Anzaha G, et al. (2011) High doses of clopidogrel to overcome genetic resistance (the CLOVIS-2 study). J Am Coll Cardiol Intv 4:392–402CrossRefGoogle Scholar
  17. 17.
    Hulot JS, Collet JP, Silvain J, et al. (2010) Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor co-administration: a systematic meta-analysis. J Am Coll Cardiol 56(2):134–143CrossRefPubMedGoogle Scholar
  18. 18.
    http://www.fda.gov/Drugs/DrugSafety/Postmarket FDSC reduced effectiveness of P (clopidogrel) in patients who are poor metabolizers of the drug. A at:, DrugSafetyInformationforPatientsandProviders/ucm203888.htm. Accessed April 28 2010. FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug.
  19. 19.
    Roberts JD, Wells GA, Le May MR, et al. (2012) Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial: the RAPID GENE trial. Lancet 379(9827):1705–1711. doi:10.1016/S0140-6736(12)60161–5CrossRefPubMedGoogle Scholar
  20. 20.
    Mega JL, Hochholzer W, Frelinger 3rd AL, et al. (2011) Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA 306(20):2221–2228CrossRefPubMedGoogle Scholar
  21. 21.
    Frelinger 3rd AL, Bhatt DL, Lee RD, et al. (2013) Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or control of polymorphisms (CYP2C19, ABCB1, PON1), noncompliance, diet, smoking, co-medications (including proton pump inhibitors), and pre-existent variability in platelet function. J Am Coll Cardiol 61(8):872–879CrossRefPubMedGoogle Scholar
  22. 22.
    Price MJ, Murray SS, Angiolillo DJ, et al. (2012) Influence of genetic polymorphisms on the effect of high- and standard-dose clopidogrel after percutaneous coronary intervention: the GIFT (Genotype Information and Functional Testing) study. J Am Coll Cardiol 59(22):1928–1937CrossRefPubMedGoogle Scholar
  23. 23.
    Fontana P, Cattaneo M, Combescure C, Reny J-L. Tailored thienopyridine therapy: no urgency for CYP2C19 genotyping. J Am Heart Assoc. 2013;2(2):e000131–e000131.Google Scholar
  24. 24.
    Bauer T, Bouman HJ, van Werkum JW, Ford NF, ten Berg JM, Taubert D (2011) Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ 343:d4588PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Paré G, Mehta SR, Yusuf S, et al. (2010) Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med 363(18):1704–1714CrossRefPubMedGoogle Scholar
  26. 26.
    Bhatt DL, Paré G, Eikelboom JW, et al. (2012) The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients: the CHARISMA genetics study. Eur Heart J 33(17):2143–2150CrossRefPubMedGoogle Scholar
  27. 27.
    Holmes MV, Perel P, Shah T, Hingorani AD, Casas JP (2011) CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. JAMA J Am Med Assoc 306(24):2704–2714CrossRefGoogle Scholar
  28. 28.
    Kerneis M, Silvain J, Abtan J, et al. (2013) Switching acute coronary syndrome patients from prasugrel to clopidogrel. JACC Cardiovasc. Interv. 6(2):158–165CrossRefPubMedGoogle Scholar
  29. 29.
    Tantry US, Bonello L, Aradi D, et al. (2013) Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol 62(24):2261–2273CrossRefPubMedGoogle Scholar
  30. 30.
    COLLET J, Kerneis M, Hulot JS, et al.; Point-of-care genetic profiling in acute coronary syndrome: the GAMMA Study. JESFC Paris 2015. Abstract 0466.Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Jean-Philippe Collet
    • 1
  • Jean-Sébastien Hulot
    • 1
  • Thomas Cuisset
    • 5
  • Grégoire Rangé
    • 2
  • Guillaume Cayla
    • 3
  • Eric Van Belle
    • 4
  • Simon Elhadad
    • 6
  • Hélène Rousseau
    • 7
    • 8
  • Pierre Sabouret
    • 1
  • Stephen A. O’Connor
    • 1
  • Jérémie Abtan
    • 1
  • Mathieu Kerneis
    • 1
  • Christophe Saint-Etienne
    • 9
  • Olivier Barthélémy
    • 1
  • Farzin Beygui
    • 10
  • Johanne Silvain
    • 1
  • Eric Vicaut
    • 7
    • 8
  • Gilles Montalescot
    • 1
  • for the ARCTIC investigators
  1. 1.ACTION Study Group, Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (APHP)Sorbonne Universités UPMC (Paris 6)ParisFrance
  2. 2.Les Hôpitaux de ChartresLe CoudrayFrance
  3. 3.ACTION study group, CardiologieCHU CarémeauNîmesFrance
  4. 4.Department of Cardiology, Lille University HospitalINSERM UMR 1011, University Lille 2LilleFrance
  5. 5.Département de CardiologieCHU La TimoneMarseilleFrance
  6. 6.CardiologieCH de Lagny-Marne la ValléeLagny-sur-MarneFrance
  7. 7.ACTION Study GroupUnité de Recherche Clinique-Hôpital Lariboisière (APHP)ParisFrance
  8. 8.Université Denis DiderotParisFrance
  9. 9.CHU TrousseauToursFrance
  10. 10.ACTION study GroupCHU CaenCaenFrance

Personalised recommendations