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

  • Pharmacodynamics
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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.

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Acknowledgments

ARCTIC-GENE was funded by the PHRC 2009 (01-29).

Conflict of interest

Pr. Collet reports receiving research grants from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, Medtronic, Boston Scientific, Cordis, Stago, Fondation de France, INSERM, Nanospheres, Fédération Française de Cardiologie, and Société Française de Cardiologie; consulting fees from Sanofi-Aventis, Eli Lilly, and Bristol-Myers Squibb; and lecture fees from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, and AstraZeneca.

Dr. Silvain reports grants from Sanofi-Aventis, Daiichi-Sankyo, Eli Lilly, Brahms, INSERM, Fédération Française de Cardiologie, and Société Française de Cardiologie; consulting fees from Daiichi-Sankyo and Eli Lilly; and speakers’ honoraria from AstraZeneca, Daiichi Sankyo, Eli Lilly, and Servier.

Dr. Kerneis reports a grant from Fédération Française de Cardiologie.

Dr. Barthélémy reports receiving lecture fees from Sanofi.

Pr. Cayla reports receiving a research grant from la Fédération Française de Cardiologie, la Fondation Coeur et Recherche; consultant fees from Abbott Vascular, AstraZeneca, CLS Behring, Daiichi Sankyo, and Eli Lilly; and lecture fees from Abbott Vascular, AstraZeneca, Biotronik, Boston, Bristol Myers Squibb, CLS Behring, Daiichi Sankyo, Eli Lilly, Iroko Cardio, and Pfizer.

Pr. Van Belle reports research grants from Sanofi-Aventis, Medtronic, Cordis, Boston Scientific, Fondation SGAM, Fondation de France, ACTION, and APHP; consulting fees from Pfizer, Eli Lilly, Sanofi, LFB, Abbott, and Frensenius; grant from Boehringer Ingelheim; and lecture fees from Merck and Pfizer.

Dr. Sabouret reports receiving honoraria for advisory board/lectures from AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Johnson and Johnson, Merck-Sharp and Dhome, and Pfizer.

Pr. Montalescot reports receiving consulting fees from Bayer, Boehringer Ingelheim, Cardiovascular Research Foundation, Europa Organisation, the Gerson Lehrman Group, Iroko Cardio International, Lead-Up, Luminex, McKinsey & Company, Inc., Remedica, Servier, TIMI Study Group, WebMD, Wolters Kluwer Health, Bristol-Myers Squibb, AstraZeneca, Biotronik, Eli Lilly, The Medicines Company, Menarini Group, Roche, Sanofi-Aventis, Pfizer, Daiichi-Sankyo, and Medtronic; and grant support from Bristol-Myers Squibb, AstraZeneca, Biotronik, Eli Lilly, The Medicines Company, Menarini Group, Sanofi-Aventis, Pfizer, Roche, Accumetrics, Medtronic, Abbott Laboratories, Daiichi-Sankyo, Nanosphere Inc., and Stentys.

Pr. Vicaut reports receiving fees for board membership from CERC, consulting fees from Pfizer, Sanofi-Aventis, LFB, Abbott, Fresenius, Medtronic, and Hexacath, lecture fees from Novartis, and grant support from Sanofi-Aventis and Boehringer Ingelheim.

Pr. Hulot discloses the following relationships: Data Monitoring Committees: Assistance Publique Hôpitaux de Paris; honoraria: American College of Cardiology Foundation (Lecturer), Eli Lilly (Steering Committee), and Servier (Lecturer); consulting fees: Daiichi Sankyo (consultant) and Imaxio (consultant); and research grants: Bayer Pharma, Celladon, Cellectis Stem Cells, French Ministry of Health (AOM09191), Institute for Cardiometabolism and Nutrition Foundation, NIH/NHLBI (R01 HL113497), and NIH/NGRI (1U01HG006380).

The other authors report no conflicts of interest.

Study investigators

Centers

- CHU Pitié-Salpêtrière, Paris, Prs Montalescot/Collet

- Hôpital Cardiologique du Haut Lévêque, Pessac, Pr. Coste

- Hôpital Pontchaillou, Rennes, Pr. Le Breton

- CH de Lagny, Marne-la-Vallée, Drs. Elhadad/Cohen

- Hôpital privé Beauregard, Marseille, Dr. Wittenberg

- Hôpital Arnaud de Villeneuve, Montpellier, Pr. Leclercq

- Hôpital Cochin, Paris, Dr. Varenne

- CHU Carémeau, Nîmes, Drs. Ledermann/Cayla

- Hôpital de la Timone, Marseille, Prs Bonnet/Cuisset

- Hôpital Cardiologique Albert Calmette, Lille, Dr. Van Belle

- Hôpital Lariboisière, Paris, Pr. Henry

- CHU Jean Minjoz, Besançon, Pr. Bassand

- Hôpital Cardio-Vasculaire Louis Pradel, Lyon, Pr. Finet

- Hôpital Nord Marseille, Dr. Paganelli

- Hôpital de Rangueil, Toulouse, Dr. Carrié

- Clinique de l’Orangerie, Strasbourg, Dr. Aleil

- CH de la Région Annecienne, Annecy, Dr. Belle

- Clinique Nantaise, Nantes, Dr. Brunel

- CH de Chartres, Dr. Rangé

- CH d’Avignon, Drs. Pansieri/Barney

- GH du Centre Alsace, Drs. Lhoest/Levai

- CH Marie Lannelongue, Le Plessis-Robinson, Dr. Caussin

- CH de Cannes, Drs. Tibi/Zemour

- Hôpital François Mitterrand, Pau, Dr. Delarche

- Hôpital Saint-Joseph, Marseille, Dr. D’Houdain

- CHU de Poitiers, Dr. Christiaens

- Clinique Sainte Clothilde, La Réunion, Dr. Pouillot

- Polyclinique de Bordeaux Caudéran, Bordeaux, Dr. Casteigt

- Hôpital Pasteur, Nice, Pr. Ferrari

- CH Dijon, Pr. Cottin

- CHR Strasbourg, Pr. Ohlmann

- CH Lens, Dr. Pecheux

- CH de Compiègne, Dr. Sayah

- CH Clermont-Ferrand, Dr. Motreff

- Clinique du Tonkin, Villeurbanne, Dr. Champagnac

- Clinique de l’Europe, Amiens, Dr. Py

- Clinique du Parc, Castelnau-le-Lez, Dr. Shadfar

Author information

Authors and Affiliations

  1. ACTION Study Group, Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (APHP), Sorbonne Universités UPMC (Paris 6), Paris, France

    Jean-Philippe Collet, Jean-Sébastien Hulot, Pierre Sabouret, Stephen A. O’Connor, Jérémie Abtan, Mathieu Kerneis, Olivier Barthélémy, Johanne Silvain & Gilles Montalescot

  2. Les Hôpitaux de Chartres, Le Coudray, France

    Grégoire Rangé

  3. ACTION study group, Cardiologie, CHU Carémeau, Nîmes, France

    Guillaume Cayla

  4. Department of Cardiology, Lille University Hospital, INSERM UMR 1011, University Lille 2, Lille, France

    Eric Van Belle

  5. Département de Cardiologie, CHU La Timone, Marseille, France

    Thomas Cuisset

  6. Cardiologie, CH de Lagny-Marne la Vallée, Lagny-sur-Marne, France

    Simon Elhadad

  7. ACTION Study Group, Unité de Recherche Clinique-Hôpital Lariboisière (APHP), Paris, France

    Hélène Rousseau & Eric Vicaut

  8. Université Denis Diderot, Paris, France

    Hélène Rousseau & Eric Vicaut

  9. CHU Trousseau, Tours, France

    Christophe Saint-Etienne

  10. ACTION study Group, CHU Caen, Caen, France

    Farzin Beygui

Authors
  1. Jean-Philippe Collet
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  2. Jean-Sébastien Hulot
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  3. Thomas Cuisset
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  4. Grégoire Rangé
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  5. Guillaume Cayla
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  6. Eric Van Belle
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  7. Simon Elhadad
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  8. Hélène Rousseau
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  9. Pierre Sabouret
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  10. Stephen A. O’Connor
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  11. Jérémie Abtan
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  14. Olivier Barthélémy
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  15. Farzin Beygui
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  16. Johanne Silvain
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  17. Eric Vicaut
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  18. Gilles Montalescot
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Consortia

for the ARCTIC investigators

Corresponding author

Correspondence to Gilles Montalescot.

Additional information

ARCTIC-GENE: Assessment by a double Randomization of a Conventional antiplatelet strategy versus a monitoring-guided strategy for drug-eluting stent implantation and, of Treatment Interruption versus Continuation one year after stenting-GENE

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Collet, JP., Hulot, JS., Cuisset, T. et al. Genetic and platelet function testing of antiplatelet therapy for percutaneous coronary intervention: the ARCTIC-GENE study. Eur J Clin Pharmacol 71, 1315–1324 (2015). https://doi.org/10.1007/s00228-015-1917-9

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