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


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.
ACTION Study Group, Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (APHP), Sorbonne Universités UPMC (Paris 6), Paris, France.
Jean-Philippe
JP
Collet
ACTION Study Group, Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (APHP), Sorbonne Universités UPMC (Paris 6), Paris, France.
Jean-Sébastien
JS
Hulot
Département de Cardiologie, CHU La Timone, Marseille, France.
Thomas
T
Cuisset
Les Hôpitaux de Chartres, Le Coudray, France.
Grégoire
G
Rangé
ACTION study group, Cardiologie, CHU Carémeau, Nîmes, France.
Guillaume
G
Cayla
Department of Cardiology, Lille University Hospital, INSERM UMR 1011, University Lille 2, Lille, France.
Eric
E
Van Belle
Cardiologie, CH de Lagny-Marne la Vallée, Lagny-sur-Marne, France.
Simon
S
Elhadad
ACTION Study Group, Unité de Recherche Clinique-Hôpital Lariboisière (APHP), Paris, France.|Université Denis Diderot, Paris, France.
Hélène
H
Rousseau
ACTION Study Group, Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (APHP), Sorbonne Universités UPMC (Paris 6), Paris, France.
Pierre
P
Sabouret
ACTION Study Group, Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (APHP), Sorbonne Universités UPMC (Paris 6), Paris, France.
Stephen A
SA
O'Connor
ACTION Study Group, Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (APHP), Sorbonne Universités UPMC (Paris 6), Paris, France.
Jérémie
J
Abtan
ACTION Study Group, Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (APHP), Sorbonne Universités UPMC (Paris 6), Paris, France.
Mathieu
M
Kerneis
CHU Trousseau, Tours, France.
Christophe
C
Saint-Etienne
ACTION Study Group, Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (APHP), Sorbonne Universités UPMC (Paris 6), Paris, France.
Olivier
O
Barthélémy
ACTION study Group, CHU Caen, Caen, France.
Farzin
F
Beygui
ACTION Study Group, Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (APHP), Sorbonne Universités UPMC (Paris 6), Paris, France.
Johanne
J
Silvain
ACTION Study Group, Unité de Recherche Clinique-Hôpital Lariboisière (APHP), Paris, France.|Université Denis Diderot, Paris, France.
Eric
E
Vicaut
ACTION Study Group, Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (APHP), Sorbonne Universités UPMC (Paris 6), Paris, France. gilles.montalescot@aphp.fr.
Gilles
G
Montalescot
D000368:Aged; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010979:Platelet Function Tests; D015607:Stents / Q000009:adverse effects; D013927:Thrombosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
Antiplatelet therapy; Clopidogrel; Pharmacogenetic; Platelet reactivity; Stent thrombosis