Clopidogrel loading dose adjustment according to platelet reactivity monitoring in patients carrying the 2C19*2 loss of function polymorphism.
OBJECTIVE
We aimed to investigate the biological impact of a tailored clopidogrel loading dose (LD) according to platelet reactivity monitoring in carriers of the cytochrome (CYP) 2C19*2 loss-of-function polymorphism undergoing percutaneous coronary intervention for an acute coronary syndromes.


BACKGROUND
CYP2C19*2 polymorphism is associated with reduced clopidogrel metabolism and a worse prognosis after percutaneous coronary intervention.


METHODS
A prospective multicenter study enrolling 411 patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention was performed. Platelet reactivity was measured using the vasodilator-stimulated phosphoprotein (VASP) index, and a cutoff value of ≥ 50% was used to define high on-treatment platelet reactivity (HTPR). The genetic polymorphism of CYP2C19 was determined by allele-specific polymerase chain reaction. In patients carrying CYP2C19*2 and exhibiting HTPR after a first 600-mg LD of clopidogrel, dose adjustment was performed by using up to 3 additional 600 mg LDs to obtain a VASP index <50%.


RESULTS
One hundred thirty-four patients (35.3%) carried at least one 2C19*2 allele (11 homozygotes [2.7%] and 123 heterozygotes [32.6%]). The VASP index in these patients was significantly higher than in homozygotic patients for the wild-type alleles (61.7 ± 18.4% vs. 49.2 ± 24.2%; p < 0.001). Of the 134 carriers of the loss-of-function polymorphism, 103 were considered to have HTPR. After a second clopidogrel LD, the VASP index was significantly decreased in these patients (69.7 ± 10.1% vs. 50.6 ± 17.6%; p < 0.0001). Finally, dose adjustment according to platelet reactivity monitoring, enabled 88% of 2C19*2 carriers exhibiting HTPR to reach a VASP index <50%.


CONCLUSIONS
Increased and tailored clopidogrel loading dose according to platelet reactivity monitoring overcome HTPR in carriers of the loss-of-function CYP2C19*2 polymorphism.
Bonello
Laurent
L
Département de cardiologie, Hôpital Universitaire Nord, Faculté de médecine, Université de la méditerranée, Marseille, France. laurentbonello@yahoo.fr
Armero
Sébastien
S
Ait Mokhtar
Omar
O
Mancini
Julien
J
Aldebert
Philippe
P
Saut
Noémie
N
Bonello
Nathalie
N
Barragan
Paul
P
Arques
Stéphane
S
Giacomoni
Marie-Paule
MP
Bonello-Burignat
Caroline
C
Bartholomei
Marie-Noelle
MN
Dignat-George
Françoise
F
Camoin-Jau
Laurence
L
Paganelli
Franck
F
D054058:Acute Coronary Syndrome / Q000097:blood / Q000235:genetics / Q000628:therapy*; D000483:Alleles; D015906:Angioplasty, Balloon, Coronary / Q000379:methods*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001798:Blood Proteins; D015815:Cell Adhesion Molecules / Q000097:blood / Q000187:drug effects; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D004247:DNA / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000097:blood / Q000187:drug effects; D008875:Middle Aged; D008991:Monitoring, Physiologic; D010750:Phosphoproteins / Q000097:blood / Q000187:drug effects; D015539:Platelet Activation / Q000187:drug effects* / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016896:Treatment Outcome; D000098662:Vasodilator-Stimulated Phosphoprotein
D001798:Blood Proteins; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D058921:Purinergic P2Y Receptor Antagonists; D000098662:Vasodilator-Stimulated Phosphoprotein; D004247:DNA; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine