The influence of CYP2C19*2 and *17 on on-treatment platelet reactivity and bleeding events in patients undergoing elective coronary stenting.
OBJECTIVE
To investigate the impact of genotypes on the basis of the loss-of-function variant CYP2C19*2 and the gain-of-function variant CYP2C19*17 on on-treatment platelet reactivity and on the occurrence of Thrombolysis in Myocardial Infarction (TIMI) major bleedings in 820 clopidogrel-treated patients who underwent elective coronary stenting.


METHODS
On-treatment platelet reactivity was quantified using ADP-induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay. Postdischarge TIMI major bleedings within 1 year after enrollment were recorded.


RESULTS
In total, 25 major bleedings (3.0% of the study population) were observed. Patients with the CYP2C19*1/*17 and *17/*17 diplotypes exhibited a lower magnitude of platelet reactivity as compared with patients with the CYP2C19*1/*1 diplotype (for the light transmittance aggregometry-adjusted mean difference: -5.8%, 95% confidence interval: -9.6 to -2.1, P=0.002). Patients with the *1/*17 and *17/*17 genotype had a 2.7-fold increased risk in the occurrence of major bleedings [adjusted hazard ratio: 2.7, 95% confidence interval: 1.1-7.0, P=0.039]. The diplotypes *2/*17, *1/*2, and *2/*2 exhibited higher on-treatment platelet reactivity as compared with the wild type (P<0.0001). However, this was not translated into an altered risk on major bleedings as compared with the wild type [hazard ratio: 1.3 (0.45-4.0), P=0.60]. Results have not been adjusted for multiple testing.


CONCLUSIONS
Patients with the CYP2C19*1/*17 and *17/*17 diplotype have a lower magnitude of on-treatment platelet reactivity and are at a 2.7-fold increased risk of postdischarge TIMI major bleeding events after coronary stenting than patients with the *1/*1 genotype. The diplotypes *2/*17, *1/*2, and *2/*2 are associated with increased on-treatment platelet reactivity; however, this is not translated into a lower risk of bleeding events.
St Antonius Center for Platelet Function Research, St Antonius Hospital, Nieuwegein, The Netherlands.
Ankie M
AM
Harmsze
Jochem W
JW
van Werkum
Christian M
CM
Hackeng
Hendrik J T
HJ
Ruven
Johannes C
JC
Kelder
Heleen J
HJ
Bouman
Nicoline J
NJ
Breet
Jurriën M
JM
Ten Berg
Olaf H
OH
Klungel
Anthonius
A
de Boer
Vera H M
VH
Deneer
D000483:Alleles; D015906:Angioplasty, Balloon, Coronary; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics* / Q000628:therapy; D065731:Cytochrome P-450 CYP2C19; D005500:Follow-Up Studies; D005838:Genotype; D006470:Hemorrhage / Q000235:genetics / Q000473:pathology; D006801:Humans; D015539:Platelet Activation / Q000235:genetics*; D010974:Platelet Aggregation / Q000235:genetics; D011110:Polymorphism, Genetic
D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19