A polymorphism in one of the genes responsible for metabolizing
clopidogrel to its active form has been shown to be associated with
an increased risk of stent thrombosis in patients undergoing PCI [1].

The study, published online February 4, 2009 in the European Heart
Journal, was conducted by a group led by Dr Dirk Sibbing (Deutsches
Herzzentrum, Munich, Germany).

Sibbing told heartwire that the mutant *2 allele of the CYP2C19 gene
occurs with a frequency of about 15%. In the current study, 25% of
patients had one copy of the genotype (ie, were heterozygous) and 2%
of the group were homozygous. "We clearly saw a gene dose effect, so
that patients who were heterozygous had an increased risk of stent
thrombosis compared with those without this genotype, and those who
were homozygous had a higher risk again. We are the first group to
describe this," Sibbing said.

A previous study by a group from Harvard has shown similar results,
but that study was smaller than this one and had a less specific end
point. "Our study is larger and used definite stent thrombosis as the
end point, whereas the Harvard study had definite or probable stent
thrombosis as the end point. We also did a multivariate analysis
showing that this genotype is an independent predictor of stent
thrombosis."

In the current study, 2485 consecutive patients undergoing coronary
stent placement after pretreatment with 600 mg of clopidogrel were
genotyped. The primary end point of the study was the incidence of
definite stent thrombosis within 30 days following PCI. Of the
patients studied, 1805 (73%) were CYP2C19 wild-type homozygotes
(*1/*1), 633 (25%) were CYP2C19*2 heterozygotes (*1/*2), and 47 (2%)
were homozygous (*2/*2) for the mutant CYP2C19*2 allele. The
cumulative 30-day incidence of stent thrombosis was significantly
higher in CYP2C19*2 allele carriers compared with those without this
polymorphism. In addition, the incidence of ST-segment-elevation MI
(STEMI) and ischemic stroke was significantly higher in CYP2C19*2
allele carriers vs CYP2C19 wild-type homozygotes.

The risk of stent thrombosis was highest (2.1%) in patients carrying
two of the mutant CYP2C19 alleles (*2/*2 genotype), and the p value
for this trend was significant (p=0.002).

The authors conclude: "The results of the present study identify
patients at high risk for stent thrombosis and provide a rationale
for administration of an intensified antiplatelet treatment in
patients scheduled for coronary stent placement. Genetic
determination of the CYP2C19 loss-of-function polymorphism may be
beneficial in this setting, as high-risk patients can be identified
prior to the planned procedure. High clopidogrel maintenance dosing
or the use of novel and more potent P2Y12-receptor antagonists, such
as prasugrel, may be potential treatment options for tailored
antiplatelet therapy in CYP2C19*2 carriers."

To heartwire, Sibbing noted that they do not routinely test for this
genotype at present, as there is not yet a point-of-care assay that
would give a quick result. "But if such an assay became available, we
would test all our patients and intensify treatment in those who
tested positive," he said.

He added that the next step would be to conduct a randomized trial in
which patients with this genotype are randomized to clopidogrel at
the regular dose or to a more potent regimen such as clopidogrel at a
higher maintenance dosage or prasugrel. He says he hopes such a study
will be done.

The study was funded by Deutsches Herzzentrum, Munich, Germany.
Sibbing reports receiving speaker fees from Dynabyte. Other authors
involved in the study report receiving speaker fees from Eli Lilly,
Sanofi-Aventis, and Bristol-Myers Squibb, and fees for advisory-board
activities from Eli Lilly and Sanofi-Aventis


Sibbing D, Stegherr J, Latz W, et al. Cytochrome P450 2C19 loss-of-
function polymorphism and stent thrombosis following percutaneous
coronary intervention. Eur Heart J 2009;
DOIi:10.1093/eurheartj/ehp041. Available at:
http://eurheartj.oxfordjournals.org. 19193675