Acute-MI patients who possess the genetic variant linked previously
with variability in the antiplatelet response to clopidogrel
(Plavix, Bristol-Myers Squibb/Sanofi-Aventis) are at an increased
risk of death, recurrent MI, and urgent coronary revascularization
when placed long-term on the antiplatelet regimen [1].

"Our study shows a strong relation between the presence of the
CYP2C19*2 allelic variant and recurrent thrombotic coronary events
in clopidogrel-treated patients predominantly of European ancestry
who survived a myocardial infarction before 45 years of age," write
lead investigator Dr Jean-Philippe Collet (INSERM, Paris, France)
and colleagues in a paper published online December 23, 2008 in the
Lancet.

In their paper, the group explains that variability in the gene that
encodes the cytochrome P450 2C19 enzyme is thought to contribute to
the effectiveness of clopidogrel as an antiplatelet agent. This
enzyme is active in the biochemical pathway that converts
clopidogrel into an active metabolite, and the loss-of-function
polymorphism, known as CYP2C19*2, is associated with reduced
clopidogrel responsiveness.

In addition to this study, Dr Tabassome Simon (Université Pierre et
Marie Curie, Paris, France) and colleagues also examine the
subsequent risk of cardiovascular events among acute-MI patients
with the CYP2C19 alleles receiving clopidogrel [2].

Publishing findings from the French Registry of Acute ST-Segment
Elevation and Non-ST-elevation Myocardial Infarction (FAST-MI) study
online December 22, 2008 in the New England Journal of Medicine, the
investigators show that patients carrying any two of the CYP2C19
loss-of-function alleles, which included CYP2C19*2, CYP2C19*3,
CYP2C19*4, or CYP2C19*5, were at a significantly greater risk of
death, MI, or stroke.

A third study, from the Thrombolysis in Myocardial Infarction (TIMI)
study group, showed that, among clopidogrel-treated subjects,
carriers of the reduced-function CYP2C19 alleles had a more than 50%
increased risk in the primary end point of death from cardiovascular
causes, MI, or stroke, when compared with noncarriers, as well as a
threefold increase in the risk of stent thrombosis [3].

Speaking with heartwire, Dr Eric Topol (Scripps Translational
Science Institute, La Jolla, CA), who was not part of any of the
studies, called the results "major findings in cardiovascular
medicine," especially since clopidogrel is the second-most-
prescribed drug in the world.

"At this moment in time in cardiovascular medicine, this is perhaps
the most striking, practical, pharmacogenetic relationship
demonstrated," said Topol. "It has practical implications for
managing patients and for patients getting a stent and clopidogrel.
At least one-third, if not more, depending on ancestry, are at
considerably higher risk for stent thrombosis, and this information
isn't being taken into account."

The CYP2C19 variant is extremely common, occurring in 30% of
individuals of European ancestry, 40% of individuals of African
ancestry, and in more than 50% of individuals of Asian ancestry,
noted Topol.

Loss-of-Function Alleles and Clopidogrel Resistance

In the FAST-MI paper, Simon and colleagues report their findings
based on data from 2208 patients with an acute MI treated with
clopidogrel. In addition to CYP2C19, the researchers also assessed
the relationship between variants of genes modulating clopidogrel
absorption, such as ABCB1, as well as genes modulating metabolic
activation and biologic activity, and the risk of cardiovascular
events during one year of follow-up.

During the follow-up period, there were 225 deaths and 94 nonfatal
MIs or strokes. Patients with two variant alleles of ABCB1 had a
significantly greater risk of death from any cause, nonfatal stroke,
or MI at one year compared with individuals with the ABCB1 wild-type
genotype.

Among patients carrying any two variants of CYP2C19, there was a
doubling in the risk of cardiovascular events at one year compared
with individuals without any of the loss-of-function alleles.

This increased risk was even more pronounced among those who
underwent PCI during hospitalization. Among these 1535 PCI patients,
the rate of cardiovascular events among those with two CYP2C19 loss-
of-function alleles was 3.5 times greater than among those without
the genetic polymorphism.

Analysis From TRITON-TIMI-38

The TIMI study group also gets in on the clopidogrel-genetics action
in the study by Dr Jessica Mega (Brigham and Women's Hospital,
Boston, MA), which is also published online December 22, 2008 in the
New England Journal of Medicine.

In an analysis of the Trial to Assess Improvement in Therapeutic
Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON–
TIMI) 38, the researchers tested the association between functional
genetic variants in cytochrome P450 genes, plasma concentrations of
active drug metabolite, and platelet inhibition in response to
clopidogrel in 162 healthy subjects.

Carriers of at least one CYP2C19 loss-of-function allele had a 30%
relative reduction in plasma exposure to the active metabolite of
clopidogrel when compared with noncarriers. In addition, these
carriers also had a significant 9% absolute reduction in maximal
platelet aggregation in response to clopidogrel.

In terms of cardiovascular outcomes among clopidogrel-treated
subjects, carriers had a more than 50% increased risk in the primary
end point of death from cardiovascular causes, MI, or stroke
compared with noncarriers, as well as a threefold increase in the
risk of stent thrombosis.

Lancet Study Also Published

In the Lancet study, the researchers assessed whether the CYP2C19*2
polymorphism is associated with clinical outcomes of acute-MI
patients treated long-term with clopidogrel. Using data from the
large Appraisal of Risk Factors in Young Ischemic Patients
Justifying Aggressive Intervention (AFIJI) registry, they identified
259 patients younger than 45 years who survived a first MI and were
exposed to clopidogrel for at least one month. All patients
underwent genetic testing for the CYP2C19*2 polymorphism.

After a median exposure of 1.07 years, the primary end point, a
composite of death, nonfatal MI, and urgent revascularization,
occurred more frequently in carriers vs noncarriers of CYP2C19*2. In
total, there were 11 events in individuals without the CYP2C19*2
allele and 15 events in those heterozygous and homozygous for
CYP2C19*2.

"The magnitude of the detrimental effect of the CYP2C19*2 genetic
variant was unexpected in view of the clinical benefits that were
recorded with clopidogrel in previous studies that used similar
clinical end points," write Collet and colleagues.

The group notes that at the last follow-up visit, 213 patients were
still receiving a maintenance dose of 75 mg per day of clopidogrel,
and nearly all of these were receiving low-dose aspirin in
combination. They note that it is unknown whether higher doses of
clopidogrel would override the detrimental effect of the loss-of-
function CYP2C19*2 polymorphism, but this warrants further
investigation.

Speaking with heartwire, Topol noted there are inconsistencies
across the three studies, mainly in that the TRITON-TIMI-38 analysis
and the study by Collet and colleagues documented a higher risk of
cardiovascular events among carriers, with threefold and sixfold
increases in the risk of stent thrombosis, respectively.

In contrast, carriers of the gene included in the FAST-MI analysis
appeared to be at lower risk. "It's a very peculiar finding," said
Topol.

Overall, however, Topol said the findings, taken together to include
ABCB1 and CYP2C19, as well as the reduced-function CYP2B6 allele
that appears to affect the amount of active metabolite in the TRITON-
TIMI analysis, suggest that multiple genes are at work.

"There are other things lurking besides this very important CYP2C19,
and probably with larger samples and more events you'd have enough
power to pick up CYP2B6 and further demonstrate the importance of
ABCB1," said Topol.

The findings also need to be independently replicated before being
extrapolated to older patients or those of non-European ancestry,
write Collet and colleagues. The results, however, raise the
question of whether or not the prognostic information associated
with the CYP2C19*2 genotype can be used to guide management of these
patients.

In an editorial accompanying the Lancet study [4], Dr Robert Storey
(University of Sheffield, UK) called the degree of risk associated
with the variant "remarkable," partly because the conversion of
clopidogrel to its active metabolite can be achieved through several
cytochrome P450 enzymes. Other mechanisms should be explored and
further testing carried out to determine whether having the
CYP2C19*2 variant is associated with other genetic determinants of
risk, he writes.

Regarding the possibility of genotyping patients with acute coronary
syndrome to identify CYP2C19*2 carriers for risk stratification,
Storey believes the concept is attractive, but several factors are
likely to dampen enthusiasm. "The results of such an analysis would
be unlikely to be available at the time of starting clopidogrel and
during the high-risk phases of an acute coronary syndrome," he
writes. Other drugs, he notes, including prasugrel, are currently in
development and could potentially provide solutions to the problems
of variability in the response to clopidogrel.

Regarding genotyping patients to identify the CYP2C19 variant, Topol
said he thinks genotyping could be incorporated into daily practice.
If two million patients are getting stents annually, then some 700
000 individuals are at increased for stent thrombosis based on their
genetics.

Sources


Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19
polymorphism in young patients treated with clopidogrel after
myocardial infarction: a cohort study. Lancet 2008;
DOI:10.1016/S0140-6736(08)61845-0. Available at:
http://www.thelancet.com.
Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of
response to clopidogrel and cardiovascular events. N Engl J Med
2009; DOI 10.1056/NEJMoa0808227. Available at: http//www.nejm.org.
Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms
and response to clopidogrel. N Engl J Med 2009; DOI:
10.1056/NEJMoa0809171. Available at: http://www.nejm.org.
Storey R. Clopidogrel in acute coronary syndrome: to genotype or
not? Lancet 2008; DOI:10.1016/S0140-6736(08)61846-2. Available at:
http://www.thelancet.com.