Generic clopidogrel As antiplatelet therapy enters a transitional phase to generic clopidogrel, will this change drive more patient-tailored treatment?
Since the FDA approved clopidogrel in 1997, this
antiplatelet agent has revolutionized interven-
tional cardiology and transformed therapy for
non-STEMI, STEMI, and PCI-treated patients.
Clopidogrel enjoyed a remarkable 15-year “home run”
marketed under the name Plavix (Bristol-Myers Squibb/
Sanofi Pharmaceuticals Partnership, New York, NY),
amassing tens of billions of dollars in sales and serving an estimated 115 million patients internationally and
tors having more predictable pharmacodynamic profiles.
50 million patients in the United States alone. The evolu-
In 2005, the important relation of high on-treatment
tion continues with the expiration of the Plavix patent
platelet reactivity (HPR) to poststenting ischemic risk was
last month coupled with the FDA’s swift approval of
reported in the single-center PREPARE POST-STENTING
generic forms of both the 75-mg daily dose and the
study.2 Since then, numerous observational studies involv-
ing thousands of patients worldwide have confirmed the
One of the largest barriers to patient compliance and
seminal findings of PREPARE POST-STENTING.3
long-term therapy with branded clopidogrel was cost.
Finally, in 2010, the first genome-wide association
Generic versions should substantially lower that barrier
study identified a sole single nucleotide polymorphism
and may improve compliance and patient outcomes,
associated with clopidogrel response variability. This
single nucleotide polymorphism is CYP2C19*2. In the same publication, we reported the results of a valida-
tion study clearly demonstrating the increased risk of
poststenting ischemic event occurrence in CYP2C19*2
Clinicians need to be cautious to avoid allowing cost
carriers.4 The roles of genetic and platelet function test-
to be the most important factor in selecting a treat-
ing in clinical practice are now addressed in the most
ment option. Patients taking generic clopidogrel face
recent American and European treatment guidelines.
the same pharmacodynamic limitations as with Plavix.
Thus, in the last 15 years, important strides have been
In 2003, we first reported the unpredictable antiplate-
made in understanding the role of genetics, drug-drug
let response to Plavix therapy and the important fact
interactions, and many other factors influencing clopi-
that approximately 30% of the PCI population had a
dogrel metabolism and its pharmacodynamic effect. A
negligible or absent pharmacodynamic effect.1 This
strong relation has now been established between HPR
report was initially met with disbelief and opposition
and poststenting ischemic event occurrence.
by many thought leaders. However, these findings have
Arguably, P2Y blockade is the most important and
now been validated in thousands of patients studied
potentially life-saving pharmacologic strategy that we
can provide to a stent patient. However, it may be risky
The unpredictable and, in some cases, absent phar-
to prescribe generic clopidogrel to patients without
macodynamic effect following clopidogrel therapy laid
confirming an adequate pharmacodynamic response.
the groundwork for the development new P2Y inhibi-
Direct confirmation is provided by platelet function
May/june 2012 cardiac interventions today 25
testing, whereas genetic testing provides indirect evi-
could be variations in potency and consistency from
batch to batch. Concerns have also been raised about
Payers are now more apt to demand this type of
the purity of generics after some clopidogrel pills manu-
testing as well. Some progressive insurers are already
factured in India were proven to contain significant levels
requiring testing to determine the suitability of patients of methyl chloride, a known carcinogen.6 for the more expensive new P2Y inhibitors, prasugrel
(Effient, Daiichi Sankyo Company, Limited, Parsippany,
NJ; Eli Lilly and Company, Indianapolis, IN) and
ticagrelor (Brilinta, AstraZeneca Pharmaceuticals LP,
Although clopidogrel will likely remain the most
popular nonaspirin antiplatelet agent, the new P2Y
Various companies are leading the way in point-of-
inhibitors, particularly prasugrel, continue to gain market
care platelet function testing. With a defined HPR cut-
share. Ticagrelor and prasugrel have more predictable
point in place and recommendations in the guidelines,
and potent pharmacodynamic profiles and a more rapid
more cardiologists are now confirming the response to
onset of action than clopidogrel. These pharmacody-
clopidogrel rather than relying on blind faith. Exciting
namic advantages have translated to fewer ischemic
preliminary evidence suggests that there may be a
event occurrences but more bleeding in acute coronary
syndrome patients who were studied in two large-scale
With regard to the role of genetic testing in the
trials. For the interventional cardiologist, a reduction in
PCI-treated patient, the presence of a homozygote for
stent thrombosis is particularly notable.
a loss-of-function allele should be a strong indication
Clinicians should strive to find an antiplatelet therapy
to use an alternative P2Y inhibitor to clopidogrel.
that achieves the optimal level of platelet inhibition for
Similarly, a heterozygote for the loss-of-function allele
the patient, regardless of cost. If generic clopidogrel is
may undergo platelet function testing to confirm the
indeed pharmacodynamically effective in the patient,
adequacy of the response to clopidogrel, and if inade-
offering them this less-expensive option appears to be a
quate, an alternative P2Y inhibitor can be considered.
win/win. The introduction of generic clopidogrel holds
Platelet function testing in clopidogrel-treated patients
the strong possibility of inducing a change in practice
should allow for a maximal pharmacodynamic effect to
whereby genetic and platelet function testing are per-
occur. Therefore, 5 days of maintenance therapy, or at
formed more frequently in patients receiving a stent.
least 8 hours after an initial loading dose, would be suit-
This will allow the patient’s platelet physiology to decide
able times to test, and this strategy has been employed
the course of treatment instead of the price tag on the
The role of follow-up testing is unresolved and
understudied. Essentially, all of the major published
Paul A. Gurbel, MD, is the Director of the Sinai Center
data linking platelet function to post-PCI event occur-
for Thrombosis Research at Sinai Hospital of Baltimore,
rence has been based on one measurement of platelet
and Associate Professor of Medicine at The Johns Hopkins
function performed in-hospital after allowance for
University School of Medicine in Baltimore, Maryland.
an adequate steady state pharmacodynamic effect to
He has disclosed that he has received honoraria and/or
occur. The introduction of generic clopidogrel to the
grants from Astra Zeneca, Bayer, Bristol Myers Squibb,
market could be a catalyst that drives clinicians to
Lilly/Daiichi Sankyo, Nanosphere, Iverson Genetics,
embrace platelet function testing and genotyping and
Accumetrics, and Haemonetics. Dr. Gurbel may be
potentially provide improved patient care while at the
reached at pgurbel@lifebridgehealth.org.
1. Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003;107:2908-2913.
2. Gurbel PA, Bliden KP, Guyer K, et al. Platelet reactivity in patients and recurrent events post-stenting: results of
the PREPARE POST-STENTING study. J Am Coll Cardiol. 2005;46:1820-1826.
It is vital to remember that the pharmacodynamic
3. Bonello L, Tantry US, Marcucci R, et al. Working Group on High On-Treatment Platelet Reactivity. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll
response, safety, and efficacy of the generic versions of
clopidogrel have not been vetted in clinical trials. There
4. Shuldiner AR, O’Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009;302:849-857.
are potentially serious issues that have yet to be com-
5. Gurbel PA, Tantry US. Do platelet function testing and genotyping improve outcome in patients treated with
pletely examined and studied. The lack of longitudinal
antithrombotic agents? Platelet function testing and genotyping improve outcome in patients treated with
data on these generic medicines is sobering. The reliabil-
antithrombotic agents. Circulation. 2012;125:1276-1287. 6. Wahi R, Rao G, Thethi I, Pathak L. Prevalence of free methyl chloride as an impurity in generic clopidogrel
ity of generic clopidogrel has not been tested, and there
preparations: safety implications in cardiovascular patients. Circulation. 2010;122:A17290.
26 cardiac interventions today May/june 2012
RESUME DE THESE Domaine : Sciences de la Vie Spécialité : Biochimie et Génétique Moléculaire UFR : Biologie Appliquée et Valorisation des Ressources Naturelles Encadrant de thèse : Pr. Mohamed NHIRI Co-Encadrant de thèse : Pr. Franscisco Miguel CANOVAS RAMOS Responsable de l’UFR : Professeur Fouad SAYAH Titre de la thèse : Interaction
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