Genotype Guided Comparison of Clopidogrel and Prasugrel Outcomes Study
This is a prospective, non-randomized, open-label, non-inferiority comparative effectiveness
outcomes trial comparing clopidogrel EMs (confirmed by CYP2C19 genotype)and receiving
clopidogrel at 75 mg/day with subjects receiving prasugrel at 5 and/or 10 mg/day. The
antiplatelet drug clopidogrel is a commonly prescribed therapy in patients following ACS,
stroke, PCI with or without stent placement, and in patients with peripheral artery disease.
However, recent research suggests that in vitro anti-platelet response to clopidogrel may be
limited or lost in up to 30% of treated individuals, and may be associated with inferior
The antiplatelet effect of clopidogrel requires conversion of the parent compound to an
active thiol. This active thiol metabolite inhibits adenosine diphosphate (ADP)-induced
platelet aggregation by blocking the platelet P2Y12 receptor, resulting in a reduction of
ADP-mediated platelet aggregation. Conversion of clopidogrel to its active metabolite is a
relatively inefficient process during which 85% of the pro-drug is converted to an inactive
metabolite by esterases, and the remaining 15% is oxidized to the active form by cytochrome
P-450 (CYP) enzymes.
The variability of clopidogrel response is associated with variability in CYP enzyme genetic
expression and activity, primarily CYP2C19 which is principally responsible for the
conversion of clopidogrel into its active metabolite. CYP2C19 is genetically polymorphic,
with alleles that produce both reduced and enhanced drug metabolism. These polymorphisms
include the loss-of-function alleles CYP2C19 *2, *3,*4 and *5 and the ultra-rapid
metabolizer CYP2C19 *17.
Subjects carrying the wild-type allele for CYP2C19 (*1/*1 or extensive metabolizers, EM) are
able to efficiently metabolize clopidogrel and have the greatest exposure to the active
metabolite, as well as the highest levels of platelet inhibition following clopidogrel
exposure. Intermediate metabolizers (IM), those individuals carrying one reduced function
allele (e.g.*1/*2, *1/*3, etc), have their circulating active drug metabolite level reduced
by over 30% compared to EMs resulting in a 25% reduction in platelet inhibition. These
results are consistent with other studies also demonstrating that individuals carrying the
CYP2C19*2 allele have decreased levels platelet aggregation inhibition following clopidogrel
administration as compared to the *1/*1 wild type.
A series of recent articles have explored the effect of genetic polymorphisms in CYP2C19 on
the anti-platelet activity of clopidogrel as well as clinical outcomes following PCI.
Collett, et al. examined 259 patients <45 years of age who were treated with clopidogrel
following a MI. Carriers for the CYP2C19*2 allele had an increased incidence of death, MI
and urgent coronary revascularization (p=0.0005, HR = 3.69). Simon, et al. examined 2,208
patients that presented with acute MI and received clopidogrel therapy and found individuals
that carried one or more CYP2C19 loss-of-function allele(s) had higher rates of
cardiovascular events than non-carriers. The risk of death, non-fatal MI or cardiovascular
stroke at 1 year after PCI was 3.58 times greater in patients carrying two loss-of-function
alleles compared to wild-type patients. Trenk, et al., associated elevated platelet activity
and poor clinical outcomes in patients with the*2 allele in 797 patients followed for one
year after PCI.
Prasugrel is a third generation thienopyridine, and appears to have increased antiplatelet
efficacy compared to clopidogrel. Like clopidogrel, prasugrel is a pro-drug that requires
metabolic activation. However, esterases that are known to inactivate clopidogrel act on
prasugrel to prime it for activation by a single CYP-dependant oxidation step. This more
direct pathway results in a more efficient activation pathway of prasugrel.
The efficacy of prasugrel and clopidogrel have been compared head-to-head in the TRITON-TIMI
38 study. This trial enrolled 13,608 ACS patients scheduled for PCI and compared prasugrel
(60-mg loading dose and then 10-mg daily maintenance dose) against clopidogrel
(300-mg/75-mg), both in combination with aspirin. Results indicated that prasugrel reduced
the combined rate of death from cardiovascular causes, nonfatal myocardial infarction, or
nonfatal stroke (12.1% for clopidogrel vs. 9.9% for prasugrel) at 15 months post-ACS. These
favorable effects on cardiovascular events were offset by an increased rate of serious
bleeding (1.4%, vs. 0.9% in the clopidogrel group) and fatal bleeding (0.4% vs. 0.1%).
Overall mortality did not differ between the two treatment groups.
A genetic substudy subsequently published by Mega, et al. examined the association between
CYP2C19 genotypes and cardiovascular outcome in a subset of 1,477 clopidogrel-treated
subjects enrolled in the TRITON-TIMI 38 study. This study demonstrated that carriers of one
or more reduced-function CYP2C19 alleles had a 53% increase in the composite primary
efficacy outcome compared with non-carriers (12.1% vs 8.0%, p=0.01) over 15 months of
follow-up. In contrast, outcomes in a subset of prasugrel-treated patients were similar
across CYP2C19 genotypes. Unfortunately, the in-trial response to clopidogrel among the
genetic substudy participants differed from that of the overall clopidogrel study cohort,
thus preventing direct comparisons of clopidogrel to prasugrel as a function of CYP2C19
On March 12, 2010 the FDA added a Boxed Warning to the Plavix prescribing information. The
Boxed Warning concerns patients who do not effectively metabolize the drug (i.e. "poor
metabolizers") and therefore may not receive the full benefits of the drug. This label
modification affirms the impact of the CYP2C19 genotype on the pharmacokinetics of
clopidogrel's active metabolite and, most importantly, confirmed the effect of reduced
anti-platelet response with a higher rate of cardiovascular events in IM and PM populations.
The event rate for clopidogrel extensive metabolizers alone has never been directly
compared to prasugrel.
Upon review of data extracted from Medco's integrated claims database, the "real-world"
prescribing practice of physicians for Plavix and Effient varies significantly from the
narrow indication of ACS studied in the TRITON-TIMI 38 study, and from the current Effient
approved labeling. Only 27% of patients new to Plavix therapy have experienced an ACS
event within 6 months of the new prescription. Similarly, only 13% of new Effient users
have evidence of an ACS event within 6 months of a new prescription for that agent.
Overall, approximately ½ of all new Plavix users and over 80% of new Effient users have no
evidence of any hospitalization event for ACS, stroke, percutaneous coronary intervention,
or peripheral arterial disease, indicating that instead they have stable cardiovascular
These data justify expanding the entry criteria for the GeCCO study to include patients with
a recent prescription for clopidogrel or prasugrel but without a precipitating ACS event.
The purpose of this study is to compare outcomes of cardiovascular disease patients
prescribed Plavix or Effient in a real-world population. If, as is the case here, the
population receiving these drugs includes significant numbers of patients either without
recent hospitalization for ACS and/or with stable coronary disease, then the population of
the GeCCO study may justifiably be expanded to include these new indications. This will
afford the opportunity to fulfill its comparative effectiveness research intent through
investigation of outcomes on these therapies as they are being utilized by physicians in the
Observational Model: Cohort, Time Perspective: Prospective
Non-inferiority of clopidogrel therapy in CYP2C19 extensive metabolizers with cardiovascular disease
To assess the non-inferiority of clopidogrel therapy in patients with cardiovascular disease who are CYP2C19 extensive metabolizers (identified by genetic testing) compared to prasugrel therapy (non-genotyped) on the composite primary end point of cardiovascular death, hospitalization for acute coronary syndrome (nonfatal MI or unstable angina), nonfatal stroke or coronary revascularization
Eric J Stanek, Pharm.D.
Medco Health Solutions, Inc.
United States: Institutional Review Board
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