Identification of Clopidogrel CYP2C19 Metabolizer and Thienopyridine Treatment After an Acute Coronary Syndrome
Information source: Assistance Publique - H魀itaux de Paris
ClinicalTrials.gov processed this data on August 20, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Acute Coronary Syndrome
Phase: Phase 4
Status: Completed
Sponsored by: Assistance Publique - H魀itaux de Paris Official(s) and/or principal investigator(s): Jean Philippe COLLET, PUPH, Principal Investigator, Affiliation: Assistance Publique - H么pitaux de Paris
Summary
To demonstrate that a strategy of fast genetic testing performed in outpatient clinic allows
to select adequately one of the 2 antiplatelet treatments approved in the same indication
(ACS with PCI - prasugrel 10mg MD or clopidogrel 75mg MD). Patients will reach similar
levels of platelet inhibition with the 2 different thienopyridines suggesting optimal
risk/benefit ratio in most patients with individualized therapy.
Clinical Details
Official title: Bedside Genetic Approach to Identify Clopidogrel CYP2C19 Metabolizer and Optimize Maintenance Thienopyridine Treatment After an Acute Coronary Syndrome: The GAMMA Study
Study design: Observational Model: Cohort, Time Perspective: Prospective
Primary outcome: proportion of patients who are within the optimal prespecified window of P2Y12 inhibition
Secondary outcome: proportion of patients who are within the optimal prespecified window of P2Y12 inhibition
Detailed description:
Rationale: There are thresholds of on-treatment platelet reactivity that appear to expose
patients either to a risk of thrombotic events (high on-treatment platelet reactivity) or to
a risk of bleeding events (low on-treatment platelet reactivity). Clopidogrel is an oral
platelet P2Y12 receptor inhibitor that requires metabolic activation catalyzed by several
Cytochromes P450 (CYP) isoforms. The loss-of-function polymorphism 2C19*2, carried by 30% of
individuals, is associated with high-on-treatment platelet reactivity (low level of P2Y12
inhibition) and a higher risk of stent thrombosis in patients exposed to clopidogrel
(OR=3. 45 (2. 14-5. 57)). The gain-of-function polymorphism 2C19*17 is associated with
low-on-treatment platelet reactivity (high level of P2Y12 inhibition) with a higher risk of
TIMI major bleeding (OR=1. 85 (1. 19 - 2. 86). Prasugrel is a new thienopyridine drug with
improved ischemic outcomes compared with clopidogrel in acute coronary syndrome patients
undergoing PCI but the drug was also associated with more bleeding complications. Prasugrel
is a more potent irreversible P2Y12inhibitor than clopidogrel, but it also requires a
metabolic conversion that is less or not affected by CYP2C19 variants, unlike clopidogrel.
The recent pharmacogenetic literature suggests that individualized treatment (choice between
clopidogrel or prasugrel which both are possible in this indication) based on the genetic
information rapidly obtained, is possible. This would improve the risk/benefit of therapy.
Both common gain- and loss-of function CYP2C19 alleles can be combined to identify two
metabolizers status: rapid metabolizer (ultra fast or UF: *17/*17, 5% of all comers and
normal metabolizers or NM : *1/*1 et *1/*17, 50% of all comers) at potential higher risk of
bleeding and slow metabolizer (Intermediate Metabolizers or IM, *1/*2 and *2/*17, 40% of all
comers and Poor Metabolizers or PM, *2/*2, 5% of all comers) at potential higher risk of
thrombosis. Primary hypothesis ("genetic hypothesis") : the proportion of rapid metabolizers
treated with a 75mg clopidogrel MD within the optimal range of P2Y12 inhibition at 30 days,
(defined as a threshold of 220 AU路min up to 350 AU路min of ADP-induced platelet aggregation
measured by the Multiple Electrode platelet Aggregometry - Multiplate analyzer, DYNABYTE,
Munich, Germany or a % inhibition between 30% up to 80% using the VerifyNowTMP2Y12
platform), is non inferior to the proportion of slow metabolizers treated with prasugrel
10mg MD. Secondary hypothesis ("functional hypothesis"): At 30 days, patients outside the
pre-specified target of P2Y12 inhibition level will be adjusted (prasugrel 10mg or
clopidogrel 75mg). The hypothesis is that PFT on top of genetic testing will improve the
number of patients reaching the prespecified optimal target of P2Y12 inhibition. Thus, the
proportion of slow metabolizers within the target at D45 is non inferior to that of rapid
metabolizer as determined by the POC PFT. Objectives: To demonstrate that a strategy of
fast genetic testing performed in outpatient clinic allows to select adequately one of the 2
antiplatelet treatments approved in the same indication (ACS with PCI - prasugrel 10mg MD or
clopidogrel 75mg MD). Patients will reach similar levels of platelet inhibition with the 2
different thienopyridines suggesting optimal risk/benefit ratio in most patients with
individualized therapy. Study population: ACS patients who recently underwent stent PCI, who
are stable and eligible for prasugrel or clopidogrel therapy. Study design:
Prospective,multicenter study. Genetic metabolizer status will be determined using the
VerigeneTM (Nanosphere technology) platform during outpatient follow-up visit.
Thienopyridine treatment at enrolment will not affect eligibility. Rapid metabolizers (UF
and NM) will be treated by 75mg clopidogrel MD while slow metabolizers (IM and PM) will be
allocated to prasugrel 10mg MD. A first evaluation of platelet reactivity will be performed
one month after to allow the comparison of the proportion of patients who are within the
optimal prespecified window of P2Y12 inhibition (primary hypothesis). The investigators will
evaluate the hypothesis that a treatment adjustment based on the results obtained by this
pharmacodynamic evaluation will improve the rate of success. In this second phase, patients
with a level of P2Y12 inhibition >80% (<220AU. min) or <30% (>350 AU. min) will be switched to
75mg clopidogrel MD and or to prasugrel 10mg MD, respectively. A second evaluation of the
level of platelet reactivity will be performed at day 45 to allow the comparison of
proportions of patients within the prespecified optimal window of P2Y12 inhibition between
rapid and slow metabolizer genotypes. Duration of inclusion: 12 months Duration of
participation of the patient: 60 days Primary endpoint: Proportion of patient who are within
the optimal prespecified window of P2Y12 inhibition at 30 days defined as a threshold of 220
AU路min up to 350 AU路min of ADP-induced platelet aggregation measured by the Multiple
Electrode platelet Aggregometry - Multiplate analyzer, DYNABYTE, Munich, Germany or a %
inhibition between 30% up to 80% using the VerifyNowTMP2Y12 platform. Number of patients: The
investigators have estimated the proportion of prasugrel-treated patients within the
prespecified target of P2Y12 inhibition to be 75%. The investigators have formulated the
hypothesis that 80% of rapid metabolizers on clopidogrel 75mg MD will stand in the optimal
prespecified window of P2Y12 inhibition and the investigators wish to demonstrate that this
proportion is not inferior to that of prasugrel-treated patients. Considering a power of
80%, an alpha-risk error of 0. 05 and a non-inferiority margin of - 10%, a sample size of 122
patients per group are required. Expected results: The GAMMA study will provide answers to
a major challenge that is whether rapid genetic information on 2C19 genotype can help in
reaching the optimal target of IPA using 2 different thienopyridine, that have different
sensitivity to the CYP2C19 variants. Statistical analysis: The non inferiority will be
considered as demonstrated (according to the consent risk) if the non inferiority margin of
the 95% confidence interval of the difference in percentages is superior to the non
inferiority margin (ICH Statistical Procedures). The non-inferiority margin has been
established at - 10% according to clinical considerations based on an acceptable maximal lost
of efficacy.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- ACS patients who underwent Percutaneous coronary intervention
Exclusion Criteria:
- Anemia <10g/dL
- Indication for VKA
- Recent bleeding or planned surgery
- Thrombopenia <80 000/碌l
Locations and Contacts
ACTION-Institut de Cardiologie-Groupe Hospitalier Piti茅-Salp锚tri猫re (APHP) Universit茅 Pierre et Marie Curie (UPMC), Paris 75013, France
Additional Information
Starting date: July 2011
Last updated: February 7, 2014
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