Pharmacogenetics of Clopidogrel in Acute Coronary Syndromes

Study Overview
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Brief Summary
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The antiplatelet agent clopidogrel is an effective drug for the prevention of thrombotic events in patients with acute coronary syndromes, and is therefore one of the most frequently prescribed drugs worldwide. Accumulating data suggest that the response to clopidogrel is characterised by significant inter-patient variability in the degree of platelet inhibition and the risk of cardiovascular events. Recent research findings have highlighted the role of genetic variations in determining antiplatelet response variability, and this has aroused interest in genotyping all thienopyridine-eligible patients in order to identify those who would be at increased risk of harm if treated with clopidogrel. This is a prospective, multicentre, randomised study enrolling consecutive patients hospitalised because of an ACS with or without ST-segment elevation. The patients are randomised to undergo or not tests for CYP2C19*2, CYP2C19*17 and ABCB1 3435 genetic variants immediately after diagnosis. The genotyping is done using a Q3 System (a compact platform that enables the classic laboratory analysis of DNA by means of real-time PCR). The Q3 has been designed as a low entry-cost, portable, point-of-care instrument for foolproof use by unskilled personnel. The patients randomised to the pharmacogenomic arm receive one of the ADP receptor antagonists (clopidogrel/prasugrel/ticagrelor) on the basis of an algorithm that consider genetic and clinical variables. The patients randomised to the standard treatment arm receive clopidogrel or prasugrel or ticagrelor on the basis of the standard of care (clinical algorithm alone). For each patient, a record is made of the occurrence of cardiovascular death, non-fatal MI, stroke, BARC-defined bleeding, and definite or probable stent thrombosis. The primary endpoint is the composite of death due to cardiovascular causes, non-fatal MI and stroke. The secondary endpoints is the occurrence of definite or probable stent thrombosis, and BARC-defined major bleeding events (types 3-5).

Detailed Description
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Antiplatelet therapy is the cornerstone of medical treatment of patients experiencing an acute coronary syndrome (ACS). As a synergistic antiplatelet effect can be obtained by simultaneously inhibiting thromboxane-A2 and adenosine diphosphate P2Y12 platelet receptors, the current standard of care for all patients with ACS includes dual anti-platelet therapy with aspirin (the first choice treatment for blocking thromboxane-A2 receptors) and one of the three currently available ADP P2Y12 inhibitors: clopidogrel, prasugrel and ticagrelor. Over the last few years, the clinical availability of the new potent P2Y12 inhibitors prasugrel and ticagrelor has changed the ACS treatment paradigm. The revised European guidelines downgrade clopidogrel to patients who cannot receive prasugrel and ticagrelor, and clearly recommend the latter for patients with ACS (Recommendation Class I, Evidence Level B for both). However, the choice of the optimal drug for each individual patient is still left to clinicians, thus continuing the uncertainty as to how these new potent drugs should be incorporated into everyday clinical practice. The appropriate selection of antiplatelet agents has so far been guided only by the patients' phenotypic characteristics, but taken together, the evidence does not support a wide use of prasugrel and ticagrelor in clinical practice and considering subgroups with less clinical benefit and limitations of TRITON TIMI-38 and PLATO study design, not all 100% of patients with ACS appears eligible for treatment with new ADP receptors antagonists. Recent research has highlighted the role of CYP enzyme and ABCB1 genetic variations in determining the variability of the patients' antiplatelet response to clopidogrel, and shown a clear relationship between lower levels of clopidogrel's active metabolite, reduced platelet inhibition, and a higher rate of major adverse cardiovascular events. Specifically, post-hoc analysis concerning association of CYP2C19 and ABCB1 genetic variants to clinical outcomes showed an absolute 7.3% reduction in the risk of death from cardiovascular causes, myocardial infarction or stroke among the study population who were not carriers of a CYP2C19 reduced-function allele, ABCB1 3435 TT homozygotes, or both, compared with individuals who did carry either. The impact of CYP2C19 alleles and ABCB1 genotype seems to be restricted to patients taking clopidogrel as they do not significantly affect pharmacological or clinical outcomes in patients treated with prasugrel and ticagrelor. The aim of this project is to test the impact on clinical outcomes of strategy of conducting dual antiplatelet therapy considering both genotype data and clinical variables in comparison with a strategy based on clinical variables alone. Methodology: This is a prospective, multicentre, randomised study enrolling 3,612 consecutive patients hospitalised because of an ACS with or without ST-segment elevation. The patients are randomised to undergo or not tests for CYP2C19*2, CYP2C19*17 and ABCB1 3435 genetic variants immediately after diagnosis. The genotyping is done using a Q3 System (a compact platform that enables the classic laboratory analysis of DNA by means of real-time PCR). The Q3 has been designed as a low entry-cost, portable, point-of-care instrument for foolproof use by unskilled personnel. The patients randomised to the pharmacogenomic arm receive one of the ADP receptor antagonists (clopidogrel/prasugrel/ticagrelor) on the basis of an algorithm that consider genetic and clinical variables. The patients randomised to the standard treatment arm receive clopidogrel or prasugrel or ticagrelor on the basis of the standard of care (clinical algorithm alone). Patient enrolment is to be completed in 24 months. Each patient will be followed up for 12 months by means of outpatient visits after one, six and 12 months. For each patient, a record is made of the occurrence of cardiovascular death, non-fatal MI, stroke, BARC-defined bleeding, and definite or probable stent thrombosis. The primary endpoint is the composite of death due to cardiovascular causes, non-fatal MI and stroke. The secondary endpoints is the occurrence of definite or probable stent thrombosis, and BARC-defined major bleeding events (types 3-5). The expected rate reduction of ischemic and bleeding events is 25% for a median of 12 months of follow-up (data derived from PLATO trial) and the target relative risk reduction for genotype-guided therapy versus standard therapy is 20%. It has been defined a 95% power, a type alpha error of 5% and two-tail test. Therefore approximately 1806 patients for each arm should be enrolled.

Official Title
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Pharmacogenetics of Clopidogrel in Acute Coronary Syndromes

Conditions
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Acute Coronary Syndromes

Intervention / Treatment
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* Genetic: genetic tests for CYP2C19*2, CYP2C19*17 and ABCB1 3435
* Other: clinical algorithm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of ACS (STE-ACS or NSTE-ACS) during the index hospitalisation Age >18 years Ability to sign the informed consent form Ability to attend scheduled visits Exclusion Criteria: Cognitive or other causes of an inability to provide informed consent or follow study procedures Any contraindication to the use of ADP P2Y12 inhibitors Life expectancy <1 year Thrombolytic therapy within the previous 24 hours Known ABCB1, CYP2C19 *2 orCYP2C19 *17 genotype

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Genotype/ phenotype guided group<br>The patients randomized to the genotype/phenotype guided group undergo genetic tests for CYP2C19*2, CYP2C19*17 and ABCB1 3435 genetic variants immediately after diagnosis of ACS and receive one of the ADP receptor antagonists (clopidogrel/prasugrel/ticagrelor) on the basis of an algorithm that consider genetic and clinical variables. | Genetic: genetic tests for CYP2C19*2, CYP2C19*17 and ABCB1 3435<br>* The CYP2C19*2 (10q24.1-q24.3; rs4244285), CYP2C19*17 (10q24.1-q24.3; rs12248560) and ABCB1 3435 (7q21.1; rs1045642) genetic variants will be genotyped using an ST Q3 system. The conventional genotyping methods so far used for diagnostic purposes will not be used in this study because appropriate labs may not be readily available and the processing time is prohibitive. Q3 is a compact platform enabling the classical laboratory analysis of DNA by means of real-time PCR. The Q3 has been designed as a low entry-cost, portable, point-of-care instrument for foolproof use by unskilled personnel. Antiplatelet therapy will be choose on the basis of clinical and genetic algorithm.<br>|
| Active Comparator: phenotype only guided group<br>The patients randomized to the phenotype only guided group receive clopidogrel or prasugrel or ticagrelor on the basis of the standard of care on the basis of clinical algorithm alone. | Other: clinical algorithm<br>* Antiplatelet therapy will be choose on the basis of clinical algorithm alone<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of cardiovascular death, non fatal myocardial infarction, stroke and BARC-defined major bleeding events 3 to 5. | The primary endpoint will be the composite of cardiovascular death, non fatal myocardial infarction, stroke and BARC-defined major bleeding events 3 to 5 at 12 months follow-up. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| occurrence of definite or probable stent thrombosis. | The secondary endpoint variable will be the occurrence of definite or probable stent thrombosis at 12 months follow-up. | 12 months | 
| cardiovascular death | individual components of primary endpoint at 12 months follow-up | 12 months | 
| non fatal myocardial infarction | individual components of primary endpoint at 12 months follow-up | 12 months | 
| stroke | individual components of primary endpoint at 12 months follow-up | 12 months | 
| BARC-defined major bleeding events 3 to 5 | individual components of primary endpoint at 12 months follow-up | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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clopidogrel, pharmacogenetics, antiplatelet therapy, acute coronary syndromes