Pharmacogenomics of Anti-platelet Intervention-2 (PAPI-2) Study
It is standard treatment to take anti-platelet medication after cardiac catheterization and stent placement to help prevent the formation of blood clots that may cause heart attack or stroke. The most commonly used anti-platelet medicine is clopidogrel (Plavix®). However, researchers have found that people vary in their response to clopidogrel, in part because of differences in their genes. Prasugrel (Effient®)is another anti-platelet medication used to prevent clots. The genetic differences that affect clopidogrel response do not affect prasugrel response. Recently, the FDA added a warning to the label of clopidogrel to notify doctors and patients with certain genetic differences may not get the full benefit from clopidogrel. Despite this, genetic testing for these variations is not usually done in standard medical practice. The purpose of this study is to see if patients with certain gene differences have fewer major cardiac events after stent placement if they are given anti-platelet therapy guided by their individual genetic type compared to standard anti-platelet therapy.
Acute Coronary Syndrome
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Pharmacogenomics of Anti-platelet Intervention-2 (PAPI-2) Study: A Prospective, Multicenter, Randomized Trial of Genotype-directed (G-D)Versus Standard of Care (SOC)Anti-platelet Therapy|
- Occurrence of post-randomization cardiovascular events [ Time Frame: One year ] [ Designated as safety issue: No ]Cardiovascular events include non-fatal myocardial infarction, non-fatal stroke, definite or probable stent thrombosis (ARC definition) and death secondary to any cardiovascular cause.
- Occurrence of bleeding events [ Time Frame: One year ] [ Designated as safety issue: Yes ]Bleeding events will classified by the Bleeding Academic Research Consortium definition.
- Post-treatment platelet aggregation [ Time Frame: 10 days ] [ Designated as safety issue: No ]Platelet aggregation will be performed on a subset of subjects. Platelet aggregation studies are optional and will not be used to modulate antiplatelet therapy
- Health care resource utilization and cost-effectiveness [ Time Frame: One year ] [ Designated as safety issue: No ]
- Occurrence of adverse events [ Time Frame: One year ] [ Designated as safety issue: Yes ]
- Composite of all-cause death, MI, stroke and repeat revascularization [ Time Frame: One year ] [ Designated as safety issue: No ]
|Study Start Date:||February 2012|
|Estimated Study Completion Date:||October 2014|
|Estimated Primary Completion Date:||October 2014 (Final data collection date for primary outcome measure)|
Experimental: Genotype-directed, clopidogrel
Participants randomized to the G-D group will have CYP2C19 genotype analysis performed. CYP2C19 extensive and ultrarapid metabolizers will receive clopidogrel.
clopidogrel 75 mg/day plus aspirin 81-162 mg/day for one year
Other Name: Plavix
Experimental: Genotype-directed, prasugrel
Participants randomized to the G-D group will have CYP2C19 genotype analysis performed. CYP2C19 intermediate and poor metabolizers will receive prasugrel.
Prasugrel 5-10 mg/day plus aspirin 81-162 mg/day for one year
Other Name: Effient
No Intervention: Standard of Care
Participants randomized to the SOC group will not have CYP2C19 genotype analysis performed. They will receive dual anti-platelet therapy guided by the judgment of their treating physician according to standard medical practice irrespective of genotype.
Over a three-year period, a total of 7,200 patients undergoing percutaneous coronary intervention (PCI) in whom dual anti-platelet therapy is indicated for at least one year and meet the eligibility criteria, will be recruited from five or more clinical sites. Patients presenting to the cardiac clinics, emergency departments, catheterization laboratories, and other acute care units (e.g. CCU) who will have coronary angiography or have had angiography and PCI will be offered participation. Following informed consent, patients will have baseline data and specimens collected, and eligibility confirmed. Patients will be randomized in equal numbers to the G-D arm or SOC arm. Immediately following randomization, a blood sample from patients assigned to the G-D arm will be sent for CYP2C19 genotype analysis. Upon receipt of CYP2C19 genotype results, patients randomized to the G-D arm with the CYP2C19 *1/*1 genotype (extensive metabolizers) and *1/*17, and *17/*17 genotypes (ultrarapid metabolizers) will receive clopidogrel 75 mg/day plus aspirin 81-162 mg/day (group a). Those with *1/*2, *1/*3, *2/*17, and *3/*17 genotypes (intermediate metabolizers) and those with *2/*2, *2/*3, and *3/*3 genotypes (poor metabolizers) will receive prasugrel 5-10 mg/day plus aspirin 81-162 mg/day (group b). Patients randomized to the SOC arm will not be genotyped prospectively. They will receive dual anti-platelet therapy guided by the judgment of their treating physician according to standard medical practice irrespective of genotype (group c). Optionally, a subgroup of patients will return at 10 days after the randomization visit for platelet aggregation studies.
If our hypothesis is correct, i.e., that in intermediate and poor metabolizers, G-D anti-platelet therapy results in fewer cardiovascular events and has less or equivalent bleeding complications compared to SOC therapy, and is cost effective, this prospective randomized clinical trial will provide the evidence base to implement genotype-directed anti-platelet treatment algorithms broadly into clinical practice.
|United States, Delaware|
|Christiana Care Health System|
|Newark, Delaware, United States, 19718|
|United States, Maryland|
|University of Maryland School of Medicine|
|Baltimore, Maryland, United States, 21201|
|The Johns Hopkins University School of Medicine|
|Baltimore, Maryland, United States, 21287|
|Sinai Center for Thrombosis Research|
|Baltimore, Maryland, United States, 21209|
|United States, Pennsylvania|
|Geisinger Health System|
|Danville, Pennsylvania, United States, 17822|
|Principal Investigator:||Alan R Shuldiner, M.D.||University of Maryland|