Clinical trial NCT01452152: Pharmacogenomics of Anti-platelet Intervention-2 (PAPI-2) Study
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Cardiovascular Diseases
Acute Coronary Syndrome
Keywords: Pharmacogenomics
Platelet Aggregation Inhibitors
Lead sponsor: University of Maryland, Baltimore
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2011-10-14
Enrollment: 9
Sex: ALL
Minimum age (years): 20
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Males or non-pregnant females between the ages of 20 and 74 years, inclusive
* Not more than four days post-PCI (percutaneous coronary intervention) with placement of one or more drug eluting or bare metal stents
* One or more stent(s) delivered with final TIMI 3 flow (thrombolysis in myocardial infarction grade 3) in the stented vessel(s)
* Must have evidence of one of the following:

  1. Three vessel disease;
  2. Two vessel disease with one of the following: estimated creatinine clearance \<60, prior myocardial infarction, diabetes mellitus on treatment, peripheral artery disease, cerebrovascular disease, bifurcation stent, overlapping stents, or total stent deployment length \> 40 mm in length;
  3. Single vessel disease with two of the following: estimated creatinine clearance \<60, prior myocardial infarction, diabetes mellitus on treatment, peripheral artery disease, cerebrovascular disease, bifurcating stenting, overlapping stents, or total stent deployment length \> 40 mm in length.
* Patients with acute MI (myocardial infarction) preceding the PCI must have CK-MB (bound combination of creatine kinase M and creatine kinase B) value lower than the prior value, before randomization
* Patients with peri-procedural MI, defined by CK-MB three times greater than upper reference limit (URL), must have CK-MB value lower than the prior value, before randomization. Peri-procedural MI will be screened per clinical suspicion.
* Have an indication for one year of dual anti-platelet therapy with a P2Y12 inhibitor and aspirin
* Agreement of the treating physician to prescribe anti-platelet therapy according to randomization and study dosing algorithm
* Ability to understand and comply with planned study procedures
* Provide written informed consent prior to study entry
* Agrees to authorize the collection and release of his/her medical information for the duration of the trial or until the subject withdraws

Exclusion Criteria:

* History of a gastrointestinal bleed within three months or a major, life threatening bleeding event (e.g., sub-arachnoid or intracranial hemorrhage)
* Active pathological bleeding (e.g. GI bleeding)
* History of bleeding diathesis or coagulopathy
* History of stroke or transient ischemic attack (TIA)
* Non-cardiac surgery within the prior 3 months
* Planned cardiac or non-cardiac surgery within the next 12 months
* CYP2C19 genotype already known to subject or research team from prior genetic testing
* Post-PCI CABG (coronary artery bypass graft) before randomization
* Planned warfarin or dabigatran therapy any time during the study period
* Known allergy to aspirin, clopidogrel or prasugrel
* Platelet count \<100,000/mm3
* Hematocrit \< 25%
* Pregnancy
* Concurrent enrollment in another trial that involves an investigational stent, antithrombotic or anti-platelet agent
* Any condition that would, in the opinion of the site investigator, place them at an unacceptable risk or render them unable to meet the requirements of the protocol
* Any subject, in the opinion of the investigator, not expected to tolerate or be adherent with one year of dual antiplatelet therapy

Primary outcomes:
measure: Occurrence of Post-randomization Cardiovascular Events
timeFrame: One year
Secondary outcomes:
measure: Occurrence of Bleeding Events
timeFrame: One year
measure: Post-treatment Platelet Aggregation
timeFrame: 10 days
measure: Health Care Resource Utilization and Cost-effectiveness
timeFrame: One year
measure: Occurrence of Adverse Events
timeFrame: One year
measure: Composite of All-cause Death, Myocardial Infarction (MI), Stroke and Repeat Revascularization
timeFrame: One year
Other outcomes:
Locations:
city: Newark
country: United States
facility: Christiana Care Health System
state: Delaware
city: Baltimore
country: United States
facility: University of Maryland School of Medicine
state: Maryland
city: Baltimore
country: United States
facility: Sinai Center for Thrombosis Research
state: Maryland
city: Baltimore
country: United States
facility: The Johns Hopkins University School of Medicine
state: Maryland
city: Danville
country: United States
facility: Geisinger Health System
state: Pennsylvania
Study officials:
affiliation: University of Maryland
name: Alan R Shuldiner, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009 Aug 26;302(8):849-57. doi: 10.1001/jama.2009.1232.