Pharmacogenomics of Anti-platelet Intervention-2 (PAPI-2) Study

Condition(s) targeted: Cardiovascular Diseases; Acute Coronary Syndrome

Intervention: clopidogrel (Drug); prasugrel (Drug)

Phase: Phase 4

Status: Not yet recruiting

Sponsored by: University of Maryland

Official(s) and/or principal investigator(s):
Alan R Shuldiner, M.D., Principal Investigator, Affiliation: University of Maryland

Overall contact:
Alan R. Shuldiner, M.D., Phone: 410-706-1623, Email: ashuldin@medicine.umaryland.edu

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 prasugrel (anti-platelet therapy guided by their individual genetic type) compared to clopidogrel (standard anti-platelet therapy).

Official title: Pharmacogenomics of Anti-platelet Intervention-2 (PAPI-2) Study: A Prospective, Multicenter, Randomized Trial of Clopidogrel Versus Prasugrel Anti-platelet Therapy in Cytochrome P450 2C19 (CYP2C19) Intermediate Metabolizers

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Occurrence of post-randomization cardiovascular events

Secondary outcome:

Occurrence of bleeding events

Post-treatment platelet aggregation

Health care resource utilization and cost-effectiveness

Occurrence of adverse events

Composite of all-cause death, MI and repeat revascularization

Detailed description: Over a three-year period, a total of 7,200 patients (2,400 CYP2C19 intermediate metabolizers) 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 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, a blood sample will be obtained for CYP2C19 genotype analysis. Patients will be treated according to the standard of care practice during their initial hospitalization prior to randomization. Within this study, patients will be assigned to either the Intervention or Observational group depending on their CYP2C19 genotype status. With a combined allele frequency of CYP2C19*2 and CYP2C19*3 of ~0. 18 in the general population, the investigators will identify ~2,400 patients with the CYP2C19 *1/*2, *1/*3, *2/*17, and *3/*17 genotypes (intermediate metabolizers) will be assigned to the Intervention group for randomization and primary analyses/outcomes. The remaining ~4,800 patients with the *1/*1 genotype (extensive metabolizers), *2/*2, *2/*3, and *3/*3 genotypes (poor metabolizers), and *1/*17 and *17/*17 genotypes (ultrarapid metabolizers), will be assigned to the Observational group, informed of their genotype and followed for outcomes in a registry. Intermediate metabolizers will be randomized in equal numbers to the prasugrel or the clopidogrel arm of the study. Randomization and administration of the first dose of study guided anti-platelet therapy will begin as soon as possible after PCI is performed and genotype results are available. Study guided anti-platelet therapy will continue for a period of one year. Patients will be followed for CV events as well as bleeding and other adverse events. Optionally, a subgroup of patients from all genotypes will return at 10 days after the randomization visit for platelet aggregation studies.

If our hypothesis is correct, i. e., that prasugrel anti-platelet therapy results in fewer cardiovascular events compared to clopidogrel in CYP2C19 intermediate metabolizers, and is cost effective, this prospective randomized clinical trial will provide the evidence base to implement genotype-directed (G-D) anti-platelet treatment for intermediate metabolizers broadly into clinical practice.

Minimum age: 20 Years. Maximum age: 74 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Males or non-pregnant females between the ages of 20 and 74 years, inclusive

- Post-PCI with placement of one or more drug eluting or bare metal stents

- One or more stent(s) delivered with final TIMI 3 flow 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 a peri-procedural CK-MB value that is above the URL must have CK-MB

value lower than the prior value, prior to randomization

- 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

- Genotype (CYP2C19) already known to subject or research team from prior genetic

testing

- Post-PCI STEMI or CABG 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

Alan R. Shuldiner, M.D., Phone: 410-706-1623, Email: ashuldin@medicine.umaryland.edu

Christiana Care Health System, Newark, Delaware 19718, United States

University of Maryland School of Medicine, Baltimore, Maryland 21201, United States

The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States

Sinai Center for Thrombosis Research, Baltimore, Maryland 21209, United States

Geisinger Health System, Danville, Pennsylvania 17822, United States

Related publications:

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.

Starting date: October 2011
Last updated: October 13, 2011