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

Primary Purpose

Cardiovascular Diseases, Acute Coronary Syndrome

Status
Terminated
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
clopidogrel
prasugrel
Sponsored by
University of Maryland, Baltimore
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cardiovascular Diseases focused on measuring Pharmacogenomics, Platelet Aggregation Inhibitors

Eligibility Criteria

20 Years - 74 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Christiana Care Health System
  • University of Maryland School of Medicine
  • Sinai Center for Thrombosis Research
  • The Johns Hopkins University School of Medicine
  • Geisinger Health System

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

No Intervention

Arm Label

Genotype-directed, clopidogrel

Genotype-directed, prasugrel

Standard of Care

Arm Description

Participants randomized to the G-D group will have CYP2C19 genotype analysis performed. CYP2C19 extensive and ultrarapid metabolizers will receive clopidogrel.

Participants randomized to the G-D group will have CYP2C19 genotype analysis performed. CYP2C19 intermediate and poor metabolizers will receive prasugrel.

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.

Outcomes

Primary Outcome Measures

Occurrence of Post-randomization Cardiovascular Events
Cardiovascular events include non-fatal myocardial infarction, non-fatal stroke, definite or probable stent thrombosis (ARC definition) and death secondary to any cardiovascular cause.

Secondary Outcome Measures

Occurrence of Bleeding Events
Bleeding events will classified by the Bleeding Academic Research Consortium definition. The number of bleeding events will be tabulated.
Post-treatment Platelet Aggregation
Platelet aggregation will be performed on a subset of subjects using VerifyNow P2Y12 which measures platelet reactivity due to the effect of a P2Y12. Values less than 180 P2Y12 Reaction Units (PRU) suggest evidence of a P2Y12 inhibitor effect. Platelet aggregation studies are optional and will not be used to modulate antiplatelet therapy.
Health Care Resource Utilization and Cost-effectiveness
Occurrence of Adverse Events
The number of subjects reporting any AEs will be tabulated.
Composite of All-cause Death, Myocardial Infarction (MI), Stroke and Repeat Revascularization

Full Information

First Posted
October 10, 2011
Last Updated
March 7, 2022
Sponsor
University of Maryland, Baltimore
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT01452152
Brief Title
Pharmacogenomics of Anti-platelet Intervention-2 (PAPI-2) Study
Acronym
PAPI-2
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

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Terminated
Why Stopped
Terminated by study sponsor.
Study Start Date
February 2012 (undefined)
Primary Completion Date
July 2013 (Actual)
Study Completion Date
July 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Maryland, Baltimore
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cardiovascular Diseases, Acute Coronary Syndrome
Keywords
Pharmacogenomics, Platelet Aggregation Inhibitors

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
9 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Genotype-directed, clopidogrel
Arm Type
Experimental
Arm Description
Participants randomized to the G-D group will have CYP2C19 genotype analysis performed. CYP2C19 extensive and ultrarapid metabolizers will receive clopidogrel.
Arm Title
Genotype-directed, prasugrel
Arm Type
Experimental
Arm Description
Participants randomized to the G-D group will have CYP2C19 genotype analysis performed. CYP2C19 intermediate and poor metabolizers will receive prasugrel.
Arm Title
Standard of Care
Arm Type
No Intervention
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
clopidogrel
Other Intervention Name(s)
Plavix
Intervention Description
clopidogrel 75 mg/day plus aspirin 81-162 mg/day for one year
Intervention Type
Drug
Intervention Name(s)
prasugrel
Other Intervention Name(s)
Effient
Intervention Description
Prasugrel 5-10 mg/day plus aspirin 81-162 mg/day for one year
Primary Outcome Measure Information:
Title
Occurrence of Post-randomization Cardiovascular Events
Description
Cardiovascular events include non-fatal myocardial infarction, non-fatal stroke, definite or probable stent thrombosis (ARC definition) and death secondary to any cardiovascular cause.
Time Frame
One year
Secondary Outcome Measure Information:
Title
Occurrence of Bleeding Events
Description
Bleeding events will classified by the Bleeding Academic Research Consortium definition. The number of bleeding events will be tabulated.
Time Frame
One year
Title
Post-treatment Platelet Aggregation
Description
Platelet aggregation will be performed on a subset of subjects using VerifyNow P2Y12 which measures platelet reactivity due to the effect of a P2Y12. Values less than 180 P2Y12 Reaction Units (PRU) suggest evidence of a P2Y12 inhibitor effect. Platelet aggregation studies are optional and will not be used to modulate antiplatelet therapy.
Time Frame
10 days
Title
Health Care Resource Utilization and Cost-effectiveness
Time Frame
One year
Title
Occurrence of Adverse Events
Description
The number of subjects reporting any AEs will be tabulated.
Time Frame
One year
Title
Composite of All-cause Death, Myocardial Infarction (MI), Stroke and Repeat Revascularization
Time Frame
One year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
74 Years
Accepts Healthy Volunteers
No
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: Three vessel disease; 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; 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alan R Shuldiner, M.D.
Organizational Affiliation
University of Maryland
Official's Role
Principal Investigator
Facility Information:
Facility Name
Christiana Care Health System
City
Newark
State/Province
Delaware
ZIP/Postal Code
19718
Country
United States
Facility Name
University of Maryland School of Medicine
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
Sinai Center for Thrombosis Research
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21209
Country
United States
Facility Name
The Johns Hopkins University School of Medicine
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Geisinger Health System
City
Danville
State/Province
Pennsylvania
ZIP/Postal Code
17822
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
19706858
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.
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Pharmacogenomics of Anti-platelet Intervention-2 (PAPI-2) Study

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