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

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.

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