Pharmacodynamic Study on Efficacy of Clopidogrel With St. John's Wort

Objective The purpose of this study is to evaluate whether patients post PCI receiving
clopidogrel who are carriers of at least one CYP 2C19 loss-of-function allele may achieve
improved pharmacodynamic efficacy of clopidogrel when treated with the CYP 2C19 enzyme
inducing agent, St. John's wort, as compared with placebo.

Specific Aims

1. To identify the difference in platelet reactivity in patients receiving St. John's wort
or placebo

2. To characterize the difference in platelet inhibition in patients receiving St. John's
wort or placebo

Hypothesis

1. Reduced platelet reactivity is present in patients receiving St. John's wort as compared
to placebo when utilized in combination with clopidogrel

2. The combination or St. John's wort and clopidogrel results in enhanced platelet
inhibition

Study Design The study is a prospective, randomized, double-blind, placebo-controlled,
cross-over study of patients post PCI who require dual-antiplatelet therapy with aspirin and
clopidogrel. Approximately 84 patients will be enrolled and undergo pharmacogenetic testing
to assess clopidogrel responsiveness utilizing CYP P450 2C19 genotyping (Plavitest®). Based
upon an assumption of 30% genetic non-responsiveness and a dropout rate of 20%, to achieve a
final sample size of 20 subjects in the randomized crossover portion of the study, the
investigators need to enroll approximately 84 subjects. Patients identified as carriers of at
least one CYP 2C19 loss-of-function allele (i.e. clopidogrel reduced-metabolizers) will
remain in the study and be randomly assigned to receive placebo or St. John's wort. Patients
not carrying a CYP 2C19 loss-of-function allele (i.e. clopidogrel normal metabolizers) will
not require any further follow-up as these patients are considered to display a normal
response to clopidogrel. On day 7 following the initiation of the study drug, platelet
function testing will be performed. Following a 7 day washout period, patients will be
crossed over into the other study group to receive 7 days of study medication. On day 21, the
patients will undergo platelet function testing and the study medication will be
discontinued.

Inclusion Criteria:

- Patients age 18 or older

- Patients with a history of ACS and/or who receive PCI with stent placement at
Lancaster General Hospital requiring dual antiplatelet therapy with aspirin and
clopidogrel.

Exclusion Criteria:

- Patients with active or any known history of bleeding such as gastrointestinal,
intracranial, or any other bleeding diathesis

- History of major surgery in the last year (any surgical procedure that involves
general anesthesia or respiratory assistance)

- Clinical findings associated with an increased risk of bleeding at the judgment of the
investigator

- Patients actively receiving anticoagulation therapy

- Hemoglobin < 10 g/dL

- Platelets < 150,000/mm3

- Known hepatic dysfunction

- History of intracranial malignancy or stroke

- Patients receiving thienopyridines chronically prior to PCI

- Concurrent use of CYP P450 2C19 substrates, or inhibiting/ inducing medications with
the exception of proton pump inhibitors

- Illicit drug or alcohol abuse

- Daily treatment with nonsteroidal anti-inflammatory drugs or cyclooxygenase-2
inhibitors

- Allergy to St. Johns wort or lactose

- Patients expected to discontinue dual antiplatelet therapy prior to completion of the
study protocol

- Patients unable to adhere to the study protocol