Effects of Atorvastatin on Myonecrosis

STUDY OBJECTIVES:

1. The primary endpoint of the study is to evaluate the effects of a single high dose of
atorvastatin versus placebo on peri-procedural myonecrosis, as measured by troponin T
(TnT), during percutaneous coronary intervention (PCI) in patients presenting with acute
coronary syndromes (ACS).

2. Secondary endpoints include the measurements of other biomarkers of myocyte injury (CK,
CK-MB) and inflammation (CRP).

3. Other secondary endpoints include the relative angiographic efficacy of atorvastatin
versus placebo on the post PCI growth of tissue level perfusion circumference and the
post PCI growth of tissue level perfusion brightness using digital subtraction
angiography.

METHODS:

I. Selection and Number of Patients

The study subjects are to be selected from those patients presenting to the BIDMC for cardiac
catheterization. Eligible patients will be identified in the cardiac catheterization holding
area prior to their procedure. After obtaining informed consent, patients will be randomized
to a single dose of atorvastatin or placebo, which will be administered in the holding area
about 4 hours prior to the procedure. There will be a total of 150 subjects enrolled in the
study. There are a total of 2500 PCIs performed at the BIDMC per year, a third of which are
for ACS. We anticipate that 30-40% of patients with ACS will be eligible for study
participation.

II. Informed Consent

Informed consent will be obtained from all individuals prior to enrolment in the study
according to local Internal Review Board guidelines.

III. Pretreatment Data Collection

Baseline clinical data will be recorded at enrolment and will include: Subject's age, sex,
weight and height, diabetes, hypertension, smoking status, hypercholesterolemia (including
cholesterol levels if available), the presence of coronary or peripheral artery disease and
prior history of PCI or coronary artery bypass surgery. Further, all current medications will
be recorded. A detailed angina history will be collected from the patient and the medical
record looking for evidence of unstable angina as defined by Braunwald.

IV. Medications

A. Study Medication

Patients will be randomly assigned to atorvastatin 80 mg po or placebo in a double-blind
fashion. The study medication will be administered immediately after informed consent is
obtained and the patient is randomized to a treatment group in the cardiac catheterization
holding area. Given the typical waiting time between first presentation in the holding area
and PCI in a non-emergent case, it is estimated that the study medication will be
administered 4 hours prior to the procedure (minimal time of 2 hours). All patients will
receive a single dose of study medication prior to the procedure. After the completion of the
procedure, all statin therapy will be withheld until the next day. Eligible patients can then
receive statin therapy according to the treating physicians' preferences. All potential
adverse reactions to the study medication will be recorded.

B. Concomitant Therapy

Aspirin (325 mg/day) will be administered prior to intervention and during follow-up.
Clopidogrel (300 mg or 600 mg bolus followed by 75 mg/day) will be administered post-stent
deployment. It is expected that the majority of patients will receive a glycoprotein IIb/IIIa
inhibitor during the procedure and for 18 hours thereafter.

V. Procedures

A. Laboratory Tests

At baseline, levels of troponin, CK and CK-MB will be obtained at the time of presentation
and immediately prior to PCI. Patients with any of these serum markers above the upper limit
of normal will be excluded from the study. Post-procedural enzymes will be obtained 6-8 hours
after the procedure and the next morning (18-24 hours after the procedure). Patients with
elevated enzymes may undergo further sampling to determine the peak enzyme rise. The peak
troponin level obtained from any post-procedural blood draw will be used as the primary
endpoint. Furthermore, baseline CRP levels will be obtained prior to PCI and on the next day.

B. Digital Subtraction Angiography

To quantitate the kinetics of dye entry into the myocardium, digital subtraction angiography
can be used. Digital subtraction angiography will be performed at end diastole by aligning
cineframe images before dye filled the myocardium with the frame in which dye first reached
its peak brightness. The spine, ribs, diaphragm and the epicardial artery are then
subtracted. A representative region of the myocardium is sampled that is free of overlap by
epicardial arterial branches to determine the increase in the gray scale brightness of the
myocardium. The circumference of the myocardial blush is measured using a handheld planimeter
(Fowler, Inc). The frame count ÷ number of frames per second is used to measure the time
elapsed during angiography to quantitate the rate of rise in the growth (cm/sec) and
brightness (gray/sec) of myocardial blush. Blush will also be assessed visually using the
TIMI myocardial perfusion grade.

Inclusion Criteria:

- Patients must be aged 18 or over.

- Patients must provide written informed consent.

- Patients are presenting with unstable angina (defined as new onset chest pain,
accelerating chest pain, chest pain at rest and ST-segment depression on the
electrocardiogram [EKG])

- Patients undergoing successful coronary stent implantation of the (presumed) culprit
lesion (defined as < 50% residual stenosis).

Exclusion Criteria:

- Any patient who is unable to give written informed consent.

- Any condition which, in the investigator's opinion, would interfere with optimal
participation in the study or produce a significant risk to the patient.

- Patients presenting with an ST-elevation myocardial infarction (MI).

- Patients with elevated troponin, CK, or CK-MB (above the upper limit of normal).

- Patients already on high-dose statin therapy (defined as any statin equivalent to
atorvastatin ≥ 40 mg).

- Patients who took any statin agent within 24 hours of presentation to the cardiac
catheterization laboratory.

- Patients with active hepatic disease or myositis, in whom statin therapy is
contraindicated.

- Patients with hypersensitivity to atorvastatin.

- Patients with procedural complications, including unsuccessful percutaneous
transluminal coronary angioplasty (PTCA)/stenting, major side-branch occlusion,
flow-limiting dissections at the completion of the procedure, emergent coronary artery
bypass surgery, peri-procedural thrombus formation with distal embolization, stent
thrombosis within the first 24 hours, repeat emergent PCI within 24 hours, and death
within 24 hours.

- Cardiogenic shock.