Peri-Procedural Myocardial Infarction, Platelet Reactivity, Thrombin Generation, and Clot Strength: Differential Effects of Eptifibatide + Bivalirudin Versus Bivalirudin

Percutaneous stent implantation has revolutionized the revascularization procedure for
patients with obstructive coronary disease and angina. The major risk of coronary stenting,
both during and after the procedure, is clot formation (thrombosis) which often leads to
significant heart muscle damage. The standard medical practice for patients undergoing
coronary stenting is the use of antiplatelet (plavix, aspirin) and anticoagulant (blood
thinner) therapy. The results from our recently completed CLEAR PLATELETS I study showed
that the addition of eptifibatide (a potent antiplatelet agent) to current therapy resulted
in superior reduction in clot formation, inflammation and heart damage after elective
coronary intervention. Recent studies have also suggested the drug bivalirudin to be a safer
and more effective therapy compared to heparin, the current anticoagulant agent of choice.
It has been hypothesized that bivalirudin acts not only as an anticoagulant but also as an
antiplatelet agent, making the use of eptifibatide in current coronary therapy unwarranted.
In the CLEAR PLATELET II study, we will compare levels of clot formation (platelet
aggregation), markers of heart muscle damage, and inflammation in two groups. The first
group will be on a regimen of high-dose clopidogrel used in combination with bivalirudin
plus eptifibatide, and the second group will be on a regimen of high-dose clopidogrel with
bivalirudin alone. The antiplatelet/antithrombotic effect that bivalirudin has in
combination with these current therapies is unknown; therefore we hope to see the effect
that bivalirudin has on arresting platelet formation with and without eptifibatide.

This research will be done at Sinai Hospital of Baltimore with Paul Gurbel M.D. as the
principal investigator. It will include 200 patients who will be randomized equally between
groups.

Clopidogrel (600 mg) + eptifibatide + bivalirudin Clopidogrel (600 mg) + bivalirudin

All patients will receive treatment with clopidogrel in the cath lab immediately after
successful stenting. All patients post-stenting will receive standard antiplatelet treatment
(75mg Plavix and 325 mg aspirin). Patients will have serial assessment of platelet
reactivity, myocardial necrosis markers, and inflammatory markers (3 tablespoons of blood
per time point) at baseline, 2 hours, 8 hours, and 18- 24 hours post-stenting. All blood
work will be processed at the Sinai Center for Thrombosis Research. Clinical outcomes will
be recorded using a standard case report form. Patients will be followed up at 30 days and 1
year by telephone to assess for adverse events.

Inclusion Criteria:

- Subjects (men or women) aged ³ 18

- Patients undergoing elective coronary stenting (200 patients)

Exclusion Criteria:

- ST-segment elevation myocardial infarction within 48 hours prior to randomization

- Prior PCI within previous 4 weeks of randomization or planned staged PCI within the
subsequent month.

- Cardiogenic shock

- > 50% unprotected left main stenosis

- Any low molecular weight heparin within the prior 12 hours

- Treatment with any P2Y12 blocker (Plavix or Ticlid) within the previous 14 days
before randomization

- Treatment with any platelet GPIIb/IIIa inhibitor within the previous 30 days before
randomization

- Concurrent treatment with warfarin

- History of bleeding diathesis, or evidence of active abnormal bleeding within 30 days
of randomization.

- History of hemorrhagic stroke at any time, or stroke or TIA of any etiology within 30
days of randomization.

- Major surgery within 6 weeks prior to randomization.

- Known platelet count of <100,000/mm3.

- PT > 1.5 X control

- HCT < 25%

- Known allergy or contraindication to eptifibatide, heparin, aspirin or plavix.

- Participation in a study of experimental therapy or device 30 days prior to
randomization.

- Creatinine level of greater than 2.0 mg/dl or a creatinine clearance <30mL

- Known history of alcohol or drug abuse

- Pregnant women or women of child bearing potential not using an acceptable method of
contraception.