Comparing Bivalirudin Versus Heparin/ GP IIB/IIA in Patients Undergoing PCI

Anti-thrombotic therapies have enhanced the safety of percutaneous coronary intervention
(PCI). In addition to aspirin, heparin and platelet glycoprotein (Gp) IIB/IIIA receptor
inhibition have been used as the reference strategy to reduce the incidence of ischemic
complications during coronary interventions 1. However, the success of this strategy is
limited by increased bleeding risk, prolonged drug infusions (12 hours), and patient
inconveniences (such as lying flat for hours until blood coagulation becomes normal and
sheaths can be safely removed). Peri-procedural bleeding due to vascular complications is
one of the most frequent complications of PCI and is associated with adverse events 2.

Newer anti-thrombotic strategies may further improve outcomes after PCI. The efficacy of a
direct thrombin inhibitor bivalirudin (Angiomax™) was investigated in a randomized
controlled clinical trial as a replacement for the strategy of heparin/Gp IIB/IIIA
inhibition in patients undergoing coronary intervention. The REPLACE-2 study, which
randomized over 6000 patients found short and long-term clinical outcomes with bivalirudin
were as effective as heparin/Gp IIB/IIIA inhibition combination with evidence of
significantly less major and minor bleeding 3, 4. This led to approval of the 0.75
mg/kg/1.75 mg/kg/hr dose of Angiomax® by the Food and Drug Administration for use as an
anticoagulant in patients with unstable angina undergoing PCI.

It is now routinely accepted that early sheath removal after PCI reduces femoral access site
complications and leads to earlier ambulation, earlier discharge, improved patient
satisfaction 5. Heparin-based anticoagulation requires monitoring of the coagulation status
to determine readiness for sheath removal because of the lack of predictable duration of
anticoagulation with heparin. Because clearance of bivalirudin occurs mostly by proteolytic
cleavage by thrombin, the drug has more predictable pharmacokinetics and exhibits linear
dose relationship with respect to plasma concentrations and coagulation assay endpoints 6.
Preliminary studies indicate sheath removal 2 hours after cessation of bivalirudin without
coagulation monitoring is safe 5. While REPLACE-2 suggested that catheterization related
vascular complications were decreased with bivalirudin, specific data on these endpoints and
others such as time to ambulation and time to discharge were not collected because of the
blinded nature of the trial. Currently the rate of vascular complications at MGH for
patients undergoing PCI is 4.0% which significantly exceeds the national rate of 1.9% (95%
CI 1.1 to 3.2) 7.

We will conduct a randomized clinical trial in patients undergoing PCI to compare the rates
of vascular related complications between patients assigned to one of two arms: 1)
bivalirudin + provisional Gp IIB/IIIA use versus 2) heparin + Gp IIB/IIIA (eptifibatide
(Integrilin®)) use. The primary endpoint will be a composite of vascular related groin
complications (MAVE-major adverse vascular endpoints as defined in next section). Secondary
endpoints will be 1) time to sheath pull; 2) time to ambulation; and 3) occurrence of major
and minor bleeding peri-catheterization.

Inclusion Criteria:

Patients must meet ALL of the following criteria:

- The patients must be >18 years of age

- Patients must have been referred for percutaneous coronary intervention (PCI)

- Diagnosis of angina pectoris defined by Canadian Cardiovascular Society
Classification (CCS I, II, III, IV) OR unstable angina pectoris (Braunwald
Classification B&C, I-II-III) OR patients with documented silent ischemia;

- Treatment of lesions in native coronary vessels or bypass grafts requiring
angioplasty or stenting.

- Patient is willing to comply with the specified follow-up evaluation;

- Patient must provide written informed consent prior to the procedure using a form
that is approved by the local Institutional Review Board.

Exclusion Criteria:

Patients will be excluded if ANY of the following conditions apply:

- Patient has experienced an ST-segment elevation myocardial infarction within the
preceding 24 hours.

- Active internal bleeding or bleeding diathesis, surgery, trauma, or gastrointestinal
or genitourinary tract bleeding within past 6 weeks; prior intracranial bleeding; or
platelet count<100,000

- Woman of child-bearing potential unless demonstrated negative pregnancy test

- End Stage Renal Disease requiring hemodialysis

- Recipient of heart transplant;

- Current treatment with 1) intravenous unfractionated heparin or treatment with low
molecular weight heparin within past 8 hours; 2)bivalirudin; 3)abciximab;
4)eptifibatide; or tirofiban

- Ongoing need for warfarin or heparin therapy

- Known allergies to aspirin, clopidogrel bisulfate (Plavix®) and/or heparin;

- Any significant medical condition which in the investigator’s opinion may interfere
with the patient’s optimal participation in the study;

- Currently participating in an investigational drug or another device study;

- Any contraindication to glycoprotein IIb/IIIa inhibitor (eptifibatide (Integrilin®))
or bivalirudin therapy;

- Chronic or relapse/remitting hemolytic condition or pre-catheterization hematocrit<30
mg/dl

- Unprotected left main coronary disease with >50% stenosis;

- Platelet count <150,000