Clinical Effects of Eptifibatide Administration in High Risk Patients Presenting With Non-ST Segment Elevation Acute Coronary Syndrome (NSTE-ACS) Requiring Urgent Coronary Artery Bypass Graft Surgery in Short- and Long-Term Follow-up
Condition: Non ST Elevation Myocardial Infarction
MeSH terms: Myocardial Infarction; Non-ST Elevated Myocardial Infarction; Infarction
Intervention: Eptifibatide; Placebo
Intervention MeSH terms: Eptifibatide
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Enrollment: 140.0
Sex: All
Minimum age: 21 Years
Maximum age: 75 Years
Healthy volunteers: No

Summary:

      1. INTRODUCTION

           Through last couple of years the number of patients treated for acute coronary event
           without persistent ST segment elevation in ECG has been growing.

           This is probably an effect of improving diagnostics of myocardial infraction without
           persistent ST segment elevation in ECG, due to routine Troponin serum level evaluation
           and better primary prevention.

           This fact makes the search for the optimal treatment for patients with acute coronary
           event without persistent ST segment elevation in ECG, including both patients intended
           for pharmacological and invasive treatment percutaneous coronary intervention (PCI) or
           coronary artery byppass grafting (CABG).

           Patients undergoing invasive treatment for acute coronary event, have higher risk rate,
           than those with stabile angina pectoris.

           The authors of this study want to evaluate, whether the proportional use of platelet GP
           IIb/IIIa receptor antagonist - eptifibatide in patients undergoing CABG results in
           improvement of short-, and long time results in those patients.

           Eptifibatide ( Integrilin) a cyclic heptapeptide antagonist of the GP IIb/IIIa integrin
           receptor, is an intravenous antagonist with rapid onset and short half-life.

        2. STUDY RATIONALE

      The notion acute coronary syndrome (ACS) includes several clinical situations, such a
      unstable coronary artery disease, non-Q wave myocardial infarction and Q wave myocardial
      infarction.

      On the basis of 12-lead ECG, patients with acute coronary syndrome (ACS) can be divided into
      two groups: with and without ST segment elevation.

      Another stratification factor in patients with ACS, especially these without ST elevation is
      evaluation of biochemical markers of myocardial necrosis, such as Troponins (TnI, TnT) and
      creatinine kinase isoenzymes (CK-MB). Serum concentrations of these markers allow to
      distinguish myocardial infarction (elevation of markers' concentration) from unstable
      coronary artery disease.

      All ACS have common etiopathogenesis which is plaque rupture, thrombus formation in the lumen
      of coronary artery.

      Platelets are the key factor in this process. Platelets by means of their collagen and von
      Willebrand factor glycoprotein receptors bind to damaged artery wall. Simultaneously many
      factors cause platelet activation, which leads to changes in their shape, release of
      intraplatelet components and activation of fibrinogen-binding glycoprotein receptors IIb/IIIa
      (GP IIb/IIIa). Activated form of GP IIb/IIIa binds to GP IIb/IIIa of another platelet by
      means of fibrinogen molecule. Fibrinogen molecules form stable bridges between platelets.
      This process is referred to as aggregation, and leads to clot formation, which is further
      stabilized by fibrine fibres.

      In this way the intravascular thrombus is formed, which after totally occluding the arterial
      lumen causes acute ischemia of the relevant region of myocardium and subsequently its
      infarction.

      The key role of GP IIa/IIIb in the process of platelet clot formation has important
      therapeutic consequences. By now several specific (direct) and non-specific (indirect)
      antagonists of GP IIb/IIIa have been developed.

      There are indirect antagonists as acetylsalicylic acid, ticlopidine and clopidogrel and
      direct antagonists as abciximab, tirofiban and eptifibatide Additionally also anticoagulants
      (heparin, LMWH - low molecular weight heparin) have antiplatelet properties by inhibiting
      thrombin production.

      Clinical studies performed all over the world have proven the efficacy and safety of three
      agents from the GP Iia/IIIb group: abciximab, tirofiban and eptifibatide.

      In several big clinical studies (EPIC, EPILOG, EPISTENT, ESPRIT, CAPTURE, PURSUIT,
      PRISM-PLUS, TACTICS-TIMI 18) the high efficacy of these drugs was showed in patients with ACS
      without ST segment elevation undergoing mainly percutaneous transluminal coronary angiography
      (PTCA) and stenting. The use of GP IIa/IIIb antagonists in this group of patients
      significantly reduces the death and myocardial infarction (MI) rate during early as well as
      late follow-up period. Moreover, last observations indicate, that the biggest benefit from
      such therapeutic strategy is observed in high risk patients; those with diabetes, high
      troponin levels and ECG changes.

      During last years, there is an increase in frequency of ACS without ST segment elevation.
      This is probably due to improved diagnostics of MI without ST elevation basing on routine
      troponin evaluation, but also thanks to better primary prevention.

      Therefore determining an optimal therapeutic strategy for patients with ACS without ST
      segment elevation remains a crucial issue.

      It concerns patients qualified to medical treatment as well as those qualified to invasive
      procedures (PTCA or CABG).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subjects must have a typical anginal pain lasting at least 20 min., but no longer than
             24h.

          -  ECG confirming ischaemia

          -  ST segment depression >= 1,0 mm in at least 2 leads, or,

          -  negative T waves >= 2,0 mm in at least 2 leads.

          -  Positive troponin I (TnI).

          -  Subjects must demonstrate their willingness to participate in the study and comply
             with its procedures by signing a written informed consent and/or parent or legal
             guardian must have signed a written informed consent.

          -  Subjects must be ≥ 21 year of age, of either sex and any race.

          -  Women of childbearing potential (includes women who are less than 1 year
             postmenopausal and women who become sexually active) must be using an acceptable
             method of birth control (e.g., hormonal contraceptive, medically prescribed IUD -
             intrauterine device, condom in combination with spermicide) or be surgically
             sterilized (e.g., hysterectomy or tubal ligation).

          -  Subjects must be free of any clinically significant disease that would interfere with
             study evaluations (see exclusion criteria).

          -  Subjects must understand and be able to adhere to the dosing and visit schedules, and
             agree to record concomitant medications and adverse events.

        Exclusion Criteria:

          -  Women who are pregnant or nursing.

          -  Subjects who have not observed the designated washout periods for any of the
             prohibited medications.

          -  Subjects who have used any investigational product within 30 days prior to enrollment.

          -  Subjects who have the following clinical conditions are excluded:

        Patients with:

          -  Angina lasting longer than 24h.

          -  ST segment elevation - Pardy wave

          -  age over 75 years

          -  history of revascularization procedure during last 6 months (PTCA, CABG)

          -  chronic heart failure (NYHA III or IV) during pre-hospitalization period

          -  history of bleeding from gastrointestinal tract or genitourinary system during last 30
             days

          -  history of intracranial lesions or stroke

          -  history of major surgery or trauma during last 6 weeks

          -  history of hemorrhagic diathesis

          -  thrombocytopenia < 100 000/mm3

          -  anticoagulant therapy with INR>2,0

          -  significant hepatic failure

          -  significant renal failure with serum creatinine>2,0 mg%

          -  elevated blood pressure: SBP>200mmHg and/or DBP>110mmHg despite the antihypertensive
             treatment

          -  allergy to drugs or any therapeutic agent