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

• Sponsor: Medical University of Silesia (Other)
• Overall Status: Completed
• CT.gov ID: NCT01863134
• Collaborator: (none)
• Enrollment: 140
• Locations: 6
• Arms: 2
• Duration (Months): 71
• Patients Per Site: 23.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief 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.

1. 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).

Condition or Disease	Intervention/Treatment	Phase
Non ST Elevation Myocardial Infarction	Drug: Eptifibatide; Drug: Placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 140 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Study Start Date: Jan 1, 2005
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Eptifibatide Patients were given a bolus of eptifibatide (Integrillin; 180µg/kg of body weight) and an intravenous infusion of 2 µg/kg/min followed by acetylsalicylic acid (150mg orally daily until the day of the procedure) and enoxaparin (1mg/kg subcutaneous - with the last dose 12 hours before surgery).	Drug: Eptifibatide; Other Names: In the active treatment arm patients were additionally treated with eptifibatide (Integrillin; 180µg/kg of body weight) at an infusion rate 2 µg/kg/min
Placebo Comparator: Placebo Patients were given placebo infusion (0,9% Natrium Chloride) and an intravenous infusion of 2 µg/kg/min followed by acetylsalicylic acid (150mg orally daily until the day of the procedure) and enoxaparin (1mg/kg subcutaneous - with the last dose 12 hours before surgery).	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Major Adverse Cardiac and Cerebrovascular Events (MACCE) [Up to 12 month]

   MACCE was defined as combined death, nonfatal myocardial infarction, cerebrovascular event (stroke) and the need for re-hospitalization due to recurrent ischemia up to 12 months follow-up

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Albert Einstein College of Medicine	New York	New York	United States
2	First Department of Cardiac Surgery, Medical University of Silesia	Katowice	Slaskie	Poland	40-635
3	Center for Cardiovascular Research and Development, American Heart of Poland	Katowice		Poland
4	Department of Internal Medicine and Clinical Pharmacology	Katowice		Poland
5	First Department of Cardiology, Medical University of Silesia	Katowice		Poland
6	Division of Molecular Biology and Clinical Genetics, Jagiellonian University Medical College	Krakow		Poland

Sponsors and Collaborators

• Medical University of Silesia

Investigators

• Principal Investigator: Miroslaw Wilczynski, MD, PhD, Medical University of Silesia

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Miroslaw Wilczynski, MD, PhD, Medical University of Silesia
• ClinicalTrials.gov Identifier: NCT01863134
• Other Study ID Numbers: 2 P05C 023 27
• First Posted: May 27, 2013
• Last Update Posted: Oct 31, 2013
• Last Verified: Aug 1, 2013

• Additional relevant MeSH terms: Myocardial Infarction; Non-ST Elevated Myocardial Infarction; Infarction; Eptifibatide

Study Results

Participant Flow

Recruitment Details	Four clinical centers located within a radius of 50km of the reference center were selected for the study. From 2005 to 2010 a total of 140 patients presenting with NSTE-ACS not eligible for PCI were enrolled to the study. All CABG procedures were performed at 1st Department of Cardiac Surgery, Silesian Medical University in Katowice.

Arm/Group Title	Eptifibatide	Placebo
Arm/Group Description	Patients were given a bolus of eptifibatide (Integrillin; 180µg/kg of body weight) and an intravenous infusion of 2 µg/kg/min followed by acetylsalicylic acid (150mg PO daily until the day of the procedure) and enoxaparin (1mg/kg SC - with the last dose 12 hours before surgery).	Patients were given placebo infusion (0,9% Natrium Chloride) and an intravenous infusion of 2 µg/kg/min followed by acetylsalicylic acid (150mg PO daily until the day of the procedure) and enoxaparin (1mg/kg SC - with the last dose 12 hours before surgery).
Period Title: Overall Study
STARTED	72	68
COMPLETED	72	68
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Placebo/Control Group	Eptifibatide	Total
Arm/Group Description	In the control group patients were given identical doses of acetylsalicylic acid and enoxaparin followed by a placebo infusion of saline in lieu of the GPIIb/IIIa inhibitor.	In the treatment group patients were given a bolus of eptifibatide (Integrillin; 180µg/kg of body weight) and an intravenous infusion of 2 µg/kg/min followed by acetylsalicylic acid (150mg PO daily until the day of the procedure) and enoxaparin (1mg/kg SC - with the last dose 12 hours before surgery). The minimal and maximal periods of eptifibatide infusion were established at 12 and 48 hours respectively.	Total of all reporting groups
Overall Participants	68	72	140
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	58 85.3%	61 84.7%	119 85%
>=65 years	10 14.7%	11 15.3%	21 15%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.60 (8.32)	62.47 (10.41)	63.01 (9.39)
Sex: Female, Male (Count of Participants)
Female	19 27.9%	21 29.2%	40 28.6%
Male	49 72.1%	51 70.8%	100 71.4%
Region of Enrollment (participants) [Number]
Poland	68 100%	72 100%	140 100%

Outcome Measures

1. Primary Outcome

Title	Major Adverse Cardiac and Cerebrovascular Events (MACCE)
Description	MACCE was defined as combined death, nonfatal myocardial infarction, cerebrovascular event (stroke) and the need for re-hospitalization due to recurrent ischemia up to 12 months follow-up
Time Frame	Up to 12 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Eptifibatide
Arm/Group Description	Patients were given placebo infusion (0,9% Natrium Chloride) and an intravenous infusion of 2 µg/kg/min followed by acetylsalicylic acid (150mg PO daily until the day of the procedure) and enoxaparin (1mg/kg SC - with the last dose 12 hours before surgery).	Patients were given a bolus of eptifibatide (Integrillin; 180µg/kg of body weight) and an intravenous infusion of 2 µg/kg/min followed by acetylsalicylic acid (150mg PO daily until the day of the procedure) and enoxaparin (1mg/kg SC - with the last dose 12 hours before surgery).
Measure Participants	68	72
Number [Percentage of study group]	35.3	13.8

Adverse Events

Time Frame	12 Months
Adverse Event Reporting Description	Death up to 12 Months
Arm/Group Title	Eptifibatide		Placebo
Arm/Group Description	Patients were given a bolus of eptifibatide (Integrillin; 180µg/kg of body weight) and an intravenous infusion of 2 µg/kg/min followed by acetylsalicylic acid (150mg PO daily until the day of the procedure) and enoxaparin (1mg/kg SC - with the last dose 12 hours before surgery).		Patients were given placebo infusion (0,9% Natrium Chloride) and an intravenous infusion of 2 µg/kg/min followed by acetylsalicylic acid (150mg PO daily until the day of the procedure) and enoxaparin (1mg/kg SC - with the last dose 12 hours before surgery).
All Cause Mortality
	Eptifibatide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Eptifibatide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/72 (2.8%)		7/68 (10.3%)
General disorders
Death up to 12 Months	2/72 (2.8%)	2	7/68 (10.3%)	7
Other (Not Including Serious) Adverse Events
	Eptifibatide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/72 (4.2%)		9/68 (13.2%)
Infections and infestations
Pulmonary infection	3/72 (4.2%)	3	5/68 (7.4%)	5
Nervous system disorders
Delirium	0/72 (0%)	0	4/68 (5.9%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.