Un-fractionated Heparin Versus Bivalirudin During Percutaneous Coronary Interventions (PCI) (ISAR-REACT-3)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether bivalirudin given during PCI is associated with better outcomes compared to un-fractionated heparin.

Detailed Description
-----------------
Thrombin plays a major role in acute coronary artery occlusions during percutaneous coronary interventions. Unfractionated heparin has been traditionally used during invasive coronary procedures to reduce the risk of thrombotic occlusion. Bivalirudin, a direct antithrombin inhibitor, has several advantages over unfractionated heparin: it acts independently of antithrombin and inhibits both free and clot-bound thrombin; it is not neutralized by circulating inhibitors; exhibits consistent dose-response characteristics, and does not cause thrombocytopenia. Previous studies have shown that use of bivalirudin among patients undergoing percutaneous coronary interventions is associated with better outcomes (death, myocardial infarction, urgent repeat revascularization or in-hospital major bleeding) as compared with unfractionated heparin and adjunctive use of glycoprotein IIb/IIIa platelet receptor inhibitors. However, previous studies have included patients treated with plain balloon angioplasty or stenting after inadequate pre-treatment with thienopyridines (ticlopidine or clopidogrel). Recent guidelines recommend that all patients undergoing percutaneous coronary interventions must receive a loading dose of 300 -600 mg of clopidogrel. A 600 mg loading dose of clopidogrel eliminates the need for glycoprotein IIb/IIIa platelet receptor inhibitors in adjunct to heparin. According to existing evidence antithrombotic regimens based on either bivalirudin or pre-treatment with 600 mg of clopidogrel in addition to UFH intraprocedurally, are effective strategies to reduce ischemic and hemorrhagic complications in patients with coronary artery disease undergoing PCI. At present, it is not known whether bivalirudin is superior to UHF in patients who have been optimally pre-treated with a loading dose of clopidogrel.

Official Title
-----------------
Prospective, Randomized, Double-Blind, Active-Controlled, Multicenter Trial of Bivalirudin and Un-fractionated Heparin in Patients Undergoing Percutaneous Coronary Interventions. ISAR-REACT-3

Conditions
-----------------
Coronary Disease, Angina Pectoris

Intervention / Treatment
-----------------
* Drug: Bivalirudin
* Drug: Un-fractionated heparin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients older than 18 years of age to undergo PCI Clopidogrel loading at least 2 hrs prior to PCI according to the PCI guidelines Informed, written consent Exclusion Criteria: Recent ST-elevation myocardial infarction within the last 48 hours Cardiogenic shock ACS and positive biomarkers (Troponin T > 0.03 µg/L) Malignancies or other comorbid conditions (for example severe liver, renal and pancreatic disease) with life expectancy less than one year or that may result in protocol non-compliance Active bleeding; bleeding diathesis History of gastrointestinal or genitourinary bleeding within the last 6 weeks Presence of diseases which have a high probability of vascular lesions and subsequent bleeding such as active gastric ulcer or active ulcerous colitis Recent trauma or major surgery in the last month Ophthalmic surgery or brain surgery in the last month Retinopathies or vitreous body bleeding in the last month History of intracranial bleeding or structural abnormalities (for example aneurysm of cerebral arteries) Suspected aortic dissection; pericarditis and subacute bacterial endocarditis Patient's refusal to blood transfusion Oral anticoagulation therapy with coumarin derivative within the last 7 days Treatment with UFH within 6 hours or low-molecular weight heparin within 8 hours before randomization Treatment with bivalirudin within 24 hours before randomization Severe uncontrolled hypertension >180/110 mmHg unresponsive to therapy Planned staged PCI procedure within 30 days from index procedure or prior PCI within the last 30 days Relevant hematologic deviations:hemoglobin < 100 g/L; platelet count < 100 x 109 /L Glomerular filtration rate (GFR) < 30 ml/min or serum creatinine > 30 mg/L or dependence on renal dialysis Known allergy to the study medications: aspirin, clopidogrel, UFH, bivalirudin; stainless steel; true anaphylaxis after prior exposure to contrast media Known heparin-induced thrombocytopenia (Typ II) Previous enrollment in this trial Pregnancy (present, suspected or planned) or positive pregnancy test Spinal, peridural and epidural anesthesia Patient's inability to fully cooperate with the study protocol

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>bivalirudin is to be administered as an intravenous bolus of 0.75 mg/kg prior to the start of the intervention, followed by infusion of 1.75 mg/kg per hour for the duration of the procedure. | Drug: Bivalirudin<br>* bivalirudin to be administered as an intravenous bolus of 0.75 mg/kg prior to the start of the intervention, followed by infusion of 1.75 mg/kg per hour for the duration of the procedure.<br>* Other names: ReoPro;|
| Active Comparator: B<br>UFH given as an intravenous bolus of 140 units/kg. Double blinding will be maintained by using a double-dummy technique consisting of identical UFH and bivalirudin syringes and bivalirudin or placebo infusion bags. | Drug: Un-fractionated heparin<br>* UFH is given as an intravenous bolus of 140 units/kg followed by infusion of placebo 1.75 mg/kg per hour for the duration of the procedure.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite rate of death, myocardial infarction (MI),urgent target vessel revascularization (TVR) within 30 days or in-hospital major bleeding |  | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite rate of death, MI or urgent TVR within 30 days |  | 30 days | 
| Composite rate of death, MI or TVR at 1 year |  | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
coronary disease