Bradykinin Receptor Antagonism During Cardiopulmonary Bypass (BRAC)

Study Description

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Brief Summary:

Each year over a million patients worldwide undergo cardiac surgery requiring cardiopulmonary bypass (CPB). CPB is associated with significant morbidity including the transfusion of allogenic blood products, inflammation and hemodynamic instability. In fact, approximately 20% of all blood products transfused are associated with coronary artery bypass grafting procedures. Transfusion of allogenic blood products is associated with well-documented morbidity and increased mortality after cardiac surgery. Enhanced fibrinolysis contributes to increased blood product transfusion in the perioperative period. The current proposal tests the central hypothesis that endogenous bradykinin contributes to the hemodynamic, fibrinolytic and inflammatory response to CPB and that bradykinin receptor antagonism will reduce hypotension, inflammation and transfusion requirements. In SPECIFIC AIM 1 we will test the hypothesis that the fibrinolytic and inflammatory response to CPB differ during ACE inhibition and angiotensin II type 1 receptor antagonism. In SPECIFIC AIM 2 we will test the hypothesis that bradykinin B2 receptor antagonism attenuates the hemodynamic, fibrinolytic, and inflammatory response to CPB. In SPECIFIC AIM 3 we will test the hypothesis that bradykinin B2 receptor antagonism reduces the risk of allogenic blood product transfusion in patients undergoing CPB. These studies promise to provide important information regarding the effects of drugs that interrupt the RAS and generate new strategies to reduce morbidity in patients undergoing CPB.

Condition or disease	Intervention/treatment	Phase
Cardiopulmonary Bypass; Inflammation; Fibrinolysis; Surgery	Drug: HOE 140; Drug: Aminocaproic Acid; Drug: Placebo	Phase 2; Phase 3

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Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	150 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Prevention
Official Title:	Bradykinin Receptor Antagonism During Cardiopulmonary Bypass
Study Start Date :	May 2006
Actual Primary Completion Date :	June 2012
Actual Study Completion Date :	June 2012

Arms and Interventions

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Arm	Intervention/treatment
Experimental: HOE 140; Bradykinin receptor antagonist	Drug: HOE 140; HOE 140 (a bradykinin B2 receptor antagonist) was started in the operating room after induction of anesthesia and before heparinization, continued throughout the bypass period, and discontinued at the end of surgery. HOE 140 was given as an intravenous bolus of 22 µg/kg over one-half hour followed by an infusion of 18 µg/kg/hr.; Other Name: Icatibant
Active Comparator: Aminocaproic Acid; Antifibrinolytic	Drug: Aminocaproic Acid; Aminocaproic acid (an antifibrinolytic drug) was started in the operating room after induction of anesthesia and before heparinization, continued throughout the bypass period, and discontinued at the end of surgery. Aminocaproic acid was given as an intravenous bolus of 100 mg/kg over one-half hour followed by an infusion of 30 mg/kg/hr.; Other Names: Amicar; EACA
Placebo Comparator: Placebo; Placebo	Drug: Placebo; Normal saline (placebo) was started in the operating room after induction of anesthesia and before heparinization, continued throughout the bypass period, and discontinued at the end of surgery.; Other Name: Placebo/Normal Saline

Outcome Measures

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Primary Outcome Measures :

1. Allogenic Blood Product Transfusion Risk [ Time Frame: Patients were followed for the duration of hospital stay, an average of 6 days ]
   Blood product transfusion during hospitalization that included packed red blood cells, plasma, platelets and cryoprecipitate.

Secondary Outcome Measures :

1. Units of Packed Red Blood Cells Transfused During Hospitalization [ Time Frame: Patients were followed for the duration of hospital stay, an average of 6 days ]
   Units of Packed Red Blood Cells Transfused
2. Units of Plasma Transfused During Hospitalization [ Time Frame: Patients were followed for the duration of hospital stay, an average of 6 days ]
   Units of plasma transfused
3. Inflammatory Response as Measured by Interleukin-6 [ Time Frame: Patients were followed from the start of surgery until postoperative day 2 ]
   Interleukin-6 was measured at baseline, post-bypass and on postoperative day 1 and 2.
4. Fibrinolytic Response as Measured by D-dimer [ Time Frame: Patients were followed from the start of surgery until postoperative day 1 ]
   D-dimer concentrations were measured at baseline, 30min and 60min of bypass, post-bypass and postoperative day 1

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 80 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Subjects, 18 to 80 years of age, scheduled for elective CABG requiring CPB
2. For female subjects, the following conditions must be met:

postmenopausal for at least 1 year, or status-post surgical sterilization, or if of childbearing potential, utilizing adequate birth control and willing to undergo urine beta-hcg testing prior to drug treatment and on every study day

Exclusion Criteria:

1. Evidence of coagulopathy (INR greater than 1.7 without warfarin therapy)
2. Preoperative hematocrit less than 30%
3. Preoperative platelet count less than 100X109ml-1
4. GPIIb/IIIa antagonist within 48 hours of surgery
5. Emergency surgery
6. Impaired renal function (serum creatinine >1.6 mg/dl)
7. Pregnancy
8. Breast-feeding
9. Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult
10. History of alcohol or drug abuse
11. Treatment with any investigational drug in the 1 month preceding the study
12. Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study
13. Inability to comply with the protocol, e.g. uncooperative attitude and unlikelihood of completing the study

Contacts and Locations

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Locations

United States, Tennessee
TN Valley Healthcare System
Nashville, Tennessee, United States, 37212
Vanderbilt University
Nashville, Tennessee, United States, 37232

Sponsors and Collaborators

Vanderbilt University

Investigators

Principal Investigator:	Mias Pretorius, MBChB	Vanderbilt University

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications of Results:

Balaguer JM, Yu C, Byrne JG, Ball SK, Petracek MR, Brown NJ, Pretorius M. Contribution of endogenous bradykinin to fibrinolysis, inflammation, and blood product transfusion following cardiac surgery: a randomized clinical trial. Clin Pharmacol Ther. 2013 Apr;93(4):326-34. doi: 10.1038/clpt.2012.249. Epub 2012 Dec 24.

Responsible Party:	Mias Pretorius, Associate Professor, Vanderbilt University
ClinicalTrials.gov Identifier:	NCT00223704 History of Changes
Other Study ID Numbers:	IRB #051171; HL085740-02
First Posted:	September 22, 2005
Results First Posted:	October 11, 2013
Last Update Posted:	November 25, 2013
Last Verified:	October 2013

Keywords provided by Mias Pretorius, Vanderbilt University:

Coronary Artery Bypass; Blood Transfusion; Bradykinin Receptor Antagonism; Anti-Inflammatory Agents; Antifibrinolytic Agents

Additional relevant MeSH terms:

Inflammation; Pathologic Processes; Bradykinin; Kininogens; Aminocaproic Acid; Antifibrinolytic Agents; Icatibant; Vasodilator Agents; Cysteine Proteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Hemostatics	Coagulants; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Bradykinin B2 Receptor Antagonists; Bradykinin Receptor Antagonists; Complement Inactivating Agents; Immunosuppressive Agents; Immunologic Factors