Bradykinin Receptor Antagonism During Cardiopulmonary Bypass

NCT00223704 | Completed Phase 2 Results DMC

• 2 other identifiers: IRB #051171HL085740-02
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 2

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.

Conditions

Cardiopulmonary Bypass; Inflammation; Fibrinolysis; Surgery

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Allogenic Blood Product Transfusion Risk

  Blood product transfusion during hospitalization that included packed red blood cells, plasma, platelets and cryoprecipitate.

  Patients were followed for the duration of hospital stay, an average of 6 days

Secondary Outcomes (4)

• Units of Packed Red Blood Cells Transfused During Hospitalization

  Patients were followed for the duration of hospital stay, an average of 6 days

• Units of Plasma Transfused During Hospitalization

  Patients were followed for the duration of hospital stay, an average of 6 days

• Inflammatory Response as Measured by Interleukin-6

  Patients were followed from the start of surgery until postoperative day 2

• Fibrinolytic Response as Measured by D-dimer

  Patients were followed from the start of surgery until postoperative day 1

Study Arms (3)

HOE 140

EXPERIMENTAL

Bradykinin receptor antagonist

Drug: HOE 140

Aminocaproic Acid

ACTIVE COMPARATOR

Antifibrinolytic

Drug: Aminocaproic Acid

Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Interventions

HOE 140 DRUG

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.

Also known as: Icatibant

HOE 140

Aminocaproic Acid DRUG

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.

Also known as: Amicar, EACA

Aminocaproic Acid

Placebo DRUG

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.

Also known as: Placebo/Normal Saline

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects, 18 to 80 years of age, scheduled for elective CABG requiring CPB
• 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

You may not qualify if:

• Evidence of coagulopathy (INR greater than 1.7 without warfarin therapy)
• Preoperative hematocrit less than 30%
• Preoperative platelet count less than 100X109ml-1
• GPIIb/IIIa antagonist within 48 hours of surgery
• Emergency surgery
• Impaired renal function (serum creatinine \>1.6 mg/dl)
• Pregnancy
• Breast-feeding
• 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
• History of alcohol or drug abuse
• Treatment with any investigational drug in the 1 month preceding the study
• Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study
• Inability to comply with the protocol, e.g. uncooperative attitude and unlikelihood of completing the study

Sponsors & Collaborators

• Vanderbilt University: lead

Study Sites (2)

TN Valley Healthcare System

Nashville, Tennessee, 37212, United States

Location

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

Related Publications (1)

• 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.

  PMID: 23361105 RESULT

MeSH Terms

Conditions

Inflammation

Interventions

icatibant; Aminocaproic Acid; Saline Solution

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aminocaproates; Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Limitations and Caveats

This study was conducted in a population that predominantly underwent valve-only surgery. We cannot exclude the possibility that our results may have been different if we studied only coronary artery bypass graft surgery patients.

Results Point of Contact

• Title: Mias Pretorius, Associate Professor of Anesthesiology and Clinical Pharmacology
• Organization: Vanderbilt University

mias.pretorius@vanderbilt.edu

615-8757402

Study Officials

• Mias Pretorius, MBChB

  Vanderbilt University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: September 19, 2005
• First Posted: September 22, 2005
• Study Start: May 1, 2006
• Primary Completion: June 1, 2012
• Study Completion: June 1, 2012
• Last Updated: November 25, 2013
• Results First Posted: October 11, 2013

Record last verified: 2013-10

Locations

US (2)