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Bradykinin Receptor Antagonism During Cardiopulmonary Bypass (BRAC)

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ClinicalTrials.gov Identifier: NCT00223704
Recruitment Status : Completed
First Posted : September 22, 2005
Results First Posted : October 11, 2013
Last Update Posted : November 25, 2013
Sponsor:
Information provided by (Responsible Party):
Mias Pretorius, Vanderbilt University

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Conditions Cardiopulmonary Bypass
Inflammation
Fibrinolysis
Surgery
Interventions Drug: HOE 140
Drug: Aminocaproic Acid
Drug: Placebo
Enrollment 150
Recruitment Details Patients were enrolled by the research nurse at the time of the preoperative evaluation for surgery. All patients provided written informed consent. The study period was from June 2007 until June 2012.
Pre-assignment Details One hundred and fifty patients consented to participate in the study. Of these patients, 13 were excluded,12 withdrew before randomization, 4 had their surgeries canceled, 3 had their surgery dates changed, and 3 patients did not proceed with the study for other reasons. The remaining 115 patients were randomly assigned to one of three groups.
Arm/Group Title Placebo Group Aminocaproic Acid Group HOE 140 Group
Hide Arm/Group Description 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. 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. 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.
Period Title: Overall Study
Started 38 37 40
Completed 38 37 40
Not Completed 0 0 0
Arm/Group Title Placebo Group Aminocaproic Acid Group HOE 140 Group Total
Hide Arm/Group Description Placebo was normal saline Aminocaproic acid is an antifibrinolytic drug Bradykinin B2 receptor antagonist Total of all reporting groups
Overall Number of Baseline Participants 38 37 40 115
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 38 participants 37 participants 40 participants 115 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
25
  65.8%
23
  62.2%
24
  60.0%
72
  62.6%
>=65 years
13
  34.2%
14
  37.8%
16
  40.0%
43
  37.4%
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 38 participants 37 participants 40 participants 115 participants
60.1  (10.8) 58.5  (12.0) 61.0  (12.8) 59.9  (11.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 38 participants 37 participants 40 participants 115 participants
Female
12
  31.6%
18
  48.6%
18
  45.0%
48
  41.7%
Male
26
  68.4%
19
  51.4%
22
  55.0%
67
  58.3%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 38 participants 37 participants 40 participants 115 participants
38 37 40 115
1.Primary Outcome
Title Allogenic Blood Product Transfusion Risk
Hide Description Blood product transfusion during hospitalization that included packed red blood cells, plasma, platelets and cryoprecipitate.
Time Frame Patients were followed for the duration of hospital stay, an average of 6 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Group Aminocaproic Acid Group HOE 140 Group
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 38 37 40
Measure Type: Number
Unit of Measure: percentage of participants
Received any transfusion 47.4 56.8 52.5
Received packed red blood cells 36.8 48.6 47.5
Received plasma 31.6 24.3 17.5
Received platelets 23.7 16.2 17.5
Received cryoprecipitate 10.5 2.7 5.0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Group, Aminocaproic Acid Group, HOE 140 Group
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.72
Comments This P-value is for the main comparison of receiving any transfusion.
Method Chi-squared
Comments [Not Specified]
2.Secondary Outcome
Title Units of Packed Red Blood Cells Transfused During Hospitalization
Hide Description Units of Packed Red Blood Cells Transfused
Time Frame Patients were followed for the duration of hospital stay, an average of 6 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Group Aminocaproic Acid Group HOE 140 Group
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 38 37 40
Mean (Standard Error)
Unit of Measure: units
1.97  (0.61) 1.41  (0.30) 1.45  (0.34)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Group, Aminocaproic Acid Group, HOE 140 Group
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.88
Comments [Not Specified]
Method Kruskal-Wallis
Comments [Not Specified]
3.Secondary Outcome
Title Units of Plasma Transfused During Hospitalization
Hide Description Units of plasma transfused
Time Frame Patients were followed for the duration of hospital stay, an average of 6 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Group Aminocaproic Acid Group HOE 140 Group
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 38 37 40
Mean (Standard Error)
Unit of Measure: units
1.08  (0.37) 0.68  (0.25) 0.82  (0.36)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Group, Aminocaproic Acid Group, HOE 140 Group
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.43
Comments [Not Specified]
Method Kruskal-Wallis
Comments [Not Specified]
4.Secondary Outcome
Title Inflammatory Response as Measured by Interleukin-6
Hide Description Interleukin-6 was measured at baseline, post-bypass and on postoperative day 1 and 2.
Time Frame Patients were followed from the start of surgery until postoperative day 2
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Group Aminocaproic Acid Group HOE 140 Group
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 38 37 40
Mean (Standard Error)
Unit of Measure: pg/ml
Baseline 4.98  (0.77) 6.58  (1.50) 4.80  (0.64)
Post-bypass 68.8  (17.49) 64.65  (12.24) 142.02  (85.28)
Postoperative day 1 118.8  (19.15) 161.91  (28.19) 166.27  (49.44)
Postoperative day 2 201.5  (95.29) 122.88  (19.54) 86.54  (15.84)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Group, Aminocaproic Acid Group, HOE 140 Group
Comments The time course for Interleukin-6 concentrations were analyzed using mixed-effects models with fixed effects of drug treatment (placebo, aminocaproic acid, HOE 140) and time since randomization. We included a random subject effect and a first-order autoregressive process to account for the correlation in the response variable in the mixed-effects model
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.92
Comments The P-value reflects the difference in Interleukin-6 concentrations among the 3 treatment groups over the course of the study (baseline, post-bypass, postoperative day 1 and 2)
Method Mixed Models Analysis
Comments [Not Specified]
5.Secondary Outcome
Title Fibrinolytic Response as Measured by D-dimer
Hide Description D-dimer concentrations were measured at baseline, 30min and 60min of bypass, post-bypass and postoperative day 1
Time Frame Patients were followed from the start of surgery until postoperative day 1
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Group Aminocaproic Acid Group HOE 140 Group
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 38 37 40
Mean (Standard Error)
Unit of Measure: ng/ml
Baseline 95.5  (12.0) 103.0  (18.8) 88.1  (9.6)
30min of bypass 150.6  (17.5) 131.9  (19.7) 209.0  (49.4)
60min of bypass 287.6  (51.1) 154.3  (24.7) 363.3  (74.4)
Post-bypass 589.8  (104.5) 168.9  (22.4) 858.5  (182.5)
Postoperative day 1 390.4  (73.2) 269.5  (51.3) 337.3  (36.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Group, Aminocaproic Acid Group, HOE 140 Group
Comments The time course for D-dimer concentrations were analyzed using mixed-effects models with fixed effects of drug treatment (placebo, aminocaproic acid, HOE 140) and time since randomization. We included a random subject effect and a first-order autoregressive process to account for the correlation in the response variable in the mixed-effects model
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The P-value reflects the difference in D-dimer concentrations among the 3 treatment groups over the course of the study (baseline, 30min, 60min, post-bypass, and postoperative day 1)
Method Mixed Models Analysis
Comments [Not Specified]
Time Frame Hospitalization
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Group Aminocaproic Acid Group HOE 140 Group
Hide Arm/Group Description Placebo was normal saline Aminocaproic acid is an antifibrinolytic drug Bradykinin B2 receptor antagonist
All-Cause Mortality
Placebo Group Aminocaproic Acid Group HOE 140 Group
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Group Aminocaproic Acid Group HOE 140 Group
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/38 (2.63%)      1/37 (2.70%)      1/40 (2.50%)    
Blood and lymphatic system disorders       
Re-exploration for bleeding   1/38 (2.63%)  1 1/37 (2.70%)  1 1/40 (2.50%)  1
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Group Aminocaproic Acid Group HOE 140 Group
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   15/38 (39.47%)      11/37 (29.73%)      18/40 (45.00%)    
Cardiac disorders       
New onset postoperative atrial fibrillation   5/38 (13.16%)  5 5/37 (13.51%)  5 9/40 (22.50%)  9
Placement of permanent pacemaker   2/38 (5.26%)  2 2/37 (5.41%)  2 3/40 (7.50%)  3
Renal and urinary disorders       
Acute kidney injury   7/38 (18.42%)  7 4/37 (10.81%)  4 6/40 (15.00%)  6
Respiratory, thoracic and mediastinal disorders       
Prolonged Mechanical Ventilation (>24 hours)   4/38 (10.53%)  4 1/37 (2.70%)  1 3/40 (7.50%)  3
Indicates events were collected by systematic assessment
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.
Certain Agreements
Principal Investigators are NOT 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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Mias Pretorius, Associate Professor of Anesthesiology and Clinical Pharmacology
Organization: Vanderbilt University
Phone: 615-8757402
EMail: mias.pretorius@vanderbilt.edu
Layout table for additonal information
Responsible Party: Mias Pretorius, Vanderbilt University
ClinicalTrials.gov Identifier: NCT00223704     History of Changes
Other Study ID Numbers: IRB #051171
HL085740-02
First Submitted: September 19, 2005
First Posted: September 22, 2005
Results First Submitted: July 29, 2013
Results First Posted: October 11, 2013
Last Update Posted: November 25, 2013