Coronary Artery Disease Clinical Trial
Official title:
The RAS, Fibrinolysis and Cardiopulmonary Bypass
Verified date | September 2012 |
Source | Vanderbilt University |
Contact | n/a |
Is FDA regulated | No |
Health authority | United States: Institutional Review Board |
Study type | Interventional |
Each year over a million patients worldwide undergo cardiac surgery requiring
cardiopulmonary bypass (CPB).1 CPB is associated with significant morbidity including
hemodynamic instability, the transfusion of allogenic blood products, and inflammation.
Blood product transfusion increases mortality after cardiac surgery. Enhanced fibrinolysis
contributes to increased blood product transfusion requirements in the perioperative period.
CPB activates the kallikrein-kinin system (KKS), leading to increased bradykinin
concentrations. Bradykinin, acting through its B2 receptor, stimulates the release of nitric
oxide, inflammatory cytokines and tissue-type plasminogen activator (t-PA). Based on data
indicating that angiotensin-converting enzyme (ACE) inhibitors reduce mortality in patients
with coronary artery disease, many patients undergoing CPB are taking ACE inhibitors. While
interruption of the renin-angiotensin system (RAS) reduces inflammation in response to CPB,
ACE inhibitors also potentiate the effects of bradykinin and may augment B2-mediated change
in fibrinolytic balance and inflammation. In contrast, angiotensin II type 1 receptor
antagonism does not potentiate bradykinin and does not inhibit bradykinin metabolism.
Studies in animals suggest that bradykinin receptor antagonism inhibits reperfusion-induced
increases in vascular permeability and neutrophil recruitment.A randomized, placebo
controlled clinical trial of a bradykinin B2 receptor antagonist demonstrated some effect on
survival in patients with systemic inflammatory response syndrome and gram-negative sepsis.
In addition, we and others have shown bradykinin B2 receptor antagonism reduces vascular
t-PA release during ACE inhibition. The current proposal derives from data from our
laboratory and others elucidating the role of the KKS in the inflammatory, hypotensive and
fibrinolytic response to CPB. Specifically, we have found that CPB activates the KKS and
that ACE inhibition and smoking further increases bradykinin concentrations. During CPB,
bradykinin concentrations correlate inversely with mean arterial pressure and directly with
t-PA. Moreover, we have found that bradykinin receptor antagonism attenuates
protamine-related hypotension following CPB. The current proposal tests the central
hypothesis that the fibrinolytic and inflammatory response to cardiopulmonary bypass differ
during angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor
antagonism.
Status | Completed |
Enrollment | 111 |
Est. completion date | December 2011 |
Est. primary completion date | August 2011 |
Accepts healthy volunteers | No |
Gender | Both |
Age group | 18 Years to 80 Years |
Eligibility |
Inclusion Criteria: Inclusion Criteria 1. Subjects, 18 to 80 years of age, scheduled for elective cardiac surgery 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. Left ventricle ejection fraction less than 30% 2. History of ACE inhibitor-induced angioedema 3. Hypotension (systolic blood pressure <100 mmHg and evidence of hypoperfusion) 4. Hyperkalemia (baseline potassium >5.0 mEq/L) 5. Inability to discontinue current ACE inhibitor or AT1 receptor antagonist. 6. Emergency surgery 7. Impaired renal function (serum creatinine >1.6 mg/dl) 8. Pregnancy 9. Breast-feeding 10. 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 11. History of alcohol or drug abuse 12. Treatment with any investigational drug in the 1 month preceding the study 13. Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study 14. Inability to comply with the protocol, e.g. uncooperative attitude and unlikelihood of completing the study |
Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Country | Name | City | State |
---|---|---|---|
United States | TN Valley Healthcare System | Nashville | Tennessee |
United States | Vanderbilt University | Nashville | Tennessee |
Lead Sponsor | Collaborator |
---|---|
Vanderbilt University |
United States,
Billings FT 4th, Balaguer JM, C Y, Wright P, Petracek MR, Byrne JG, Brown NJ, Pretorius M. Comparative effects of angiotensin receptor blockade and ACE inhibition on the fibrinolytic and inflammatory responses to cardiopulmonary bypass. Clin Pharmacol The — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Tissue-type Plasminogen Activator (t-PA) Antigen Response | To compare the effects of angiotensin II type I (AT1) receptor antagonism or angiotensin-converting enzyme (ACE) inhibition versus placebo on the fibrinolytic responses to cardiopulmonary bypass (CPB) as measured by t-PA antigen response | From the start of surgery until postoperative day 2 | No |
Primary | Plasminogen Activator Inhibitor-1 (PAI-1) Response | To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the fibrinolytic responses to CPB as measured by PAI-1 response | From the start of surgery until postoperative day 2 | No |
Primary | Interleukin-6 (IL-6) Response | To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB as measured by IL-6 | From the start of surgery until postoperative day 2 | No |
Primary | Interleukin-8 (IL-8) Response | To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB as measured by IL-8 | From the start of surgery until postoperative day 2 | No |
Primary | Interleukin-10 (IL-10) Response | To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB as measured by the IL-10 response | From the start of surgery until postoperative day 2 | No |
Secondary | Blood Loss | Blood loss over 24 hours as measured by chest tube output | First 24 hours after arrival in the intensive care unit | No |
Secondary | Re-exploration for Bleeding | The percentage of patients that were taken back to the operating room for re-exploration because of bleeding | From arrival in intensive care unit until discharge from hospital | No |
Secondary | Blood Product Transfusion Requirement | Percentage of patients that received blood product transfusion | From the start of surgery until discharge from hospital | No |
Secondary | Vasopressor Drug Use | From the end of cardiopulmonary bypass until arrival in intensive care unit | No | |
Secondary | New Onset Atrial Fibrillation | New onset atrial fibrillation based on electrocardiogram (ECG) rhythm strips with a duration longer than 10 seconds | From arrival in intensive care unit until discharge from hospital | No |
Secondary | Acute Kidney Injury | Acute kidney injury (AKI) was defined according to Acute Kidney Injury Network (AKIN) criteria,specifically any increase in subject serum creatinine concentration of 50% or 0.3 mg/dL (26.5 umol/L) within 72 hours of surgery. | From the start of surgery until postoperative day 3 | No |
Secondary | Stroke | New onset neurological deficit with a duration of longer than 24 hours | From arrival in intensive care unit until discharge from hospital | No |
Secondary | Length of Hospital Stay | From the start of surgery until discharge from hospital | No |
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