Official Title: “The RAS, Fibrinolysis and Cardiopulmonary Bypass”

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment

Study Primary Completion Date: August 2011

Intervention(s) in this Clinical Trial

• Drug: Placebo
  • Placebo
• Drug: Ramipril
  • Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter
• Drug: Candesartan
  • Candesartan 16mg/d

Arms, Groups and Cohorts in this Clinical Trial

• Placebo Comparator: 1
  • Patients are randomized to placebo prior to surgery
• Active Comparator: 2
  • Patients are randomized to Ramipril prior to surgery
• Active Comparator: 3
  • Patients are randomized to Candesartan (ARB) prior to surgery

Primary Measures

• To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the fibrinolytic responses to CPB
  • Time Frame: Perioperative Period
    Safety Issue?: No

Secondary Measures

• To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB
  • Time Frame: Perioperative Period
    Safety Issue?: No

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 80 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Vanderbilt University

Overall Clinical Trial Officials and Contacts

Mias Pretorius, MBChB, MSc Principal Investigator Vanderbilt University  

Overall Contact: Patricia Wright, RN 615-3430908 patricia.wright@vanderbilt.edu

Information obtained from ClinicalTrials.gov on November 20, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00607672

Study ID Number: 051170

ClinicalTrials.gov Identifier: NCT00607672

Health Authority: United States: Institutional Review Board