The RAS, Fibrinolysis and Cardiopulmonary Bypass

NCT ID: NCT00607672

Last Updated: 2012-10-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 111 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-08-31
• Study Completion Date: 2011-12-31

Brief Summary

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.

Conditions

Coronary Artery Disease; Angiotensin Converting Enzyme; Angiotensin Receptor Blockers; Cardiopulmonary Bypass; Fibrinolysis; Inflammation

Keywords

Angiotensin Converting Enzyme; Angiotensin Receptor Blockers; Cardiopulmonary Bypass; Fibrinolysis; Inflammation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

1

Patients are randomized to placebo prior to surgery

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo

2

Patients are randomized to Ramipril prior to surgery

Group Type: ACTIVE_COMPARATOR

Ramipril

Intervention Type: DRUG

Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter

3

Patients are randomized to Candesartan (ARB) prior to surgery

Group Type: ACTIVE_COMPARATOR

Candesartan

Intervention Type: DRUG

Candesartan 16mg/d

Interventions

Placebo

Placebo

Intervention Type: DRUG

Ramipril

Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter

Intervention Type: DRUG

Candesartan

Candesartan 16mg/d

Intervention Type: DRUG

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Vanderbilt University

OTHER

Sponsor Role: lead

Responsible Party

Mias Pretorius

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Mias Pretorius, MBChB, MSc

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University

Locations

TN Valley Healthcare System

Nashville, Tennessee, United States

Vanderbilt University

Nashville, Tennessee, United States

Countries

United States

References

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 Ther. 2012 Jun;91(6):1065-73. doi: 10.1038/clpt.2011.356.

Reference Type: RESULT

PMID: 22549281 (View on PubMed)

Gamboa JL, Pretorius M, Sprinkel KC, Brown NJ, Ikizler TA. Angiotensin converting enzyme inhibition increases ADMA concentration in patients on maintenance hemodialysis--a randomized cross-over study. BMC Nephrol. 2015 Oct 22;16:167. doi: 10.1186/s12882-015-0162-x.

Reference Type: DERIVED

PMID: 26494370 (View on PubMed)

Other Identifiers

HL 085740-01

Identifier Type: -

Identifier Source: secondary_id

051170

Identifier Type: -

Identifier Source: org_study_id