The RAS, Fibrinolysis and Cardiopulmonary Bypass

Coronary Artery Disease Clinical Trial

Official title:

The RAS, Fibrinolysis and Cardiopulmonary Bypass

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00607672
• Other study ID #: 051170
• Secondary ID: HL 085740-01
• Status: Completed
• Phase: Phase 4
• First received: February 4, 2008
• Last updated: September 7, 2012
• Start date: August 2006
• Est. completion date: December 2011

Study information

• Verified date: September 2012
• Source: Vanderbilt University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• 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

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Angiotensin Converting Enzyme
• Angiotensin Receptor Blockers
• Cardiopulmonary Bypass
• Coronary Artery Disease
• Coronary Disease
• Fibrinolysis
• Inflammation
• Myocardial Ischemia

Intervention

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

Locations

Country	Name	City	State
United States	TN Valley Healthcare System	Nashville	Tennessee
United States	Vanderbilt University	Nashville	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Vanderbilt University

Country where clinical trial is conducted

United States, 

References & Publications (1)

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

Outcome

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