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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


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
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