The RAS, Fibrinolysis and Cardiopulmonary Bypass

Study Overview
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Brief Summary
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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.

Official Title
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The RAS, Fibrinolysis and Cardiopulmonary Bypass

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

Intervention / Treatment
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* Drug: Placebo
* Drug: Ramipril
* Drug: Candesartan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion Criteria Subjects, 18 to 80 years of age, scheduled for elective cardiac surgery requiring CPB 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: Left ventricle ejection fraction less than 30% History of ACE inhibitor-induced angioedema Hypotension (systolic blood pressure <100 mmHg and evidence of hypoperfusion) Hyperkalemia (baseline potassium >5.0 mEq/L) Inability to discontinue current ACE inhibitor or AT1 receptor antagonist. Emergency surgery Impaired renal function (serum creatinine >1.6 mg/dl) Pregnancy Breast-feeding 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 History of alcohol or drug abuse Treatment with any investigational drug in the 1 month preceding the study Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study Inability to comply with the protocol, e.g. uncooperative attitude and unlikelihood of completing the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 1<br>Patients are randomized to placebo prior to surgery | Drug: Placebo<br>* Placebo<br>|
| Active Comparator: 2<br>Patients are randomized to Ramipril prior to surgery | Drug: Ramipril<br>* Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter<br>|
| Active Comparator: 3<br>Patients are randomized to Candesartan (ARB) prior to surgery | Drug: Candesartan<br>* Candesartan 16mg/d<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Loss | Blood loss over 24 hours as measured by chest tube output | First 24 hours after arrival in the intensive care unit | 
| 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 | 
| Blood Product Transfusion Requirement | Percentage of patients that received blood product transfusion | From the start of surgery until discharge from hospital | 
| Vasopressor Drug Use |  | From the end of cardiopulmonary bypass until arrival in intensive care unit | 
| 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 | 
| 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 | 
| Stroke | New onset neurological deficit with a duration of longer than 24 hours | From arrival in intensive care unit until discharge from hospital | 
| Length of Hospital Stay |  | From the start of surgery until discharge from hospital | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Angiotensin Converting Enzyme, Angiotensin Receptor Blockers, Cardiopulmonary Bypass, Fibrinolysis, Inflammation