The RAS, Fibrinolysis and Cardiopulmonary Bypass

Phase 4

Completed

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

Interventions: Drug: Ramipril
Drug: Candesartan
Drug: Placebo

Registration Number: NCT00607672

Lead Sponsor: Vanderbilt University

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 111

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
2	Ramipril	Patients are randomized to Ramipril prior to surgery
3	Candesartan	Patients are randomized to Candesartan (ARB) prior to surgery
1	Placebo	Patients are randomized to placebo prior to surgery

Primary Outcome Measures

Name	Time	Method
Tissue-type Plasminogen Activator (t-PA) Antigen Response	From the start of surgery until postoperative day 2	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
Plasminogen Activator Inhibitor-1 (PAI-1) Response	From the start of surgery until postoperative day 2	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
Interleukin-6 (IL-6) Response	From the start of surgery until postoperative day 2	To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB as measured by IL-6
Interleukin-8 (IL-8) Response	From the start of surgery until postoperative day 2	To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB as measured by IL-8
Interleukin-10 (IL-10) Response	From the start of surgery until postoperative day 2	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

Secondary Outcome Measures

Name	Time	Method
Blood Loss	First 24 hours after arrival in the intensive care unit	Blood loss over 24 hours as measured by chest tube output
Re-exploration for Bleeding	From arrival in intensive care unit until discharge from hospital	The percentage of patients that were taken back to the operating room for re-exploration because of bleeding
Blood Product Transfusion Requirement	From the start of surgery until discharge from hospital	Percentage of patients that received blood product transfusion
Vasopressor Drug Use	From the end of cardiopulmonary bypass until arrival in intensive care unit
New Onset Atrial Fibrillation	From arrival in intensive care unit until discharge from hospital	New onset atrial fibrillation based on electrocardiogram (ECG) rhythm strips with a duration longer than 10 seconds
Acute Kidney Injury	From the start of surgery until postoperative day 3	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.
Stroke	From arrival in intensive care unit until discharge from hospital	New onset neurological deficit with a duration of longer than 24 hours
Length of Hospital Stay	From the start of surgery until discharge from hospital