The RAS, Fibrinolysis and Cardiopulmonary Bypass

• ClinicalTrials.gov Identifier: NCT00607672
• Recruitment Status: Completed
• First Posted: February 6, 2008
• Results First Posted: October 10, 2012
• Last Update Posted: October 10, 2012
• Sponsor: Vanderbilt University
• Information provided by (Responsible Party): Mias Pretorius, Vanderbilt University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Coronary Artery Disease; Angiotensin Converting Enzyme; Angiotensin Receptor Blockers; Cardiopulmonary Bypass; Fibrinolysis; Inflammation	Drug: Placebo; Drug: Ramipril; Drug: Candesartan	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 111 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The RAS, Fibrinolysis and Cardiopulmonary Bypass
• Study Start Date: August 2006
• Actual Primary Completion Date: August 2011
• Actual Study Completion Date: December 2011

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: 1; Patients are randomized to placebo prior to surgery	Drug: Placebo; Placebo
Active Comparator: 2; Patients are randomized to Ramipril prior to surgery	Drug: Ramipril; Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter
Active Comparator: 3; Patients are randomized to Candesartan (ARB) prior to surgery	Drug: Candesartan; Candesartan 16mg/d

Outcome Measures

Primary Outcome Measures :

1. Tissue-type Plasminogen Activator (t-PA) Antigen Response [ Time Frame: 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
2. Plasminogen Activator Inhibitor-1 (PAI-1) Response [ Time Frame: 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
3. Interleukin-6 (IL-6) Response [ Time Frame: 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
4. Interleukin-8 (IL-8) Response [ Time Frame: 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
5. Interleukin-10 (IL-10) Response [ Time Frame: 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 :

1. Blood Loss [ Time Frame: First 24 hours after arrival in the intensive care unit ]
   Blood loss over 24 hours as measured by chest tube output
2. Re-exploration for Bleeding [ Time Frame: 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
3. Blood Product Transfusion Requirement [ Time Frame: From the start of surgery until discharge from hospital ]
   Percentage of patients that received blood product transfusion
4. Vasopressor Drug Use [ Time Frame: From the end of cardiopulmonary bypass until arrival in intensive care unit ]
5. New Onset Atrial Fibrillation [ Time Frame: 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
6. Acute Kidney Injury [ Time Frame: 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.
7. Stroke [ Time Frame: From arrival in intensive care unit until discharge from hospital ]
   New onset neurological deficit with a duration of longer than 24 hours
8. Length of Hospital Stay [ Time Frame: From the start of surgery until discharge from hospital ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Tennessee

TN Valley Healthcare System

Nashville, Tennessee, United States, 37212

Vanderbilt University

Nashville, Tennessee, United States, 37232

Sponsors and Collaborators

Vanderbilt University

Investigators

• Principal Investigator: Mias Pretorius, MBChB, MSc; Vanderbilt University

More Information

Publications of Results:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Mias Pretorius, Associate Professor, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT00607672
• Other Study ID Numbers: 051170; HL 085740-01
• First Posted: February 6, 2008
• Results First Posted: October 10, 2012
• Last Update Posted: October 10, 2012
• Last Verified: September 2012

Keywords provided by Mias Pretorius, Vanderbilt University:

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

Additional relevant MeSH terms:

Coronary Artery Disease; Inflammation; Pathologic Processes; Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Candesartan; Ramipril; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Molecular Mechanisms of Pharmacological Action; Angiotensin-Converting Enzyme Inhibitors; Protease Inhibitors; Enzyme Inhibitors