The RAS, Fibrinolysis and Cardiopulmonary Bypass

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Mias Pretorius, Vanderbilt University
ClinicalTrials.gov Identifier:
NCT00607672
First received: February 4, 2008
Last updated: September 7, 2012
Last verified: September 2012
  Purpose

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 Intervention Phase
Coronary Artery Disease
Angiotensin Converting Enzyme
Angiotensin Receptor Blockers
Cardiopulmonary Bypass
Fibrinolysis
Inflammation
Drug: Placebo
Drug: Ramipril
Drug: Candesartan
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The RAS, Fibrinolysis and Cardiopulmonary Bypass

Resource links provided by NLM:


Further study details as provided by Vanderbilt University:

Primary Outcome Measures:
  • Tissue-type Plasminogen Activator (t-PA) Antigen Response [ Time Frame: From the start of surgery until postoperative day 2 ] [ Designated as safety issue: No ]
    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 [ Time Frame: From the start of surgery until postoperative day 2 ] [ Designated as safety issue: No ]
    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 [ Time Frame: From the start of surgery until postoperative day 2 ] [ Designated as safety issue: No ]
    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 [ Time Frame: From the start of surgery until postoperative day 2 ] [ Designated as safety issue: No ]
    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 [ Time Frame: From the start of surgery until postoperative day 2 ] [ Designated as safety issue: No ]
    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:
  • Blood Loss [ Time Frame: First 24 hours after arrival in the intensive care unit ] [ Designated as safety issue: No ]
    Blood loss over 24 hours as measured by chest tube output

  • Re-exploration for Bleeding [ Time Frame: From arrival in intensive care unit until discharge from hospital ] [ Designated as safety issue: No ]
    The percentage of patients that were taken back to the operating room for re-exploration because of bleeding

  • Blood Product Transfusion Requirement [ Time Frame: From the start of surgery until discharge from hospital ] [ Designated as safety issue: No ]
    Percentage of patients that received blood product transfusion

  • Vasopressor Drug Use [ Time Frame: From the end of cardiopulmonary bypass until arrival in intensive care unit ] [ Designated as safety issue: No ]
  • New Onset Atrial Fibrillation [ Time Frame: From arrival in intensive care unit until discharge from hospital ] [ Designated as safety issue: No ]
    New onset atrial fibrillation based on electrocardiogram (ECG) rhythm strips with a duration longer than 10 seconds

  • Acute Kidney Injury [ Time Frame: From the start of surgery until postoperative day 3 ] [ Designated as safety issue: No ]
    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 [ Time Frame: From arrival in intensive care unit until discharge from hospital ] [ Designated as safety issue: No ]
    New onset neurological deficit with a duration of longer than 24 hours

  • Length of Hospital Stay [ Time Frame: From the start of surgery until discharge from hospital ] [ Designated as safety issue: No ]

Enrollment: 111
Study Start Date: August 2006
Study Completion Date: December 2011
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
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
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00607672

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:
Responsible Party: Mias Pretorius, Associate Professor, Vanderbilt University
ClinicalTrials.gov Identifier: NCT00607672     History of Changes
Other Study ID Numbers: 051170, HL 085740-01
Study First Received: February 4, 2008
Results First Received: August 2, 2012
Last Updated: September 7, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by Vanderbilt University:
Angiotensin Converting Enzyme
Angiotensin Receptor Blockers
Cardiopulmonary Bypass
Fibrinolysis
Inflammation

Additional relevant MeSH terms:
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Inflammation
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Pathologic Processes
Ramipril
Candesartan
Candesartan cilexetil
Angiotensin Receptor Antagonists
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Angiotensin II Type 1 Receptor Blockers

ClinicalTrials.gov processed this record on July 24, 2014