The RAS, Fibrinolysis and Cardiopulmonary Bypass

NCT00607672 | Completed Phase 4 Results

• 2 other identifiers: 051170HL 085740-01
• Study Type: interventional
• Target: 111
• Locations: 1 country
• Sites: 2

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.

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (8)

• Blood Loss

  First 24 hours after arrival in the intensive care unit

• Re-exploration for Bleeding

  From arrival in intensive care unit until discharge from hospital

• Blood Product Transfusion Requirement

  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

  From arrival in intensive care unit until discharge from hospital

Study Arms (3)

1

PLACEBO COMPARATOR

Patients are randomized to placebo prior to surgery

Drug: Placebo

2

ACTIVE COMPARATOR

Patients are randomized to Ramipril prior to surgery

Drug: Ramipril

3

ACTIVE COMPARATOR

Patients are randomized to Candesartan (ARB) prior to surgery

Drug: Candesartan

Interventions

Placebo DRUG

Placebo

1

Ramipril DRUG

Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter

2

Candesartan DRUG

Candesartan 16mg/d

3

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Vanderbilt University: lead

Study Sites (2)

TN Valley Healthcare System

Nashville, Tennessee, 37212, United States

Location

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

Related Publications (2)

• 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.

  PMID: 22549281 RESULT

• 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.

  PMID: 26494370 DERIVED

MeSH Terms

Conditions

Coronary Artery Disease; Inflammation

Interventions

Ramipril; candesartan

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

We cannot exclude the possibility that our results may have been different if we studied a homogenous surgery population.

Results Point of Contact

• Title: Dr. Mias Pretorius
• Organization: Vanderbilt University School of Medicine

mias.pretorius@vanderbilt.edu

16153430665

Study Officials

• Mias Pretorius, MBChB, MSc

  Vanderbilt University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: February 4, 2008
• First Posted: February 6, 2008
• Study Start: August 1, 2006
• Primary Completion: August 1, 2011
• Study Completion: December 1, 2011
• Last Updated: October 10, 2012
• Results First Posted: October 10, 2012

Record last verified: 2012-09

Locations

US (2)