Coronary Artery DiseasePhase 4NCT00607672
The RAS, Fibrinolysis and Cardiopulmonary Bypass
A Phase 4 study testing Ramipril and Candesartan in people with Coronary Artery Disease and Angiotensin Converting Enzyme, run by Vanderbilt University at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Coronary Artery Disease, Angiotensin Converting Enzyme, Angiotensin Receptor Blockers
- What is being tested?
- Ramipril and Candesartan
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 111 participants
- Where
- 2 sitesUnited States
- Study dates
- Aug 2006to Dec 2011
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 14Show fewer
- 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
Trial locations and contacts
2 sites in 1 country.
United States2 sites
TN Valley Healthcare System
Nashville, Tennessee, 37212
Vanderbilt University
Nashville, Tennessee, 37232
About this study
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
- Being tested
- Placebo, Ramipril, Candesartan
- Keywords
- Angiotensin Converting Enzyme, Angiotensin Receptor Blockers, Cardiopulmonary Bypass, Fibrinolysis, Inflammation
- Medical subject headings
- Coronary Artery Disease, Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PlaceboDrug
Placebo
RamiprilDrug
Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter
CandesartanDrug
Candesartan 16mg/d
| Study group | Role | What they receive |
|---|---|---|
| 1 | Placebo comparator | Patients are randomized to placebo prior to surgery Receives: Drug: Placebo |
| 2 | Active comparator | Patients are randomized to Ramipril prior to surgery Receives: Drug: Ramipril |
| 3 | Active comparator | Patients are randomized to Candesartan (ARB) prior to surgery Receives: Drug: Candesartan |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: From the start of surgery until postoperative day 2
Secondary outcomes (8)
Blood Loss
Blood loss over 24 hours as measured by chest tube output
Measured: 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
Measured: From arrival in intensive care unit until discharge from hospital
Blood Product Transfusion Requirement
Percentage of patients that received blood product transfusion
Measured: From the start of surgery until discharge from hospital
Vasopressor Drug Use
Measured: 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
Measured: 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.
Measured: From the start of surgery until postoperative day 3
Stroke
New onset neurological deficit with a duration of longer than 24 hours
Measured: From arrival in intensive care unit until discharge from hospital
Length of Hospital Stay
Measured: From the start of surgery until discharge from hospital
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Feb 2008 (estimated)
- Study startAug 2006
- Primary completionAug 2011
- Study completionDec 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Coronary Artery DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 111 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vanderbilt University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Mias Pretorius, Vanderbilt University
- Investigators
- Mias Pretorius, MBChB, MSc, Principal investigator, Vanderbilt University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00607672
- Sponsor's protocol ID
- 051170
- Other IDs
- HL 085740-01
- Status last verified
- Sep 2012
- First submitted
- 4 Feb 2008
- Last updated
- 10 Oct 2012
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
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.
PubMed 22549281Gamboa 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.
PubMed 26494370
Study at a glance
From the registry record, last updated by the sponsor on 10 Oct 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The RAS, Fibrinolysis and Cardiopulmonary Bypass
- ClinicalTrials.gov ID
- NCT00607672
- Acronym / sponsor ID
- 051170
- 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
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 111 participants (actual)
- Lead sponsor
- Vanderbilt UniversityUniversity, hospital or other
- Study start
- Aug 2006
- Primary completion
- Aug 2011 (actual)
- Study completion
- Dec 2011 (actual)
- First posted
- 6 Feb 2008 (estimated)
- Results
- Posted 10 Oct 2012
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| 1 | Placebo comparator | Drug: PlaceboPatients are randomized to placebo prior to surgery |
| 2 | Active comparator | Drug: RamiprilPatients are randomized to Ramipril prior to surgery |
| 3 | Active comparator | Drug: CandesartanPatients are randomized to Candesartan (ARB) prior to surgery |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (14 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PlaceboPlacebo | Drug | 1 |
| RamiprilRamipril 2.5mg day 1 and 2 and then 5mg/d thereafter | Drug | 2 |
| CandesartanCandesartan 16mg/d | Drug | 3 |
Primary outcome
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
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
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
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
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
8 secondary outcomes
Blood Loss
Time frame: First 24 hours after arrival in the intensive care unit
Re-exploration for Bleeding
Time frame: From arrival in intensive care unit until discharge from hospital
Blood Product Transfusion Requirement
Time frame: From the start of surgery until discharge from hospital
Vasopressor Drug Use
Time frame: From the end of cardiopulmonary bypass until arrival in intensive care unit
New Onset Atrial Fibrillation
Time frame: From arrival in intensive care unit until discharge from hospital
Acute Kidney Injury
Time frame: From the start of surgery until postoperative day 3
Stroke
Time frame: From arrival in intensive care unit until discharge from hospital
Length of Hospital Stay
Time frame: From the start of surgery until discharge from hospital
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Oct 2012.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 22549281Billings 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.
- Derived from this study: PubMed 26494370Gamboa 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mias Pretorius, MBChB, MSc principal investigator
Vanderbilt University
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Ramipril and Candesartan in people with Coronary Artery Disease and Angiotensin Converting Enzyme, run by Vanderbilt University at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Oct 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 10 Oct 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Tissue-type Plasminogen Activator (t-PA) Antigen Response (time frame: From the start of surgery until postoperative day 2). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00607672, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Oct 2012.