Back to resultsRenin-angiotensin-aldosterone System (RAAS), Inflammation, and Post-Operative Atrial Fibrillation (AF)
Primary Purpose
Atrial Fibrillation
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Placebo
Ramipril
Spironolactone
Sponsored by
About this trial
This is an interventional prevention trial for Atrial Fibrillation focused on measuring atrial fibrillation, cardiac surgery
Eligibility Criteria
Inclusion Criteria: Undergoing elective valvular heart surgery, coronary artery bypass grafting If female, must be postmenopausal for at least 1 year, 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 throughout the study Exclusion Criteria History of AF other than remote paroxysmal AF Ejection fraction less than 30% Evidence of coagulopathy (INR greater than 1.7 without warfarin therapy) Emergency surgery History of ACE inhibitor-induced angioedema Low blood pressure (systolic blood pressure less than 100 mmHg and evidence of hypoperfusion) Hyperkalemia (potassium level greater than 5.0 milliequivalents (mEq)/L at study entry) Impaired kidney function (serum creatinine level greater than 1.6 mg/dl) Any underlying or acute disease requiring regular medication that could possibly cause complications or make implementation of the study or interpretation of the study results difficult Inability to discontinue current ACE inhibitor, AT1 receptor antagonist, or aldosterone receptor antagonist therapy History of alcohol or drug abuse Treatment with any investigational drug in the month prior to study entry Mental condition that makes it impossible to understand the nature, scope and possible consequences of the study Inability to comply with the study procedures (e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study) Pregnant or breastfeeding
Sites / Locations
- Vanderbilt University
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Placebo Comparator
Experimental
Experimental
Arm Label
Placebo
Ramipril
Spironolactone
Arm Description
matched placebo pills daily beginning 4-7 days before surgery and continuing through discharge
Ramipril daily (2.5mg, increased to 5mg) beginning 4 to 7 days before surgery and continuing through discharge
Spironolactone 25mg daily beginning 4 to 7 days before surgery and continuing through discharge
Outcomes
Primary Outcome Measures
Postoperative Atrial Fibrillation
The primary endpoint of the study was the percentage of patients with electrocardiographically confirmed AF of at least 10 secs duration at any time following the end of surgery until hospital discharge, an average from 5.7 days in the ramipril group to 6.8 days in the placebo group. Patients were monitored continuously on telemetry throughout the postoperative period until discharge. Electrocardiograms were obtained for any rhythm changes detected on telemetry monitoring, and in addition, electrocardiograms were performed preoperatively, at admission to the intensive care unit, and daily starting on postoperative day 1. All electrocardiograms and rhythm strips were reviewed in a blinded fashion by a single cardiac electrophysiologist.
Secondary Outcome Measures
Acute Renal Failure
Percentage of patients with a creatinine concentrations >2.5mg/dl
Hypotension
Percentage of patients with hypotension defined as a systolic blood pressure <90 mmHg and/or prolonged requirement for vasopressor use.
Hypokalemia
Percentage of patients who had a serum potassium concentrations <3.5 milliequivalents (mEq)/L
Time to Tracheal Extubation
It is the time in minutes that it took to extubate the patient after surgery.
Length of Hospital Stay (Days)
Death
The percentage of patients in each study arm who died.
Stroke
Percentage of patients in each study group who experience a cerebrovascular event, confirmed by CT.
Perioperative Interleukin(IL)-6 Concentrations
Interleukin-6 was measured at several time points (see time points in table) over the course of the study
Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations
Plasminogen activator inhibitor-1 (PAI-1) was measured at several time points (see table) over the course of the study.
Perioperative C-reactive Protein (CRP) Concentrations
C-reactive protein was measured at several time points (see table) over the course of the study.
Full Information
NCT ID
NCT00141778
First Posted
August 30, 2005
Last Updated
February 19, 2013
Sponsor
Vanderbilt University
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
1. Study Identification
Unique Protocol Identification Number
NCT00141778
Brief Title
Renin-angiotensin-aldosterone System (RAAS), Inflammation, and Post-Operative Atrial Fibrillation (AF)
Official Title
RAAS, Inflammation, and Post-operative AF
Study Type
Interventional
2. Study Status
Record Verification Date
February 2013
Overall Recruitment Status
Completed
Study Start Date
April 2005 (undefined)
Primary Completion Date
July 2010 (Actual)
Study Completion Date
August 2010 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt University
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Atrial fibrillation (AF) is the most prevalent, sustained type of irregular heartbeat and affects over 2 million Americans. Post-operative AF, which leads to significant morbidity and a prolonged hospital stay, complicates 20% to 40% of cardiopulmonary bypass (CPB) surgical procedures. While recent studies indicate that interruption of the renin-angiotensin-aldosterone system by either angiotensin-converting enzyme (ACE) inhibition or AT1 receptor antagonism decreases the incidence of AF following a heart attack or cardioversion (electric shock to the heart), its effect on the incidence of post-operative AF has not been throughly studied. Studies in both animals and humans suggest that inflammation-induced atrial remodeling plays an important role in the cause of AF. Recent studies also provide evidence that activation of the renin-angiotensin-aldosterone system induces inflammation, myocyte injury, proarrhythmic electrical remodeling, and fibrosis through aldosterone.
Detailed Description
AF is the most prevalent, sustained type of irregular heartbeat and affects over 2 million Americans. Post-operative atrial fibrillation(AF), which leads to significant morbidity and a prolonged hospital stay, complicates 20% to 40% of CPB surgical procedures. While recent studies indicate that interruption of the renin-angiotensin-aldosterone system by either angiotensin-converting enzyme(ACE) inhibition or angiotensin II subtype 1 (AT1) receptor antagonism decreases the incidence of AF following a heart attack or cardioversion (electric shock to the heart), its effect on the incidence of post-operative AF has not been throughly studied. Studies in both animals and humans suggest that inflammation-induced atrial remodeling plays an important role in the cause of AF. Recent studies also provide evidence that activation of the renin-angiotensin-aldosterone system induces inflammation, myocyte injury, proarrhythmic electrical remodeling, and fibrosis through aldosterone.
This study will evaluate the effectiveness of ACE inhibition and aldosterone receptor antagonism at decreasing inflammation and AF following cardiopulmonary bypass (CPB) surgery.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Atrial Fibrillation
Keywords
atrial fibrillation, cardiac surgery
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
455 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
matched placebo pills daily beginning 4-7 days before surgery and continuing through discharge
Arm Title
Ramipril
Arm Type
Experimental
Arm Description
Ramipril daily (2.5mg, increased to 5mg) beginning 4 to 7 days before surgery and continuing through discharge
Arm Title
Spironolactone
Arm Type
Experimental
Arm Description
Spironolactone 25mg daily beginning 4 to 7 days before surgery and continuing through discharge
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Placebo tablet
Intervention Description
Matching placebo taken once a day
Intervention Type
Drug
Intervention Name(s)
Ramipril
Other Intervention Name(s)
Angiotensin-converting enzyme inhibitor
Intervention Description
Taken orally, once a day
Intervention Type
Drug
Intervention Name(s)
Spironolactone
Other Intervention Name(s)
Mineralocorticoid Receptor Antagonist
Intervention Description
Taken orally, once a day
Primary Outcome Measure Information:
Title
Postoperative Atrial Fibrillation
Description
The primary endpoint of the study was the percentage of patients with electrocardiographically confirmed AF of at least 10 secs duration at any time following the end of surgery until hospital discharge, an average from 5.7 days in the ramipril group to 6.8 days in the placebo group. Patients were monitored continuously on telemetry throughout the postoperative period until discharge. Electrocardiograms were obtained for any rhythm changes detected on telemetry monitoring, and in addition, electrocardiograms were performed preoperatively, at admission to the intensive care unit, and daily starting on postoperative day 1. All electrocardiograms and rhythm strips were reviewed in a blinded fashion by a single cardiac electrophysiologist.
Time Frame
Measured from admission to the ICU until discharge from hospital
Secondary Outcome Measure Information:
Title
Acute Renal Failure
Description
Percentage of patients with a creatinine concentrations >2.5mg/dl
Time Frame
Measured until the time of hospital discharge, from 5.7 to 6.8 days on average, depending on the study group.
Title
Hypotension
Description
Percentage of patients with hypotension defined as a systolic blood pressure <90 mmHg and/or prolonged requirement for vasopressor use.
Time Frame
Measured during and after surgery, until discharge, from 5.7 to 6.8 days on average.
Title
Hypokalemia
Description
Percentage of patients who had a serum potassium concentrations <3.5 milliequivalents (mEq)/L
Time Frame
Measured until the time of hospital discharge, which was an average of 5.7 to 6.8 days depending on the treatment arm.
Title
Time to Tracheal Extubation
Description
It is the time in minutes that it took to extubate the patient after surgery.
Time Frame
It is the time (in minutes) from admission to the ICU until tracheal extubation
Title
Length of Hospital Stay (Days)
Time Frame
Measured from the day of surgery until the time of hospital discharge
Title
Death
Description
The percentage of patients in each study arm who died.
Time Frame
Measured until the time of hospital discharge
Title
Stroke
Description
Percentage of patients in each study group who experience a cerebrovascular event, confirmed by CT.
Time Frame
Measured until the time of hospital discharge, from 5.7 to 6.8 days on average depending on the study arm.
Title
Perioperative Interleukin(IL)-6 Concentrations
Description
Interleukin-6 was measured at several time points (see time points in table) over the course of the study
Time Frame
Perioperative period
Title
Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations
Description
Plasminogen activator inhibitor-1 (PAI-1) was measured at several time points (see table) over the course of the study.
Time Frame
Perioperative period
Title
Perioperative C-reactive Protein (CRP) Concentrations
Description
C-reactive protein was measured at several time points (see table) over the course of the study.
Time Frame
Perioperative period
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Undergoing elective valvular heart surgery, coronary artery bypass grafting
If female, must be postmenopausal for at least 1 year, 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 throughout the study
Exclusion Criteria
History of AF other than remote paroxysmal AF
Ejection fraction less than 30%
Evidence of coagulopathy (INR greater than 1.7 without warfarin therapy)
Emergency surgery
History of ACE inhibitor-induced angioedema
Low blood pressure (systolic blood pressure less than 100 mmHg and evidence of hypoperfusion)
Hyperkalemia (potassium level greater than 5.0 milliequivalents (mEq)/L at study entry)
Impaired kidney function (serum creatinine level greater than 1.6 mg/dl)
Any underlying or acute disease requiring regular medication that could possibly cause complications or make implementation of the study or interpretation of the study results difficult
Inability to discontinue current ACE inhibitor, AT1 receptor antagonist, or aldosterone receptor antagonist therapy
History of alcohol or drug abuse
Treatment with any investigational drug in the month prior to study entry
Mental condition that makes it impossible to understand the nature, scope and possible consequences of the study
Inability to comply with the study procedures (e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study)
Pregnant or breastfeeding
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nancy J. Brown, M.D.
Organizational Affiliation
Vanderbilt University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Vanderbilt University
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
20599398
Citation
Billings FT 4th, Pretorius M, Siew ED, Yu C, Brown NJ. Early postoperative statin therapy is associated with a lower incidence of acute kidney injury after cardiac surgery. J Cardiothorac Vasc Anesth. 2010 Dec;24(6):913-20. doi: 10.1053/j.jvca.2010.03.024.
Results Reference
result
PubMed Identifier
18824641
Citation
Fleming GA, Murray KT, Yu C, Byrne JG, Greelish JP, Petracek MR, Hoff SJ, Ball SK, Brown NJ, Pretorius M. Milrinone use is associated with postoperative atrial fibrillation after cardiac surgery. Circulation. 2008 Oct 14;118(16):1619-25. doi: 10.1161/CIRCULATIONAHA.108.790162. Epub 2008 Sep 29.
Results Reference
result
PubMed Identifier
22824930
Citation
Pretorius M, Murray KT, Yu C, Byrne JG, Billings FT 4th, Petracek MR, Greelish JP, Hoff SJ, Ball SK, Mishra V, Body SC, Brown NJ. Angiotensin-converting enzyme inhibition or mineralocorticoid receptor blockade do not affect prevalence of atrial fibrillation in patients undergoing cardiac surgery. Crit Care Med. 2012 Oct;40(10):2805-12. doi: 10.1097/CCM.0b013e31825b8be2.
Results Reference
result
PubMed Identifier
25468655
Citation
Sidorova TN, Mace LC, Wells KS, Yermalitskaya LV, Su PF, Shyr Y, Atkinson JB, Fogo AB, Prinsen JK, Byrne JG, Petracek MR, Greelish JP, Hoff SJ, Ball SK, Glabe CG, Brown NJ, Barnett JV, Murray KT. Hypertension is associated with preamyloid oligomers in human atrium: a missing link in atrial pathophysiology? J Am Heart Assoc. 2014 Dec 2;3(6):e001384. doi: 10.1161/JAHA.114.001384.
Results Reference
derived
PubMed Identifier
22626819
Citation
Billings FT 4th, Pretorius M, Schildcrout JS, Mercaldo ND, Byrne JG, Ikizler TA, Brown NJ. Obesity and oxidative stress predict AKI after cardiac surgery. J Am Soc Nephrol. 2012 Jul;23(7):1221-8. doi: 10.1681/ASN.2011090940. Epub 2012 May 24.
Results Reference
derived
Learn more about this trial
Renin-angiotensin-aldosterone System (RAAS), Inflammation, and Post-Operative Atrial Fibrillation (AF)
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