Atrial FibrillationPhase 2/3NCT00141778
Renin-angiotensin-aldosterone System (RAAS), Inflammation, and Post-Operative Atrial Fibrillation (AF)
A Phase 2/3 study testing Ramipril and Spironolactone in people with Atrial Fibrillation, run by Vanderbilt University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Atrial Fibrillation
- What is being tested?
- Ramipril and Spironolactone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 455 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 2005to Aug 2010
- Phase
- Phase 2/3
- 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
- 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
Who cannot join
- 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)
Show all 15Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: RAAS, Inflammation, and Post-operative AF
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.
Read the 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.
- Conditions
- Atrial Fibrillation
- Being tested
- Placebo, Ramipril, Spironolactone
- Keywords
- atrial fibrillation, cardiac surgery
- Medical subject headings
- Atrial Fibrillation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PlaceboDrug
Also called Placebo tablet
Matching placebo taken once a day
RamiprilDrug
Also called Angiotensin-converting enzyme inhibitor
Taken orally, once a day
SpironolactoneDrug
Also called Mineralocorticoid Receptor Antagonist
Taken orally, once a day
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | matched placebo pills daily beginning 4-7 days before surgery and continuing through discharge Receives: Drug: Placebo |
| Ramipril | Experimental | Ramipril daily (2.5mg, increased to 5mg) beginning 4 to 7 days before surgery and continuing through discharge Receives: Drug: Ramipril |
| Spironolactone | Experimental | Spironolactone 25mg daily beginning 4 to 7 days before surgery and continuing through discharge Receives: Drug: Spironolactone |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Measured from admission to the ICU until discharge from hospital
Secondary outcomes (10)
Acute Renal Failure
Percentage of patients with a creatinine concentrations >2.5mg/dl
Measured: Measured until the time of hospital discharge, from 5.7 to 6.8 days on average, depending on the study group.
Hypotension
Percentage of patients with hypotension defined as a systolic blood pressure <90 mmHg and/or prolonged requirement for vasopressor use.
Measured: Measured during and after surgery, until discharge, from 5.7 to 6.8 days on average.
Hypokalemia
Percentage of patients who had a serum potassium concentrations <3.5 milliequivalents (mEq)/L
Measured: Measured until the time of hospital discharge, which was an average of 5.7 to 6.8 days depending on the treatment arm.
Time to Tracheal Extubation
It is the time in minutes that it took to extubate the patient after surgery.
Measured: It is the time (in minutes) from admission to the ICU until tracheal extubation
Length of Hospital Stay (Days)
Measured: Measured from the day of surgery until the time of hospital discharge
Death
The percentage of patients in each study arm who died.
Measured: Measured until the time of hospital discharge
Stroke
Percentage of patients in each study group who experience a cerebrovascular event, confirmed by CT.
Measured: Measured until the time of hospital discharge, from 5.7 to 6.8 days on average depending on the study arm.
Perioperative Interleukin(IL)-6 Concentrations
Interleukin-6 was measured at several time points (see time points in table) over the course of the study
Measured: Perioperative period
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.
Measured: Perioperative period
Perioperative C-reactive Protein (CRP) Concentrations
C-reactive protein was measured at several time points (see table) over the course of the study.
Measured: Perioperative period
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Sep 2005 (estimated)
- Study startApr 2005
- Primary completionJul 2010
- Study completionAug 2010
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 (6)Papers the sponsor has linked to this study.
- Other trials for Atrial FibrillationStudies 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 2/3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 455 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vanderbilt University
- Sponsor type
- University, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Principal investigator, Nancy J. Brown, Vanderbilt University
- Investigators
- Nancy J. Brown, M.D., Principal investigator, Vanderbilt University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00141778
- Sponsor's protocol ID
- 040385
- Other IDs
- R01HL077389
- Status last verified
- Feb 2013
- First submitted
- 30 Aug 2005
- Last updated
- 22 Mar 2013
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 20599398Fleming 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.
PubMed 18824641Pretorius 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.
PubMed 22824930Hashimoto H, Yamada H, Murata M, Watanabe N. Diuretics for preventing and treating acute kidney injury. Cochrane Database Syst Rev. 2025 Jan 29;1(1):CD014937. doi: 10.1002/14651858.CD014937.pub2.
PubMed 39878152Sidorova 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.
PubMed 25468655Billings 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.
PubMed 22626819
Study at a glance
From the registry record, last updated by the sponsor on 22 Mar 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- RAAS, Inflammation, and Post-operative AF
- ClinicalTrials.gov ID
- NCT00141778
- Acronym / sponsor ID
- 040385
- Conditions
- Atrial Fibrillation
- Keywords
- atrial fibrillation, cardiac surgery
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 455 participants (actual)
- Lead sponsor
- Vanderbilt UniversityUniversity, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- Apr 2005
- Primary completion
- Jul 2010 (actual)
- Study completion
- Aug 2010 (actual)
- First posted
- 1 Sep 2005 (estimated)
- Results
- Posted 22 Mar 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: Placebomatched placebo pills daily beginning 4-7 days before surgery and continuing through discharge |
| Ramipril | Experimental | Drug: RamiprilRamipril daily (2.5mg, increased to 5mg) beginning 4 to 7 days before surgery and continuing through discharge |
| Spironolactone | Experimental | Drug: SpironolactoneSpironolactone 25mg daily beginning 4 to 7 days before surgery and continuing through discharge |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- 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
Key exclusion criteria (15 listed)
- 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
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 |
|---|---|---|
| PlaceboAlso: Placebo tabletMatching placebo taken once a day | Drug | Placebo |
| RamiprilAlso: Angiotensin-converting enzyme inhibitorTaken orally, once a day | Drug | Ramipril |
| SpironolactoneAlso: Mineralocorticoid Receptor AntagonistTaken orally, once a day | Drug | Spironolactone |
Primary outcome
Postoperative Atrial Fibrillation
Time frame: Measured from admission to the ICU until discharge from hospital
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.
10 secondary outcomes
Acute Renal Failure
Time frame: Measured until the time of hospital discharge, from 5.7 to 6.8 days on average, depending on the study group.
Hypotension
Time frame: Measured during and after surgery, until discharge, from 5.7 to 6.8 days on average.
Hypokalemia
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.
Time to Tracheal Extubation
Time frame: It is the time (in minutes) from admission to the ICU until tracheal extubation
Length of Hospital Stay (Days)
Time frame: Measured from the day of surgery until the time of hospital discharge
Death
Time frame: Measured until the time of hospital discharge
Stroke
Time frame: Measured until the time of hospital discharge, from 5.7 to 6.8 days on average depending on the study arm.
Perioperative Interleukin(IL)-6 Concentrations
Time frame: Perioperative period
Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations
Time frame: Perioperative period
Perioperative C-reactive Protein (CRP) Concentrations
Time frame: Perioperative period
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Mar 2013.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 20599398Billings 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 publication: PubMed 18824641Fleming 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 publication: PubMed 22824930Pretorius 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.
- Derived from this study: PubMed 39878152Hashimoto H, Yamada H, Murata M, Watanabe N. Diuretics for preventing and treating acute kidney injury. Cochrane Database Syst Rev. 2025 Jan 29;1(1):CD014937. doi: 10.1002/14651858.CD014937.pub2.
- Derived from this study: PubMed 25468655Sidorova 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.
- Derived from this study: PubMed 22626819Billings 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.
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Atrial Fibrillation (AF)
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.
Nancy J. Brown, M.D. principal investigator
Vanderbilt University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Ramipril and Spironolactone in people with Atrial Fibrillation, run by Vanderbilt University at 1 site 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 2 inclusion and 15 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 22 Mar 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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 combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
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 22 Mar 2013). 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?
Postoperative Atrial Fibrillation (time frame: Measured from admission to the ICU until discharge from hospital). 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 NCT00141778, which also lists 6 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 22 Mar 2013.