| ID | Type | Description | Link |
|---|---|---|---|
| R01HL077389 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | matched placebo pills daily beginning 4-7 days before surgery and continuing through discharge |
|
| Ramipril | Experimental | Ramipril daily (2.5mg, increased to 5mg) beginning 4 to 7 days before surgery and continuing through discharge |
|
| Spironolactone | Experimental | Spironolactone 25mg daily beginning 4 to 7 days before surgery and continuing through discharge |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Placebo | Drug | Matching placebo taken once a day |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 from admission to the ICU until discharge from hospital |
| Measure | Description | Time Frame |
|---|---|---|
| Acute Renal Failure | Percentage of patients with a creatinine concentrations >2.5mg/dl | Measured until the time of hospital discharge, from 5.7 to 6.8 days on average, depending on the study group. |
| Hypotension |
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Inclusion Criteria:
Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| Nancy J. Brown, M.D. | Vanderbilt University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Vanderbilt University | Nashville | Tennessee | 37232 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20599398 | Result | 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. | |
| 18824641 | Result | 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. |
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One week to four days prior to surgery, patients were randomized to treatment with placebo, ramipril or spironolactone. Preexisting ACE inhibitor, angiotensin receptor blocker, or MR antagonist use was stopped at randomization. Four hundred and fifty-eight patients met inclusion and were randomized
Patients were recruited between 2005 and 2010 from Vanderbilt University Medical Center and Brigham and Women's Hospital
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | Placebo Group |
| FG001 | Ramipril | Angiotensin-Converting Enzyme Inhibitor Group. Ramipril was given as 2.5 mg the first 3 days followed by 5 mg/day, with the dose reduced to 2.5 mg/day on the first postoperative day only. |
| FG002 | Spironolactone | Mineralocorticoid Receptor (MR) Antagonist Group.Spironolactone was given as 25 mg/day. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Randomization Prior to Study Med |
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| ||||||||||||||||||
| Started Study Medication |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | Placebo Group |
| BG001 | Ramipril | Angiotensin-converting enzyme inhibitor group |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Four hundred fifty-eight patients were randomized. Of these 445 took study medication and were included in the intention-to-treat analysis. | Posted | Number | percentage of patients | Measured from admission to the ICU until discharge from hospital |
|
Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm.
The intention-to-treat analysis included all subjects who received any study drug.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | Placebo Group |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Death | General disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypotension | Cardiac disorders | Systematic Assessment |
We excluded patients with an ejection fraction less than 30% or a creatinine above 1.6 and therefore the results are not applicable to patients with left ventricular dysfunction or more severe chronic kidney disease.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Mias Pretorius | Vanderbilt University School of Medicine | 16153430665 | mias.pretorius@vanderbilt.edu |
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| ID | Term |
|---|---|
| D001281 | Atrial Fibrillation |
| ID | Term |
|---|---|
| D001145 | Arrhythmias, Cardiac |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| D017257 | Ramipril |
| D000806 | Angiotensin-Converting Enzyme Inhibitors |
| D013148 | Spironolactone |
| D000451 | Mineralocorticoid Receptor Antagonists |
| ID | Term |
|---|---|
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D011480 | Protease Inhibitors |
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| Ramipril | Drug | Taken orally, once a day |
|
|
| Spironolactone | Drug | Taken orally, once a day |
|
|
Percentage of patients with hypotension defined as a systolic blood pressure <90 mmHg and/or prolonged requirement for vasopressor use.
| 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 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. | It is the time (in minutes) from admission to the ICU until tracheal extubation |
| Length of Hospital Stay (Days) | Measured from the day of surgery until the time of hospital discharge |
| Death | The percentage of patients in each study arm who died. | Measured until the time of hospital discharge |
| Stroke | Percentage of patients in each study group who experience a cerebrovascular event, confirmed by CT. | 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 | 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. | 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. | Perioperative period |
| 22824930 | Result | 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. |
| 39878152 | Derived | Hashimoto 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. |
| 25468655 | Derived | 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. |
| 22626819 | Derived | 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. |
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|
| BG002 |
| Spironolactone |
Mineralocorticoid Receptor (MR) Antagonist group |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Placebo |
Placebo Group |
| OG001 | Ramipril | Angiotensin-converting enzyme inhibitor group |
| OG002 | Spironolactone | Mineralocorticoid Receptor (MR) Antagonist group |
|
|
|
| Secondary | Acute Renal Failure | Percentage of patients with a creatinine concentrations >2.5mg/dl | The intention-to-treat analysis included anyone who had received any study medication. | Posted | Number | percentage of patients | Measured until the time of hospital discharge, from 5.7 to 6.8 days on average, depending on the study group. |
|
|
|
|
| Secondary | Hypotension | Percentage of patients with hypotension defined as a systolic blood pressure <90 mmHg and/or prolonged requirement for vasopressor use. | The intention-to-treat analysis included anyone who had received any medication. | Posted | Number | percentage of patients | Measured during and after surgery, until discharge, from 5.7 to 6.8 days on average. |
|
|
|
|
| Secondary | Hypokalemia | Percentage of patients who had a serum potassium concentrations <3.5 milliequivalents (mEq)/L | Posted | Number | percentage of patients | Measured until the time of hospital discharge, which was an average of 5.7 to 6.8 days depending on the treatment arm. |
|
|
|
|
| Secondary | Time to Tracheal Extubation | It is the time in minutes that it took to extubate the patient after surgery. | The intention-to-treat analysis included all patients who received any study medication. | Posted | Mean | Standard Deviation | minutes | It is the time (in minutes) from admission to the ICU until tracheal extubation |
|
|
|
|
| Secondary | Length of Hospital Stay (Days) | The intention-to-treat analysis included anyone who had received any study medication. | Posted | Mean | Standard Deviation | days | Measured from the day of surgery until the time of hospital discharge |
|
|
|
|
| Secondary | Death | The percentage of patients in each study arm who died. | The intention-to-treat analysis included all patients who received any study medication. | Posted | Number | percentage of patients | Measured until the time of hospital discharge |
|
|
|
|
| Secondary | Stroke | Percentage of patients in each study group who experience a cerebrovascular event, confirmed by CT. | The intention-to-treat analysis included all those who received any study drug. | Posted | Number | percentage of patients | Measured until the time of hospital discharge, from 5.7 to 6.8 days on average depending on the study arm. |
|
|
|
|
| Secondary | Perioperative Interleukin(IL)-6 Concentrations | Interleukin-6 was measured at several time points (see time points in table) over the course of the study | All participants included in the intention-to-treat analysis who had available plasma samples. | Posted | Mean | Standard Deviation | pg/ml | Perioperative period |
|
|
|
| Secondary | 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. | PAI-1 was measured in all subjects in the intention-to-treat analysis for which plasma was available. | Posted | Mean | Standard Deviation | ng/mL | Perioperative period |
|
|
|
| Secondary | Perioperative C-reactive Protein (CRP) Concentrations | C-reactive protein was measured at several time points (see table) over the course of the study. | CRP was measured in all subjects from the intention-to-treat analysis for which plasma was available at those time points. | Posted | Mean | Standard Deviation | ug/mL | Perioperative period |
|
|
|
| 8 |
| 147 |
| 17 |
| 147 |
| EG001 | Ramipril | Angiotensin-converting enzyme inhibitor group | 6 | 151 | 21 | 151 |
| EG002 | Spironolactone | Mineralocorticoid Receptor (MR) Antagonist group | 5 | 147 | 15 | 147 |
| Acute renal failure | Renal and urinary disorders | Systematic Assessment | Creatinine >2.5mg/dL |
|
| Stroke | Nervous system disorders | Systematic Assessment |
|
| Pneumonia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Hypokalemia | General disorders | Systematic Assessment | Potassium <3.5 milliequivalents (mEq)/L postoperative day 1-4 |
|
| Hyperkalemia | General disorders | Systematic Assessment | Potassium >5.5 milliequivalents (mEq)/L |
|
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| D013568 |
| Pathological Conditions, Signs and Symptoms |
| D004791 | Enzyme Inhibitors |
| D045504 | Molecular Mechanisms of Pharmacological Action |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D006727 | Hormone Antagonists |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D045505 | Physiological Effects of Drugs |
| D062865 | Diuretics, Potassium Sparing |
| D004232 | Diuretics |
| D045283 | Natriuretic Agents |
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| 60min intraop |
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| Postop |
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| Postoperative day 1 |
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| Postoperative day 2 |
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|
| 60min intraop |
|
| Postop |
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| Postoperative day 1 |
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| Postoperative day 2 |
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| Postoperative day 2 |
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| Postoperative day 3 |
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| Postoperative day 4 |
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