Atrial Fibrillation
Conditions
Keywords
atrial fibrillation, cardiac surgery
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.
Interventions
DRUGPlacebo
Matching placebo taken once a day
DRUGRamipril
Taken orally, once a day
DRUGSpironolactone
Taken orally, once a day
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Vanderbilt University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Undergoing elective valvular heart surgery, coronary artery bypass grafting 2. 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
1. History of AF other than remote paroxysmal AF 2. Ejection fraction less than 30% 3. Evidence of coagulopathy (INR greater than 1.7 without warfarin therapy) 4. Emergency surgery 5. History of ACE inhibitor-induced angioedema 6. Low blood pressure (systolic blood pressure less than 100 mmHg and evidence of hypoperfusion) 7. Hyperkalemia (potassium level greater than 5.0 milliequivalents (mEq)/L at study entry) 8. Impaired kidney function (serum creatinine level greater than 1.6 mg/dl) 9. 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 10. Inability to discontinue current ACE inhibitor, AT1 receptor antagonist, or aldosterone receptor antagonist therapy 11. History of alcohol or drug abuse 12. Treatment with any investigational drug in the month prior to study entry 13. Mental condition that makes it impossible to understand the nature, scope and possible consequences of the study 14. Inability to comply with the study procedures (e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study) 15. Pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Postoperative Atrial Fibrillation | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hypotension | Measured during and after surgery, until discharge, from 5.7 to 6.8 days on average. | Percentage of patients with hypotension defined as a systolic blood pressure \<90 mmHg and/or prolonged requirement for vasopressor use. |
| Hypokalemia | Measured until the time of hospital discharge, which was an average of 5.7 to 6.8 days depending on the treatment arm. | Percentage of patients who had a serum potassium concentrations \<3.5 milliequivalents (mEq)/L |
| Time to Tracheal Extubation | It is the time (in minutes) from admission to the ICU until tracheal extubation | It is the time in minutes that it took to extubate the patient after surgery. |
| Length of Hospital Stay (Days) | Measured from the day of surgery until the time of hospital discharge | — |
| Acute Renal Failure | Measured until the time of hospital discharge, from 5.7 to 6.8 days on average, depending on the study group. | Percentage of patients with a creatinine concentrations \>2.5mg/dl |
| Stroke | Measured until the time of hospital discharge, from 5.7 to 6.8 days on average depending on the study arm. | Percentage of patients in each study group who experience a cerebrovascular event, confirmed by CT. |
| Perioperative Interleukin(IL)-6 Concentrations | Perioperative period | 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 | Perioperative period | 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 | Perioperative period | C-reactive protein was measured at several time points (see table) over the course of the study. |
| Death | Measured until the time of hospital discharge | The percentage of patients in each study arm who died. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited between 2005 and 2010 from Vanderbilt University Medical Center and Brigham and Women's Hospital
Pre-assignment details
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
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo Group | 147 |
| Ramipril Angiotensin-converting enzyme inhibitor group | 151 |
| Spironolactone Mineralocorticoid Receptor (MR) Antagonist group | 147 |
| Total | 445 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Randomization Prior to Study Med | Withdrawal by Subject | 5 | 2 | 6 |
| Started Study Medication | Chest Discomfort | 0 | 0 | 1 |
| Started Study Medication | Difficulty Swallowing | 0 | 1 | 0 |
| Started Study Medication | Met safety criteria for discontinuation | 2 | 4 | 3 |
| Started Study Medication | Withdrawal by Subject | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Ramipril | Spironolactone | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 50 Participants | 48 Participants | 53 Participants | 151 Participants |
| Age, Categorical Between 18 and 65 years | 101 Participants | 99 Participants | 94 Participants | 294 Participants |
| Age Continuous | 58.7 years STANDARD_DEVIATION 12.3 | 59.2 years STANDARD_DEVIATION 12.3 | 60.0 years STANDARD_DEVIATION 12 | 59.3 years STANDARD_DEVIATION 12.2 |
| Region of Enrollment United States | 151 participants | 147 participants | 147 participants | 445 participants |
| Sex: Female, Male Female | 45 Participants | 51 Participants | 53 Participants | 149 Participants |
| Sex: Female, Male Male | 106 Participants | 96 Participants | 94 Participants | 296 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 17 / 147 | 21 / 151 | 15 / 147 |
| serious Total, serious adverse events | 8 / 147 | 6 / 151 | 5 / 147 |
Outcome results
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.
Time frame: Measured from admission to the ICU until discharge from hospital
Population: Four hundred fifty-eight patients were randomized. Of these 445 took study medication and were included in the intention-to-treat analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Postoperative Atrial Fibrillation | 27.2 percentage of patients |
| Ramipril | Postoperative Atrial Fibrillation | 27.8 percentage of patients |
| Spironolactone | Postoperative Atrial Fibrillation | 25.9 percentage of patients |
Comparison: Discrete variables were compared among treatment groups with a chi-square test.p-value: 0.95Chi-squared
Secondary
Acute Renal Failure
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.
Population: The intention-to-treat analysis included anyone who had received any study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Acute Renal Failure | 5.4 percentage of patients |
| Ramipril | Acute Renal Failure | 0.7 percentage of patients |
| Spironolactone | Acute Renal Failure | 0.7 percentage of patients |
p-value: 0.006Chi-squared
Secondary
Death
The percentage of patients in each study arm who died.
Time frame: Measured until the time of hospital discharge
Population: The intention-to-treat analysis included all patients who received any study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Death | 1.4 percentage of patients |
| Ramipril | Death | 2.0 percentage of patients |
| Spironolactone | Death | 0 percentage of patients |
p-value: 0.38Chi-squared
Secondary
Hypokalemia
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Hypokalemia | 11.6 percentage of patients |
| Ramipril | Hypokalemia | 13.8 percentage of patients |
| Spironolactone | Hypokalemia | 6.8 percentage of patients |
p-value: 0.14Chi-squared
Secondary
Hypotension
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.
Population: The intention-to-treat analysis included anyone who had received any medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Hypotension | 5.4 percentage of patients |
| Ramipril | Hypotension | 10.6 percentage of patients |
| Spironolactone | Hypotension | 10.2 percentage of patients |
p-value: 0.15Chi-squared
Secondary
Length of Hospital Stay (Days)
Time frame: Measured from the day of surgery until the time of hospital discharge
Population: The intention-to-treat analysis included anyone who had received any study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Length of Hospital Stay (Days) | 6.8 days | Standard Deviation 8.2 |
| Ramipril | Length of Hospital Stay (Days) | 5.7 days | Standard Deviation 3.2 |
| Spironolactone | Length of Hospital Stay (Days) | 5.8 days | Standard Deviation 3.4 |
p-value: 0.15Kruskal-Wallis
Secondary
Perioperative C-reactive Protein (CRP) Concentrations
C-reactive protein was measured at several time points (see table) over the course of the study.
Time frame: Perioperative period
Population: CRP was measured in all subjects from the intention-to-treat analysis for which plasma was available at those time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Perioperative C-reactive Protein (CRP) Concentrations | Initiation of surgery | 4.1 ug/mL | Standard Deviation 6.8 |
| Placebo | Perioperative C-reactive Protein (CRP) Concentrations | Postoperative day 3 | 128.3 ug/mL | Standard Deviation 88.7 |
| Placebo | Perioperative C-reactive Protein (CRP) Concentrations | Postoperative day 4 | 94.1 ug/mL | Standard Deviation 67.3 |
| Placebo | Perioperative C-reactive Protein (CRP) Concentrations | Postoperative day 1 | 51.4 ug/mL | Standard Deviation 40 |
| Placebo | Perioperative C-reactive Protein (CRP) Concentrations | Postoperative day 2 | 134.8 ug/mL | Standard Deviation 137.4 |
| Ramipril | Perioperative C-reactive Protein (CRP) Concentrations | Postoperative day 2 | 131.0 ug/mL | Standard Deviation 281.5 |
| Ramipril | Perioperative C-reactive Protein (CRP) Concentrations | Postoperative day 1 | 49.9 ug/mL | Standard Deviation 38.5 |
| Ramipril | Perioperative C-reactive Protein (CRP) Concentrations | Initiation of surgery | 4.3 ug/mL | Standard Deviation 10.8 |
| Ramipril | Perioperative C-reactive Protein (CRP) Concentrations | Postoperative day 4 | 105.2 ug/mL | Standard Deviation 96.6 |
| Ramipril | Perioperative C-reactive Protein (CRP) Concentrations | Postoperative day 3 | 164.8 ug/mL | Standard Deviation 416.5 |
| Spironolactone | Perioperative C-reactive Protein (CRP) Concentrations | Postoperative day 4 | 126.5 ug/mL | Standard Deviation 95.4 |
| Spironolactone | Perioperative C-reactive Protein (CRP) Concentrations | Postoperative day 3 | 189.4 ug/mL | Standard Deviation 476 |
| Spironolactone | Perioperative C-reactive Protein (CRP) Concentrations | Initiation of surgery | 3.9 ug/mL | Standard Deviation 7.3 |
| Spironolactone | Perioperative C-reactive Protein (CRP) Concentrations | Postoperative day 1 | 64.3 ug/mL | Standard Deviation 115 |
| Spironolactone | Perioperative C-reactive Protein (CRP) Concentrations | Postoperative day 2 | 127.8 ug/mL | Standard Deviation 84.8 |
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
Time frame: Perioperative period
Population: All participants included in the intention-to-treat analysis who had available plasma samples.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Perioperative Interleukin(IL)-6 Concentrations | Initiation of surgery | 4.7 pg/ml | Standard Deviation 6.7 |
| Placebo | Perioperative Interleukin(IL)-6 Concentrations | 30min intraop | 12.0 pg/ml | Standard Deviation 18.4 |
| Placebo | Perioperative Interleukin(IL)-6 Concentrations | 60min intraop | 15.6 pg/ml | Standard Deviation 20.1 |
| Placebo | Perioperative Interleukin(IL)-6 Concentrations | Postop | 130.0 pg/ml | Standard Deviation 213.7 |
| Placebo | Perioperative Interleukin(IL)-6 Concentrations | Postoperative day 1 | 119.0 pg/ml | Standard Deviation 143.1 |
| Placebo | Perioperative Interleukin(IL)-6 Concentrations | Postoperative day 2 | 100.3 pg/ml | Standard Deviation 106.8 |
| Ramipril | Perioperative Interleukin(IL)-6 Concentrations | Postoperative day 2 | 95.5 pg/ml | Standard Deviation 90.8 |
| Ramipril | Perioperative Interleukin(IL)-6 Concentrations | Initiation of surgery | 4.6 pg/ml | Standard Deviation 7.1 |
| Ramipril | Perioperative Interleukin(IL)-6 Concentrations | Postop | 202.1 pg/ml | Standard Deviation 668.7 |
| Ramipril | Perioperative Interleukin(IL)-6 Concentrations | Postoperative day 1 | 171.0 pg/ml | Standard Deviation 208.6 |
| Ramipril | Perioperative Interleukin(IL)-6 Concentrations | 30min intraop | 20.5 pg/ml | Standard Deviation 72.6 |
| Ramipril | Perioperative Interleukin(IL)-6 Concentrations | 60min intraop | 28.8 pg/ml | Standard Deviation 100.9 |
| Spironolactone | Perioperative Interleukin(IL)-6 Concentrations | 30min intraop | 11.3 pg/ml | Standard Deviation 20.2 |
| Spironolactone | Perioperative Interleukin(IL)-6 Concentrations | 60min intraop | 17.4 pg/ml | Standard Deviation 29.4 |
| Spironolactone | Perioperative Interleukin(IL)-6 Concentrations | Postoperative day 2 | 109.6 pg/ml | Standard Deviation 116.9 |
| Spironolactone | Perioperative Interleukin(IL)-6 Concentrations | Postop | 145.7 pg/ml | Standard Deviation 427.1 |
| Spironolactone | Perioperative Interleukin(IL)-6 Concentrations | Initiation of surgery | 6.6 pg/ml | Standard Deviation 10.2 |
| Spironolactone | Perioperative Interleukin(IL)-6 Concentrations | Postoperative day 1 | 164.9 pg/ml | Standard Deviation 200.2 |
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.
Time frame: Perioperative period
Population: PAI-1 was measured in all subjects in the intention-to-treat analysis for which plasma was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations | Initiation of surgery | 19.6 ng/mL | Standard Deviation 16.6 |
| Placebo | Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations | 30min intraop | 19.2 ng/mL | Standard Deviation 10.7 |
| Placebo | Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations | 60min intraop | 21.0 ng/mL | Standard Deviation 10.9 |
| Placebo | Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations | Postop | 36.4 ng/mL | Standard Deviation 24.6 |
| Placebo | Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations | Postoperative day 1 | 55.2 ng/mL | Standard Deviation 43.8 |
| Placebo | Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations | Postoperative day 2 | 28.1 ng/mL | Standard Deviation 20.4 |
| Ramipril | Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations | Postoperative day 2 | 25.7 ng/mL | Standard Deviation 17.9 |
| Ramipril | Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations | Initiation of surgery | 16.2 ng/mL | Standard Deviation 11.9 |
| Ramipril | Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations | Postop | 38.9 ng/mL | Standard Deviation 28 |
| Ramipril | Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations | Postoperative day 1 | 47.9 ng/mL | Standard Deviation 31.4 |
| Ramipril | Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations | 30min intraop | 19.7 ng/mL | Standard Deviation 12.5 |
| Ramipril | Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations | 60min intraop | 22.0 ng/mL | Standard Deviation 13.7 |
| Spironolactone | Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations | 30min intraop | 17.3 ng/mL | Standard Deviation 10.9 |
| Spironolactone | Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations | 60min intraop | 20.1 ng/mL | Standard Deviation 11.7 |
| Spironolactone | Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations | Postoperative day 2 | 31.0 ng/mL | Standard Deviation 30.5 |
| Spironolactone | Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations | Postop | 34.0 ng/mL | Standard Deviation 22.3 |
| Spironolactone | Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations | Initiation of surgery | 17.3 ng/mL | Standard Deviation 12 |
| Spironolactone | Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations | Postoperative day 1 | 48.9 ng/mL | Standard Deviation 35 |
Secondary
Stroke
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.
Population: The intention-to-treat analysis included all those who received any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Stroke | 2.7 percentage of patients |
| Ramipril | Stroke | 1.3 percentage of patients |
| Spironolactone | Stroke | 2.0 percentage of patients |
p-value: 0.65Chi-squared
Secondary
Time to Tracheal Extubation
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
Population: The intention-to-treat analysis included all patients who received any study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Time to Tracheal Extubation | 1091.3 minutes | Standard Deviation 3067.3 |
| Ramipril | Time to Tracheal Extubation | 970.1 minutes | Standard Deviation 3548.1 |
| Spironolactone | Time to Tracheal Extubation | 576.4 minutes | Standard Deviation 761.5 |
p-value: 0.56Kruskal-Wallis