Atrial Fibrillation
Conditions
Keywords
Cardiac Surgery, Postoperative Complications, Autonomic Nerve Block
Brief summary
In this study, the investigators aim to determine whether injecting botulinum toxin into epicardial fat pads is efficacious and safe for decreasing postoperative atrial fibrillation (POAF) after cardiac surgery. The investigators will test the hypothesis that botulinum toxin injected into the epicardial fat pads reduces POAF and length of stay (LOS) without increasing adverse events. This will be a prospective randomized trial of 130 patients undergoing coronary artery bypass graft (CABG), valve surgery or CABG + valve surgery with cardiopulmonary bypass. Patients will be randomized to receive either botulinum toxin (50 units per fat pad, n=65) or normal saline/placebo (1 mL per fat pad, n=65) injected into epicardial fat pads. All patients will receive standardized anesthetic, surgical, and post-surgical care. The primary outcome in this study will be time to occurrence of in-hospital POAF. Based on previous work and a pilot trial showing a pronounced reduction (relative risk reduction 77%) in POAF after injecting botulinum into the epicardial fat pads, the investigators anticipate a significant reduction in the risk for POAF with epicardial botulinum in this cohort, which includes valve surgery patients.
Detailed description
Purpose of the study: A pilot study to determine whether injecting botulinum toxin into epicardial fat pads is efficacious and safe for decreasing postoperative atrial fibrillation (POAF) after cardiac surgery Hypothesis to be tested: Botulinum toxin injected into the epicardial fat pads reduces POAF. Design and Procedures: This will be a prospective randomized pilot trial of 130 patients undergoing coronary artery bypass graft (CABG), valve surgery or CABG + valve surgery via median sternotomy with cardiopulmonary bypass. Patients \<50 years of age, with chronic atrial fibrillation, prior cardiac surgery, EF\<25%, preoperative inotropic support, hepatic or renal failure, known sensitivity to botulinum toxin, debilitating neuromuscular disease, or those with a history of atrioventricular block will be excluded from the study. Prior to surgery, all patients will have baseline Mini-Mental State Examination (MMSE) and blood sampling from an indwelling arterial line or venipuncture for measurement of inflammatory and genomic markers. Half of the patients will be randomized to receive injection of epicardial botulinum toxin in addition to standard of care, as described below. The other half will receive epicardial injection of normal saline. Institution of cardiopulmonary bypass will be performed according to the routine surgical protocol. After instituting CPB, botulinum toxin (or normal saline) injections will be performed by the surgeon. This dose was selected given the prior report of its effectiveness in preventing POAF after cardiac surgery in a small pilot study.(Pokushalov et al., 2014) After completion of surgery and separation from CPB, patients will proceed along the institutional Cardiac Surgical Caremap. All patients will be monitored with continuous ECG (telemetry) until hospital discharge. POAF will be diagnosed by telemetry or 12-lead ECG, and will be defined as new-onset if it occurs postoperatively at any time before hospital discharge. POAF, if it occurs, will be treated as per routine of care. POAF will be defined as any detectable atrial fibrillation before discharge that lasts \>30 seconds. On postoperative day (POD) 4, a member of the study team will visit each patient to administer the MMSE and capture a 5-minute ECG with a Holter monitor. In addition, patients will be contacted monthly for 4 months and at one year after surgery for follow up, and medical records will be reviewed for evidence of readmissions, arrhythmias, or other adverse events.
Interventions
DRUGBotulinum Toxin Type A
The botulinum toxin will be injected into epicardial fat pads shortly after cardiopulmonary bypass is initiated.
DRUGPlacebo
Sponsors
Foundation for Anesthesia Education and Research
American Heart Association
Joseph Mathew, M.D.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Undergoing cardiac surgery with cardiopulmonary bypass via median sternotomy * coronary artery bypass graft (CABG) * valve surgery * CABG + valve surgery
Exclusion criteria
* \< 50years of age * \> 90years of age * chronic AF or AF at the time of screening * preoperative heart block (second degree or greater) * LVEF \< 25% * renal failure * hepatic failure * known sensitivity to Botulinum toxin * debilitating neuromuscular disease * preoperative need for inotropes/vasopressors or intra-aortic balloon pump * planned MAZE procedure * history of catheter ablation for AF * use of Vaughan-Williams class I or III drugs within 5 elimination half lives (or within 2 months for amiodarone) * undergoing minimally-invasive cardiac surgery * prior cardiac surgery
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to In-hospital Post-operative Atrial Fibrillation (POAF) | From the time of ICU arrival until the time of first documented POAF, or discharge whichever came first, assessed up to 2 weeks | Patients will be seen on a daily basis and the timing of POAF compared between groups. The occurrence of in-hospital POAF will be tracked throughout the hospitalization (up to two weeks) and the time from surgery to the first and subsequent episodes of POAF recorded and compared between groups. POAF will be determined by ECG or telemetry. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With In-hospital POAF | The incidence of in-hospital POAF will be tracked throughout the hospitalization (up to two weeks) | Patients will be seen on a daily basis and the occurrence of POAF compared between groups. |
| Length of Stay | ICU length of stay was measured from time of surgery to time of ICU discharge. Post-operative length of stay was measured from time of surgery to time of hospital discharge. | Total and ICU length of stay will be determined by examining medical records for the length of inpatient hospitalization, assessed over the entire study period (up to two years). ICU and hospital LOS will be recorded and compared between groups |
| Number of Participants With Adverse Events | Adverse events from the time of surgery through hospital discharge, up to 2 weeks | The total number of postoperative complications (including infectious, neurologic, and renal complications, as well as mortality) and the number of subjects with complications will be monitored and compared between groups. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Epicardial Botulinum After instituting cardiopulmonary bypass (CPB), botulinum toxin injections will be performed by the surgeon as follows: Using a standard sterile insulin syringe with a 27g needle, surgeons will inject each of the epicardial fat pads with 50U (1mL) of botulinum toxin (OnabotulinumtoxinA, Botox®). After completion of surgery and separation from CPB, patients will proceed along the institutional Cardiac Surgical Caremap. All patients will be monitored with continuous ECG (telemetry) until hospital discharge. POAF will be diagnosed by telemetry or 12-lead ECG, and will be defined as new-onset if it occurs postoperatively at any time before hospital discharge.
Botulinum Toxin Type A: The botulinum toxin will be injected into epicardial fat pads shortly after cardiopulmonary bypass is initiated. | 63 |
| Epicardial Placebo After instituting cardiopulmonary bypass (CPB), placebo (normal saline) injections will be performed by the surgeon as follows: Using a standard sterile insulin syringe with a 27g needle, surgeons will inject each of the epicardial fat pads with 1mL of normal saline. After completion of surgery and separation from CPB, patients will proceed along the institutional Cardiac Surgical Caremap. All patients will be monitored with continuous ECG (telemetry) until hospital discharge. POAF will be diagnosed by telemetry or 12-lead ECG, and will be defined as new-onset if it occurs postoperatively at any time before hospital discharge.
Placebo | 67 |
| Total | 130 |
Baseline characteristics
| Characteristic | Epicardial Botulinum | Total | Epicardial Placebo |
|---|---|---|---|
| Age, Continuous | 66.5 years STANDARD_DEVIATION 8.6 | 67.0 years STANDARD_DEVIATION 8.9 | 67.5 years STANDARD_DEVIATION 9.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 61 Participants | 128 Participants | 67 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 15 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 55 Participants | 112 Participants | 57 Participants |
| Region of Enrollment United States | 63 participants | 130 participants | 67 participants |
| Sex: Female, Male Female | 17 Participants | 40 Participants | 23 Participants |
| Sex: Female, Male Male | 46 Participants | 90 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 63 | 1 / 67 |
| other Total, other adverse events | 10 / 63 | 14 / 67 |
| serious Total, serious adverse events | 27 / 63 | 30 / 67 |
Outcome results
Primary
Time to In-hospital Post-operative Atrial Fibrillation (POAF)
Patients will be seen on a daily basis and the timing of POAF compared between groups. The occurrence of in-hospital POAF will be tracked throughout the hospitalization (up to two weeks) and the time from surgery to the first and subsequent episodes of POAF recorded and compared between groups. POAF will be determined by ECG or telemetry.
Time frame: From the time of ICU arrival until the time of first documented POAF, or discharge whichever came first, assessed up to 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Epicardial Botulinum | Time to In-hospital Post-operative Atrial Fibrillation (POAF) | 224.38 hours | Standard Error 19.31 |
| Epicardial Placebo | Time to In-hospital Post-operative Atrial Fibrillation (POAF) | 194.76 hours | Standard Error 18.36 |
p-value: 0.1895% CI: [0.41, 1.19]Regression, Cox
Secondary
Length of Stay
Total and ICU length of stay will be determined by examining medical records for the length of inpatient hospitalization, assessed over the entire study period (up to two years). ICU and hospital LOS will be recorded and compared between groups
Time frame: ICU length of stay was measured from time of surgery to time of ICU discharge. Post-operative length of stay was measured from time of surgery to time of hospital discharge.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Epicardial Botulinum | Length of Stay | ICU LOS in hours | 25.7 time in hours |
| Epicardial Botulinum | Length of Stay | Post-operative LOS in hours | 145 time in hours |
| Epicardial Placebo | Length of Stay | ICU LOS in hours | 23.1 time in hours |
| Epicardial Placebo | Length of Stay | Post-operative LOS in hours | 149 time in hours |
Comparison: ICU length of stay hoursp-value: 0.16Wilcoxon (Mann-Whitney)
Comparison: Hospital LOSp-value: 0.51Wilcoxon (Mann-Whitney)
Secondary
Number of Participants With Adverse Events
The total number of postoperative complications (including infectious, neurologic, and renal complications, as well as mortality) and the number of subjects with complications will be monitored and compared between groups.
Time frame: Adverse events from the time of surgery through hospital discharge, up to 2 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Epicardial Botulinum | Number of Participants With Adverse Events | 44 Participants |
| Epicardial Placebo | Number of Participants With Adverse Events | 47 Participants |
p-value: 0.97Chi-squared
Secondary
Number of Participants With In-hospital POAF
Patients will be seen on a daily basis and the occurrence of POAF compared between groups.
Time frame: The incidence of in-hospital POAF will be tracked throughout the hospitalization (up to two weeks)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Epicardial Botulinum | Number of Participants With In-hospital POAF | 23 Participants |
| Epicardial Placebo | Number of Participants With In-hospital POAF | 32 Participants |
p-value: 0.1995% CI: [0.31, 1.27]Regression, Logistic