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Temporary Autonomic Blockade to Prevent Atrial Fibrillation After Cardiac Surgery

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ClinicalTrials.gov Identifier: NCT02498769
Recruitment Status : Active, not recruiting
First Posted : July 15, 2015
Results First Posted : December 7, 2018
Last Update Posted : December 7, 2018
Sponsor:
Collaborators:
Foundation for Anesthesia Education and Research
American Heart Association
Information provided by (Responsible Party):
Joseph Mathew, M.D., Duke University

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.

Condition or disease Intervention/treatment Phase
Atrial Fibrillation Drug: Botulinum Toxin Type A Drug: Placebo Phase 1 Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 130 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Temporary Autonomic Blockade to Prevent Atrial Fibrillation After Cardiac Surgery
Actual Study Start Date : September 2015
Actual Primary Completion Date : September 28, 2017
Estimated Study Completion Date : December 1, 2018


Arm Intervention/treatment
Experimental: 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.
Drug: Botulinum Toxin Type A
The botulinum toxin will be injected into epicardial fat pads shortly after cardiopulmonary bypass is initiated.
Other Names:
  • Botox
  • Onabotulinumtoxin A

Placebo Comparator: 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.
Drug: Placebo
Other Name: normal saline




Primary Outcome Measures :
  1. Time to In-hospital Post-operative Atrial Fibrillation (POAF) [ 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 ]
    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 Outcome Measures :
  1. Number of Participants With In-hospital POAF [ Time Frame: 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.

  2. Length of Stay [ 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. ]
    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

  3. Number of Participants With Adverse Events [ Time Frame: 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.



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Ages Eligible for Study:   50 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02498769


Locations
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Joseph Mathew, M.D.
Foundation for Anesthesia Education and Research
American Heart Association
  Study Documents (Full-Text)

Documents provided by Joseph Mathew, M.D., Duke University:

Publications:
Responsible Party: Joseph Mathew, M.D., Jerry Reves, MD, Professor of Cardiac Anesthesiology and Chairman, Department of Anesthesiology, Duke University
ClinicalTrials.gov Identifier: NCT02498769     History of Changes
Other Study ID Numbers: Pro00061607
First Posted: July 15, 2015    Key Record Dates
Results First Posted: December 7, 2018
Last Update Posted: December 7, 2018
Last Verified: November 2018

Keywords provided by Joseph Mathew, M.D., Duke University:
Cardiac Surgery
Postoperative Complications
Autonomic Nerve Block

Additional relevant MeSH terms:
Atrial Fibrillation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Botulinum Toxins
Botulinum Toxins, Type A
onabotulinumtoxinA
abobotulinumtoxinA
Acetylcholine Release Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Neuromuscular Agents
Peripheral Nervous System Agents