Transcutaneous (Tragus) Vagal Nerve Stimulation for Post-op Afib

Not Applicable

Recruiting

• Conditions: Atrial Fibrillation
• Interventions: Device: active tVNS; Device: sham tVNS

• Registration Number: NCT04514757
• Lead Sponsor: University of California, Los Angeles

Brief Summary

Patients undergoing cardiac surgery are at high risk of developing atrial fibrillation (AF), with estimated rates of 30-50% and occurs at approximately 2-4 days after surgery. The autonomic nervous system is known to play a key role in AF. Animal studies have indicated that duration and inducibility of AF can be decreased with intermittent vagus nerve stimulation (VNS). In humans, literature suggests that transcutaneous (tragus) VNS (tVNS) can serve as a potentially non-invasive therapy for treatment of post-operative AF (POAF) by reducing inflammation and increasing atrial refractory period. The purpose of this study is to determine the value of tVNS in reducing the burden of POAF and days of hospitalization after cardiac surgery.

Detailed Description

The trial will have two study arms: active tVNS vs. sham tVNS. Patients will be randomized to active tVNS vs. sham tVNS and will receive optimal post-op care in both arms. Active tVNS (Parasym device, Parasym Health, Inc, London, UK) will be performed with a clip attached to the ear at 20 hertz (Hz), 250 microseconds (ms) at a current just below discomfort threshold for one hour twice a day, starting on post-day 0. For sham tVNS, Parasym device will be attached to the ear twice a day, turned on but current set to 0 milliamp (mA), starting on post-op day 0. Stimulation will continue until 5 days post-op or discharge. Discomfort threshold will be determined in both arms pre-operatively in the conscious state. This current will be used for stimulation for this patient until they are awake and extubated after surgery. The stimulation threshold may be reassessed once the patient is able to provide feedback.

Patients will be approached and recruited prior to their scheduled cardiac surgery. Recruited patients who give informed consent will have the discomfort stimulation threshold (current that leads to discomfort at the tragus) determined prior to surgery. Post-operatively, stimulation will be performed in the tVNS group at just below discomfort threshold. In the sham group, the stimulator will be turned on but current set at 0 mA. Stimulations will be performed within 12 hours of arrival to the ICU after surgery, and then twice a day between the hours of 7:00-9:00 am and 6:00-8:00 pm. If POAF develops in either arm, stimulation will be continued for the full 5 days. Ten ml of blood will be drawn within 12 hours of arrival to the ICU after surgery and on day 3 post-op for measurement of biomarkers. Serum will be stored at -80 Celsius and processed in batches of 10-15 samples.

Sample Size:

The investigators expect cardiac surgery to be associated with 40% incidence of POAF. The investigators expect tVNS to reduce this incidence by 40%. A sample size of 133 subjects per arm will be able to achieve 80% power at alpha of 0.05. If interim analysis is planned, Pocock method will be used and a p value of 0.03 will be used for interim and 0.03 for final analysis. Data will be analyzed according to the intention-to-treat principle.

Randomization:

A 1:1 randomization ratio for the tVNS vs. sham will be utilized. Patients who meet all of the inclusion and none of the exclusion criteria will be randomized in the order of their enrollment. After completing the Informed Consent process, the subject is then randomized following completion of the baseline and demographics information case report forms. Randomization should occur prior to any study-related tests or procedures. The subjects will be considered enrolled in the study once randomization has occurred.

Randomization will be stratified by clinical center and post-operative amiodarone use. A computer-generated randomization list with random permuted block of a variable will be produced for each clinical center. Investigators and other study staff members should not be able to identify the study assignment until this time. If a randomization assignment is inadvertently disclosed prior to use, the assignment will never be used.

A report of randomization compliance will be generated at the conclusion of the study.

Study Timeline

• Study First Submitted: 2020-07-29
• Study First Submitted QC: 2020-08-12
• Study First Posted: 2020-08-17
• Study Start: 2021-09-20
• Status Verified: 2023-10
• Last Update Submitted: 2023-10-12
• Last Update Posted: 2023-10-16
• Primary Completion: 2024-08
• Study Completion: 2024-09

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 266

Inclusion Criteria

1. Patients scheduled to undergo coronary artery bypass surgery, major vascular/aneurysm repair requiring bypass, valvular replacement or repair, or both, for clinically indicated reasons.
2. Age ≥ 18 years.
3. Sinus rhythm at baseline.
4. Provision of signed informed consent and stated willingness to comply with all study procedures for duration of the study

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Exclusion Criteria

1. Emergent surgery
2. Anticipated amiodarone use
3. Patients with permanent or persistent atrial fibrillation
4. Planned concomitant atrial Maze procedure
5. Complex congenital heart disease
6. Women who are pregnant (as evidenced by pregnancy test if pre-menopausal).
7. Left ventricular assist device or status post orthotopic heart or lung transplantation
8. Unable or unwilling to comply with protocol requirements.
9. Known channelopathy such as Brugada syndrome, long QT syndrome, or Catecholaminergic monomorphic ventricular tachycardia
10. Symptomatic sinus bradycardia or sinus node dysfunction at baseline without an implantable pacemaker.
11. Complete heart block or trifascicular block without an implantable pacemaker
12. Recurrent vasovagal syncope
13. Unilateral or bilateral vagotomy
14. Chronic amiodarone use

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Intervention Group	active tVNS	Active tVNS (Parasym device, Parasym Health, Inc, London, UK) will be performed with a clip attached to ear at 20 Hz, 250ms at a current just below discomfort threshold for one hour twice a day, starting on post-day 0. Stimulation will continue until 5 days post-operatively or discharge.
Control Group	sham tVNS	Sham tVNS will be performed by attaching the Parasym device to the ear and setting output to 0. Stimulation will continue until 5 days post-operatively or discharge.

Primary Outcome Measures

Name	Time	Method
Atrial Fibrillation	6 days	Incidence of post-operative atrial fibrillation for postoperative day 0-5 (postop day 0 is the day of the surgery and is the first day of the time frame and postoperative day 5 is the 6th day).

Secondary Outcome Measures

Name	Time	Method
Sympathetic neural markers	Postop day 3 (1 day)	Reduction in sympathetic neural markers including norepinephrine, Neuropeptide Y (NPY), and galanin.
Inflammatory markers	Within 12 hours of arrival to the ICU after surgery and on postop day 3 (2 days)	Reduction in inflammatory markers including C-reactive protein (CRP), Interleukin 10 (IL-10), Tumour Necrosis Factor alpha (TNF-alpha), Interleukin 6 (IL-6), and Interleukin 1 beta (IL-1β)
Pain assessment	6 days	Pain scores will be assessed on postoperative days 0-5 using the visual analog score (Scale 0-10). Zero for no pain and ten being the worst pain experienced. They will be obtained and recorded into the medical record by the nurse monitoring the subject as part of standard care. Postop day 0 is the day of the surgery and is the first day of the time frame and postoperative day 5 is the 6th day.
Heart rate during atrial fibrillation	6 days	The heart rate during each incidence of postoperative atrial fibrillation for postop days 0-5 (postop day 0 is the day of the surgery and is the first day of the time frame and postoperative day 5 is the 6th day).
Days of hospitalization	Postop day 0 until discharge from the hospital, an average of 1 week.	Number of days in the hospital from postoperative day 0 to discharge.
Narcotic Usage	6 days	Total narcotic consumption will be calculated each day for postoperative days 0-5. Narcotic amount will be converted to a standard unit equivalent for comparison. Postop day 0 is the day of the surgery and is the first day of the time frame and postoperative day 5 is the 6th day.
Duration of post-op atrial fibrillation	6 days	How many hours or days for each incidence of postoperative atrial fibrillation for postoperative days 0-5 (postop day 0 is the day of the surgery and is the first day of the time frame and postoperative day 5 is the 6th day).

Trial Locations

Locations (2)

University of Oklahoma; 🇺🇸 Oklahoma City, Oklahoma, United States

University of California, Los Angeles; 🇺🇸 Los Angeles, California, United States