Low Level Transcutaneous Electrical Vagus Nerve Stimulation To Suppress Atrial Fibrillation
Phase: NA
Conditions: Atrial Fibrillation
Sponsor: Medical University of Vienna

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Study protocol: 
Low-Level Transcutaneous Electrical Vagus Nerve 
Stimulation to Suppress Atrial Fibrillation 
 
 
 
 
 
Investigator 
Prof. Alfred KOCHER 
 
Study Coordinator 
Ferenc MARKUS 
 
Clinical Trial Center 
Clinical Department of Cardiac Surgery 
Medical University of Vienna 
Währinger Gürtel 18-20 
1090 Vienna 

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Abbreviations 
 
 
AF  
 
Atrial Fibrillation 
CABG  
Coronary Artery Bypass Grafting 
CI  
 
Claudicatio Intermittens 
PAOD  
Peripheral Artery Occlusive Disease 
 
 

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Table of contents 
 
1 
SCIENTIFIC BACKGROUND ............................................................................................ 4 
2 
AIM OF THE PROJECT ..................................................................................................... 5 
3 
STUDY POPULATION ....................................................................................................... 5 
3.1 
INCLUSION CRITERIA ........................................................................................... 5 
3.2 
EXCLUSION CRITERIA .......................................................................................... 5 
4 
METHODS .......................................................................................................................... 6 
5 
BENEFIT OF STUDY ......................................................................................................... 6 
6 
RISK OF STUDY ................................................................................................................ 6 
7 
INVESTIGATIONAL PROCEDURE ................................................................................... 6 
8 
DOCUMENTATION ............................................................................................................ 7 
9 
STATISTICAL ANALYSIS ................................................................................................. 7 
10 
RANDOMIZATION ........................................................................................................... 8 
11 
DATA PROTECTION ....................................................................................................... 8 
12 
REFERENCES ................................................................................................................. 9 
 
 

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1 Scientific Background 
Nearly 30% of patients undergoing coronary artery bypass grafting (CABG), 40% of 
patients undergoing valvular heart surgery and over 50% of patients with combined 
coronary and valvular procedures develop atrial fibrillation (AF) [1]. 
Postoperative AF occurs mostly due to conditions like chronic kidney diseases, 
emergency surgery, age >75 years, cardiopulmonary bypass time >180 min and due 
to lacking postoperative application of aldosterone- and beta-blockers [2].  
An overview of pre- intra- and postoperative risks for AF is listed in Table 1: Pre-, 
intra-, postoperative risks for AF [1]. 
Preoperative 
Intraoperative 
Postoperative 
High age 
Male gender 
Previous cardiac surgery  
Valvular heart disease  
Chronic lung disease  
Chronic renal failure  
Leſt atrium enlargement  
Leſt ventricular hypertrophy  
Withdrawal of beta-blocker medication  
History of AF Hypertension 
Obesity  
Diabetes 
Metabolic syndrome  
Endotracheal tube insertion  
Intraoperative IABP  
Leſt ventricular venting  
Aortic cross-clamp time  
Extracorporeal circulation  
Myocardial ischemia  
Venous cannulation  
Damage to the atrium  
Excess inotropic requirements  
Acute volume change 
 
Return to intensive care unit  
Ventilation longer than 24 hours  
Volume overload  
Pneumonia  
Electrolyte imbalances  
Imbalance of auton. nervous system  
Atrial extrasystole  
Increased postop adrenergic status  
Increased aſterload  
Inflammation  
Hypotension 
 
Table 1: Pre-, intra-, postoperative risks for AF [1] 
Several theories describe the emergence of AF like “multiple-wavelet re-entry”, “focal 
mechanism” and “mother rotor” but the exact underlying mechanisms are still not well 
understood [1]. 
Prevention and treatment of postoperative AF are managed with conservative 
medication therapies including e.g. beta-blockers and other clinical interventions 
include radio frequency catheter ablation, cardioversion and occlusion of the left atrial 
appendage [3]. 
A novel approach for suppression of AF utilizing low-level transcutaneous electrical 
vagus nerve stimulation has been described recently in the Journal of the American 
College of Cardiology [4]. The newly developed “DUCEST Neurostimuator V” device 
(manufactured by Biegler Medizinelektronik GmbH Mauerbach, Austria) offers similar 
action as in [4]. This Neurostimulator device is designed to emit small direct current 
electrical pulses (0-1,2mA) to stimulate the R.auricularis of the vagus nerve located 
at the Fossa triangularis. The target population are patients with de-novo 
postoperative AF. The stimulation is achieved with the attachment of two needle-
electrodes and connection of the electrodes to the Neurostimulator.  

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Following the stimulation of the vagus nerve positive effects were already achieved in 
chronical wound healing, peripheral artery occlusive disease (PAOD), Claudicatio 
intermittens (CI) and chronic pain patients [5][6][7][8]. 
 
2 Aim of the project 
The current study will evaluate the potential of stimulating the R.auricularis of the 
vagus nerve located at the Fossa triangularis to ameliorate or suppress AF in the 
study population. 
 
3 Study population 
The target population are patients with de-novo postoperative AF who underwent 
bypass operation and/or aortic valve replacement. 
3.1 Inclusion Criteria 
• De-novo postoperative AF 
• CABG or aortic valve replacement 
• Age of 18-80 years 
• Willing and able to understand, sign and date the informed consent form that 
has been approved by the institutional review board 
3.2 Exclusion Criteria 
• Pacemaker or ICD 
• Impaired EF < 30% 
• Patients with acute myocardial infarction within the past 14 days 
• Pregnant or lactating patients 
• Any condition that, in the judgement of the investigator, would place the 
patient at undue risk 
• Any concurrent disease or condition that, in the opinion of the investigator, 
would make the subject unsuitable for participation in the study 
• Treatment and/or an uncompleted follow-up treatment of any investigational 
therapy within 6 months before procedure and intent to participate in any other 
investigational drug or cell therapy study during the follow-up period of this 
study 
• Active 
participation 
in 
other 
research 
therapy 
for 
cardiovascular 
repair/regeneration 
 
 

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4 Methods 
Patients are randomized to a treatment or a sham group. The corresponding device 
is prepared by a third person according to the double-blind setting for the surgeon. 
The DUCEST Neurostimulator V needle-electrodes are applied post-operatively to 
stimulate the R.auricularis of the vagus nerve located at the Fossa triangularis. 
Connecting the needle-electrode cables to the Neurostimulator V activates the 
device. (The stimulation intensity can be adjusted from 0,05mA to 1,2mA, default 
value is 0,4mA). The starting stimulation intensity will be adjusted to 1mA and takes 
place at 1Hz continuously for 40 minutes, followed by a 20 minute break. The built-in 
3V battery lasts for approx. 14 days. After 7 days the electrodes are replaced and 
applied to the other ear of the patient. A plaster with a plastic mounting clip is 
attached on the shoulder of the patient. The Neurostimulator is connected to the 
mounting clip. After 14 days or at hospital discharge of the patient, the device is 
unmounted and the needle-electrodes are removed. 
 
5 Benefit of study 
Postoperative AF is a significant morbidity in cardiac surgery which is associated with 
decreased survival in the long term. Even a slight decrease in postoperative AF is 
highly desirable. Our goal is to evaluate if the DUCEST Neurostimulator V is a safe 
and effective alternative to current treatment options for AF. 
6 Risk of study 
Possible local inflammation at needle-electrodes during prolonged use (>7d) 
7 Investigational Procedure 
Patients will be randomized double-blind into a treatment and sham group. Each 
group will consist of 20 Patients (please see “9 Statistical Analysis”). The follow-up 
covers the post-op hospital stay (approx 7-14 days). Inflammation markers will be 
assessed at day 0 (at device attachment), +2 and +7 days post device attachment. 
CRP, TNF-alpha, IL-6, and IL-10 will be assessed. Safety measures will include 
screening for and treatment of any occurring adverse events, vital signs, physical 
examination, ECG, 24-hour continuous ambulatory ECG, heart rate variability, 
laboratory safety tests, infection assessment, inflammation screen. In the event of 
procedure-related cardiac arrhythmias, ACC/AHA/ESC 2006 Practice Guidelines for 
management of subjects with ventricular arrhythmias and the prevention of sudden 
cardiac death will be implemented. 
 
 

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8 Documentation 
Patients participating in the study will be monitored for:  
Atrial Fibrillation, Mortality, Life threatening events, Physical impairment, Prolonged 
and additional hospitalisation. 
 
Safety measures will include the following examinations: 
Adverse Events, Vital Signs, Physical examination, ECG, Laboratory safety tests, 
Infection assessment, Inflammation screening. 
 
In the event of procedure-related cardiac arrhythmias, ACC/AHA/ESC 2006 Practice 
Guidelines for management of subjects with ventricular arrhythmias and the 
prevention of sudden cardiac death will be implemented.  
 
9 Statistical Analysis 
Power and samplesize calculation 
Two-sample test to determine whether the mean in group A, µA, is different from the 
mean in group B, µB. The hypotheses are  
H0:µA−µB=0 
H1:µA−µB≠0. 
Where the ratio between the sample sizes of the two groups is κ=nAnB 
 
Formulas to compute sample size and power, respectively: 
nA=κnB and nB=(1+1/κ)*(σ*(z1−α/2+z1−β)/(µA−µB))2 
 
1−β=Φ(z−z1−α/2)+Φ(−z−z1−α/2),  z=(µA−µB)/(σ*√(1/nA+1/nB)) 
 
where 
κ=nA/nB is the matching ratio 
σ is standard deviation 
Φ is the standard Normal distribution function 
Φ−1 is the standard Normal quantile function 
α is Type I error 
β is Type II error, meaning 1−β is power 
 
 

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utilizing the values: 
Group 'A' mean, µA = 20 (estimates for mean TNF-α in pg/ml in treatment group) 
Group 'B' mean, µB = 30 (estimates for mean TNF-α in pg/ml in sham group) 
Standard Deviation, σ = 10 (estimates for TNF-α standard deviation) 
Sampling Size nA = 20 (treatment group size) 
Sampling Size nB = 20 (sham group size) 
Sampling Ratio, κ=nA/nB = 1 
Type I error, α = 0,05 
 
calculates the Power, 1−β = 0,8859 which is an acceptable value. 
 
For the statistical evaluation of the study data the software Graphpad Prism will be 
used. The evaluation of the double-blind data will be performed by a competent 
person utiliziling appropriate statistical measures. 
 
Primary Endpoint 
Incidence of Atrial Fibrillation events in routine ECG following SOPs of clinical 
department of cardiac surgery. 
Secondary Endpoint 
Markers for IL-6, IL-10, CRP, TNF-alpha. 
Utilizing paired t-Tests. 
 
10 Randomization 
The randomization procedure will be conducted utilizing the MUW randomizer 
(https://www.meduniwien.ac.at/randomizer) to achieve a 50% / 50% assignment of 
patients to the treatment and the sham group. 
 
11 Data Protection 
Participating patients are pseudonymized using an alphanumeric combination. 
Collected data are stored on a password-protected work PC in the room 20.E5.02.4. 
Access to personal data is only available to the sponsor / investigator Prof. Alfred 
Kocher and by the sponsor authorized persons. 
 

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12 References 
[1] 
G. Tokmaji, R. S. McClure, T. Kaneko, and S. F. Aranki, “Management strategies in cardiac 
surgery for postoperative atrial fibrillation: Contemporary prophylaxis and futuristic 
anticoagulant possibilities,” Cardiol. Res. Pract., vol. 1, no. 1, 2013. 
[2] 
A. Sezai, K.-I. Nakata, M. Iida, I. Yoshitake, S. Wakui, S. Osaka, H. Kimura, K. Takahashi, Y. 
Ishi, H. Yaoita, M. Arimoto, H. Hata, M. Shiono, T. Takayama, and A. Hirayama, “A Study on 
the Occurrence and Prevention of Perioperative Stroke after Coronary Artery Bypass Grafting,” 
Ann. Thorac. Cardiovasc. Surg., pp. 1–7, 2015. 
[3] 
“Treatment Guidelines of Atrial Fibrillation (AFib or AF).” [Online]. Available: 
http://www.heart.org/HEARTORG/Conditions/Arrhythmia/AboutArrhythmia/Treatment-
Guidelines-of-Atrial-Fibrillation-AFib-or-AF_UCM_423779_Article.jsp. [Accessed: 12-Jun-2015]. 
[4] 
S. Stavrakis, M. B. Humphrey, B. J. Scherlag, Y. Hu, W. M. Jackman, H. Nakagawa, D. 
Lockwood, R. Lazzara, and S. S. Po, “Low-Level Transcutaneous Electrical Vagus Nerve 
Stimulation Suppresses Atrial Fibrillation,” J. Am. Coll. Cardiol., vol. 65, no. 9, pp. 867–875, 
2015. 
[5] 
K. Nocon, C. Moosmann, F. Margenfeld, and C. Trummer, “Erste klinische Erfahrungen von 
vagaler Nervenstimulation über das Ohr bei Patienten mit chronischem Schmerzsyndrom und 
Wunden der unteren Extremität bei pAVk Stadium IV,” Universitätsklinikum Freiburg. 
[6] 
T. Payrits, “Vagale Stimulation - eine neue Möglichkeit zur konservativen Therapie der 
Claudication intermittens,” in 28. Jahrestagung der Deutschen Gesellschaft für Gefässchirurgie 
und Gefässmedizin, 2012. 
[7] 
R.-U. Kuehnel, “Neurovagale Stimulation und Vakuumtherapie bei der Behandlung von 
chronischen Wunden der unteren Extremitäten,” Wund Manag. Sonderh., vol. 2, 2013. 
[8] 
T. Payrits, “Veränderungen des TcPO2 durch die vagale Stimulation bei Patienten mit PAVK.”