TREAT AF (Transcutaneous Electrical Vagus Nerve Stimulation to Suppress Atrial Fibrillation): A Randomized Clinical Trial

Abstract

Objectives: This study was a sham-controlled, double-blind, randomized clinical trial to examine the effect of chronic low level tragus stimulation (LLTS) in patients with paroxysmal AF.

Background: Low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve at the tragus (LLTS) acutely suppresses atrial fibrillation (AF) in humans, but the chronic effect remains unknown.

Methods: LLTS (20 Hz, 1 mA below the discomfort threshold) was delivered using an ear clip attached to the tragus (active arm) (n = 26) or the ear lobe (sham control arm) (n = 27) for 1 h daily over 6 months. AF burden over 2-week periods was assessed by noninvasive continuous electrocardiogram monitoring at baseline, 3 months, and 6 months. Five-minute electrocardiography and serum were obtained at each visit to measure heart rate variability and inflammatory cytokines, respectively.

Results: Baseline characteristics were balanced between the 2 groups. Adherence to the stimulation protocol (≤4 sessions lost per month) was 75% in the active arm and 83% in the control arm (p > 0.05). At 6 months, the median AF burden was 85% lower in the active arm compared with the control arm (ratio of medians: 0.15; 95% confidence interval: 0.03 to 0.65; p = 0.011). Tumor necrosis factor-alpha was significantly decreased by 23% in the active group relative to the control group (ratio of medians: 0.77; 95% confidence interval: 0.63 to 0.94; p = 0.0093). Frequency domain indices of heart rate variability were significantly altered with active versus control stimulation (p < 0.01). No device-related side effects were observed.

Conclusions: Chronic, intermittent LLTS resulted in lower AF burden than did sham control stimulation, supporting its use to treat paroxysmal AF in selected patients. (Transcutaneous Electrical Vagus Nerve Stimulation to Suppress Atrial Fibrillation [TREAT-AF]; NCT02548754).

Keywords: atrial fibrillation; neuromodulation; randomized clinical trial.

Figure 1.

Representative examples of active (A) and sham control (B) stimulation. For active stimulation, the ear clip was attached to the tragus, which is innervated by the auricular branch of the vagus nerve (A). For sham control stimulation, the ear clip was attached to the ear lobe, which is devoid of vagal innervation (B). A schematic representation of the study design and timeline of events is shown in (C).

Figure 2.

Flow diagram of participant recruitment and follow-up

Figure 3.

Comparison of atrial fibrillation (AF) burden between the 2 groups. The data are presented as median values and interquartile range. The p-value is based on a comparison of median AF burden levels at the 6-month time point after adjusting for baseline measures.

Figure 4.

Patient-level data on atrial fibrillation (AF) burden change in the 2 groups. Patients whose AF burden decreased by >75% at follow up were categorized as responders. The proportion of responders was significantly larger in the active compared to the sham control group (47% vs. 5%, respectively, p=0.003). B = baseline; 3M = 3 months; 6M = 6 months.

Figure 5.

Linear regression of the change in AF burden at follow up (Δ AF burden) as a function of the respective change in low frequency to high frequency ratio (Δ LF/HF) in the active (n=13; r=−0.51, p=0.077) and sham control group (n=11; r=−0.14, p=0.67).

Central illustration.

Noninvasive neuromodulation using low level tragus stimulation (LLTS) significantly decreased atrial fibrillation (AF) burden and decreased tumor necrosis factor (TNF)-α levels. The potential mechanisms of this effect are shown. Also shown are the neural pathways involved in this effect. LLTS targets the auricular branch of the vagus nerve, an afferent nerve (blue arrows) which relays information to central vagal projections in the brain stem. The signal undergoes processing in the brain stem and in higher centers (green arrows), which in turn provide the efferent neural signal to the heart (red arrows), which reaches the target organ through the vagus nerve.