After occurrence of two cardiac events (one newly diagnosed LBBB and one sinusarrhythmic episode) the two cases were analyzed in detail. In addition, we conducted an analysis of all ECG recordings performed during the course of the study up to this time point as an interim analysis, in order to address safety issues.
For the whole sample missing values for visit 2 (55%) and 3 (82%) were high; thus, we concentrated on contrasts between screening/baseline (5%
1 value missing for QRS), visit 1 (14% missing), and last available visit (32% missing). In two patients cardiac adverse events during tVNS had occurred.
years old female (patient 1) developed a palpitation episode that was monitored and treated in an intensive care unit. This event was therefore classified as a severe adverse event and reported immediately to the sponsor and the local ethics committee. The patient had noticed palpitation on a hot Saturday in the summer of 2010 that worsened in the course of the day and led to consultation of a physician in the evening. She was initially supplied with Calcium and Magnesium formula but when the complaints persisted even on the following day she sought help in a hospital and was initially observed in an intensive care unit after administration of nitroglycerine inhaler. After normal results were obtained at echocardiography, duplex sonography of the carotids, 24
h ECG monitoring, and thoracal X-ray she was dismissed from hospital without complaints 1
day later. Elevation of the dosage of her beta-blocking antiarrhythmic drug from 2.5
mg b.i.d. to 5
mg b.i.d. was recommended. Further exploration revealed that the patient had suffered comparable events earlier in the past but in-patient-treatment had not been necessary so far. tVNS treatment had been stopped immediately in this patient and she was retracted from the study.
year-old male patient (patient 2) displayed a LBBB with atrioventricular conduction time of 160
ms in a routine echocardiographic control performed after 8
weeks of tVNS, which had not been there at baseline and at the prior visits (screening/baseline, week 2, week 4). Prior echocardiography had not revealed any pathological results as shown in Figure . The patient himself did not experience any symptoms, the LBBB was detected in a routine control ECG according to the study protocol (see Figure ). For improvement of mood and sleep he was on medication with mirtazapine (15
mg/day) and pre-existing arterial hypertension was treated with metoprolol 200
mg/day. Additional cardiac risk factors included smoking (10–15
cigarettes/day for almost 50
years), obesity (180
), and hyperlipidemia. Extensive internal check-up including several ECG and sonographic examinations revealed a concentric hypertrophy of the left ventricle without regional cardiac movement disorders. Heart catheter examinations were recommended but refused by the patient. The LBBB was completely reversible, further ECG controls did not show similar episodes so far (see Figure ). tVNS stimulation was immediately stopped after detecting the LBBB at week 8 study visit. This event was not classified as a severe adverse event as it did not lead to hospitalization of the patient or other grave impairment.
ECG of patient 2 at baseline, week 2 and week 4 visit.
ECG displaying LBBB at week 8 visit (patient 2).
ECG at follow-up 6 weeks after LBBB (patient 2).
Further reported adverse events included headache (3×), breathing difficulties (3×), chest sensation (3×), dizziness (2×), subjective hearing impairment (2×), worsening of tinnitus, neck pain, croakiness, and sleeping disorder. Notably, all these complaints were reported to have been perceived transiently, they could not be objectified and no specific actions were taken. For none of these side effects there was a clear hint for a causal relationship to the intervention itself.
Side effects clearly related to the intervention were technical problems [contact problems (4×)] and local problems [local electrode pressure (11×); pain at stimulation with high intensity (3×)].
Statistical analyses were performed on various ECG parameters [heart beats per minute, PQ interval (ms), QRS complex (ms), and QTc (ms)] both for the whole sample (n
24) and the sample without the two patients with adverse events (n
22; see Figure ). For the whole sample none of the analyzed parameters showed significant differences between the three time points, effect sizes were small (all p
0.246; all d
0.312). When the two patients with cardiac averse events were excluded from analysis, a significant reduction of the QRS complex with a medium effect size (p
0.541) from screening to the termination emerged; all other contrasts were not significant with small effect sizes (all p
0.382; all d
0.206). All results are displayed in detail in Figure .
Cardiac parameters during tVNS stimulation for both the whole sample and the sample without the 2 patients experiencing adverse cardiac events.