VANS
Research type
Research Study
Full title
Vagal Autonomic Neuromodulation by transcutaneous nerve stimulation in acute ischaemic Stroke requiring mechanical thrombectomy: a phase 2A, sham controlled randomised trial
IRAS ID
314067
Contact name
Gareth Ackland
Contact email
Sponsor organisation
Queen Mary University of London
Clinicaltrials.gov Identifier
Duration of Study in the UK
0 years, 5 months, 29 days
Research summary
Research Summary
Removing blood clots from the brain by mechanical thrombectomy has revolutionised the management of stroke, but more than 50% of patients do not regain functional independence. Blood pressure (BP) control is important, since low and high BP are strongly associated with poor patient outcomes after thrombectomy. Intact autonomic function is required to control BP and potentially improve recovery after stroke. Impairment of baroreflex autonomic function, due to reduced vagal activity is associated with extreme BP variability, leading to further brain injury and cardiovascular complications. Reduced baroreflex control is related to poor patient outcomes after stroke, independent of absolute blood pressure. Reversing baroreflex and vagal dysfunction is, therefore, widely held to have the potential to improve cardiovascular control and patient outcome in this context.
Vagal nerve stimulation improves autonomic control and reverses baroreflex dysfunction but this has previously required surgically implanted devices which are expensive and impractical in the context of acute stroke. Afferent Electronic have achieved the same effect as these implantable devices by non-invasive transcuTANeous autonomic neuromodulation (TAN). Our investigational device might be an improvement on currently available pharmacological treatments, since it is non-pharmacological and is readily accessible to all patients including after discharge from hospital. Compliance with device use can be monitored remotely to optimize therapeutic effect. We will examine the effect of TAN versus sham stimulation to ensure any effects are not attributable to placebo effect. The intervention has no impact on standard of care with other (pharmacological) therapies.
Summary of Results
The primary outcome measured was the variation in systolic blood pressure (BP) over the first 24 hours after starting treatment. The variation for the active treatment group was 0.106, while for the sham therapy group it was 0.107. The difference between these two groups was not statistically significant (p=0.93), meaning the treatment did not have a notable effect on the variation in systolic BP compared to the sham therapy.
The secondary outcome results are as follows:
Blood pressure variability: Additional measures of blood pressure variability including standard deviation of systolic blood pressure were less variable after active treatment following the first intervention.
Heart rate variability: Heart rate was lower after active stimulation was initiated, accompanied by a reduction in low frequency power in heart rate variability with increased high-frequency peak power. Accordingly, the LF:HF ratio after active therapy was restored towards higher vagal tone - indicating better autonomic function.
Neurological recovery NIH Stroke (NIHSS):
The change in NIHSS scores from admission levels was similar between groups, being 1.89(4.1) after active treatment, compared to 2.94 (7.7) after sham treatment (mean (SD) values).
Arrythmias:
There were 5 cardiac arrythmias recorded in both active and sham groups.
Myocardial Injuries:
The change in plasma troponin from admission levels was similar between groups, being -1.5ng/L (6.5) after active treatment, compared to -8.3 ng/L (18.1) after sham treatment (mean (SD) values).
Systemic inflammation: Active stimulation was associated with the upregulation of 88 genes and downregulation of 5 genes, correcting for a p<0.01 false-discovery rate. Analysis of differentially expressed genes identified active stimulation restored pro-inflammatory signalling pathways that are typically suppressed early after acute ischaemic stroke.This intervention is safe and readily deliverable at scale. These phase 2/proof of concept data suggest that active transauricular nerve stimulation may modify autonomic function favourably.
Acute peripheral neuromodulation during acute stroke results in physiologic changes indicate that the manipulation of autonomic control results in restoration of autonomic balance and neuroimmunomodulation.
The following limitations apply to this investigation: small sample size, lack of longer-term neurologic follow-up.
This safe intervention shows potentially favourable impact on two key determinants of outcome after stroke- autonomic dysfunction and immunosuppression. Given the safety profile and ease of use, larger scale studies are feasible to determine whether neurologic outcomes may be improved over the longer term.REC name
Wales REC 6
REC reference
23/WA/0013
Date of REC Opinion
16 Mar 2023
REC opinion
Further Information Favourable Opinion