VANQUISH
Noninvasive vagus nerve stimulation in spontaneous subarachnoid hemorrhage (VANQUISH): A randomized safety and feasibility study
Year of Publication: 2024
Authors: Tania Rebeiz, Tagir Sabirov, Timothy G. White, ..., Richard E. Temes
Journal: Brain Stimulation
Citation: Brain Stimulation 17 (2024) 543–549
Link: https://doi.org/10.1016/j.brs.2024.04.004
PDF: https://www.brainstimjrnl.com/action/sho...%2824%2900062-7
PDF: Clinical Question
Is noninvasive vagus nerve stimulation safe, feasible, and effective in reducing headache intensity and opiate consumption in patients with spontaneous subarachnoid hemorrhage admitted to the ICU?
Study Overview
Objective
To evaluate the safety, feasibility, and efficacy of noninvasive vagus nerve stimulation (nVNS) in reducing headache intensity and opiate consumption in patients with spontaneous subarachnoid hemorrhage
Study Summary
- nVNS was safe and feasible with no serious device-related adverse events; only increased nausea (16.7% vs 2.0%, p<0.05)
- Significant reduction in post-stimulation headache intensity in nVNS group (p=0.005) but no significant difference in morphine equivalent dose reduction (10% at day 7, 15% at day 14, p>0.05)
Intervention
GammaCore® noninvasive transcutaneous vagus nerve stimulation device: two 2-minute stimulations (0-40 a.u. intensity) four times daily (6:30am, 11:30am, 4:30pm, 9:30pm) applied to cervical vagus nerve vs identical sham device
Patients per Arm
19 patients in active nVNS group, 21 patients in sham group (40 total randomized, 39 analyzed)
Bottom Line
Noninvasive vagus nerve stimulation is potentially safe and feasible in critical SAH patients, significantly reduces post-stimulation headache intensity, and shows a trend toward reduced opiate consumption (10-15% reduction in morphine equivalents) without serious adverse events.
Major Points
- First randomized double-blind sham-controlled trial of nVNS in SAH patients
- Multicenter pilot study at 3 Northwell Health hospitals in New York
- GammaCore device FDA-approved for migraine and cluster headaches
- No serious device-related adverse events (no hemodynamic instability, symptomatic bradycardia, or arrhythmias)
- Significant within-group reduction in post-stimulation headache intensity in active nVNS (p<0.001); between-group pre-to-post difference p=0.005 vs sham
- Trend toward reduced opiate consumption: 10% at day 7, 15% at day 14 (not statistically significant)
- 75% of scheduled stimulations completed; 12% missed due to bradycardia, 19% declined by patients
- Lower incidence of cerebral infarction in nVNS group (5.6% vs 23.8%, p=0.19)
- Median stimulation duration 9 days with 2 sessions per day
- Significant differences in expected non-serious side effects with active device vs sham: nausea/vomiting (4 vs 0, p=0.03), muscle twitching (8 vs 2, p=0.02), and lip pulling (6 vs 0, p=0.005)
Design
Study Type: Multicenter randomized double-blind sham-controlled pilot feasibility study
Randomization: 1
Blinding: Double-blind. Active and sham devices identical in appearance, sound, and operation. Only unblinded research assistant maintained randomization log. Patients, clinicians, investigators, and outcome assessors all blinded.
Enrollment Period: October 30, 2019 to June 20, 2022
Follow-up Duration: Through hospital discharge (median 16-18 days)
Centers: 3
Countries: United States
Sample Size: 40
Analysis: Modified intention-to-treat (mITT) analysis. Mixed Model Repeated Measures (MMRM) with REML for morphine equivalent dose. Unstructured covariance structure. Kenward-Roger approximation for degrees of freedom. Log-transformation of MED. Fisher's exact test for categorical variables, Student's t-test or Wilcoxon rank-sum for continuous variables. Significance at p<0.05. SAS Version 9.4.
Inclusion Criteria
- Age 18-75 years
- Admitted with severe headache (VAS ≥7)
- Diagnosed with aneurysmal or perimesencephalic subarachnoid hemorrhage
- Cerebral aneurysm secured (if diagnosed) prior to nVNS initiation
- Able to verbalize pain score at enrollment and throughout study
Exclusion Criteria
- Contraindication for cervical vagus nerve nVNS (implantable devices, history of internal carotid artery atherosclerosis)
- History of current alcohol abuse
- Substance addiction present at enrollment
- Chronic opiate use present at enrollment
- History of heart block or ventricular arrhythmia
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Number of patients | 21 | 19 |
| Mean age (years) | 51 (11) | 54 (13) |
| Female | 13 (62%) | 14 (74%) |
| Male | 8 (38%) | 5 (26%) |
| Hunt-Hess 1 | 7 (33%) | 5 (26%) |
| Hunt-Hess 2 | 11 (52%) | 10 (53%) |
| Hunt-Hess 3 | 2 (10%) | 2 (10%) |
| Hunt-Hess 4 | 1 (5%) | 2 (11%) |
| Modified Fisher 1 | 2 (10%) | 4 (21%) |
| Modified Fisher 2 | 2 (9%) | 1 (5%) |
| Modified Fisher 3 | 9 (43%) | 8 (42%) |
| Modified Fisher 4 | 8 (38%) | 6 (32%) |
| Aneurysm clipping | 8 (42%) | 7 (41%) |
| Aneurysm coiling | 11 (58%) | 10 (59%) |
| Aneurysmal SAH | 19 (89%) | 17 (88%) |
| Perimesencephalic SAH | 2 (11%) | 2 (12%) |
Arms
| Field | Control | Active nVNS |
|---|---|---|
| Intervention | Identical sham device (no electrical output) applied to cervical vagus nerve. Two 2-minute 'stimulation' sessions at 6:30am, 11:30am, 4:30pm, and 9:30pm if hemodynamically stable (HR >60 bpm, SBP >100 mmHg, MAP >60 mmHg). Continued throughout ICU stay. | GammaCore® noninvasive transcutaneous electrical vagus nerve stimulation device. Two electrodes on cervical vagus nerve, peak voltage 24V, peak current 60 mA, adjustable intensity 0-40 a.u. Two 2-minute stimulations at 6:30am, 11:30am, 4:30pm, and 9:30pm if hemodynamically stable. Patient self-selected stimulation side (usually side of greatest headache). Intensity increased to maximum tolerated level. Continued throughout ICU stay. |
| Duration | Median 9 days | Median 9 days |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Safety: Number of serious adverse effects related to nVNS including hemodynamically unstable hypotension, symptomatic bradycardia, arrhythmias, neurologic deterioration during stimulation and during delayed cerebral ischemia period. Feasibility: Patient compliance measured by number of stimulations received when deemed appropriate. Pooled across both arms: of 1260 total nVNS attempts, 950 (75%) completed, 133 (12%) missed due to sinus bradycardia, 40 (3%) missed due to patient unavailability; of 1087 attempted stimulations, 172 (19%) declined by patients. | Primary | n=21; 1 death (cerebral infarction with malignant brain edema progressing to brain death); no device-related serious AEs | n=18 analyzed; no device-related serious AEs (no hemodynamic instability, symptomatic bradycardia, or arrhythmias); 0 deaths | No significant difference in serious AEs | |
| Change in morphine equivalent dose (MED) from baseline - primary efficacy | Secondary | Baseline 14.50 mg (SD 12.60); Day 7: 24.29 mg (SD 20.11); Day 14: 23.21 mg (SD 18.06) | Baseline 14.69 mg (SD 13.28); Day 7: 21.99 mg (SD 21.4); Day 14: 19.91 mg (SD 19.13) | MMRM: F(1,47.4)=-0.19 mg, p=0.66 overall; no group×treatment day interaction (p=0.57); Day 7 p=0.93; Day 14 p=0.79 | |
| Post-stimulation headache intensity (VAS 0-10) | Secondary | No significant within-group reduction (p=0.21) | Significant within-group reduction (p<0.001) | p=0.005 between groups for pre-to-post change | |
| Change in systolic blood pressure during stimulation | Secondary | No significant change | Significant decrease within group (p=0.02) | p=0.68 between groups; trend interaction p=0.06 | |
| Change in diastolic blood pressure during stimulation | Secondary | No significant change | No significant change | p>0.05 | |
| Change in heart rate during stimulation | Secondary | No significant change | No significant change | p>0.05 | |
| Modified Rankin Scale 0-2 at discharge | Secondary | 16/20 (80.0%) | 17/18 (94.4%) | p=0.34 | |
| Hospital length of stay - median (IQR) days | Secondary | 18 (13-22) days | 16 (15-17) days | p=0.14 | |
| New cerebral infarction on neuroimaging | Secondary | 5/21 (23.8%) | 1/18 (5.6%) | p=0.19 | |
| Neurologic deterioration from cerebral vasospasm | Secondary | 6 (31%) | 3 (19%) | >0.05 | |
| Nausea/vomiting during stimulation | Adverse | 0/21 (0%) | 4/18 (22.2%); occurred in 7/433 stimulations (1.6%) | p=0.03 | |
| Muscle twitching | Adverse | 2/21 (9.5%) | 8/18 (44.4%) | p=0.02 | |
| Lip pulling | Adverse | 0/21 (0%) | 6/18 (33.3%) | p=0.005 | |
| Facial droop | Adverse | 0/21 (0%) | 0/18 (0%) | N/A | |
| Tingling at stimulation site | Adverse | 5/21 (23.8%) | 9/18 (50%) | p=0.15 | |
| Pain at stimulation site | Adverse | 2/21 (9.5%) | 6/18 (33.3%) | p=0.1 | |
| Dizziness | Adverse | 2/21 (9.5%) | 0/18 (0%) | p=0.4 | |
| Shortness of breath | Adverse | 0/21 (0%) | 1/18 (5.6%) | p=0.46 | |
| Hemodynamically unstable hypotension | Adverse | 0/21 | 0/18 | N/A | |
| Symptomatic bradycardia | Adverse | 0/21 | 0/18 | N/A | |
| Arrhythmia | Adverse | 0/21 | 0/18 | N/A | |
| Death | Adverse | 1/21 (4.8%) - cerebral infarction with brain edema | 0/18 | >0.05 |
Subgroup Analysis
None reported. Median time from admission to aneurysm treatment: 1 day (IQR 0-1). Median time from aneurysm treatment to first stimulation: 2 days (IQR 1-3). Pooled feasibility across both arms: of 1260 attempted stimulations, 950 (75%) completed, 133 (12%) missed due to bradycardia, 40 (3%) missed due to patient unavailability; of 1087 attempted stimulations, 172 (19%) declined by patients.
Criticisms
- Small pilot study (n=40) limits generalizability and statistical power
- No sample size calculation performed (feasibility study)
- Active stimulation can cause muscle twitching and sensations, potentially unblinding participants
- No long-term follow-up beyond hospital discharge
- High rate of sinus bradycardia in SAH population led to 12% of missed stimulations
- 19% of stimulations declined by patients (fatigue, perceived lack of benefit, no pain at scheduled time)
- Limited to patients able to verbalize pain scores, excluding more severe SAH patients
- Stimulation timing fixed to avoid shift changes rather than optimized for pain patterns
- No assessment of optimal stimulation side or intensity
- Exploratory outcomes (cerebral infarction, DCI) not powered for statistical significance
- Median 9 days of stimulation may not capture long-term effects
- Most patients had low-grade SAH (Hunt-Hess 1-2), limiting generalizability to severe SAH
- Unclear whether nVNS prevents headache or only treats existing pain
- Potential confounding from nimodipine causing bradycardia
- No assessment of mechanism (anti-inflammatory, antinociceptive, or other)
Funding
The trial was funded by ElectroCore, Inc. The company provided active and sham devices and funds to support research staff for the conduct of the clinical trial and journal submission fees, but had no role in study design, data collection, analysis, or manuscript writing.
Based on: VANQUISH (Brain Stimulation, 2024)
Authors: Tania Rebeiz, Tagir Sabirov, Timothy G. White, ..., Richard E. Temes
Citation: Brain Stimulation 17 (2024) 543–549
Content summarized and formatted by NeuroTrials.ai.