PDF: VANQUISH
(2024)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
• 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
Inclusion Criteria
Age 18-75 years, severe headache (VAS ≥7), aneurysmal or perimesencephalic SAH, aneurysm secured (if present), able to verbalize pain score
Study Design
Arms: Active nVNS (n=19) vs Sham nVNS (n=21); stimulation started after aneurysm treatment, continued throughout ICU stay
Patients per Arm: 19 patients in active nVNS group, 21 patients in sham group (40 total randomized, 39 analyzed)
Outcome
• Significant post-stimulation headache reduction in nVNS group (p=0.005)
• Mean MED at day 7: 21.99 mg (nVNS) vs 24.29 mg (sham), p=0.93
• Mean MED at day 14: 19.91 mg (nVNS) vs 23.21 mg (sham), p=0.79
• Median length of stay: 16 days (nVNS) vs 18 days (sham), p=0.14
• New cerebral infarction: 5.6% (nVNS) vs 23.8% (sham), p=0.19
• mRS 0-2 at discharge: 94.4% (nVNS) vs 80.0% (sham), p=0.34
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 reduction in post-stimulation headache intensity (p=0.005) compared to 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
- Only adverse event difference: nausea (16.7% nVNS vs 2.0% sham, p<0.05)
- Muscle twitching more common with active device (44.4% vs 9.5%, p=0.03)
Study Design
- Study Type
- Multicenter randomized double-blind sham-controlled pilot feasibility study
- Randomization
- Yes
- 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.
- Sample Size
- 40
- Follow-up
- Through hospital discharge (median 16-18 days)
- Centers
- 3
- Countries
- United States
Primary Outcome
Definition: 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.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 48/51 (94.1%) had TEAE; 1 death from cerebral infarction; compliance: 75% of stimulations completed | 53/54 (96.1%) had TEAE; no serious device-related AEs; 0 deaths; compliance: 75% of stimulations completed; 12% missed due to bradycardia, 19% declined by patients | - | No significant differences in serious AEs |
Limitations & 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)
Citation
Brain Stimulation 17 (2024) 543–549