title: Effects of non-invasive vagus nerve stimulation on attack frequency over time and expanded response rates in patients with chronic cluster headache: a post hoc analysis of the randomised, controlled PREVA study.
abstract: BACKGROUND
  In the PREVention and Acute treatment of chronic cluster headache (PREVA) study, attack frequency reductions from baseline were significantly more pronounced with non-invasive vagus nerve stimulation plus standard of care (nVNS + SoC) than with SoC alone. Given the intensely painful and frequent nature of chronic cluster headache attacks, additional patient-centric outcomes, including the time to and level of therapeutic response, were evaluated in a post hoc analysis of the PREVA study.
  
  
  RESULTS
  After a 2-week baseline phase, 97 patients with chronic cluster headache entered a 4-week randomised phase to receive nVNS + SoC (n = 48) or SoC alone (n = 49). All 92 patients who continued into a 4-week extension phase received nVNS + SoC. Compared with SoC alone, nVNS + SoC led to a significantly lower mean weekly attack frequency by week 2 of the randomised phase; the attack frequency remained significantly lower in the nVNS + SoC group through week 3 of the extension phase (P < 0.02). Attack frequencies in the nVNS + SoC group were significantly lower at all study time points than they were at baseline (P < 0.05). Response rates were significantly greater with nVNS + SoC than with SoC alone when response was defined as attack frequency reductions of ≥25%, ≥50%, and ≥75% from baseline (≥25% and ≥50%, P < 0.001; ≥75%, P = 0.009). The 100% response rate was 8% with nVNS + SoC and 0% with SoC alone.
  
  
  CONCLUSIONS
  Prophylactic nVNS led to rapid, significant, and sustained reductions in chronic cluster headache attack frequency within 2 weeks after its addition to SoC and was associated with significantly higher ≥25%, ≥50%, and ≥75% response rates than SoC alone. The rapid decrease in weekly attack frequency justifies a 4-week trial period to identify responders to nVNS, with a high degree of confidence, among patients with chronic cluster headache.
authors.affiliation: Department of Headache and Facial Pain, Migraine and Headache Clinic, Ölmühlweg 31, Königstein im Taunus, 61462, Germany. c.gaul@migraene-klinik.de.
authors.forename: Charly
authors.initials: C
authors.lastname: Gaul
authors.affiliation: Headache Research Unit, University Department of Neurology, Centre Hospitalier Régional de la Citadelle, Boulevard du 12ème de Ligne 1, 4000, Liège, Belgium.
authors.forename: Delphine
authors.initials: D
authors.lastname: Magis
authors.affiliation: electroCore, LLC, 150 Allen Road, Suite 201, Basking Ridge, 07920, NJ, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Liebler
authors.affiliation: Department of Neurology, Ludwig-Maximilian University, Marchioninistr 15, Munich, D81377, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Straube
mesh_terms: D000328:Adult; D003027:Cluster Headache / Q000503:physiopathology* / Q000628:therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement; D013997:Time Factors; D016896:Treatment Outcome; D055536:Vagus Nerve Stimulation / Q000379:methods
keywords: Attack frequency; Chronic cluster headache; Non-invasive vagus nerve stimulation; PREVA; Patient-centric outcomes; Prophylactic treatment; Prophylaxis; Response rate