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Review of Evidence on Noninvasive Vagus Nerve Stimulation for Treatment of Migraine: Efficacy, Safety, and Implications
Mkaya Mwamburi, MD, PhD; Andrew T. Tenaglia, BA; Eric J. Leibler; and Peter S. Staats, MD, MBA
Cost-effectiveness of Noninvasive Vagus Nerve Stimulation for Acute Treatment of Episodic Migraine and Role in Treatment Sequence Strategies
Mkaya Mwamburi, MD, PhD; Andrew T. Tenaglia, BA; Eric J. Leibler; and Peter S. Staats, MD, MBA
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Review of Evidence on Noninvasive Vagus Nerve Stimulation for Treatment of Migraine: Efficacy, Safety, and Implications

Mkaya Mwamburi, MD, PhD; Andrew T. Tenaglia, BA; Eric J. Leibler; and Peter S. Staats, MD, MBA
GammaCore was cleared by the FDA for the acute treatment of episodic migraine and episodic cluster headache and has 5 Conformité Européenne marks. Data indicate that gammaCore treatment is both safe and effective as an acute treatment for migraine. Current reimbursement policies need to be updated based on the growing body of evidence to reflect the established status of gammaCore that is no longer experimental. GammaCore provides substantial value to patients and to payers for consideration for pay-for-performance health coverage strategies and policies.
Am J Manag Care. 2018;24:-S0
The FDA cleared gammaCore (noninvasive vagus nerve stimulator [nVNS]; electroCore Medical, LLC, Basking Ridge, NJ) for the acute treatment of migraine in the United States in January 2018.1 GammaCore was previously approved for the treatment of episodic cluster headache in 2017 and has 5 Conformité Européenne marks for multiple indications, including one for primary headaches.2 Migraine is defined as a recurrent headache disorder manifesting in attacks lasting 4 to 72 hours, with or without aura.3-5 It may be episodic or chronic, depending on the number of headache days experienced in a month.3-5 Approximately 15% of the population in the United States suffer from migraine, accounting for 35 million individuals.3-5 Additionally, migraine is responsible for a substantial and disproportionate amount of clinical and economic burden.4-6 Although numerous medications are approved and used for acute treatment of episodic and chronic migraine, such as nonsteroidal anti-inflammatory drugs (NSAIDs), opiate-based analgesics, triptans, and ergotamine tartrate, among others, an estimated 3 million patients are dissatisfied with the available treatment options.4-8 Outside the United States, gammaCore is used for multiple indications.9,10 Prior to its FDA clearance, gammaCore has been shown to be safe and effective across a range of migraine populations in both the United States and Europe. Various treatment strategies have been evaluated with clinical, safety, and quality of life outcomes at varying study durations. A review of the evidence is critical when evaluating this newly approved treatment for migraine, to inform and update practice guidelines and reimbursement policies.

We performed a qualitative review of the literature, focusing on available evidence regarding the efficacy and safety of gammaCore in migraine. The purpose was to understand data highlighting the potential long-term benefits of gammaCore in managing patients with migraine, particularly those that remain dissatisfied by the available medications.

Methods

In addition to reviewing literature related to the efficacy and safety of gammaCore in the treatment of migraine, we evaluated studies that assessed the effects of gammaCore on various outcomes through quantitative and qualitative analysis of the evidence.

Sources of Evidence

Evidence from the following sources were reviewed:
  1. Research published before January 31, 2018, in English, that focused on efficacy and safety of gammaCore for treatment of migraine in humans.
    • The search strategy was defined by search terms in PubMed using key terms and their respective variations and Medical Subject Headings equivalents for “noninvasive vagus nerve stimulation,” “nVNS,” or “gammaCore.”
    • Primary studies were excluded if they were:
    • Non-migraine studies
    • Focused on other nVNS (non-gammaCore)
    • Studies identified in bibliographies of qualifying research studies
  2. Studies presented from 2015 to 2017 at conferences focused on gammaCore treatment or effectiveness of migraine, specifically. ElectroCore provided a complete list of publications, abstracts, and posters presented at conferences, including those of the American Headache Society, American Academy of Neurology, European Headache Federation, and European Headache and Migraine Trust International Congress.


Study Selection

All publications and conference presentations on gammaCore were reviewed. The search yields from PubMed and conference proceedings were combined, and duplicate studies were removed. If studies were published as full-text peer-reviewed journal articles and presented in conference proceedings, the most recent cumulative information of the studies from all sources were included.

Qualitative Analysis

Data were analyzed qualitatively in the following categories:

Randomized trials

Single-arm studies of gammaCore and case series

Results

The PubMed search yield was 32 studies; the search from conferences was 6 studies. Of the total of 38 studies, 30 were rejected (4 were duplicates and 26 were non-migraine studies). Of  the 8 qualifying studies, 2 were sham-controlled randomized trials, 3 were observational studies about patients with migraine, and 3 were observational studies of patients with migraine.11-18 Study  attrition is shown in the PRISMA diagram (see Figure 1).

Randomized Trials

Two sham-controlled randomized trials were reported, evaluating efficacy and safety of gammaCore in the treatment of migraine.

Trial Designs

The prospective study of nVNS for the acute treatment of migraine (PRESTO) and the noninvasive neurostimulation for the prevention of chronic migraine (EVENT) trial are prospective, double-blind, sham-controlled, randomized trials with optional open-label extension phases.16 PRESTO evaluated the superiority of gammaCore plus standard of care (SOC), compared to SOC alone, in the acute treatment in patients with episodic migraine in 10 sites in Italy between January 2016 and March 2017. Patients in the trial remained on their migraine medications or SOC but were not allowed to start new prevention medications during the trial period. In PRESTO, patients with 15 headache days or fewer per month were evaluated in a 4-week run-in period, a 4-week double-blind randomization phase, and a 4-week open-label extension phase in which patients who completed the double-blind phase optionally received additional gammaCore in addition to SOC treatment.

The EVENT study evaluated efficacy of gammaCore plus SOC in comparison with SOC alone in preventive treatment of patients with chronic migraine.15 EVENT was a prospective, multicenter, open-label, randomized, controlled trial in patients with 15 or more headache days per month that was conducted in 6 tertiary care headache centers in the United States between October 2012 and April 2014. Patients were randomized to receive gammaCore plus SOC versus SOC alone for 2 months, followed by an open-label phase of gammaCore plus SOC treatment for 6 months.

In both trials, patients were randomized to gammaCore, which produces a proprietary low-voltage electrical signal comprising a 5 kHz sine wave burst lasting for 1 millisecond (5 sine waves, each lasting 200 microseconds). Such bursts repeated once every 40 milliseconds (25 Hz) generating a 24 V peak voltage and 60 mA peak output current.19 The sham device produced a low-frequency (0.1 Hz) biphasic signal that did not stimulate the vagus nerve or generally cause muscle contraction.

Trial Results

In both trials, the mean age of patients was approximately 39 years, mostly female (at least 74%). Patients reported at baseline that the average number of headaches per month was approximately 6 for the PRESTO study, and approximately 21 for the EVENT study. Baseline characteristics for PRESTO and the EVENT studies are shown in Table 1.11-18

PRESTO consisted of a study population of 243 episodic patients with migraine for acute treatment (gammaCore, n = 120 vs sham, n = 123). For the first treated migraine attack, the pain-free rate was higher in gammaCore than in sham patients at 30 minutes (gammaCore, 12.7% vs sham, 4.2%; = .012) and 60 minutes (gammaCore, 21.0% vs sham, 10.0%; = .023). It was not higher at 120 minutes in gammaCore than in sham patients (gammaCore, 30.4% vs sham, 19.7%; = .067). A repeated-measures test across the 30-, 60-, and 120-minute findings demonstrated superiority of gammaCore over sham patients for the pain-free outcome with an odds ratio of 2.3 (95% CI, 1.2-4.4, = .012). Mild or no pain responder rates and reductions in pain score are shown in Table 2.11-18 The safety profiles for gammaCore and sham were similar. All device-related adverse events (AEs) reported were mild and transient with no serious device-related AEs reported. Twenty-two patients (18%) reported at least 1 AE in the gammaCore group, compared with 23 (18%) in the sham group. The number of patients reporting at least 1 device-related AE was 7 (6%) in the gammaCore group, compared with 10 (8%) in the sham group.

In the EVENT study, 59 chronic patients with migraine for prevention treatment formed the study population (gammaCore, n = 30 vs sham, n = 29). The mean change in number of headache days in the gammaCore versus sham groups were –1.4 (95% CI, –3.7 to

0.77; P = .44) versus –0.2 (95% CI, –1.5 to 1.1; P = .72). Persistent prophylactic gammaCore use was associated with continued reductions in the number of headache days. After the open-label phase, participants initially assigned to gammaCore had a mean change from a baseline of –2.5 (95% CI, –5.0 to –0.04; P = .06) and –3.6 (95% CI, –6.3 to –0.87; P = .02) after 6 and 8 months of treatment. The mean changes in the number of headache days analyzed without last observation carried forward imputation from baseline at months 4, 6, and 8 were –3.7, –6.1, and –8.0 headache days respectively in the gammaCore group (month 4, P <.05; months 6 and 8, P <.01). Eight months from baseline, the mean change for controls during the gammaCore extension phase was –6.0 headache days (P <.05), representing

6 months of gammaCore use. The proportion of participants from the gammaCore group that had a ≥50% response at month 2 was 10.0%, though no controls experienced a ≥50% response.

The safety profiles for gammaCore and sham were similar, and all device-related AEs reported were mild and transient, with no serious device-related AEs reported. A total of 17 participants reported at least 1 AE in the gammaCore group, with 1 participant reporting severe intensity. In the sham group, of 16 patients individuals experiencing AEs, 4 reported severe intensity.

Nonrandomized Studies

 
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