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Supplements Considerations in Non-Invasive Vagus Nerve Stimulation: Clinical Data and Expert Panel Recommendations
Mechanism of Action of Non-Invasive Cervical Vagus Nerve Stimulation for the Treatment of Primary Headaches
Bruce Simon, PhD, and Justyna Blake, MSE
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Review of Non-Invasive Vagus Nerve Stimulation (gammaCore): Efficacy, Safety, Potential Impact on Comorbidities, and Economic Burden for Episodic and Chronic Cluster Headache
Mkaya Mwamburi, MD, PhD (HEOR), MA (Econ); Eric J. Liebler, BA; and Andrew T. Tenaglia, BA
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Review of Non-Invasive Vagus Nerve Stimulation (gammaCore): Efficacy, Safety, Potential Impact on Comorbidities, and Economic Burden for Episodic and Chronic Cluster Headache

Mkaya Mwamburi, MD, PhD (HEOR), MA (Econ); Eric J. Liebler, BA; and Andrew T. Tenaglia, BA
The implications of these findings, in addition to the clearance for eCH by the FDA in the United States, include gammaCore receiving regulatory approval in Australia, Brazil, Canada, Colombia, India, Malaysia, New Zealand, the European Union, and South Africa for the acute and/or prophylactic treatment of CH and migraine. In Europe, gammaCore is used for multiple indications; in the United Kingdom, this includes the prevention and acute treatment of migraine and CH, and gammaCore is used in the National Health Service. 9,10 In the European Union, gammaCore is a class IIa medical device; it has been granted Conformité Européenne marks for use in primary headaches, bronchoconstriction, epilepsy, gastric motility disorders, and depression and anxiety.9

The scientific and physiological bases for how and why gammaCore works as a nVNS are beginning to be better understood. While the exact mode of action has not been pinpointed, there is indeed evidence that gammaCore stimulates the vagus nerve18 and that once the vagus nerve is stimulated, there are physiological consequences, some of which support the reduction in symptoms in CHs, migraines, and inflammatory disorders.18,24 There is evidence of the effect of vagal stimulation on the cortex associated with treatment of epilepsy,13,26-30 of reduction in pain in CH and migraine,31 of reduction of inflammation, and of positive effects on psychiatric disorders.11,32-34 A broader and more detailed review of the evidence around VNS and its mode of action is the subject of another review.35 The broader use of gammaCore for multiple other indications in numerous markets, regulated independently and covered for reimbursement, along with the supporting evidence of the hypothesized modes of action, further support the observations of gammaCore’s effectiveness: that it provides actual symptom relief and may have some longer-term benefits.

Based on these findings and considerations, the next logical questions are: does gammaCore add value to patients? And if so, does the value extend to payers? We examined these questions, with the focus on eCHs, in the context of current policies on reimbursement for VNS by payers in the United States. Based on findings of this review, we conclude that the use of gammaCore is beneficial to patients with eCH, safely improving their outcomes and quality of life. Simultaneously, gammaCore reduces adjunct medication use, which also translates to value for payers and should impact current reimbursement policies.

First, gammaCore is an easy, practical approach to treatment of CH. It is simple enough for patients to apply, without assistance, during an attack. The device is safe, and the delivery of treatment doses is measured; doses cannot be wasted. Also, patients have indicated a preference for using gammaCore.1 The treatment notably improves patient symptoms and results in a large reduction in the use of adjunct abortive CH medications, as well as overall utilization for comorbidities. When patients responded to gammaCore, the need for rescue medication was eliminated altogether. Therefore, for payers, gammaCore use may be associated with substantial long-term savings in patient costs.

Furthermore, gammaCore use is delivered via an electronic device, meaning that treatment delivery, adherence, and performance are relatively easier to monitor, particularly regarding treatment success, patient retention, utilization, and overall costs. This is particularly true when considering the growing trends toward performance-based coverage and that future generations of gammaCore devices will be Bluetooth-enabled and will seamlessly communicate with other devices, such as phones or laptops, for data capture.

Why is all this important to elucidate? For this reason: the current reimbursement policies for payers in the United States on VNS coverage explicitly state that primary headaches are not covered.36-39 These policies predate gammaCore and are based instead on the expensive, surgically implanted, permanent invasive vagus nerve stimulation (iVNS) device that was approved specifically for treatment of refractory seizures. The iVNS costs approximately $30,000 to be surgically inserted. At the time these policies were written, it was reasonable, in the absence of trial-based evidence of the effect of VNS on primary headaches, to exclude primary headaches from coverage for iVNS. However, with the advent of 1) significantly less expensive nVNS and 2) new evidence from the ACT trials, the need to modify the policies, both in language used and in actual coverage, is warranted. First, the current policies refer to “VNS” and do not distinguish between iVNS (requires expensive device implantation) and nVNS (practical, handheld device, simple to use, inexpensive, safe). This poses a challenge as most payers use automated coverage adjudication algorithms. New policies should explicitly separate these 2 very different modes of treatment for very different indications. Second, the new evidence on gammaCore, approved for eCH by the FDA in April 2017 and used in Europe for primary headache prevention and treatment of acute attacks since 2013, should drive payer policies to adapt and cover gammaCore for eCH.

One other advantage to consider is that results of multiple studies indicate that patients with primary headache, including those with CH, should not, particularly from the payers’ perspective, be viewed as single-morbidity patients. Instead, they should be considered as patients who commonly have multiple comorbidities; in comparison with average patients, patients with primary headache can cost payers up to 10 times more. Therefore, managing these patients adequately could not only markedly improve their health outcomes and quality of life, but also significantly reduce overall costs.

Limitations

This review, like any other, has strengths and limitations. One strength is that most evidence included in the literature review is peer-reviewed research, unless the research was very recently presented in conference proceedings and not yet published in the peer-reviewed literature. To support the legitimacy of the new evidence presented in this review, the data supporting the evidence are findings from robust, high-quality research designs. The efficacy of gammaCore in the secondary outcomes for eCH was demonstrated in double-blind, sham-controlled, randomized trials. The outcomes of the trials were clinically relevant and appropriately measured to support the hypothesis that gammaCore is superior to sham for patients with eCH.

One limitation associated with reviews is that the information available from publications that contribute to a review is as reported. This review, however, adds new information to the body of evidence, particularly in comparison with previous reviews. While authors of previous reviews had identified gammaCore as a beneficial intervention for patients with CH, they also pointed to a gap and a need for clinical trials to provide further evidence on its efficacy and safety. This review brings together the needed evidence to reduce the previously identified evidence gap.

The recommended future path for the various stakeholders—patients, researchers, electroCore, payers—is to collect real-world data that are specific to patients suffering from eCH and CH with regard to use or no use of gammaCore via a registry to monitor usage and performance measurement. Additionally, stakeholders should periodically review data from claims databases to evaluate long-term outcomes related to symptoms, utilization, cost, and reimbursement burden and the impact on comorbidities and all-cause healthcare utilization, to better understand the value associated with gammaCore use beyond symptom relief. With respect to evidence on patients with eCH, cost-effectiveness analysis using data from ACT1 and ACT2 have been published.40 Also needed are continued research efforts, using randomized controlled trials, to characterize the benefits of gammaCore in other indications, including migraine, specific inflammatory illnesses, cardiac diseases, and psychiatric disorders, to mention a few.

Conclusions

gammaCore, cleared in April 2017 by the FDA, is supported by a physiological basis for the observed effects and provides value to patients who suffer from eCHs. gammaCore would also provide value to payers, and there is sufficient evidence to support the need to modify current reimbursement policies, to differentiate nVNS from invasive iVNS, and to explicitly include coverage for gammaCore (nVNS) for eCH.

Author affiliations: electroCore Medical, LLC, Basking Ridge, NJ (EJL, ATT); profecyINTEL, LLC, Bridgewater, NJ (MM).
Funding source: This supplement was sponsored by electroCore, LLC.
Author disclosures: Mr Liebler and Mr Tenaglia have disclosed that they are employed by and own stock in electroCore, LLC. Dr Mwamburi has disclosed that he provided research services to produce the manuscript and owns stock in electroCore, LLC.
Authorship information: Acquisition of data (MM); analysis and interpretation of data (MM); concept and design (ATT, MM); critical revision of the manuscript for important intellectual content (ATT, MM); drafting of the manuscript (ATT, MM); obtaining funding (ATT); statistical analysis (MM).
Address correspondence to: mkaya.mwamburi@profecyintel.com.
 
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