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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
Participating Faculty

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
In the Prevention and Acute Treatment of Chronic Cluster Headache (PREVA) trial treatment with gammaCore plus SOC resulted in a significant reduction in number of attacks per week from baseline values: –5.9 in the gammaCore + SOC group and –2.1 in the SOC group (MD, –3.9; P = .02). Over 30% more patients had a successful response in more than 50% of their attacks (gammaCore + SOC, 18 of 45 patients [40%], vs SOC alone, 4 of 48 patients [8.3%]; P <.001).6 In addition, the patients on gammaCore + SOC experienced improvement in the EQ-5D health index (rising from 0.5 to 0.6) compared with no change in the patients who used the SOC alone during the randomization phase.6 The safety profile for gammaCore + SOC was similar to that of SOC alone. AEs, particularly device-related, were all mild and transient with no serious device-related AEs reported. The number of patients reporting at least 1 AE was 25 (52%) in the gammaCore + SOC group compared with 24 (49%) in the SOC-alone group. The number of patients reporting at least 1 device-related AE was 13 (27%) in the gammaCore + SOC group compared with 7 (14%) in the SOC-alone group. Two patients in the gammaCore + SOC group reported a serious AE not device related (1 cholecystitis, 1 hematoma after scheduled surgery), whereas 2 were reported in the SOC-alone group (1 genital herpes simplex virus infection, 1 exacerbation of CH).

Observational/Open-Label Phase Studies on Impact of gammaCore

In the unblinded extension phase of the PREVA study, Gaul et al (2017) concluded that the prophylactic use of gammaCore led to rapid and sustained reductions in chronic CH attack frequency. Attack frequency remained significantly lower in the gammaCore + SOC group through week 3 of the extension phase (P < 02).14 In a UK cohort study of 19 patients (8 episodic and 11 chronic), Nesbitt et al (2015) reported that the evidence suggested that gammaCore may be practical and effective as both an acute and a preventive treatment in patients with chronic CH. Further evaluation of this treatment using randomized sham-controlled trials was warranted at the time.17 Marin et al (2016) reported in a retrospective analysis of 30 patients with CH (1 episodic and 29 chronic) that the use of gammaCore for acute treatment for 52 weeks resulted in significant reduction in CH attacks, duration of attacks, severity of attacks, and use of acute abortive medications.20

Cost-Effectiveness Studies

In a cost-effectiveness analysis reported by Morris et al (2016) based on a subset of PREVA study data from Germany, gammaCore + SOC was cost saving compared with SOC alone, from the German payer perspective.16 In another cost-effectiveness analysis based on a subset of PREVA study data from the United Kingdom, Jenks et al (2016) found the incremental cost-effectiveness ratio (ICER) from the UK payer perspective was £13,368 per quality-adjusted life-year gained when comparing gammaCore + SOC with SOC alone.21 The UK ICER threshold is £20,000.

Burden of Illness

Polson et al (2017) conducted and reported a cost analysis based on medical and pharmacy claims data from 4 regional health plans to evaluate differences in healthcare utilization and cost in 4174 patients with CH diagnoses (chronic, episodic, or “not defined”) compared with a 1:1 control group of patients without headache-related conditions. The overall medical costs per patient for chronic (n = 724), episodic (n = 751), and nondefined (n = 2699) patients with CH were $30,502; $22,607; and $25,436, respectively, compared with $10,140 for nonheadache controls (P <.01). The overall prescription fills per patient for chronic, episodic, and patients with nondefined CH were 30.66, 23.90, and 24.79, respectively, compared with 12.34 for controls (P <.01). The corresponding overall pharmacy costs per patient for chronic, episodic, and patients with nondefined CH were $12,534; $8209; and $8570, respectively, compared with $4368 for controls (P <.01).4 Limitations include use of claims data and that the sample may include migraine patients. Evidence from primary studies is summarized in Table 3.4,14,16,17,20,21

Summary of Evidence Presented in Recent Reviews

A pooled ACT1 and ACT2 analysis was also conducted and presented.22 For patients with eCH, the pooled proportions of patients who responded (mild or pain free) to the first attack were 38.5% versus 11.7% (P <.01) for patients receiving gammaCore versus sham, respectively. The percentage of all treated attacks in the pooled analysis that were pain free at 15 minutes were 24.1% versus 7.3% (P <.01) for patients receiving gammaCore versus sham, respectively; and the pooled proportions of patients who responded (mild or pain-free) to >50% of their attacks were 42.3% versus 15.0% (P <.01) for patients receiving gammaCore versus sham, respectively.

Tepper et al (2013) reviewed the options, including gammaCore, for patients with medically refractory CH. At the time of the review, they concluded, “Because this device [gammaCore] does not require implantation, randomized controlled trials are clearly indicated.”8 Successful randomized trials have since been conducted.1,6,7

Ben-Menachem et al (2015) reviewed evidence regarding invasive versus non-invasive VNS for treatment of patients with CH. They found that the less frequent stimulation schedules used with nVNS may reduce the overall incidence of stimulation-associated AEs. Without a requirement for an expensive and potentially risky surgical procedure, nVNS may facilitate the earlier use of therapeutic VNS without the prerequisite of achieving a “treatment-refractory” status in the condition of interest.23

Holle-Lee et al (2016) reviewed clinical evidence regarding the management of patients with CH. They concluded that the advantages of nVNS lie in the safety of the technique and the low rate of associated AEs and that nVNS might be used not only as add-on prophylaxis in refractory chronic CH but also for episodic subtypes.18

Farmer et al (2016) reviewed evidence regarding VNS in clinical practice for patients with CH. They found that the vagus nerve continues to be an area of pathophysiological interest across a number of clinical disciplines. By extension, VNS, they concluded, had generated great interest and continued to be actively investigated. They noted that VNS is a potential treatment option that needs to be investigated, although its absolute place in clinical practice remains to be fully determined.12

Discussion

To summarize the findings of this review, the results from 2 double-blind, sham-controlled, randomized trials (ACT1, ACT2, and pooled analysis) demonstrated the superiority of gammaCore when added to other treatments (SOC) for episodic CHs by significantly reducing CH attack intensity, duration, and adjunct medication use. These trial findings and evidence that gammaCore does stimulate the vagus nerve contributed to the basis for the FDA clearance in April 2017 of gammaCore for treatment of pain associated with episodic CH in the United States. This clearance was granted within the context of the FDA approval process for devices and how it differs from that for pharmaceutical products.1,7

In addition, the results of PREVA, an open-label, randomized trial, indicated significant reductions in both the frequency and duration of attacks in patients with chronic CH.6,14 The result of these trials (ACT1, ACT2, and PREVA) also demonstrated the safety of gammaCore. Data from PREVA indicated that gammaCore use was cost-effective in patients with chronic CH, from the United Kingdom and German healthcare systems’ perspectives.16,21 Observational study results showed that patients with primary headaches, specifically those with CHs, often have multiple comorbidities and that these patients have significantly higher healthcare utilization and cost burden compared with patients with no reported comorbidities (eg, the average nonheadache patient).4,5 gammaCore treatment for primary headache was associated with reductions in general practitioner appointments, referrals made by general practitioners, and with improvement in quality of life.18

It is important to step back and examine what these various pieces of evidence could mean for management of pain associated with eCH. All 3 trials were designed with gammaCore being adjunct to SOC, as it would be unethical to withhold SOC. Control patients received currently available treatments for the respective CH subtype. Therefore, it should be noted that the superiority of gammaCore is over and above the current SOC. Furthermore, regarding safety, it is remarkable that gammaCore not only has a safety profile similar to that of SOC, but as an added advantage, reduces the overall need for SOC medications. These trials were conducted in patients taking a range of medications and high-flow oxygen, and yet the impact of gammaCore corresponded to significant benefits. For example, in ACT1, gammaCore patients were 3 times more likely to respond, more than twice likely to achieve 50% pain-free status, and had their duration of attacks reduced by 30 minutes. Clinical symptom decreases of similarly substantial magnitude were also seen in ACT2. The observed AEs were mild and transient, while medication use and cost burden were reduced. These findings demonstrate robust efficacy and safety in a proportion of patients, both of which present a compelling argument for the advantages of gammaCore on efficacy and safety. These advantages need to be considered for the adoption of gammaCore in practice and for subsequent coverage by payers.

To further confirm gammaCore’s contributions to the acute relief of symptoms in patients with eCH, additional evidence points to potential associated longer-term benefits, ones lasting for up to a year.17 Granted, these retrospective studies do not have experimental designs. However, it is evident, based on real-world data, that a significant proportion of patients with CH4 (or patients with primary headache5) have multiple comorbidities, with economic burdens significantly higher than those of patients without comorbidities or of the average nonheadache patients covered by payers. Furthermore, treatment of these patients with gammaCore is associated with reduction in healthcare utilization and improved quality of life.18 By deduction, it is conceivable that broad adoption and coverage of gammaCore for treatment of patients with eCH will be beneficial to patients and payers.

Findings from the PREVA study demonstrated the sustained effectiveness of gammaCore in patients with chronic CH with robust results, as well.6,14 In addition, the results of 2 cost-effectiveness studies, in the United Kingdom and in Germany, were persuasive: one showed dominance over SOC alone and the other with an ICER threshold of less than £20,000.16,21 Findings from the ACT1 and ACT2 chronic patients’ strata were not significant.

 
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