Transcutaneous non-invasive vagus nerve stimulation (gammaCore) for the treatment of cluster headache: A single technology assessment
Health technology assessment
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The aim of this single technology assessment is to assess effect, safety and health economics based on the submitted documentation from electroCore, the manufacturer of gammaCore.
Key message
Cluster headache is a relatively rare but extremely painful condition. It is part of a group of conditions known as trigeminal autonomic cephalalgias (TACs). Cluster headache involves recurrent attacks of severe, unilateral pain. Attacks occur in periods (clusters) of several weeks and may last from 15 to 180 minutes at a rate of one every other day to eight per day. GammaCore is a handheld medical device stimulating the vagus nerve with electrical impulses. According to the submitter, gammaCore can reduce the need for acute treatment with oxygen or triptans associated with attacks.
Effectiveness and safety: One study comparing gammaCore to standard treatment shows that prophylactic use of gammaCore may improve quality of life, reduce attack frequency, and reduce the use of abortive medication among patients with chronic cluster headache. Two studies comparing gammaCore versus sham in the treatment of ongoing attacks show that gammaCore may have limited impact on patients with chronic cluster headache, but patients with episodic cluster headache probably experience higher likelihood of achieving pain-free status at 15 min and reduced pain intensity.
The included studies reported few adverse events, and no serious adverse events have been reported since the introduction on the European market. However, the manufacturer warns that gammaCore’s safety and efficacy has not been evaluated for patients with cardiological disorders.
Severity: Absolute shortfall for patients with chronic cluster headache is 7.03 QALYs. The figure for patients with episodic cluster headache has not been estimated but is likely to be somewhat lower.
Economic analysis: Based on the submitters economic model gamma-Core plus standard of care are dominant over standard of care alone, i.e. the costs are lower and the benefits are higher. The submitted budget impact analysis estimates that the number of patients using gammaCore will grow from 0 to 325 over the next five years if gammaCore is adopted, resulting in a cost saving of NOK 7,140,000 at year five.
NIPH considers the economic analysis to be reasonable for patients with chronic cluster headache, but there are important uncertainties with respect to its relevance for those with episodic cluster headache.
Summary
Background
Cluster headache (CH) is a relatively rare, but extremely painful condition. It is part of a group of conditions known as trigeminal autonomic cephalalgias (TACs). CH involves recurrent attacks of severe, unilateral pain. The lifetime prevalence of CH is estimated to 0.5 to 1 per 1000 inhabitants, which for the Norwegian population means that between 2 500 and 5 000 may be diagnosed with the disease.
The attacks occur in periods (clusters) of several weeks and may last from 15 to 180 minutes at a rate of one every other day to eight per day. There are two types of cluster headache: episodic (eCH) and chronic (cCH), though patients may switch between the two variants. Episodic CH typically involves series of attacks that occur at certain times of the year, while cCH involves attacks throughout the year.
GammaCore is a handheld medical device used for non-invasive vagus nerve stimulation (nVNS) with electrical impulses. According to the submitter, use of gammaCore can reduce the need for acute treatment with oxygen or triptans associated with attacks. The submitter believes that gammaCore may be used by patients who do not benefit from existing preventive treatment, either because they are refractory or because they experience adverse events. At year five, this amounts to 325 patients who respond positively to gammaCore per year.
Objective
The aim of this single technology assessment is to assess effect, safety and health economics based on the submitted documentation from electroCore, the manufacturer of gammaCore.
Method
This report is based on an evaluation of the documentation provided by the submitter. The submission file states that the following databases were searched for clinical trials on the 30. March 2022: Medline, Embase, Medline (R) In-Process, and Cochrane Library. ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform (WHO-ICTRP) were searched for ongoing or unpublished studies. Searches were meant to update the searches reported in a submission file to the National Institute for Health and Care Excellence (NICE) from 2019. The submitter used the following PICO in the selection of clinical effect and safety studies:
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Inclusion criteria |
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Population |
Cluster headache |
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Interventions |
nVNS |
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Outcomes |
All outcomes |
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Study design |
Clinical trials |
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Language |
English |
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Publication dates |
1. January 2005- 30. March 2022 |
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Exclusion criteria |
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Study design |
Post hoc analyses, non-primary study publications, mechanistic studies, reviews |
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Publication dates |
Prior to 1. January 2005 |
Results
Effectiveness and safety
One study focusing on attack prevention for patients with cCH compared nVNS plus standard of care versus standard care alone. The study showed that prophylactic use of nVNS may reduce the attack frequency by almost four per week, reduce the need of abortive medication and improve quality of life by almost 0.2 points on EQ-5D-3L.
Two studies examined the effectiveness of nVNS in treating ongoing attacks by comparing nVNS versus sham. For patients with eCH, nVNS probably improves the number of patients who respond at 15 min to the first attack, probably improves the number of patients who are pain free status at 15 min, probably improves the sustained response rate, and may reduce the pain intensity by almost one point on a five-point Likert scale after 15 min. Patients with cCH experience less benefits from nVNS in the treatment of ongoing attacks than patient with eCH, and it seems like using nVNS in the acute phase may have little or no impact on response rates and pain intensity for patients with cCH.
GammaCore has been approved for the European market since 2011 and in the US since 2018 to treat cluster headaches. No serious adverse events have been reported since being on the European market in Medicines and Healthcare products Regulatory Agency database (MHRA), and only one event report in Manufacturer and User Facility Device Experience database (MAUDE, FDA, USA). The included studies reported few adverse events, and those reported were temporary and infrequent. However, there is very limited safety and efficacy data related to patients with cardiological histories, and the ‘instructions for use’ includes warnings stating this.
Health economics
The submitter’s health economic analysis was a Markov model in which preventative use of gammaCore together with standard of care was compared to standard of care alone for patients with chronic cluster headache. The model duration was one year, and the consequences for attack frequency, costs and quality of life were estimated. The result of the deterministic base-case analysis found that gammaCore plus standard of care was dominant (i.e. lower costs and higher benefits) over standard of care alone. The total cost of gammaCore plus standard of care was estimated to be NOK 29,494, whereas total cost of standard of care alone was estimated to be NOK 32,355, the corresponding QALYs were 0.525 and 0.441.
The most uncertain variables were the cost of oxygen and the probability of response to gammaCore. The submitter will offer gammaCore free of charge for the first 93 days to reduce the impact of uncertainties in the probability of response, and the model assumes that only responders will continue treatment beyond this period.
The budget impact analysis includes both cCH and eCH and assumes that the number of patients responding to gammaCore each year will grow from 0 to 325 over the next five years if gammaCore is adopted. Due to the expected reduction in the use of acute treatment, a cost saving of NOK 7,140,000 is projected at year 5.
Discussion
Few treatments are available for patients with cluster headache, though they may benefit from drugs such as verapamil and lithium. Triptans and oxygen may offer relief in the acute phase, but the latter is cumbersome to use and may result in patient isolation.
NIPH recognizes that cluster headache is a relatively rare disease and that it is challenging to undertake clinical trials in this field. It seems that current guidelines in preventive treatment for cluster headache tend to be based on off-label therapies supported by a small number of randomized, controlled clinical trials.
The submitter developed a health economic model based on data from patients with cCH. The submitter assumes that eCH can be included in the model, asserting that evidence regarding preventative effectiveness can be generalized from cCH to eCH. This assumption is not documented, implying that the economic benefits of gammaCore for eCH remain uncertain. Given that gammaCore seems to be effective in treating ongoing attacks in patients with eCH, it is possible that it can involve cost savings, but evidence is lacking. If gammaCore is publicly financed, the submitter proposes that a consultant neurologist should decide if the patient should continue to use the device or not every three months.
Conclusion
Our assessment of the submitted documentation is that gammaCore may provide benefits to some patients in terms of fewer attacks and more rapid pain relief. For patients with cCH the benefits of gammaCore seem to be associated with prophylactic use, whereas patients with eCH probably benefit from treatment in the acute phase.
If gammaCore is offered alongside standard of care subject to 93 days free use, it may generate cost savings to the Norwegian health care system. NIPH considers the economic analysis to be reasonable for patients with cCH, but there are important uncertainties with respect to its relevance for those with eCH.
