Medical Policy: 07.01.60
Original Effective Date: November 2000
Reviewed: September 2020
Revised: September 2018
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Vagus nerve stimulation (VNS) was initially investigated as a treatment alternative in patients with medically refractory partial-onset seizures for whom surgery is not recommended or for whom surgery has failed. Over time, the use of VNS has expanded to include generalized seizures, and it has been investigated for a range of other conditions including chronic heart failure, headaches, treatment resistant depression, essential tremor, fibromyalgia, tinnitus, obesity, upper limb impairment due to stroke and autism.
Seizures are considered paroxysomal disorders (i.e. characterized by abnormal cerebral neuronal discharge) and occur when there is errant electrical discharge activity in the brain. Seizures cause different physical symptoms depending on the location of the electrical activity in the brain. They may be mild to severe, ranging from causing slight tingling sensation or momentary confusion to causing complete loss of consciousness. Classification and subtypes of seizures are commonly diagnosed by electroencephalography (EEG). The diagnosis of seizure requires that the clinician identify that the patient has had an epileptic seizure as opposed to some other type of paroxysmal event, and then establish the type of seizure(s).
Generalized seizures are further broken down into motor and non-motor (absence) seizures. Focal seizures are further subdivided based on level of awareness (aware, impaired awareness, or unknown awareness). Additionally, focal seizures are subgrouped into motor and non-motor seizures, based on signs and symptoms at onset. Additional descriptors for both generalized and focal seizures may be added based on specific motor or nonmotor symptoms. Focal seizures can also be more clearly described based on the elemental features (cognitive, automatisms, emotional or affective, motor, autonomic, sensory, laterality).
Epilepsies can be subdivided into generalized, focal, generalized and focal and unknown (epilepsy based on seizure type).
Vagus nerve stimulation (VNS) was originally approved for the treatment of medically refractory epilepsy. Significant advances have been made since then in the surgical and medical treatment of epilepsy, and new, more recently approved medications are available. Despite these advances, however, 25% to 50% of patients with epilepsy experience breakthrough seizures or suffer from debilitating adverse effects of anti-seizure medications. VNS is typically used when a patient has had unsuccessful medical therapy, been intolerant of medical therapy, or has failed resective surgery.
While the mechanisms for the therapeutic effects VNS are not fully understood, the basic premise of VNS in the treatment of various conditions is that vagal visceral afferents (nerves that convey impulses from sense organs and other receptors to the brain or spinal cord) have diffuse central nervous system projection, and the activation of these pathways has a widespread effect upon neuronal excitability. aN Electrical stimulUS is applied to axons of the vagus nerve, which have their cell bodies in the nodose and junctional ganglia and synapse on the nucleus of the solitary tract in the brainstem. From the solitary tract nucleus, vagal afferent pathways project to multiple areas of the brain. VNS may also stimulate vagal efferent pathways that innervate the heart, vocal cords, and other laryngeal and pharyngeal muscles, and provider parasympathetic innervation to the gastrointestinal tract.VNS may also stimulate vagal efferent pathways that innervate the heart, vocal cords, and other laryngeal and pharyngeal muscles, and provider parasympathetic innervation to the gastrointestinal tract. Adverse effects of VNS therapy include headache, neck pain, cough and voice alterations.
Some of the benefits of using VNS may include less-severe or shorter seizures, a reduction in seizure frequency, improved recovery periods after seizures, and a lessening of seizure clusters. Individuals undergoing VNS must be aware that seizure control improves over time, and that although VNS may reduce the frequency and magnitude of seizure activity, the need remains for ongoing, concurrent, anti-seizure medical regimen.
Vagus nerve stimulation (VNS) is an implantable, programmable electronic pulse generator that delivers stimulation to the left vagus nerve at the carotid sheath. Surgery for implantation of a vagus nerve stimulator involves implantation of the pulse generator in the infraclavicular region and wrapping 2 spiral electrodes around the left vagus nerve within the carotid sheath. The programmable stimulator may be programmed in advance to stimulate at regular intervals or on demand by patients or family by placing a magnet against the subclavicular implant site.
The stimulator is generally activated two to four weeks after implantation, although in some cases it may be activated in the operating room at the time of implantation. The physician programs the stimulator with a small hand-held computer, programming software, and a programming wand. The strength and duration of the electrical impulses are programmed. The amount of stimulation varies by case, but is usually initiated at a low level and slowly increased to a suitable level for the individual.
Patients are provided with a handheld magnet to control the stimulator at home (which must be activated by the physician to magnet mode). When the magnet is placed over the pulse generator site and then moved away, extra stimulation is delivered, regardless of the treatment schedule. Holding the magnet over the pulse generator will turn the stimulation off. Removing it will resume the stimulation cycle. This can be done by the patient, family members, friends or caregivers.
The purpose of implantable vagus nerve stimulation (VNS) is to apply pulse electrical strategy via the vagus nerve to alter aberrant neural activity resulting in seizures.
The relevant population of interest is patients with medically refractory seizures; treatment-resistant depression; other conditions (e.g. chronic heart failure, fibromyalgia, essential tremor, headaches, obesity, tinnitus, autism, and upper limb impairment due to stroke).
The intervention being considered is implantation vagus nerve stimulation (VNS).
Surgically implanted VNS devices consist of an implantable, programmable electronic pulse generator that delivers stimulation to the left vagus nerve at the carotid sheath. The pulse generator is connected to the vagus nervevia a bipolar electrical lead. Surgery for implantation of a vagal nerve stimulator involves implantation of the pulse generator in the infraclavicular region and wrapping 2 spiral electrodes around the left vagus nerve within the carotid sheath. The programmable stimulator may be programmed in advance to stimulate at regular intervals or on demand by patients or a family member by placing a magnet against the subclavicular implant site.
VNS is typically used when a patient has had unsuccessful medical standard therapy, or has been intolerant of medical standard therapy, or has failed resective surgery.
For treatment of refractory seizures the following practices are currently being used: resective surgery, additional trial of conventional antiepileptic drugs and/or ketogenic diet.
For treatment resistant depression, additional therapy such as adding a different class of medication or adding psychotherapy, switching to a different therapy such as a different antidepressant or electroconvulsive therapy are practices that may be used.
For treatment of refractory epilepsy, the outcomes of interest are seizure frequency and severity, reduction in seizure frequency by >50%, quality of life and functional outcomes, cognitive function, mediation use and treatment-related morbidity.
For treatment-resistant depression, the outcomes of interest are depression symptoms as measured by the Montgomery-Asberg Depression Rating Scale or Hamilton Depression Rating Scale, response and remission global impression of change, suicide, quality of life and functional outcomes, and treatment-related morbidity. Relief of depression symptoms can be assessed by any one of many different depression symptom rating scales. A 50% reduction from baseline score is considered to be a reasonable measure of treatment response. Improvement in depression symptoms may allow reduction of pharmacologic therapy for depression, with a reduction in adverse events related to that form of treatment. In the studies evaluating VNS therapy, the 4 most common instruments used were the Hamilton Rating Scale for Depression, Clinical Global Impression, Montgomery and Asberg Depression Rating Scale, and the Inventory of Depressive Symptomatology (IDS).
For treatment-resistant depression, data on outcomes related to depression symptoms are needed over the short-term (2 to 6 months) and the long-term (1 to 2 years).
The evidence in the peer-reviewed scientific literature have shown that VNS may be a viable option to reduce the severity and shorten the duration of seizures in those patients who remain refractory despite optimal drug therapy or surgical intervention, as well as in those with debilitating side effects of antiepileptic medications. Seizure frequency is usually reduced by 50%, which is similar to the result of many drugs but without the side effects.
There are treatment modalities for which there is substantial evidence of effectiveness in the treatment of a major depressive episode (MDE): pharmacotherapy with antidepressant drugs (ADDs), specific forms of psychotherapy (e.g., cognitive behavior and interpersonal therapy), transcranial magnetic stimulation (TMS) and electroconvulsive therapy (ECT). ADDs are the usual first-line treatment for depression. Clinical trials have demonstrated efficacy for a number of pharmacologic classes of ADDs. Physicians usually reserve ECT for treatment-resistant cases or when they determine a rapid response to treatment is desirable. For those patients who do not respond to initial antidepressant treatment, physicians generally use one or more of the following strategies: 1) switching to an alternative first-line ADD; 2) switching to a second line ADD; 3) adding psychotherapy, a second ADD, or an augmentation agent (not generally considered to have significant antidepressant activity when administered alone). Additional options for treatment-resistant patients, especially for patients who fail on the above alternatives, include monoamine oxidase inhibitors and ECT. For treatment-resistant cases that exhibit a marked seasonal pattern, adding phototherapy to pharmacotherapy may also be an option. VNS has been proposed as an adjunct therapy in patients with major depressive disorder or bipolar disorder.
In 2017, Aaronson et. al. reported long-term outcomes from the five-year post-marketing surveillance study of individuals with treatment resistance depression treated with VNS or “treatment as usual.” The prospective, open-label, nonrandomized, observational registry study, was conducted at 61 U.S. sites. The study included a total of 795 patients who were experiencing a major depressive episode (unipolar or bipolar depression) of at least two years’ duration or had three or more depressive episodes (including the current episode), and who had failed four or more depression treatments (including ECT). Patients with a history of psychosis or rapid-cycling bipolar disorder were excluded. The primary efficacy measure was response rate, defined as a decrease of ≥50% in baseline Montgomery Åsberg Depression Rating Scale (MADRS) score at any post baseline visit during the five-year study. Secondary efficacy measures included remission. Patients had chronic moderate to severe depression at baseline (the mean MADRS score was 29.3 [SD=6.9] for the treatment-as-usual group and 33.1 [SD=7.0] for the adjunctive VNS group). The registry results indicate that the adjunctive VNS group had better clinical outcomes than the treatment- as-usual group, including a significantly higher five-year cumulative response rate (67.6% compared with 40.9%) and a significantly higher remission rate (cumulative first-time remitters, 43.3% compared with 25.7%). A sub-analysis demonstrated that among patients with a history of response to ECT, those in the adjunctive VNS group had a significantly higher five-year cumulative response rate than those in the treatment-as-usual group (71.3% compared with 56.9%). A similar significant response differential was observed among ECT nonresponders (59.6% compared with 34.1%). The naturalistic, observational study design did not allow for random assignment of participants to treatment groups; thus, participants were not blinded to treatment. A significant number of participants in both groups withdrew early from the study. Of the 358 patients (45%) who withdrew early, 195 were from the VNS arm (40%) and 163 were from the treatment-as-usual arm (54%). The reasons for early withdrawal were similar between the treatment arms. The significantly higher treatment response rate observed in the VNS arm may represent a treatment effect, as participants with an implanted device may have had a higher expectation of therapeutic improvement.
Based on the evidence of peer reviewed scientific literature regarding vagus nerve stimulation for treatment resistant depression. The evidence is considered low-quality based on several observational and uncontrolled studies for treatment with VNS improving depression symptoms in patients with treatment-resistant depression (TRD). There is a lack of consistent supporting evidence of the efficacy of VNS from well-designed randomized controlled trials and a lack of thorough safety data regarding the device, and the substantial burden of TRD. For adults with treatment-resistant rapid-cycling bipolar disorder (BPD) there is a very-low-quality and insufficient evidence base for this patient population. The clinical benefit of VNS for TRD remains controversial and it is unclear whether the possible benefits associated with VNS therapy outweigh any risks. Larger, randomized, appropriately controlled studies are necessary to establish VNS as a safe and effective alternative treatment for these patients.
VNS has been proposed for use in a number of other indications including, but not limited to: addiction, Alzheimer’s disease, anxiety, autism, chronic heart failure, essential tremor, fibromyalgia, headache, headaches/migraine, obesity, tinnitus, and traumatic brain injury. The peer-reviewed scientific literature regarding the use of VNS for these other indications is limited by small sample size and lack of a comparator and therefore conclusions about safety and efficacy cannot be made at this time. VNS devices are not FDA-approved for treatment of these indications. The evidence is insufficient to determine the effects of the technology on net health outcomes.
For individual who have seizures refractory to medical treatment that have received vagus nerve stimulation (VNS), the evidence includes randomized controlled trials (RCTs) and multiple observational studies. The RCTs have reported significant reductions in seizure frequency for patients with partial-onset seizures. The uncontrolled studies have consistently reported large reductions in a broader range of seizure types in both adults and children. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who have treatment resistant depression who receive vagus nerve stimulation (VNS), the evidence includes randomized controlled trial (RCT), nonrandomized comparative studies, and case series. The RCT only reported short-term results and found no significant improvement in the primary outcome. Other available studies are limited by small sample sizes, potential selection bias, and lack of a control groups in the case series. The evidence is insufficient to determine the effects of the technology on net health outcomes.
Transcutaneous vagus nerve stimulation (tVNS) is being investigated as a noninvasive alternative to surgery for implantable vagus nerve stimulation (VNS) and is being investigated for a number of indications including but not limited to headaches (migraine and cluster), psychiatric disorders (depression, schizophrenia), epilepsy, traumatic brain injury (TBI) and impaired glucose tolerance.
A non-implantable transcutaneous vagus nerve stimulation (tVNS) (gammaCore®) is a hand-held battery powered stimulation unit that sends gentle, patented stimulation through the skin to activate the vagus nerve. The stimulation treatment is administered by the individual for several hours per day.
A non-implantable transcutaneous vagus nerve stimulation (tVNS) hand-held battery powered stimulation units may also include an ear electrode to stimulate the auricular branch of the vagus nerve through the skin over the concha of the outer ear to deliver treatment.
The purpose of non-implantable/noninvasive transcutaneous vagus nerve stimulation (NVNS or tVNS) is to non-invasively apply low-voltage electrical currents to stimulate the cervical branch of the vagus nerve. Non-implantable/noninvasive transcutaneous vagus nerve stimulation (NVNS or tVNS) has been tested primarily in the setting of headache. Non-implantable/noninvasive transcutaneous vagus nerve stimulation (NVNS or tVNS) has been proposed as an intervention to relieve pain in acute attacks of cluster or migraine headaches as an alternative to standard care and to reduce the frequency of attacks for both cluster headaches and migraine as an adjunct to standard care. Proposed uses have been tested in other neurologic, psychiatric, or metabolic disorders as well.
The relevant population of interest is patients with cluster headache or migraine. The International Headache Society's International Classification of Headache Disorders classifies types of primary and secondary headaches. A summary of cluster and migraine headache based on the International Classification of Headache Disorders criteria are below.
Cluster headaches are primary headaches classified as trigeminal autonomic cephalalgias that can be either episodic or chronic. The diagnostic criteria for cluster headaches states that these are attacks of severe, unilateral orbital, supraorbital, and/or temporal pain that lasts 15-180 minutes and occurs from once every other day to 8 times a day and further requires for the patient to have had at least 5 such attacks with at least 1 of the following symptoms or signs, ipsilateral to the headache: conjunctival injection and/or lacrimation; nasal congestion and/or rhinorrhoea; eyelidedema; forehead and facial sweating; miosis and/or ptosis, or; a sense of restlessness or agitation. The diagnostic criteria for episodic cluster headache requires at least 2 cluster periods lasting from 7 days to 1 year if untreated and separated by pain-free remission periods of ≥3 months. The diagnostic criteria for chronic cluster headache require cluster headaches occurring for 1 year or more without remission, or with remission of less than 3 months. The age at onset for cluster headaches is generally 20-40 years and men are affected 3 times more often than are women.
Migraines are primary headaches that can occur with or without aura. Migraines without aura meet the following diagnostic criteria: at least 5 attacks lasting 4 to 72 hours if untreated or unsuccessfully treated and with at least 2 of the following 4 features: unilateral location; pulsating quality; moderate or severe pain; aggravation by or causing avoidance of routine physical activity, and having either nausea and/or vomiting and/or photophobia and phonophobia during the headache. The diagnostic criteria for migraine with aura requires 2 attacks with fully reversible visual, sensory, speech and/or language, motor, brainstem and/or retinal aura symptoms and at least 3 of the following: 1 or more aura symptoms spread gradually over ≥5 minutes; 2 or more aura symptoms in succession; each individual aura symptom lasts 5-60 minutes; 1 or more aura symptoms are unilateral; 1 or more aura symptoms are positive; the aura is accompanied, or followed within 60 minutes, by headache. Migraines are most common in ages 30 to 39 and women are more frequently affected than men.
The setting is outpatient care by a specialist in headache (e.g., neurologist).
The intervention being considered is non-implantable/noninvasive transcutaneous vagus nerve stimulation (NVNS or tVNS) as an alternative to standard care for acute headache or as an adjunct to standard care for prevention of headache.
Noninvasive devices that transcutaneously stimulate the vagus nerve on the side of the neck have been developed. The patient administers nVNS using a handheld device by placing the device on the side of the neck, over the cervical branch of the vagus nerve and positioning the metal stimulation surfaces in front of the sternocleidomastoid muscle, over the carotid artery. The frequency and timing of stimulation vary depending on the indication. NVNS can be used multiple times a day.
The standard of care (SOC) treatment to stop or prevent attacks of cluster headache or migraine is medical therapy. Guideline-recommended treatments for acute cluster headache attacks include oxygen inhalation and triptans (eg, sumatriptan and zolmitriptan). Oxygen is preferred first-line, if available because there are no documented adverse effects for most adults. Triptans have been associated with primarily nonserious adverse events; some patients experience nonischemic chest pain and distal paresthesia. Use of oxygen may be limited by practical considerations and the FDA-approved labeling for subcutaneous sumatriptan limits use to 2 doses per day. Steroids injections may be used to prevent or reduce the frequency of cluster headaches. Verapamil is also frequently used for prophylaxis although the best evidence supporting its effectiveness is a placebo-controlled RCT including 30 patients.
SOC treatments for acute migraine attacks include analgesics and/or triptans. Antiemetics and ergots may be used as monotherapy or as an adjunct for treatment of acute migraine. Beta-blockers (eg, metoprolol, propranolol, or timolol), antidepressants (eg, amitriptyline or venlafaxine) and anticonvulsants (topiramate or sodium valproate) may be used to prevent or reduce the frequency of migraine attacks along with lifestyle measures. Choosing which preventive medical therapy to use depends on patient characteristics and comorbid conditions, medication adverse events, and patient preference. Calcitonin gene-related peptide antagonists have also been approved for migraine prevention.
Given the high placebo response rate in both cluster and migraine headache, trials with sham non-implantable/noninvasive transcutaneous vagus nerve stimulation (NVNS or tVNS) are most relevant.
The general outcomes of interest are headache intensity and frequency, the effect on function and quality of life and adverse events.
The most common outcome measures for treatment of acute cluster or migraine headache are headache relief measured as a proportion of patients with reduction on a pain relief scale by a specified time (usually 15, 30, 60 or 120 minutes after administration), proportion of patients who are pain-free by a specified time, sustaining reduction or pain-free for 24 hours, time to reduction or pain-free, and use of rescue medication. International Headache Society (IHS) guidelines for RCTs of drugs for migraine recommends the proportion of patients with pain score of zero (pain-free) at 2 hours before rescue medication as the primary efficacy measure in RCTs with earlier time points also being considered. IHS guidelines also state that sustained pain freedom or relapse and recurrence within 48 hours is an important efficacy outcome and that standardized, validated tools to assess the changes in ability to function and quality of life should be secondary outcomes.
The most common outcome measures for prevention of cluster or migraine headache are decrease in headache days per month compared with baseline and the proportion of responders to the treatment, defined as those patients who report more than a 50%, 75% or 100% decrease in headache days per month compared to pre-treatment. IHS guidelines recommend 2 primary efficacy outcomes for migraine prevention: number of migraine attacks per evaluation interval and number of migraine days per evaluation interval.
The effect of treatment on stopping acute headache should be measured over 15 minutes to 48 hours. Continued response may be measured over many months.
The IHSC guidelines suggest that effect of treatment on preventing migraine headache should be measured over at least 3 months in phase II RCTs and up to 6 months in phase III RCTs.
The FDA approval for gammaCore® was based on subgroup analyses from two clinical trials for the Acute Treatment of Cluster Headache (ACT1 and ACT2). Both trials were prospective, double-blind, placebo controlled, randomized controlled trials (RCTs) evaluating the use of gammaCore® (non-invasive VNS [nVNS]) versus sham treatment.
Gaul et. al. (2016) conducted a randomized controlled study (PREVA) on non-invasive vagus nerve stimulation (nVNS) as adjunctive prophylactic treatment of chronic cluster headache (CH). PREVA was a prospective, open-label, randomized study that compared adjunctive prophylactic nVNS (n = 48) with standard of care (SoC) alone (control (n = 49)). A two-week baseline phase was followed by a four-week randomized phase (SoC plus nVNS vs control) and a four-week extension phase (SoC plus nVNS). The primary end point was the reduction in the mean number of CH attacks per week. Response rate, abortive medication use and safety/tolerability were also assessed. During the randomized phase, individuals in the intent-to-treat population treated with SoC plus nVNS (n = 45) had a significantly greater reduction in the number of attacks per week vs controls (n = 48) (-5.9 vs -2.1, respectively) for a mean therapeutic gain of 3.9 fewer attacks per week (95% CI: 0.5, 7.2; p = 0.02). Higher ≥50% response rates were also observed with SoC plus nVNS (40% (18/45)) vs controls (8.3% (4/48); p < 0.001). No serious treatment-related adverse events occurred. The study lacked a sham placebo control group, which might have resulted in placebo response in the tVNS group.
Silberstein et. al. (2016) evaluated non-invasive vagus nerve stimulation (nVNS) for the acute treatment of cluster headaches in a randomized, double-blind, shame controlled ACT1 study. One hundred fifty individuals were enrolled and randomized (1:1) to receive nVNS or sham treatment for ≤1 month during a double-blind phase; completers could enter a 3-month nVNS open-label phase. The primary end point was response rate, defined as the proportion of subjects who achieved pain relief (pain intensity of 0 or 1) at 15 minutes after treatment initiation for the first CH attack without rescue medication use through 60 minutes. Secondary end points included the sustained response rate (15-60 minutes). Subanalyses of episodic cluster headache (eCH) and chronic cluster headache (cCH) cohorts were prespecified. The intent-to-treat population comprised 133 individuals: 60 nVNS treated (eCH, n = 38; cCH, n = 22) and 73 sham-treated (eCH, n = 47; cCH, n = 26). A response was achieved in 26.7% of nVNS-treated subjects and 15.1% of sham-treated subjects (P = .1). Response rates were significantly higher with nVNS than with sham for the eCH cohort (nVNS, 34.2%; sham, 10.6%; P = .008) but not the cCH cohort (nVNS, 13.6%; sham, 23.1%; P = .48). Sustained response rates were significantly higher with nVNS for the eCH cohort (P = .008) and total population (P = .04). Adverse device effects (ADEs) were reported by 35/150 (nVNS, 11; sham, 24) subjects in the double-blind phase and 18/128 subjects in the open-label phase. No serious ADEs occurred. Importantly, the study was not powered to demonstrate independent statistical significance for the subgroup analyses, nor were the P values adjusted for multiple comparisons. The authors concluded the response rate was not significantly different (vs sham) for the total population; nVNS provided significant, clinically meaningful, rapid, and sustained benefits for eCH but not for cCH, which affected the results in the total population. This represents a novel and promising option for eCH.
In 2018, Goadsby et. al. reported on a randomized, double-blind, sham controlled ACT2 study for non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache. This study compared nVNS with a sham device for acute treatment in patients with episodic or chronic CH (eCH, cCH). Methods After completing a 1-week run-in period, subjects were randomly assigned (1:1) to receive nVNS or sham therapy during a 2-week double-blind period. The primary efficacy endpoint was the proportion of all treated attacks that achieved pain-free status within 15 minutes after treatment initiation, without rescue treatment. The Full Analysis Set comprised 48 nVNS-treated (14 eCH, 34 cCH) and 44 sham-treated (13 eCH, 31 cCH) subjects. For the primary endpoint, nVNS (14%) and sham (12%) treatments were not significantly different for the total cohort. In the eCH subgroup, nVNS (48%) was superior to sham (6%; p < 0.01). No significant differences between nVNS (5%) and sham (13%) were seen in the cCH subgroup. The authors concluded, combining both eCH and cCH patients, nVNS was no different to sham. For the treatment of CH attacks, nVNS was superior to sham therapy but not in cCH. These results confirm extended previous findings regarding the efficacy, safety, and tolerability of nVNS for the treatment of eCH.
In 2017, Tso et. al. evaluated the records of 15 patients treated with noninvasive vagus nerve stimulation (nVNS) (gammaCore) for paroxysmal hemicrania (n=6) or hemicrania continue (n=9) as primary treatment or as an adjunct to indomethacin. Symptom related outcomes included reduction of pain severity and reduced frequency of attacks: for the first, 7 hemicrania continua patients saw improvement with tVNS therapy, as did 3 patients with paroxysmal hemicranias. The frequency of attacks was reduced for 2 hemicrania continua patients and 2 paroxysmal hemicranias patients. Some adverse events were reported in all patients, although not detailed. The authors concluded, the initial experience suggests that nVNS may be an important alternative or adjunctive therapy for patients with these indomethacin sensitive TACs (trigeminal autonomic cephalgias) who are unable to tolerate indomethacin. Conducting a prospective, randomized, and sham-controlled study seems warranted, although given the rarity of the problem, this will be a considerable challenge.
Vagus nerve stimulation (VNS) is being investigated to augment recovery from traumatic brain injury. It is proposed that early stimulation of the vagus nerve accelerates the rate and extent of behavioral and cognitive recovery after fluid percussion brain injury in rats. Shi et. al. (2013) received FDA approval to conduct a pilot prospective randomized trial to demonstrate objective improvement in clinical outcome by placement of VNS in individuals who are recovering from severe traumatic brain injury. If this study demonstrates that VNS can be safely and positively impact outcome, then a larger randomized prospective crossover trial will be proposed.
There is currently an ongoing clinical trial NCT02974959, single center prospective randomized (1:1), double blind, sham controlled parallel arm pilot study to provide initial evidence of the use of the noninvasive vagus nerve stimulator (VNS) for treatment in patients recovering from concussion and moderate traumatic brain injury to improve clinical recovery. The study is comparing the safety and effectiveness of an active gammaCore treatment against sham treatment. This is a Phase I study, looking to recruit 30 participants with an estimated completion date of June 2019. Per clinicaltrials.gov this study shows still recruiting and no results posted at this time (accessed September 2020).
Two small case series were identified using transcutaneous vagus nerve stimulation (t-VNS) for treatment of medication refractory seizures.
Stefan et. al. (2012) reported on a proof of concept trial on transcutaneous vagus nerve stimulation (t-vns) in pharmacoresistant epilepsies. t-VNS was applied to 10 patients with pharmacoresistant epilepsies. Stimulation via the auricular branch of the vagus nerve of the left tragus was delivered three times per day for 9 months. Subjective documentation of stimulation effects was obtained from patients' seizure diaries. For a more reliable assessment of seizure frequency, prolonged outpatient video-electroencephalography (EEG) monitoring was carried out. In addition, computerized testing of cognitive, affective, and emotional functions was performed. Three patients aborted the study. Of the remaining seven patients, an overall reduction of seizure frequency was observed in five patients after 9 months of t-VNS. The authors concluded, t-VNS stimulation might be an alternative treatment option for patients with epilepsy.
In 2013, He et. al. investigated in a pilot trial the safety and efficacy of transcutaneous auricular vagus nerve stimulation (ta-VNS) for the treatment of pediatric epilepsy. Fourteen pediatric patients with intractable epilepsy were treated by ta-VNS of the bilateral auricular concha using an ear vagus nerve stimulator. The baseline seizure frequency was compared with that after 8weeks, from week 9 to 16 and from week 17 to the end of week 24, according to the seizure diaries of the patients. One patient dropped out after 8weeks of treatment due to lack of efficacy, while the remaining 13 patients completed the 24-week study without any change in medication regimen. The mean reduction in seizure frequency relative to baseline was 31.83% after week 8, 54.13% from week 9 to 16 and 54.21% from week 17 to the end of week 24. The responder rate was 28.57% after 8weeks, 53.85% from week 9 to 16 and 53.85% from week 17 to the end of week 24. No severe adverse events were reported during treatment. The authors concluded, transcutaneous auricular VNS (ta-VNS) may be a complementary treatment option for reducing seizure frequency in pediatric patients with intractable epilepsy and should be further studied.
One randomized controlled trial (RCT) was identified. Aihua et. al. (2014) explored the efficacy and safety of transcutaneous vagus nerve stimulation (t-VNS) in patients with pharmacoresistant epilepsy in a controlled trial. A total of 60 patients were randomly divided into two groups based on the stimulation zone: the Ramsay-Hunt zone (treatment group) and the earlobe (control group). Before and after the 12-month treatment period, all patients completed the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS), the Liverpool Seizure Severity Scale (LSSS), and the Quality of Life in Epilepsy Inventory (QOLIE-31). Seizure frequency was determined according to the patient's seizure diary. During the study, the antiepileptic drugs were maintained at a constant level in all subjects. After 12 months, the monthly seizure frequency was lower in the treatment group than in the control group (8.0 to 4.0; P=0.003). This reduction in seizure frequency was correlated with seizure frequency at baseline and duration of epilepsy (both P>0.05). Additionally, all patients showed improved SAS, SDS, LSSS, and QOLIE-31 scores that were not correlated with a reduction in seizure frequency. The side effects in the treatment group were dizziness (1 case) and daytime drowsiness (3 cases), which could be relieved by reducing the stimulation intensity. In the control group, compared with baseline, there were no significant changes in seizure frequency (P=0.397), SAS, SDS, LESS, or QOLIE-31. There were also no complications in this group.
Hein et. al. (2013) reported on results of a randomized controlled pilot study on auricular transcutaneous electrical nerve stimulation in the treatment of major depressive disorder. A total of 37 patients suffering from major depression were included in two randomized sham controlled add-on studies. Patients were stimulated five times a week on a daily basis for the duration of 2 weeks. On days 0 and 14, the Hamilton Depression Rating Scale (HAMD) and the Beck Depression Inventory (BDI) were assessed. In contrast to sham-treated patients, electrically stimulated persons showed a significantly better outcome in the BDI. Mean decrease in the active treatment group was 12.6 (SD 6.0) points compared to 4.4 (SD 9.9) points in the sham group. HAMD score did not change significantly in the two groups. An antidepressant effect of a new transcutaneous auricular nerve stimulation technique has been shown for the first time in this controlled pilot study. Regarding the limitations of psychometric testing, the risk of unblinding for technical reasons, and the small sample size, further studies are necessary to confirm the present results and verify the practicability of tVNS in clinical fields.
In 2014, Shiozawa et. al. conducted a systematic review of studies evaluating trigeminal nerve stimulation (TNS) and transcutaneous vagus nerve stimulation (t-VNS). They found 4 studies addressing t-VNS for psychiatric disorders (total N=84 subjects). Overall the studies assessed were limited by small size and poor generalizability.
Hasan et. al. (2015) reported on a bicentric randomized controlled pilot study for transcutaneous noninvasive vagus nerve stimulation (t-VNS) in the treatment of schizophrenia. The objective of the study was to investigate the feasibility, safety and efficacy. This bicentric randomized, sham-controlled, double-blind trial was conducted from 2010 to 2012. Twenty schizophrenia patients were randomly assigned to one of two treatment groups. The first group (active tVNS) received daily active stimulation of the left auricle for 26 weeks. The second group (sham tVNS) received daily sham stimulation for 12 weeks followed by 14 weeks of active stimulation. Primary outcome was defined as change in the Positive and Negative Symptom Scale total score between baseline and week 12. Various other secondary measures were assessed to investigate safety and efficacy. The intervention was well tolerated with no relevant adverse effects. They did not observe a statistically significant difference in the improvement of schizophrenia psychopathology during the observation period. Neither psychopathological and neurocognitive measures nor safety measures showed significant differences between study groups. Application of tVNS was well tolerated, but did not improve schizophrenia symptoms in the 26-week trial. While unsatisfactory compliance questions the feasibility of patient-controlled neurostimulation in schizophrenia, the overall pattern of symptom change might warrant further investigations in this population.
In 2014, Huang et. al. conducted pilot randomized clinical trial comparing the efficacy of transcutaneous auricular vagus nerve stimulation (ta-VNS) and sham ta-VNS on patients with impaired glucose tolerance (IGT)-. Seventy-two participants with IGT were single-blinded and were randomly allocated by computer-generated envelope to either taVNS or sham ta-VNS treatment groups. In addition, 30 IGT adults were recruited as a control population and not assigned treatment so as to monitor the natural fluctuation of glucose tolerance in IGT patients. All treatments were self-administered by the patients at home after training at the hospital. Patients were instructed to fill in a patient diary booklet each day to describe any side effects after each treatment. The treatment period was 12 weeks in duration. Baseline comparison between treatment and control group showed no difference in weight, BMI, or measures of systolic blood pressure, diastolic blood pressure, fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG), or glycosylated hemoglobin (HbAlc). One hundred participants completed the study and were included in data analysis. Two female patients (one in the ta-VNS group, one in the sham ta-VNS group) dropped out of the study due to stimulation-evoked dizziness. The symptoms were relieved after stopping treatment. Compared with sham ta-VNS, ta-VNS significantly reduced the two-hour glucose tolerance (F(2) = 5.79, p = 0.004). In addition, ta-VNS significantly decreased (F(1) = 4.21, p = 0.044) systolic blood pressure over time compared with sham ta-VNS. Compared with the no-treatment control group, patients receiving ta-VNS significantly differed in measures of FPG (F(2) = 10.62, p < 0.001), 2hPG F(2) = 25.18, p < 0.001) and HbAlc (F(1) = 12.79, p = 0.001) over the course of the 12 week treatment period. There were several limitations in this study: treatments in this study were self-administered by the patients, thus patient compliance may have influenced the observed results; the treatment was only 12 weeks in duration, therefore the results obtained only represent its short or mid-term effect, further study is warranted to evaluate the long-term effects of this treatment option; blood glucose levels were measured at three time points (baseline, after 6 weeks, and after 12 weeks) for statistic analysis, since blood glucose levels may be affected by food intake of the previous day a more frequent measurement in the future study may provide more reliable information for the influence of treatment on blood glucose levels; and no treatment control group was not included in the randomization scheme, as were the other two treatment groups. The authors concluded that this pilot study demonstrates that ta-VNS can reduce two hour glucose tolerance and systolic blood pressure, however, further studies are warranted to include longer follow-up to evaluate the long-term effects of this treatment option.
For individuals with episodic cluster headaches who receive transcutaneous vagus nerve stimulation (t-VNS), the evidence includes three randomized controlled trials (RCTs). One RCT showed a reduction in headache frequency but did not include a sham treatment group. Two randomized, double-blind, sham-controlled studies showed efficacy of achieving pain free status within 15 minutes of treatment with noninvasive VNS in patients with episodic cluster headaches but not in patients with chronic cluster headaches. The RCTs for episodic cluster headaches are promising, however, additional studies with larger relevant populations are required to establish the treatment efficacy. The evidence is insufficient to determine the effects of the technology on net health outcomes.
For individuals with neurologic, psychiatric, or metabolic disorders (e.g. epilepsy, depression, schizophrenia, non-cluster headaches (migraines), traumatic brain injury and impaired glucose tolerance) who receive transcutaneous vagus nerve stimulation (t-VNS), the evidence includes RCTs and case series for some of the conditions. The RCTs are small and have various methodologic problems. None showed definitive efficacy of transcutaneous vagus nerve stimulation (t-VNS) in improving patient outcomes. The evidence is insufficient to determine the effects of the technology on net health outcomes.
The purpose of vagal nerve blocking therapy for the treatment of obesity is to provide a treatment option that is an alternative to or an improvement on existing therapies.
The relevant population of interest is patients with morbid obesity who have been unsuccessful with lifestyle management for weight reduction.
The intervention being considered is vagal nerve blocking therapy for the treatment of obesity. Vagus nerve blocking therapy involves the intermittent blocking of signals to the intra-abdominal vagus nerve, with the intent of disrupting hunger sensations and inducing feelings of satiety. Patients with obesity who receive vagal nerve blocking therapy would require follow-up for 6-12 months to ascertain weight loss success and early device complications. Follow-up of maintenance of weight loss or obesity-associated conditions are life-long.
The following therapies and practices are currently being used to make decisions about the treatment of obesity; lifestyle interventions, specifically changes to diet and exercise, are the first-line treatment of obesity. These interventions can be enhanced by participation in a structured weight loss program and/or by psychological interventions such as cognitive-behavioral therapy. There are also prescription weight loss medications available, most notably orlistat (which blocks digestion and absorption of fat) and lorcaserin (which decreases appetite and promotes satiety). Weight loss medications have limited evidence of efficacy and there are adverse events (eg, oily stool, nausea, dizziness) associated with their use. Weight loss (bariatric) surgery is a potential option for obese patients who have failed conservative treatments.
The general outcomes of interest are weight reduction and maintenance of weight reduction, disease status changes such as the development of medical complications of obesity, and treatment-related morbidity.
More than one-third (36.5%) of U.S. adults have obesity which is defined as a body max index (BMI) 30.0 or higher (based on the U.S. Centers for Disease Control and Prevention). Obesity is a major cause of premature death and is linked to serious illnesses including heart disease, type 2 diabetes, stroke, sleep apnea, osteoarthritis, and certain types of cancer. Lifestyle interventions, especially changes to diet and exercise are the first line treatment of obesity. These interventions can be enhanced by participating in a structured weight loss program and/or by psychological interventions. There are also prescription weight loss medications available which have limited evidence of efficacy and there are adverse effects associated with their use. Weight loss (bariatric) surgery is another potential option for patients who have failed conservative treatments.
Vagus nerve blocking therapy is being investigated as another potential treatment option for obese patients. The vagus nerve consists of 2 long cranial nerves that extend from the brain to the viscera. The vagus nerve winds through the abdomen and has branches that come into contact with the heart, lung, stomach, and other body parts. The vagus nerves plays a major role in autonomic and sympathetic nervous system functioning, including regulation of heartbeat and breathing. It is also involved in regulation of the digestive system, although its exact role in controlling appetite and feelings of satiety is unknown. Vagus nerve blocking therapy involves intermittent blocking of signals to the intra-abdominal vagus nerve, with the intent of disrupting hunger sensations and inducing feelings of satiety.
In January 2015, the U.S. Food and Drug Administration (FDA) approved a medical device specifically designed to provide vagal nerve blocking therapy for regulation of weight in obese patients. This device, the Maestro Rechargeable system, includes neuroblocking pulse generator that is implanted subcutaneously on the thoracic sidewall and flexible leads approximately 47 cm in length that are placed on the abdominal anterior and posterior vagal nerve trunks. External components include mobile charge, a transmit coil, a programmable microprocessor, and customized software. The system delivers high-frequency pulses of electrical current to vagus nerve trunks; therapy parameters and the treatment schedule can be customized by a clinician. Like other surgical interventions, there is the potential for adverse effects. In addition, there may be other unintended consequences of disrupting signals to a particular portion of the vagus nerve.
The published literature on vagus nerve blocking for obesity consists of two ra ndomized controlled trials (RCTs) (EMPOWER and ReCharge), both of which were industry sponsored, multicenter, double-blind and sham-controlled. Although both trials included a sham treatment group, protocols differed. In the 2012 EMPOWER trial, all participants had devices implanted and leads placed. However, external controllers were programmed differently such that if the controllers were worn for 10 hours a day, total charge delivered was 3.9 coulombs (C) to patients in the treatment and a negligible amount (0.0014 C), to the sham group. In the 2014 ReCharge trial, all participants had devices implanted, but no leads were placed in the sham group.
Sarr et. al. (2012) conducted a randomized, prospective, double-blind, multicenter trial of vagal blockade to induce weight loss in morbid obesity, the EMPOWER study. This controlled trial was conducted in the U.S. and Australia. Five hundred three subjects were enrolled at 15 centers. After informed consent, 294 subjects were implanted with the vagal blocking system and randomized to the treated (n = 192) or control (n = 102) group. Main outcome measures were percent excess weight loss (percent EWL) at 12 months and serious adverse events. Subjects controlled duration of therapy using an external power source; therapy involved a programmed algorithm of electrical energy delivered to the subdiaphragmatic vagal nerves to inhibit afferent/efferent vagal transmission. Devices in both groups performed regular, low-energy safety checks. Data are mean ± SEM (standard error of the mean). Study subjects consisted of 90 % females, body mass index of 41 ± 1 kg/m(2), and age of 46 ± 1 years. Device-related complications occurred in 3 % of subjects. There was no mortality. 12-month percent EWL was 17 ± 2 % for the treated and 16 ± 2 % for the control group. Weight loss was related linearly to hours of device use; treated and controls with ≥ 12 h/day use achieved 30 ± 4 and 22 ± 8 % EWL, respectively. The authors concluded, VBLOC therapy to treat morbid obesity was safe, but weight loss was not greater in treated compared to controls; clinically important weight loss, however, was related to hours of device use. Post-study analysis suggested that the system electrical safety checks (low charge delivered via the system for electrical impedance, safety, and diagnostic checks) may have contributed to weight loss in the control group.
Ikramuddin et. al. (2014) conducted a randomized, double-blind, sham-controlled clinical trial to evaluate the effectiveness and safety of intermittent, reversible vagal nerve blockade therapy for obesity treatment, the ReCharge study. This trial was conducted at 10 sites in the U.S. and Australia between May and December 2011. The 12 month blinded portion of the 5 year study was completed in January 2013. The trial involved 239 participants who had a body mass index of 40 to 45 or 35 to 40 and 1 or more obesity-related condition. One hundred sixty-two patients received an active vagal nerve block device and 77 received a sham device. All participants received weight management education. The co-primary efficacy objectives were to determine whether the vagal nerve block was superior in mean percentage excess weight loss to sham by a 10-point margin with at least 55% of patients in the vagal block group achieving a 20% loss and 45% achieving a 25% loss. The primary safety objective was to determine whether the rate of serious adverse events related to device, procedure, or therapy in the vagal block group was less than 15%. In the intent-to-treat analysis, the vagal nerve block group had a mean 24.4% excess weight loss (9.2% of their initial body weight loss) vs 15.9% excess weight loss (6.0% initial body weight loss) in the sham group. The mean difference in the percentage of the excess weight loss between groups was 8.5 percentage points (95% CI, 3.1-13.9), which did not meet the 10-point target (P = .71), although weight loss was statistically greater in the vagal nerve block group (P = .002 for treatment difference in a post hoc analysis). At 12 months, 52% of patients in the vagal nerve block group achieved 20% or more excess weight loss and 38% achieved 25% or more excess weight loss vs 32% in the sham group who achieved 20% or more loss and 23% who achieved 25% or more loss. The device, procedure, or therapy-related serious adverse event rate in the vagal nerve block group was 3.7% (95% CI, 1.4%-7.9%), significantly lower than the 15% goal. The adverse events more frequent in the vagal nerve block group were heartburn or dyspepsia and abdominal pain attributed to therapy; all were reported as mild or moderate in severity. The authors concluded, among patients with morbid obesity, the use of vagal nerve block therapy compared with sham control device did not meet wither of the prescribed co-primary efficacy objectives, although weight loss in the vagal block group was statistically greater than in the sham device group. The treatment was well tolerated, having met the primary safety objective.
The primary efficacy outcomes were not met in either RTC. The difference in mean percent excess weight loss (EWL) was the sole primary efficacy outcome in the EMPOWER study and a co-primary outcome in the ReCharge study. This outcome was evaluated in both trials using a superiority margin of 10% (i.e. the efficacy objective would be met only if there was > 10% difference between groups in EWL). U.S. Food and Drug Administration (FDA) documents (Summary of Safety and Effectiveness Data [SEED]) have indicated that the unattained 10% margin was considered to indicate a clinically meaningful difference in weight loss between active and sham treatment groups.
The outcome used in these studies was percent EWL, and modest changes in this outcome may translate to a relatively small amount of weight loss relative to total weight for patients with morbid obesity. Mean initial body weight in the ReCharge trial was 113 kilograms (249 pounds) in the active treatment group and 116 kilograms (255 pounds) in the sham group. Mean excess body weight was 44 kilograms (97 pounds) in the treatment group and 45 kilograms (99 pounds) in the sham group. A difference of 10% EWL, used in the primary analyses, represents a difference of only about 5 kilograms (10 pounds) in absolute weight loss and a 4% difference in absolute body weight.
Additional information on the ReCharge trial design and findings has been reported in FDA documents (Summary of Safety and Effectiveness Data [SEED]). The trial was designed to evaluate primary end points at 12 months and to follow patients for 5 years post implant. Patients were blinded until 12 months and unblinding began once all patients had completed the 12 month follow-up. After the 12 month follow-up, sham patients had the option to cross over into the active treatment group. At 18 months, follow-up data (n=159) were reported for 117 (72%) patients initially assigned to the active treatment group and 42 (55%) assigned to the sham treatment group. The number of patients in the sham group who crossed over to active treatment and the timing of unblinding were not reported. At 18 months, the mean percent EWL (excess weight loss) was 25.3% in the active treatment group and 11.7% in sham group; the mean between group difference was 13.5% (95% CI, 5.7% to 21.3%). In this analysis, the treatment group maintained the weight loss they achieved at 12 months, and the control group gained weight. Nearly half of the patients initially randomized to the sham group were not included in the 18 month analysis, which limits ability to draw conclusions about these data. In addition, the 18 month analysis could have been biased by unblinding, which occurred after all patients completed the 12 month follow-up. In the 12 month sham intervention phase of the trial, patients in both groups experienced decreased hunger, increased cognitive restraint, and decreased food intake. It is likely that unblinding could have had an impact on these factors. FDA documents also reported longer term safety data. Analyses of data up to 48 months from the EMPOWER trial and 18 month data from the ReCharge trial did not identify any deaths or unanticipated serious adverse events. There were 13 surgical explants through 12 months (5 in active treatment group, 8 in sham group) and an additional 16 explantations between 12 and 18 months. Reasons for explant included patient decision, pain, and need for MRI.
In 2015, Shikora et. al. published the 18 month follow-up data from the ReCharge trial. They reported on a larger proportion of the patient population than that discussed in the FDA documents: in addition to the 159 (67%) of 239 randomized patients who completed the 18 month follow-up, the 2015 analysis included 30 patients who missed the 18 month analysis but had a visit at 16 or 17 months. The additional patients included 11 from the active treatment group and 19 from the sham group, comprising 188 patients (79% of those originally randomized). At 18 months, the mean percent EWL noted was 23.5% (95% CI, 20.8% to 26.3%) in the active treatment group and 10.2% (95% CI, 6.0% to 14.4%) in the sham group. The mean between group difference in percent EWL was 13.4% (95% CI, 8.4% to 18.4%). The authors also evaluated the potential impact of blinding on outcomes and found no statistically significant effect; their findings were similar to the analysis restricted to patients who remained blinded at 18 months. The percentages of EWL at 18 months in this 2015 analysis of ReCharge trial data were also similar to those previously reported in FDA documents, although this sample size was larger, reducing potential bias from missing data. The authors concluded, follow-up through 18 months of the ReCharge study showed sustained weight loss with intermittent vagal nerve block but not with sham surgery and device intervention. vBloc therapy continued to be safe and well tolerated. Additional long-term data and continued follow-up of the ReCharge study are needed to further characterize the safety and effectiveness profile of vBloc therapy.
Apovian et. al. (2017) published two year outcomes of vagal nerve blocking (vBloc) for the treatment of obesity in the ReCharge trial. Participants with body mass index (BMI) 40 to 45 kg/m2, or 35 to 40 kg/m2 with at least one comorbid condition were randomized to either vBloc therapy or sham intervention for 12 months. After 12 months, participants randomized to vBloc continued open-label vBloc therapy and are the focus of this report. Weight loss, adverse events, comorbid risk factors, and quality of life (QOL) will be assessed for 5 years. The investigators noted that the sham arm was no longer a valid comparator at 24 months due to crossovers, dropouts, and patient unblended at 12 months. Participants who presented at 24 months (n = 103) had a mean excess weight loss (EWL) of 21 % (8 % total weight loss [TWL]); 58 % of participants had ≥5 % TWL and 34 % had ≥10 % TWL. Among the subset of participants with abnormal preoperative values, significant improvements were observed in mean LDL (-16 mg/dL) and HDL cholesterol (+4 mg/dL), triglycerides (-46 mg/dL), HbA1c (-0.3 %), and systolic (-11 mmHg) and diastolic blood pressures (-10 mmHg). QOL measures were significantly improved. Heartburn/dyspepsia and implant site pain were the most frequently reported adverse events. The primary related serious adverse event rate was 4.3 %. The analysis lacked a blinded comparison group, and, like the 18 month data, was post hoc.
For individuals with obesity who receive vagus nerve blocking therapy, the evidence includes 2 sham-controlled randomized trials. The primary efficacy outcome (at least a 10% difference between groups at 12 months) was not met for either trial. In the first trial (EMPOWER), the observed differences in excess weight loss (EWL) between groups at 12 months was 1%. In the more recent trial (ReCharge), the observed difference in excess weight loss (EWL) between groups at 12 months was 8.5%; a post hoc analysis found this difference statistically significant, but the magnitude of change may not be viewed as clinically significant according to investigators original trial decisions. Post hoc analysis of longer-term data have been published and are subject to various biases, including missing data and unblinding at 12 months. Based on the trials the treatment was well tolerated, having met the primary safety objective. Additional studies are needed to compare effectiveness of vagal nerve blocking therapy with other obesity treatments and to assess long-term durability of weight loss and safety. The evidence is insufficient to determine the effects of the technology on net health outcomes.
In 2013, the American Academy of Neurology (AAN) issued an evidence based guideline update on vagus nerve stimulation for the treatment of epilepsy, that stated:
The American Psychiatric Association guidelines on treatment of major depressive disorder in adults, updated in November 2010, includes the following statement on the use of VNS: “electroconvulsive therapy (ECT) remains the treatment of best established efficacy against which other stimulation treatments (e.g. vagus nerve stimulation (VNS), deep brain stimulation, transcranial magnetic stimulation, other electromagnetic stimulation therapies) should be compared. Vagus nerve stimulation (VNS) may be an additional option for individuals who have not responded to at least four adequate trials of antidepressant treatment, including ECT, with a level of evidence III (May be recommended on the basis of individual circumstances).”
In 2013, the European Headache Federation issued a consensus statement on neuromodulation treatments for chronic headaches, which makes the following statement about the use of VNS: “Due to the lack of evidence, VNS should only be employed in chronic headache suffers using a randomized placebo controlled trial design.”
In 2014, the American Headache Society issued information regarding stimulators for the treatment of headache and stated the following regarding vagal nerve stimulation (VNS): “Stimulation of the vagal nerve has been described as a means to treat both migraine and cluster headache in patients who have not responded to conventional treatment. A hand held device was developed to make this far more convenient and less dangerous than implanted stimulators. The device is called a noninvasive vagal nerve stimulator (nVNS). The device is held by the patient to the neck on the same side as the pain, and a low level electrical stimulation is discharged. This can be used preventatively or at onset of pain. However, it is important to state that no scientific studies with placebo have been published on the nVNS as of early 2014, and the evidence for its safety and effectiveness is merely the reports of the less than 50 patients who have used it and reported its effects. nVNS does not have FDA approval for use in the United States at this time.”
In 2016, the American Society for Metabolic and Bariatric Surgery published a position statement that included the following conclusions and recommendations on vagus nerve blocking therapy for the treatment of obesity:
In 1997, the NeuroCybernetic Prosthesis (NCP) system (Cyberonics), a vagus nerve stimulation (VNS) device was approved by the U.S. Food and Drug Administration (FDA) through the premarket approval (PMA) process for use in conjunction with drugs or surgery, as adjunctive treatment for adults and children 12 years of age and older with medically refractory partial onset seizures.
July 2005, Cyberonics received PMA supplement approval by FDA for the VNS therapy system for the adjunctive long-term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments.
Cerbomed has developed a transcutaneous vagal nerve stimulator (tVNS) system that uses a combined stimulation unit and ear electrode to stimulate the auricular branch of the vagus nerve, which supplies the skin over the concha of the ear. Patients self- administer electrical stimulation for several hours a day; no surgical procedure is required. The device received European clearance (CE mark) in 2011, but has not been FDA approved for use in the United States.
January 2015 Maestro Rechargeable System (EnteroMedics, St. Paul, MN) was approved by the U.S. Food and Drug Administration (FDA) through the premarket approval process for use in adults aged 18 years and older who have a body mass index (BMI) of 40 to 45 kg/m2 or a BMI of 35 to 39.9 kg/m2 with 1 or more obesity related conditions such as high blood pressure or high cholesterol and have failed at least 1 supervised weight management program within the past 5 years. Implantable components are incompatible with magnetic resonance imaging. Additional contraindications to use of the device include conditions such as cirrhosis of the liver, portal hypertension and clinically significant hiatal hernia, and the presence of a previously implanted medical device. FDA product code: PIM.
The commercial availability of the Maestro System is unclear. On the FDA's Weight-Loss and Weight-Management Devices webpage (content noted as current as of 09/05/2019), the Maestro Rechargeable System is described as "no longer marketed as of September 2018". Additionally, on the ReShape Lifesciences website (previously EnteroMedics), the Maestro Rechargeable System, is not listed among their current portfolio of medical devices to treat obesity and metabolic disease. However, updates to the Maestro Rechargeable System were noted in the FDA Premarket Approval database (P130019) subsequent to September 2018, including updates to the circuit assembly and application firmware of the mobile charger (01/25/2019) and approval of modifications to the follow-up schedule for the post-approval study protocol.
April 2017, the U.S. Food and Drug Administration (FDA) approved gammaCore Non-invasive Vagus Nerve Stimulator ( ElectroCore LLC, Basking Ridge, New Jersey) intended to provide non-invasive vagus nerve stimulation (nVNS) on the side of the neck. The gammaCore device is indicated for the acute treatment of pain associated with episodic cluster headache in adult patients.
Implantable vagus nerve stimulation (VNS) may be considered medically necessary when all of the following criteria are met:
Note: Medically refractory seizures are defined as seizures that occur in spite of therapeutic levels of antiepileptic drugs or seizures that cannot be treated with therapeutic levels of antiepileptic drugs because of intolerable adverse effects of these drugs.
Replacement or revisions of an implantable vagus nerve stimulator and/or leads is considered medically necessary in an individual that meets the above criteria and the existing generator/lead/electrodes/programmer is no longer under warranty and/or cannot be repaired.
Vagus Nerve Stimulation (VNS) is considered investigational as treatment of all other conditions, including but not limited to the following:
Based on peer reviewed literature the use of vagus nerve stimulation has been examined for additional indications. The evidence includes randomized controlled trials, nonrandomized comparative studies and case series. Randomized controlled trials reported short term results and found no significant improvement in the primary outcomes. Other available studies are limited by small sample sizes, potential selection bias, and lack of a control group in the case series. Additional larger prospective randomized sham-controlled studies are needed to determine safety and effectiveness. The evidence is insufficient evidence to determine the effectiveness of the technology on net health outcomes.
Transcutaneous vagus nerve stimulation (tVNS) devices are considered investigational for all indications, including but not limited to the following:
The evidence for transcutaneous vagal nerve stimulation (tVNS) includes small randomized trias, case series and systematic review. Studies are all small and have various methodologic problems. The evidence is insufficient in showing definitive efficacy of transcutaneous vagal nerve stimulation (tVNS) in improving outcomes among patients. Current studies are limited by lack of a comparator and small sample sizes. Further studies are needed. The evidence is insufficient to determine the effects of this technology on net health outcomes.
Intra-abdominal vagus nerve blocking therapy is considered investigational for all indications, including but not limited to the treatment of obesity.
Based on the peer reviewed medical literature the evidence includes two sham-controlled randomized trials in which the primary efficacy outcome was not met for either trial. Additional studies are needed to compare effectiveness of vagal nerve blocking therapy with other obesity treatments and to assess long-term durability of weight loss and safety. The evidence is insufficient to determine the effects of this technology on net health outcomes.
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