VAGUS NERVE STIMULATION

Transcription

MEDICAL POLICY
VAGUS NERVE STIMULATION
Policy Number: 2014T0101R
Effective Date: August 1, 2014
Table of Contents
COVERAGE RATIONALE...........................................
BACKGROUND...........................................................
CLINICAL EVIDENCE.................................................
U.S. FOOD AND DRUG ADMINISTRATION...............
CENTERS FOR MEDICARE AND MEDICAID
SERVICES (CMS).......................................................
APPLICABLE CODES.................................................
REFERENCES............................................................
POLICY HISTORY/REVISION INFORMATION..........
Policy History Revision Information
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Related Medical
Policies:
• Bariatric Surgery
• Deep Brain Stimulation
• Transcranial Magnetic
Stimulation
Related Behavioral
Health Guidelines:
• Vagus Nerve
Stimulation for Major
Depressive Disorder
INSTRUCTIONS FOR USE
This Medical Policy provides assistance in interpreting UnitedHealthcare benefit plans. When
deciding coverage, the enrollee specific document must be referenced. The terms of an
enrollee's document (e.g., Certificate of Coverage (COC) or Summary Plan Description (SPD))
may differ greatly. In the event of a conflict, the enrollee's specific benefit document supersedes
this Medical Policy. All reviewers must first identify enrollee eligibility, any federal or state
regulatory requirements and the plan benefit coverage prior to use of this Medical Policy. Other
Policies and Coverage Determination Guidelines may apply. UnitedHealthcare reserves the right,
in its sole discretion, to modify its Policies and Guidelines as necessary. This Medical Policy is
provided for informational purposes. It does not constitute medical advice.
UnitedHealthcare may also use tools developed by third parties, such as the MCG™ Care
Guidelines, to assist us in administering health benefits. The MCG™ Care Guidelines are
intended to be used in connection with the independent professional medical judgment of a
qualified health care provider and do not constitute the practice of medicine or medical advice.
COVERAGE RATIONALE
Vagus nerve stimulation (VNS) is proven for treating epilepsy in persons without a history
of left or bilateral cervical vagotomy.
The U.S. Food and Drug Administration (FDA) identifies a history of left or bilateral cervical
vagotomy as a contraindication to vagus nerve stimulation.
Vagus nerve stimulation is unproven for treating all other indications, including the
following:
• Alzheimer's disease
• Anxiety disorder
• Autism
• Back and neck pain
• Bipolar disorder
• Bulimia
• Cerebral palsy
Vagus Nerve Stimulation: Medical Policy (Effective 08/01/2014)
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Proprietary Information of UnitedHealthcare. Copyright 2014 United HealthCare Services, Inc.
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Chronic pain syndrome
Cluster headaches
Depression
Fibromyalgia
Heart failure
Migraines
Morbid obesity
Narcolepsy
Obsessive-compulsive disorder
Paralysis agitans
Sleep disorders
Tourette's syndrome
Available studies on the use of vagus nerve stimulation for treating severe, major depression or
bipolar disorder refractory to medical therapy contain methodological flaws such as lack of control
group, small sample size, potential bias, lack of randomization and blinding and lack of statistical
power analysis. There is a substantial placebo effect associated with depression treatments and
the lack of data from prospective randomized controlled or comparative clinical studies
considerably limits the conclusions that can be drawn from the available evidence. Furthermore,
preliminary analysis of a randomized controlled trial did not find a statistically significant
difference between sham and active VNS. Definitive patient selection criteria for vagus nerve
stimulation (VNS) in patients with treatment-resistant depression have not yet been established,
and significant predictors of response have also not been identified.
Early research has examined the use of vagus nerve stimulation for additional indications.
However, because of limited studies, small sample sizes and weak study designs, there is
insufficient data to conclude that vagus nerve stimulation is safe and/or effective for treating these
indications.
Information Pertaining to Medical Necessity Review (When Applicable)
Vagus nerve stimulation (VNS) is medically necessary for treating epilepsy in patients with
medically refractory epileptic seizures who are not surgical candidates or have failed surgical
intervention.
It is an expectation that the physician have experience and expertise in the use of vagus nerve
stimulation.
BACKGROUND
The vagus nerve, a large nerve in the neck, connects the lower part of the brain to the heart,
lungs and intestines. Vagus nerve stimulation (VNS) uses short bursts of electrical energy
directed into the brain via the vagus nerve. The system, implanted subcutaneously in the upper
chest, includes a pulse generator/neurostimulator and electrode that deliver pulses of current to
the left vagus nerve. Following implantation, the generator is programmed to stimulate the vagus
nerve at a rate determined by the patient and physician.
CLINICAL EVIDENCE
Epilepsy
There is high-quality evidence from randomized controlled trials comparing high-stimulation with
low-stimulation placebo vagus nerve stimulation (VNS) and long-term studies regarding the
benefit and safety of VNS to conclude that VNS reduces seizure rates in some patients older than
12 years of age with medically refractory partial epileptic seizures who are not suitable candidates
for surgery or in whom surgical treatment has failed. The strongest evidence is composed of 2
randomized placebo-controlled trials (Vagus Nerve Stimulation Studies #E03 and #E05) (Holder
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et al., 1992; Ben-Menachem et al., 1994; George et al., 1994; Vagus Nerve Stimulation Study
Group, 1995; Salinsky et al., 1996; Handforth et al., 1998).
Englot et al. (2011) performed a meta-analysis of VNS efficacy in epilepsy, identifying 74 clinical
studies with 3321 patients suffering from intractable epilepsy. These studies included 3 blinded,
randomized controlled trials (Class I evidence); 2 non-blinded, randomized controlled trials (Class
II evidence); 10 prospective studies (Class III evidence); and numerous retrospective studies.
After VNS, seizure frequency was reduced by an average of 45%, with a 36% reduction in
seizures at 3-12 months after surgery and a 51% reduction after > 1 year of therapy. At the last
follow-up, seizures were reduced by 50% or more in approximately 50% of the patients. Patients
with generalized epilepsy and children benefited significantly from VNS despite their exclusion
from initial approval of the device. Furthermore, posttraumatic epilepsy and tuberous sclerosis
were positive predictors of a favorable outcome. The authors concluded that VNS is an effective
and relatively safe adjunctive therapy in patients with medically refractory epilepsy not amenable
to resection. However, the authors commented further that complete seizure freedom is rarely
achieved using VNS and that a quarter of patients do not receive any benefit from therapy.
Elliott et al. (2011a) assessed the efficacy and safety of vagus nerve stimulation in a consecutive
series of adults and children with treatment-resistant epilepsy (TRE). The study included 220
(50.5%) females and 216 (49.5%) males ranging in age from 1 to 76 years at the time of
implantation. Thirty-three patients (7.6%) in the primary implantation group had inadequate
follow-up (<3 months from implantation) and three patients had early device removal because of
infection and were excluded from seizure control outcome analyses. Mean seizure frequency
significantly improved following implantation. Seizure control ≥ 90% was achieved in 22.5% of
patients, ≥ 75% seizure control in 40.5% of patients, ≥ 50% improvement in 63.75% of patients,
and <50% improvement in 36.25% of patients. Permanent injury to the vagus nerve occurred in
2.8% of patients. The authors concluded that vagus nerve stimulation is a safe and effective
palliative treatment option for focal and generalized TRE in adults and children. The authors
stated that when used in conjunction with a multidisciplinary and multimodality treatment regimen
including aggressive antiepileptic drug regimens and epilepsy surgery when appropriate, more
than 60% of patients with TRE experienced at least a 50% reduction in seizure burden.
Elliott et al. (2011) evaluated the impact of failed intracranial epilepsy surgery (IES) and other
surrogate marker of severe epilepsy on VNS effectiveness. The study included 376 patients (188
females; 265 adults; mean age of 29.4 years at implantation) with treatment resistant epilepsy
(TRE) who underwent VNS implantation and had at least 1 year of follow-up. One hundred ten
patients (29.3%) had failed one or more prior craniotomies for TRE and 266 (70.7%) had no
history of IES. The mean duration of VNS therapy was 5.1 years. Patients with prior IES were
more commonly male and adult, had a greater number of seizure types, and more commonly had
focal or multifocal versus generalized seizures. There was no significant difference in the mean
percentage seizure reduction between patients with and without a history of IES. There was no
correlation between type of failed IES (callosotomy versus resection) and seizure reduction with
VNS therapy. The authors concluded that failed IES did not affect the response to VNS therapy.
Unlike prior reports, patients with callosotomy did not respond better than those who had
resective surgery. Nearly 50% of patients experienced at least 50% reduction in seizure
frequency. The authors stated that VNS should be considered a palliative treatment option for
patients with TRE, including patients who failed cranial epilepsy surgeries.
Vale et al. (2011) evaluated the efficacy of vagus nerve stimulation therapy in patients with
intractable epilepsy who have failed surgical and medical therapy. Thirty-seven patients who had
persistent seizures after cranial surgery who subsequently underwent vagus nerve stimulator
(VNS) placement were included in the study. Minimum follow-up was 18 months. Overall, 24
(64.9%), 9 (24.3%), 4 (10.8%) patients reported less than 30%, between 30% and 60% and
greater than 60% reduction in seizure frequency after VNS placement, respectively at a mean of
5 years follow-up period. The authors concluded that VNS therapy in patients who have failed
medical and surgical therapies only provides marginal improvement in seizure control but has
greater likelihood to improve subjective QoL issues. In addition, VNS has the potential to reduce
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anti-epileptic drug burden without adversely impacting seizure management. The authors stated
that given the low surgical risk of VNS placement, vagus nerve stimulation as a therapeutic
modality should be individualized to achieve best clinical response and fewest side effects.
There is evidence that the use of VNS provides significant health benefits for refractory seizures
in pediatric patients. Elliott et al. (2011) analyzed the efficacy of vagus nerve stimulation (VNS) in
a large consecutive series of children 18 years of age and younger with treatment-resistant
epilepsy and compared the safety and efficacy in children under 12 years of age with the
outcomes in older children. The authors retrospectively reviewed 141 consecutive cases involving
children (75 girls and 66 boys) with treatment-resistant epilepsy in whom primary VNS
implantation was performed and who had at least 1 year of follow-up since implantation. The
patients' mean age at vagus nerve stimulator insertion was 11.1 years (range 1-18 years). Eightysix children (61.0%) were younger than 12 years at time of VNS insertion (which constitutes offlabel usage of this device). Over 50% of patients experienced at least 50% reduction in seizure
burden. Children younger than 12 years had a response similar to that of older children with no
increase in complications. There was no difference in efficacy or complications between children
12 years of age and older (FDA-approved indication) and those younger than 12 years of age
(off-label usage). The authors concluded that vagus nerve stimulation is a safe and effective
treatment for treatment-resistant epilepsy in young adults and children. The authors state that
given the efficacy of this device and the devastating effects of persistent epilepsy during critical
developmental epochs, randomized trials are needed to potentially expand the indications for
VNS to include younger children.
In a randomized controlled trial, Klinkenberg et al. (2012) evaluated the effects of vagus nerve
stimulation (VNS) on seizure frequency and severity in 41 children with intractable epilepsy.
Some of the patients were treated with high-output stimulation and others with low-frequency
stimulation. VNS reduced seizure frequency by half or more in 16% of the high-output stimulation
group and in 21% of the low-output stimulation group. During a second phase of the research,
VNS was found to reduce seizure frequency by 50% or more in 26% of participants. However,
since this is an extremely small population sample, the applicability of these conclusions to
clinical practice is limited.
In a 2012 clinical guideline for the diagnosis and management of epilepsy, the National Institute
for Health and Care Excellence (NICE) stated that vagus nerve stimulation is indicated for use as
an adjunctive therapy in reducing the frequency of seizures in adults, children, and young people
who are refractory to antiepileptic medication but who are not suitable for resective surgery. This
includes adults whose epileptic disorder is dominated by focal seizures (with or without secondary
generalization) or generalized seizures (NICE 2012).
Professional Societies
American Academy of Neurology: In a practice parameter update on vagus nerve stimulation
for epilepsy, AAN stated that VNS is indicated for adults and adolescents over 12 years of age
with medically intractable partial seizures who are not candidates for potentially curative surgical
resections, such as lesionectomies or mesial temporal lobectomies. The degree of improvement
in seizure control from VNS remains comparable to that of new antiepileptic drugs (AEDs) but is
lower than that of mesial temporal lobectomy in suitable surgical resection candidates. Because
VNS rarely causes complete seizure remission, and is moderately invasive and expensive, use of
VNS is more appropriate in individuals unable to tolerate or benefit from antiepileptic drugs
(AEDs), and for whom a partial reduction in seizure frequency will significantly improve their
quality of life. Sufficient evidence exists to rank VNS for epilepsy as effective and safe, based on
a preponderance of Class I evidence (Fisher, 1999).
Depression
The current available evidence is insufficient to permit conclusions regarding the efficacy and
safety of vagus nerve stimulation (VNS) as an adjunct therapy in adult patients with treatmentresistant major depression disorder and bipolar disorder. While a moderate treatment effect was
observed in the uncontrolled studies, a published randomized controlled study (Rush, 2005a)
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failed to demonstrate a significant difference in primary outcomes after 10 weeks of active or
sham VNS. Based on evidence from uncontrolled studies lasting up to 24 months, VNS improved
depression and maintained the treatment benefit in a large number of patients. The lack of data
from prospective, randomized, controlled clinical studies considerably limits the conclusions that
can be drawn from the available evidence. VNS can cause severe complications. It is necessary
to know who is at risk and for which patients the potential benefits are clearly outweighing the
risks (Hayes, Vagus Nerve Stimulation for Depression, 2009).
D01 – D06 Studies Reported to the FDA
Most of the available evidence regarding the safety and efficacy of VNS for depression comes
from studies funded by or performed in collaboration with Cyberonics, Inc. Data from these
studies were presented to the U.S. Food and Drug Administration (FDA) to support the Premarket
Approval application. Overall, six studies were performed, designated D01 to D06. Complete data
sets have not been published for all of the studies. In these studies, VNS was performed using
the NeuroCybernetic Prosthesis (NCP®) System, also referred to as the VNS Therapy™ System.
In a double blind randomized controlled trial, Rush, et al. (2005a) (D02 trial) reported on vagus
nerve stimulation that involved 235 patients with major depressive disorder or depressed phase
bipolar disorder. All patients had a VNS implanted. After two weeks, the unit was activated in half
of the patients. The patients were evaluated ten weeks later. After ten weeks, 15% of the active
treatment and 10% of the sham treatment showed a response. It is noted that evaluation
occurred in 222 patients without explanation of what happened to the balance of the participants.
The authors concluded that VNS did not demonstrate short term efficacy in the treatment of
depression. These same authors completed a twelve month follow up study of 205 of the same
patients. (Rush, 2005b)The previously treated patients received another 9 months of VNS and
the participants in the sham group received 12 months of VNS. The results showed a 27%
response rate and a 15.8% remission rate. This study was flawed by the concomitant use of
antidepressants and adjusted treatments of both the VNS and drugs during the study period and
the lack of comparative group. Thirty of the participants required hospitalization for worsened
depression. The authors concluded that VNS was well tolerated but that comparative long term
data are needed to determine if the benefits are attributable to VNS.
The D01 study was a prospective, open-label, nonrandomized, uncontrolled clinical study. The
D01 study initially enrolled 30 patients and was reported by Rush et al. (2000). Their results
suggest that VNS provided symptom relief in 40% of the patients with major depression and
bipolar disorders and that an additional 16% of the patients had remission of symptoms following
VNS. The study limitations include lack of control group, small sample size, lack of power
analysis and ten week follow-up. An additional 30 patients were enrolled and results were
reported by Sackheim et al. (2001). They concluded that mean time from response to treatment
was 48.1 days. Based on the HDRS and MADRS, the results were 30.5%-34% at the 10 week
follow-up. Remission was reported in 15.3% of the patients. This study had similar limitations to
the Rush study.
Marangell et al. (2002) (D01 trial) studied the effectiveness of twelve months of VNS therapy in
the 30 patients that were enrolled in the Rush (2000) study. Twelve of the patients had greater
than or equal to 50% improvement on the HDRS and 15 showed the same level of improvement
on the MADRS. Approximately 29% of the patients achieved remission in this time frame.
Limitations of this study included lack of control group, small sample size, and lack of statistical
power analysis.
Nahas, et al. (2005) (D01 trial) completed a two year outcome study of 60 patients with VNS for
the treatment of major depressive episodes. The results indicate that remissions rates were 15%
at 3 months, 27% after 12 months and 22% after 2 years. Response rates were 31%, 44% and
42% at 3 month, 12 month and 24 month respectively. The authors concluded that the VNS
treatment may show long term benefit. The lack of a control group, the concurrent medication
therapy and financial relationship with the manufacturer limits the validity of the results.
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Nierenberg et al. (2008) (D02 trial) described the outcome of VNS for bipolar treatment-resistant
depression (TRD) patients participating in the acute and longitudinal pivotal trials and compared
their outcome with unipolar TRD patients in the same trials. Of 235 participants enrolled in the
acute study, 25 (11%) were diagnosed with DSM-IV bipolar I or II disorder. A sham-controlled 12week trial of VNS preceded 2 years of open treatment. Bipolar and unipolar subjects were
compared on baseline characteristics as well as acute and long-term outcomes. At baseline,
bipolar TRD was as severe as unipolar TRD but with depressive episodes of shorter duration and
more failed antidepressant trials/year. Acute, 1-year, and 2-year outcomes were similar for both
groups, even when the definition of response for bipolar TRD was expanded to include lack of
manic symptoms. The study reported that 33% of patients with unipolar depressive symptoms
and 38% of patients with depressive bipolar disease demonstrated a response at 24 months
compared with baseline. According to the investigators, in this hypothesis-generating analysis,
VNS short- and long-term effects on bipolar and unipolar TRD were similar. Because these
analyses were post hoc, these findings should not be interpreted as warranting clinical inference
regarding effectiveness of VNS in patients with bipolar depression.
A case series that included 74 patients with treatment resistant depression found a 34% response
rate to VNS at 3 months (end of active treatment period), which increased to 47% at the 12 month
follow-up (Schlaepfer, 2008) (D03 trial). There was no comparison group in this study, so
response with a different treatment or no treatment is not known. Also, patients were not blinded,
and they had regular clinic visits, both of which could affect responses to a subjective outcome
measure.
George, et al. (2005) (D04 trial) completed a one year comparison of 205 patients with VNS and
treatment as usual (ECT plus medications) to 124 patients who received only ECT and
antidepressant therapy. The VNS group showed a 27% improvement in the HRSD compared to
13% improvement for the non VNS group This study was flawed by the lack of randomization,
blinding and the non VNS group had at least 10 prior major depressive episodes. All principal
investigators disclosed a financial relationship with the manufacturer.
Other Clinical Trials
Berry et al. (2013) performed a meta-analysis to compare the response and remission rates in
depressed patients with chronic treatment-resistant depression (TRD) treated with vagus nerve
stimulation (VNS) plus treatment as usual (VNS + TAU) or TAU. The six clinical studies included
in the meta‑analysis were two single‑arm studies of VNS + TAU, a randomized trial of VNS +
TAU versus TAU, a single arm study of patients who received TAU, a randomized trial of VNS +
TAU comparing different VNS stimulation intensities, and a nonrandomized registry of patients
who received either VNS + TAU or TAU. Response was based on the Montgomery-Åsberg
Depression Rating Scale (MADRS) and the Clinical Global Impressions scale's Improvement
subscale (CGI-I), as these were the two clinician-rated measures common across all or most
studies. Outcomes were compared from baseline up to 96 weeks of treatment with VNS + TAU (n
= 1035) versus TAU (n = 425). MADRS response rate for VNS + TAU at 12, 24, 48, and 96
weeks were 12%, 18%, 28%, and 32% versus 4%, 7%, 12%, and 14% for TAU. The MADRS
remission rate for VNS + TAU at 12, 24, 48, and 96 weeks were 3%, 5%, 10%, and 14% versus
1%, 1%, 2%, and 4%, for TAU. Adjunctive VNS Therapy was associated with a greater likelihood
of response and remission compared with TAU. For patients who had responded to VNS + TAU
at 24 weeks, sustained response was more likely at 48 weeks and at 96 weeks. Similar results
were observed for CGI-I response. The authors concluded that for patients with chronic TRD,
VNS + TAU has greater response and remission rates that are more likely to persist than TAU.
According to the authors, the primary limitation of the meta‑analysis involved the individual study
designs; namely, that the TAU group data is limited to two trials for the CGI-I scale and one trial
for the MADRS scale; in addition, the nonrandomized study and the randomized, sham‑controlled
study represent the only concurrent head‑to‑head comparisons of VNS + TAU and TAU.
Martin and Martin-Sanchez (2012) conducted a systematic review and meta-analysis of analytical
studies to determine the efficacy of vagus nerve stimulation (VNS) for treatment of depression.
Fourteen studies met the selection criteria and were included in the review. The meta-analysis of
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efficacy for uncontrolled studies showed a significant reduction in scores at the Hamilton
Depression Rating Scale endpoint and the percentage of responders was 31.8%. However, the
randomized control trial which covered a sample of 235 patients with depression, reported no
statistically significant differences between the active intervention and placebo groups. To study
the cause of this heterogeneity, a meta-regression was performed. The adjusted coefficient of
determination was 0.84, which implies that an 84% variation in effect size across the studies was
explained by baseline severity of depression. The authors stated that insufficient data are
available to conclude whether or not VNS is effective in the treatment of depression. In addition, it
cannot be ruled out that the positive results observed in the uncontrolled studies might have been
mainly due to a placebo effect.
Daban et al. (2008) evaluated the safety and efficacy of vagus nerve stimulation (VNS) in
treatment-resistant depression (TRD) by means of systematic review using the major databases
(Medline, Psychological Abstracts, Current Contents), beginning in January 2000 and ending in
September 2007. Ninety-eight references were found, but only 18 add-on studies (n=1251) met
the required quality criteria and were included in the review. Only one double-blind, randomized
study was available and therefore a meta-analysis was not feasible. In a majority of the
preliminary open studies selected for the review, VNS was associated with a significant reduction
of the depressive symptoms (primary outcome: Hamilton Depression Rating Scale, HDRS) in the
short and long term. Unfortunately, the only double-blind study gave rather inconclusive results.
Generally, VNS is reported to be a safe and feasible procedure, despite its invasive nature. The
authors concluded that VNS seems to be an interesting new approach to treating TRD. However,
despite the promising results reported mainly in open studies, further clinical trials are needed to
confirm its efficacy in major depression.
In a multicenter, double blind study, Aaronson et al. (2013) compared the safety and
effectiveness of different stimulation levels of adjunctive vagus nerve stimulation (VNS) therapy
for the treatment of treatment-resistant depression (TRD). A total of 331 patients with TRD were
randomized to one of three dose groups: Low (0.25 mA current, 130 μs pulse width), Medium
(0.5-1.0 mA, 250 μs), or High (1.25-1.5 mA, 250 μs). A highly treatment-resistant population
(>97% had failed to respond to ≥6 previous treatments) was enrolled. Response and adverse
effects were assessed for 22 weeks (end of acute phase), after which output current could be
increased, if clinically warranted. Assessments then continued until week 50 (end of long-term
phase). During the acute phase, all groups showed statistically significant improvement on the
primary efficacy endpoint (change in Inventory of Depressive Symptomatology-Clinician
Administered Version [IDS-C]), but not for any between-treatment group comparisons. In the
long-term phase, mean change in IDS-C scores showed continued improvement. Post-hoc
analyses demonstrated a statistically significant correlation between total charge delivered per
day and decreasing depressive symptoms; and analysis of acute phase responders
demonstrated significantly greater durability of response at Medium and High doses than at the
Low dose. The authors concluded that TRD patients who received adjunctive VNS showed
significant improvement at study endpoint compared with baseline, and the effect was durable
over 1 year. The lack of a controlled standard treatment comparator group limits the conclusions
that can be reached from this study.
In a small, prospective, nonrandomized, controlled study, Sperling et al. (2009) measured
improvement in depression (HDRS28) for 12 months. Changes in the duration of depressionrelated hospitalization and the number of psychiatric treatments per year were also evaluated.
The study enrolled 9 patients receiving VNS as an adjunct to pharmacotherapy and
psychotherapy and 9 patients, sex-matched and age-matched to the VNS group, who continued
pharmacotherapy and psychotherapy but did not undergo device implantation. VNS significantly
improved HDRS28 scores from 23.7 to 10.2 points at 12 months. There was no significant
change in the control group. VNS also significantly decreased the yearly number of days
hospitalized from 65 to 44, while the hospitalization rate in the control group did not change. VNS
also reduced the number of psychiatric treatments from 33 to 24 per year. There was no
statistically significant change in this parameter for the control group. The respective values for
the control group were 24.9 and 25.3 treatments per year. While the study results suggest that
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VNS may improve depression, the study used only one instrument to assess this outcome and
did not include a sham control; therefore, the result must be interpreted with caution since a
placebo effect may have confounded the results. However, the additional outcomes, duration of
hospitalization, and number of psychiatric treatments are indirect measures, suggesting that VNS
may improve depression severity. Nevertheless, the small sample size and lack of blinded
assessment are additional factors compromising the quality of the evidence.
Bajbouj et al. (2010) assessed the efficacy and the safety of VNS in 74 patients with therapyresistant major depressive disorder. Psychometric measures were obtained after 3, 12, and 24
months of VNS. Mixed-model repeated-measures analysis of variance revealed a significant
reduction at all the 3 time points in the 28-item Hamilton Rating Scale for Depression (HRSD28)
score, the primary outcome measure. The proportion of patients who fulfilled the remission
criteria remained constant as the duration of VNS treatment increased. Voice alteration, cough,
and pain were the most frequently reported adverse effects. Two patients committed suicide
during the study; no other deaths were reported. No statistically significant differences were seen
in the number of concomitant antidepressant medications. According to the investigators, the
results of this 2-year open-label trial suggest a clinical response and a comparatively benign
adverse effect profile among patients with treatment-resistant depression. The lack of a control
group limits the validity of the results of this study.
According to the World Federation of Societies of Biological Psychiatry (WFSBP) that includes
members from the Department of Psychiatry, University of Bonn, Germany; Department of
Psychiatry and Behavioral Sciences, The Johns Hopkins University, Baltimore; Department of
Psychiatry, Medical University of South Carolina, Charleston; and Department of Psychiatry,
Emory University, Atlanta, there is no Class I evidence for efficacy in acute or chronic depression.
Despite the clear lack of Class I evidence, based on the substantial safety literature and
experience with epilepsy, and positive depression studies to date (which were uncontrolled but
studied larger patient numbers), the WFSBP recommends that psychiatrists consider using VNS
along with other options in highly treatment-resistant patients with a chronic course who have
tried and failed more than three other antidepressants. Prior response to ECT seems to be a
predictor of response to VNS. There is insufficient evidence to recommend VNS for other
neuropsychiatric disorders, except epilepsy where it is an established and recommended
treatment option (Schlaepfer, 2010).
A Comparative Effectiveness Review was prepared for the Agency for Healthcare Research and
Quality (AHRQ) on Nonpharmacologic Interventions for Treatment-Resistant Depression in
Adults. The report identified only one study (Rush 2005) comparing VNS to sham, conducted in a
Tier 1 major depressive disorder (MDD)/bipolar mix population. According to the AHRQ report,
the majority of measures used by this study found no difference between VNS and sham on
changes in depressive severity or rates of response and remission. Since only a single study was
identified for this comparison, further assessment by key variables was not possible (Gaynes et
al. 2011).
A Blue Cross Blue Shield TEC assessment on VNS for treatment-resistant depression concluded
that VNS does not meet the TEC criteria. The clinical trials reviewed reported weak evidence that
did not demonstrate efficacy (Blue Cross Blue Shield TEC, 2006).
In a 2009 guidance document, the National Institute for Health and Care Excellence (NICE)
stated that the current evidence on the safety and efficacy of vagus nerve stimulation (VNS) for
treatment resistant depression is inadequate in quantity and quality. Therefore this procedure
should be used only with special arrangements for clinical governance, consent and audit or
research. It should be used only in patients with treatment-resistant depression (NICE, 2009).
Professional Societies
American Psychiatric Association (APA): In a clinical practice guideline for the treatment of
patients with major depressive disorder, the APA states that electroconvulsive therapy remains
the treatment of best established efficacy against which other stimulation treatments (e.g., VNS,
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deep brain stimulation, transcranial magnetic stimulation, other electromagnetic stimulation
therapies) should be compared. The APA states that vagus nerve stimulation (VNS) may be an
additional option for individuals who have not responded to at least four adequate trials of
depression treatment, including ECT [III]. For patients whose depressive episodes have not
previously responded to acute or continuation treatment with medications or a depression
focused psychotherapy but who have shown a response to ECT, maintenance ECT may be
considered [III]. Maintenance treatment with VNS is also appropriate for individuals whose
symptoms have responded to this treatment modality [III]. According to the APA, relative to other
antidepressive treatments, the role of VNS remains a subject of debate. However, it could be
considered as an option for patients with substantial symptoms that have not responded to
repeated trials of antidepressant treatment. The three APA rating categories represent varying
levels of clinical confidence:
I: Recommended with substantial clinical confidence
II: Recommended with moderate clinical confidence
III: May be recommended on the basis of individual circumstances (Gelenberg et al. 2010)
Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety
Treatments (CANMAT): In 2008-2009, the Canadian Psychiatric Association and the CANMAT
partnered to produce evidence-based clinical guidelines for the treatment of depressive disorders.
Among the four forms of neurostimulation for depression reviewed in the guidelines,
electroconvulsive therapy (ECT) had the most extensive evidence, spanning seven decades.
Repetitive transcranial magnetic (rTMS) and vagus nerve stimulation (VNS) have been approved
to treat depressed adults in both Canada and the United States with a much smaller evidence
base. Compared to other modalities for the treatment of major depressive disorder (MDD), the
data based is limited by the relatively small numbers of randomized controlled trials (RCTs) and
small sample sizes. The investigators concluded that there is the most evidence to support ECT
as a first-line treatment under specific circumstances and rTMS as a second-line treatment.
Evidence to support VNS is less robust and deep brain stimulation remains an investigational
treatment (Kennedy, 2009).
Other Conditions
The use of vagus nerve stimulation has been investigated for other conditions including
Alzheimer’s disease (Merrill et al. 2006), anxiety (George, 2008), autism (Levy, 2010), obsessivecompulsive disorder (George et al. 2008), pain (Napadow et al. 2012; Ness et al. 2000),
headaches (Cecchini et al. 2009; Mauskop, 2005; Hord et al. 2003), obesity (Sarr et al. 2012;
Pardo et al. 2007), sleep disorders (Marlow, 2001), heart disease/congestive heart failure
(Deferrari et al. 2011), asthma (Steyn et al. 2013; Miner et al. 2012), and fibromyalgia (Lange et
al. 2011). However, because of limited studies, small sample sizes and weak study designs, there
is insufficient data to conclude that vagus nerve stimulation is safe and/or effective for treating
these indications. Further clinical trials demonstrating the clinical usefulness of vagus nerve
stimulation are necessary before it can be considered proven for these conditions.
Additional Search Terms
Lennox-Gastaut syndrome, neuromodulation, pneumogastric nerve, vagal stimulation
U.S. FOOD AND DRUG ADMINISTRATION (FDA)
®
The FDA approved the NeuroCybernetic Prosthesis (NCP) System (Cyberonics, Inc.) in July
1997 (P970003) for use as an adjunctive therapy in reducing the frequency of seizures in adults
and adolescents over 12 years of age with medically refractory, partial-onset seizures. Since the
original approval, there have been a number of modifications to the device, the instruments used
to implant the electrodes and the stimulator, and the software used to control and program the
stimulator. The NCP System cannot be used in patients after a left or bilateral cervical vagotomy.
Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf/p970003.pdf Accessed May 2014.
In August 2001, manufacturers of neurostimulation devices advised against the use of shortwave,
microwave or therapeutic ultrasound diathermy for persons implanted with the devices. Diathermy
9
may potentially cause the generator or leads to heat up and damage tissue, causing pain and
discomfort.
On May 10, 2005, the FDA issued a Public Health Notification regarding MRI-caused injuries in
patients with implanted neurostimulators. Available at:
http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/PublicHealthNotifications/ucm06212
5.htm Accessed May 2014.
In July 2005, the VNS Therapy™ System (Cyberonics, Inc.) was approved for marketing by the
FDA 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 (PMA Supplement 50).
Available at:
http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearan
ces/Recently-ApprovedDevices/ucm078532.htm Accessed May 2014.
To locate marketing clearance information for a specific device or manufacturer, search the
Center for Devices and Radiological Health (CDRH) 510(k) database or the Premarket Approval
(PMA) database by product and/or manufacturer name. Use product code LYJ (stimulator,
autonomic nerve, implanted for epilepsy.
CENTERS FOR MEDICARE AND MEDICAID SERVICES (CMS)
Medicare covers vagus nerve stimulation. Refer to the National Coverage Determination (NCD)
for Vagus Nerve Stimulation (160.18). Local Coverage Determinations (LCDs) do exist. Refer to
the LCDs for Vagus Nerve Stimulation. (Accessed August 13, 2013)
APPLICABLE CODES
The codes listed in this policy are for reference purposes only. Listing of a service or device code
in this policy does not imply that the service described by this code is a covered or non-covered
health service. Coverage is determined by the benefit document. This list of codes may not be all
inclusive.
®
CPT Code
61885
64553
64568
64570
95970
Description
Insertion or replacement of cranial neurostimulator pulse generator or
receiver, direct or inductive coupling; with connection to a single
electrode array
Percutaneous implantation of neurostimulator electrode array; cranial
nerve
Incision for implantation of cranial nerve (e.g., vagus nerve)
neurostimulator electrode array and pulse generator
Removal of cranial nerve (e.g., vagus nerve) neurostimulator
electrode array and pulse generator
Electronic analysis of implanted neurostimulator pulse generator
system (eg, rate, pulse amplitude, pulse duration, configuration of
wave form, battery status, electrode selectability, output modulation,
cycling, impedance and patient compliance measurements); simple or
complex brain, spinal cord, or peripheral (ie, cranial nerve, peripheral
nerve, sacral nerve, neuromuscular) neurostimulator pulse
generator/transmitter, without reprogramming
10
®
CPT Code
95974
95975
Description
cycling, impedance and patient compliance measurements); complex
cranial nerve neurostimulator pulse generator/transmitter, with
intraoperative or subsequent programming, with or without nerve
interface testing, first hour
cycling, impedance and patient compliance measurements); complex
cranial nerve neurostimulator pulse generator/transmitter, with
intraoperative or subsequent programming, each additional 30
minutes after first hour (List separately in addition to code for primary
procedure)
CPT® is a registered trademark of the American Medical Association.
HCPCS Code
C1767
C1778
L8679
L8680
L8681
L8682
L8683
L8685
L8686
L8687
L8688
Description
Generator, neurostimulator (implantable), nonrechargeable
Lead, neurostimulator (implantable)
Implantable neurostimulator, pulse generator, any type
Implantable neurostimulator electrode (with any number of contact
points), each
Patient programmer (external) for use with implantable programmable
neurostimulator pulse generator, replacement only
Implantable neurostimulator radiofrequency receiver
Radiofrequency transmitter (external) for use with implantable
neurostimulator radiofrequency receiver
Implantable neurostimulator pulse generator, single array,
rechargeable, includes extension
Implantable neurostimulator pulse generator, single array, nonrechargeable, includes extension
Implantable neurostimulator pulse generator, dual array,
rechargeable, includes extension
Implantable neurostimulator pulse generator, dual array, nonrechargeable, includes extension
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treatment-resistant depression. J Clin Psychopharmacol. 2010 Jun;30(3):273-81.
Ben-Menachem E, Mañon-Espaillat R, Ristanovic R, et al. Vagus nerve stimulation for treatment
of partial seizures: 1. A controlled study of effect on seizures. First International Vagus Nerve
Stimulation Study Group. Epilepsia. 1994;35(3):616-626.
Berry SM, Broglio K, Bunker M, et al. A patient-level meta-analysis of studies evaluating vagus
nerve stimulation therapy for treatment-resistant depression. Med Devices (Auckl). 2013;6:17-35.
11
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Depression.vBlueCross BlueShield Association Technology Evaluation Center, Vol. 21, Tab 7.
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migraine with depression: preliminary data. Neurol Sci. 2009 May;30 Suppl 1:S101-4.
Daban C, Martinez-Aran A, Cruz N et al. (2008) Safety and efficacy of vagus nerve stimulation in
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vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur
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Heart Failure. January 2013.
ECRI Institute. Hotline Response. Implantable vagus nerve stimulator for epilepsy. April 2009.
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2012.
Elliott RE, Morsi A, Geller EB, et al. Impact of Failed Intracranial Epilepsy Surgery on the
Effectiveness of Subsequent Vagus Nerve Stimulation. Neurosurgery. 2011 May 6.
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Elliott, RE, Rodgers, SD, Bassani, L, et al. Vagus nerve stimulation for children with treatmentresistant epilepsy: a consecutive series of 141 cases. J Neurosurg Pediatr. 2011;7(5):491-50.
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Gaynes BN, Lux L, Lloyd S, et al. Nonpharmacologic Interventions for Treatment-Resistant
Depression in Adults. Comparative Effectiveness Review No. 33. (Prepared by RTI InternationalUniversity of North Carolina (RTI-UNC) Evidencebased Practice Center under Contract No. 29002-0016I.) AHRQ Publication No. 11-EHC056-EF. Rockville, MD: Agency for Healthcare
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Gelenberg AJ, Freeman MP, Markowitz JL, et al.; Work Group on Major Depressive Disorder.
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rd
with Major Depressive Disorders, 3 ed. Am J Psychiatry. 2010;167(10S). American Psychiatric
Association (APA) Web site. Available at: http://psychiatryonline.org/guidelines.aspx Accessed
May 2014.
George MS, Nahas Z, Bohning DE, et al. Vagus nerve stimulation therapy: a research update.
Neurology. 2002;59:S56-S61.
12
George R, Salinsky M, Kuzniecky R, et al. Vagus nerve stimulation for treatment of partial
seizures: 3. Long-term followup on first 67 patients exiting a controlled study. First International
Vagus Nerve Stimulation Study Group. Epilepsia. 1994;35(3):637-643.
George MS, Rush JA, Marangell, LB, et al. A one-year comparison of vagus nerve stimulation
with treatment as usual for treatment resistant depression. Biol Psychiatry. 2005;58:364-373.
George MS, Ward HE Jr, Ninan PT, et al. C. A pilot study of vagus nerve stimulation (VNS) for
treatment-resistant anxiety disorders. Brain Stimul. 2008 Apr;1(2):112-21.
Hammond EJ, Uthman BM, Reid SA, et al. Electrophysiological studies of cervical vagus nerve
stimulation in humans: I. EEG effects. Epilepsia. 1992;33(6):1013-1020.
Handforth A, DeGiorgio CM, Schachter SC, et al. Vagus nerve stimulation therapy for partialonset seizures: a randomized active-control trial. Neurology. 1998;51:48-55.
Hayes, Inc. Directory. Vagus Nerve Stimulation for Depression. October 2009. Updated October
2012.
Hayes, Inc. Directory. Vagus Nerve Stimulation for Epilepsy. October 2009. Updated October
2012.
Holder LK, Wernicke JF, Tarver WB. Treatment of refractory partial seizures: preliminary results
of a controlled study. Pacing Clin Electrophysiol. 1992;15(10 Pt 2):1557-1571.
Hord ED, Evans MS, Mueed S, et al. The effect of vagus nerve stimulation on migraines. J Pain.
2003 Nov;4(9):530-4.
Kennedy SH, Milev R, Giacobbe P, et al; Canadian Network for Mood and Anxiety Treatments
(CANMAT). Canadian Network for Mood and Anxiety Treatments (CANMAT) Clinical guidelines
for the management of major depressive disorder in adults. IV. Neurostimulation therapies. J
Affect Disord. 2009 Oct;117 Suppl 1:S44-53.
Klinkenberg S, Aalbers MW, Vles JS, et al. Vagus nerve stimulation in children with intractable
epilepsy: a randomized controlled trial. Dev Med Child Neurol. 2012 Sep;54(9):855-61.
Lange G, Janal MN, Maniker A, et al. Safety and Efficacy of Vagus Nerve Stimulation in
Fibromyalgia: A Phase I/II Proof of Concept Trial. Pain Med. 2011 Aug 3. doi: 10.1111/j.15264637.2011.01203.x.
Levy ML, Levy KM, Hoff D, et al. Vagus nerve stimulation therapy in patients with autism
spectrum disorder and intractable epilepsy: results from the vagus nerve stimulation therapy
patient outcome registry. J Neurosurg Pediatr. 2010 Jun;5(6):595-602.
Marangell LB, Rush AJ, George MS, et al. Vagus nerve stimulation (VNS) for major depressive
episodes: one year outcomes. Biol Psychiatry. 2002;51(4):280-287.
Malow BA, Edwards J, Marzec M, et al. Vagus nerve stimulation reduces daytime sleepiness in
epilepsy patients. Neurology. 2001 Sep 11;57(5):879-84.
Martin JL, Martín-Sánchez E. Systematic review and meta-analysis of vagus nerve stimulation in
the treatment of depression: variable results based on study designs. Eur Psychiatry. 2012
Apr;27(3):147-55.
Mauskop A. Vagus nerve stimulation relieves chronic refractory migraine and cluster headaches.
Cephalalgia. 2005 Feb;25(2):82-6.
13
Merrill CA, Jonsson MA, Minthon L, et al. Vagus nerve stimulation in patients with Alzheimer's
disease: Additional follow-up results of a pilot study through 1 year. J Clin Psychiatry. 2006
Aug;67(8):1171-8.
Miner JR, Lewis LM, Mosnaim GS, et al. Feasibility of percutaneous vagus nerve stimulation for
the treatment of acute asthma exacerbations. Acad Emerg Med. 2012 Apr;19(4):421-9. doi:
10.1111/j.1553-2712.2012.01329.x.
Nahas Z, Marangell LB, Husain MM, et al. Two year outcome of vagus nerve stimulation (VNS)
for treatment of major depressive episodes. J Clin Psychiatry 2005;66:1097-1104.
Napadow V, Edwards RR, Cahalan CM, et al. Evoked pain analgesia in chronic pelvic pain
patients using respiratory-gated auricular vagal afferent nerve stimulation. Pain Med. 2012
Jun;13(6):777-89.
National Institute for Health and Care Excellence (NICE).CG137. The epilepsies: the diagnosis
and management of the epilepsies in adults and children in primary and secondary care. January
2012. Available at: http://publications.nice.org.uk/the-epilepsies-the-diagnosis-and-managementof-the-epilepsies-in-adults-and-children-in-primary-and-cg137/guidance#vagus-nerve-stimulationvns Accessed May 2014.
National Institute for Health and Care Excellence (NICE). Vagus nerve stimulation for treatmentresistant depression. December 2009. Available at:
http://www.nice.org.uk/nicemedia/live/12149/46667/46667.pdf . Accessed May 2014.
Ness TJ, Fillingim RB, Randich A, et al. Low intensity vagal nerve stimulation lowers human
thermal pain thresholds. Pain. 2000 May;86(1-2):81-5.
Nierenberg AA, Alpert JE, Gardner-Schuster EE, et al. Vagus nerve stimulation: 2-year outcomes
for bipolar versus unipolar treatment-resistant depression. Biol Psychiatry. 2008 Sep
15;64(6):455-60.
Pardo JV, Sheikh SA, Kuskowski MA, et al. Weight loss during chronic, cervical vagus nerve
stimulation in depressed patients with obesity: an observation. Int J Obes (Lond). 2007
Nov;31(11):1756-9.
Rush AJ, George MS, Sackeim HA, et al. Vagus nerve stimulation (VNS) for treatment-resistant
depressions: a multicenter study. Biol Psychiatry. 2000;47(4):276-286.
Rush JA, Marangell, LB, Sackeim HA, et al. Vagus nerve stimulation for treatment-resistant
depression: A randomized controlled acute phase trial. Biol Psychiatry. 2005a;58:347-354.
Rush JA, Sackeim HA, Marangell, LB, et al. Effects of 12 months of vagus nerve stimulation in
treatment-resistant depression: A naturalistic study. Biol Psychiatry. 2005b;58:355-363.
Sackeim HA, Rush AJ, George MS, et al. Vagus nerve stimulation (VNS) for treatment-resistant
depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology.
2001;25(5):713-728.
Salinsky MC, Uthman BM, Ristanovic RK, et al. Vagus nerve stimulation for the treatment of
medically intractable seizures: results of a 1-year open-extension trial. Arch Neurol.
1996;53:1176-1180.
Sarr MG, Billington CJ, Brancatisano R, et al.; EMPOWER Study Group. The EMPOWER study:
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morbid obesity. Obes Surg. 2012 Nov;22(11):1771-82.
14
Schlaepfer TE, Frick C, Zobel A, et al. Vagus nerve stimulation for depression: efficacy and safety
in a European study. Psychol Med. 2008 May;38(5):651-61.
Schlaepfer TE, George MS, Mayberg H; WFSBP Task Force on Brain Stimulation. WFSBP
Guidelines on Brain Stimulation Treatments in Psychiatry. World J Biol Psychiatry. 2010
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2009;42(3):85-88.
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19;6(1):7.
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after failed epilepsy surgery. Seizure. 2011 Apr;20(3):244-8.
POLICY HISTORY/REVISION INFORMATION
Date
08/01/2014
•
•
Action/Description
Updated list of applicable CPT codes; removed 64569
Archived previous policy version 2013T0101Q
15

VAGUS NERVE STIMULATION

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