Vagus Nerve Stimulation for Treatment of Resistant Depression (TRD)

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CMS has determined that there is sufficient evidence to conclude that vagus nerve stimulation is not reasonable and necessary for treatment of resistant depression. Accordingly, we are issuing the following national coverage determination: Vagus nerve stimulation is not covered for treatment resistant depression.

Decision Memo: To: Administrative File: CAG-00313R Vagus Nerve Stimulation for Treatment of Resistant Depression From: Steve Phurrough, MD, MPA Director Coverage and Analysis Group Marcel E. Salive, MD, MPH Director Division of Medical and Surgical Services Beverly Lofton, MHA Lead Health Policy Analyst Division of Medical and Surgical Services; Jyme Schafer, MD, MPH Lead Medical Officer Division of Medical and Surgical Services Subject: Coverage Decision Memorandum for Vagus Nerve Stimulation for Treatment of Resistant Depression Date: May 4, 2007 I. Decision CMS has determined that there is sufficient evidence to conclude that vagus nerve stimulation is not reasonable and necessary for treatment of resistant depression. Accordingly, we are issuing the following national coverage determination: Vagus nerve stimulation is not covered for treatment resistant depression. II. Background Types of Mental Disorders Mental disorders are health conditions that are characterized by alterations in thinking, mood, or behavior (or some combination thereof) associated with distress and/or impaired functioning (Surgeon General’s Report 1999). Depression is a mental disorder characterized by alterations in mood. “Mood disorders are recurrent, life threatening (due to the risk for suicide), and a major cause of morbidity worldwide” (Nestler, Barrot et al. 2002). The symptoms of depression have been recognized as far back as ancient times, with Hippocrates referring to it as melancholia (Nestler, Barrot et al. 2002). The diagnosis of depression is not based on objective diagnostic tests (such as biopsies or serum chemistries) but on a highly variable set of symptoms (Nestler, Barrot et al. 2002). Nestler and others have suggested, “…depression should not be viewed as a single disease, but a heterogeneous syndrome comprised of numerous diseases of distinct causes and pathophysiologies” (Nestler et al., 2002; Thase, 2000). In the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM IV), the criteria for a major depressive episode (MDE) include five or more of the following symptoms, that have been present during the same 2-week period and represent a change from previous functioning, with at least one of the symptoms being either depressed mood or loss of interest or pleasure: 1. Depressed mood most of the day, nearly every day, as indicated either by subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful); 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated either by subjective account or observation made by others); 3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day; 4. Insomnia or hypersonic nearly every day; 5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) 1 ; 6. Fatigue or loss of energy nearly every day; 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick); 8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others); 9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or specific plan for committing suicide. A major depressive disorder (MDD) is characterized by one or more MDEs. MDD is a serious condition with associated morbidity and mortality. Despite intensive research, the etiology of depressive disorders is not yet completely understood (Baghai, Moller et al. 2006). The origin of this illness is believed to be multifactorial with psychological, social and biological factors interacting to cause disturbed central nervous system function (Baghai et al., 2006). Impact of Depression Depression is common. Among persons older than 65 years, 1 in 6 suffer from depression (Wang, Schneeweiss et al. 2005). In the United States, the lifetime prevalence is approximately 16%, and the 12-month period prevalence of MDD is approximately 7%, as determined by survey a of MDD (Kessler, Berglund et al. 2003). MDD is significantly associated with other psychiatric disorders, especially substance dependence, panic and generalized anxiety disorder, and several personality disorders, with 72% of patients with lifetime MDD meeting the criteria for at least one other DSM-IV disorder (Kessler et al., 2003; Hasin et al., 2005). Disparities in the treatment for MDD among minority groups are well known (Hasin, Goodwin et al. 2005). “Across the life span, the course of depression is marked by recurrent episodes of depression followed by periods of remission” (Surgeon General’s Report, 1999). Patients with depression can experience spontaneous remission. The American Psychiatric Association (APA) practice guideline notes, “Untreated, the episode [MDE] typically lasts 6 months or longer. Some patients with major depressive disorder will eventually have a manic or hypomanic episode and will then be diagnosed as having bipolar disorder” (APA Guideline, 2000). The natural course of untreated depression has rarely been examined (Schatzberg and Kraemer 2000). Mental health disorders of older adults differ from those of younger persons. Most older patients, with symptoms of depression do not meet the full criteria for major depression, with the suggestion that the standard criteria for depression may be more difficult to apply to older adults, or that older adults are reluctant to report such feelings (Surgeon General’s Report, 1999). Depression in older adults occurs in a complex psychosocial and medical context: the prevalence of clinically significant depression in later life is estimated to be highest (about 25%) in those with chronic illness, particularly those with ischemic heart disease, stroke, cancer, chronic lung disease, arthritis, Alzheimer’s disease, and Parkinson’s disease (Surgeon General’s Report, 1999). The frequency of other stressful events, such as the loss of friends and loved ones, increases with age. Bereavement is an important and well-established risk factor for depression (Surgeon General’s Report, 1999). Unfortunately, a significant number of older adults with depression are not diagnosed or treated in the primary care setting (Surgeon General’s Report 1999). Other barriers to treatment include: beliefs that depression and hopelessness are normal conditions with older age and difficulties presented by patients with cognitive deficits that make identification of depression in older adults challenging (Surgeon General’s Report 1999). Treatments for Depression Emotions appear to be regulated in many areas of the brain, and there is no consensus as to the site of pathology for depression (Nestler, Barrot et al. 2002). Some insight into chemical changes in the brain that accompany depression were discovered when two classes of medications were found (incidentally) to be effective in treating depression. 2 There are many effective treatments for depression. In a document entitled “Improving Quality of Care for People with Depression,” an Agency for Healthcare Research and Quality (AHRQ)-sponsored expert panel states that, “depression, once identified, can almost always be treated successfully” (Agency for Healthcare Research and Quality, 2000). The document concludes, “Gaps between what we know and what we need to know in the diagnosis and treatment of depression still exist, especially in how depression interacts with chronic physical illnesses, how to measure the quality of depression care, and how to provide care that results in good outcomes at an acceptable cost for all age groups. Developing more effective strategies to translate knowledge into improved care is an important area for future research.” Practice guidelines for the treatment of MDD recommend pharmacotherapy, psychotherapy, psychotherapy plus pharmacotherapy, or electroconvulsive therapy. In most cases, pharmacotherapy is the first-line treatment for MDD, though, “Choosing the agent that is most appropriate for a given patient is difficult” (Hansen, Gartlehner et al. 2005). Pharmacologic treatment for MDD includes first-generation antidepressants (tricyclic antidepressants and monoamine oxidase inhibitors) and second-generation antidepressants. Second-generation medications include: selective serotonin reuptake inhibitors (SSRIs); selective norepinephrine reuptake inhibitors, and other drugs that selectively affect the activity of neurotransmitters. There appears to be a latency of several weeks until depressive symptoms are acceptably diminished with the current pharmacotherapies. In the geriatric population, “…prescribing guidelines … are rarely based on studies actually conducted in elderly populations and often must extrapolate from studies in younger age groups” (Wang, Schneeweiss et al. 2005). Taylor states, “Studies in younger populations may not generalize to the older population as depression in the elderly differs from depression in younger individuals” (Taylor and Doraiswamy 2004). Though effective treatments exist, the AHRQ-sponsored expert panel also notes, “…appropriate treatment continues to be a pressing issue” (Agency for Healthcare Research and Quality, 2000). “Patients receiving antidepressant monotherapy may be partially or totally resistant to treatment in 10 to 30 percent of cases” (Cadieux 1998). There are several hypotheses for this therapy resistance, including: occult medical conditions causing depression, substance abuse interfering with treatment, noncompliance, abnormal metabolism, psychosocial factors, and other psychiatric comorbidities (Fava 2003; Fleck and Horwath 2005). Another common cause of treatment failure is prescribing antidepressant medication in dosages that are too low and for inadequate lengths of time (Cadieux, 1998). Numerous studies have documented relatively low rates of adequate prescribing in various treatment settings (Cadieux, 1998). For instance, a managed care setting documented adequate antidepressant therapy in only 11% of patients (Nemeroff 1996). Even in patients who have been hospitalized for major depression, Oquendo noted, “Antidepressant treatment of depressed patients is strikingly inadequate, even in suicide attempters, known to be at higher risk for suicidal acts” (Oquendo, Kamali et al. 2002). Strategies after failing a standard first line treatment are drug substitution, combination strategies (the addition to a second agent), augmentation strategies (such as thyroid hormone, benzodiazepines, estrogen, dexamethasone, or lithium), or electroconvulsive therapy (ECT). Other novel treatments are under investigation (Baghai, Moller et al. 2006). Unfortunately, “There is little evidence to guide the management of depression that has not responded to a course of antidepressants.” (Stimpson, Agrawal et al. 2002). The definitions of treatment resistance, treatment response, and remission are variable. For example, Rush (2003) proposed that, “Difficult to treat depression includes depression that inherently does not respond satisfactorily to one or more treatments that are optimally delivered (treatment-resistant depression [TRD]) and also depression treated under circumstances precluding the optimal delivery of potentially effective treatments. Such circumstances include the use of subtherapeutic doses; nonadherence; intolerable side effects that prevent an adequate dose or duration of treatment; and concurrent Axis I, II, or III conditions that reduce the likelihood of remission for adherence, pharmacokinetic, or pharmacodynamic reasons)” (Rush, Thase et al. 2003). Additionally, Thase and Rush (1997) propose a model of staging for levels of resistance of TRD, however, Fava (2003) states about this model, “…its predictive value with respect to treatment outcomes has not yet been assessed systematically.” In a systematic review by Stimpson on interventions for treatment-refractory depression, these two points are included in their conclusions (Stimpson, Agrawal et al. 2002): “In the absence of good evidence, clinicians will have to rely upon their own clinical judgment in deciding upon treatment.” “The main conclusion is that further research is required as the findings are not strong enough to support any clinical guidance.” While there are many views on what the definition of treatment resistance, treatment response, and remission should be, the psychiatric community has not agreed upon a unified definition, nor was TRD defined in the Diagnostic and Statistical Manual of Mental Disorders-Fourth Version (DSM-IV). The Diagnostic and Statistical Manual is a standard reference text for the diagnosis of mental disorders. The vagus nerve, the tenth cranial nerve, has parasympathetic outflow that regulates the autonomic (involuntary) functions of heart rate and gastric acid secretion, and also includes the primary functions of sensation from the pharynx, muscles of the vocal cords, and swallowing. It is a nerve that carries both sensory and motor information to the brain. Importantly, the vagus nerve has influence over widespread brain areas (Groves and Brown 2005). Stimulation of the brain with electricity in a living person was first documented in 1874 (Gildenberg 2004). The first reported use of VNS was in 1883 by a neurologist, James L. Corning (Groves & Brown, 2005). In the 1880’s he performed transcutaneous stimulation over the area of the vagus nerve and observed a decrease in seizures (Gildenberg, 2004). In 1997, the VNS device was approved by the FDA for the treatment of seizures in patients with refractory epilepsy. In a study of eleven epilepsy patients, improvement in mood was noted which lead to a suggestion of the use of VNS for depression and further studies (Elger, Hoppe et al. 2000). The VNS device consists of three parts: 1) a programmable pulse generator which is implanted subcutaneously in the left chest wall 2) two electrodes that are wrapped around the vagus nerve and attached to the pulse generator and 3) a programming wand for the purpose of noninvasive device programming, device diagnostics, and data retrieval. VNS is being investigated as a treatment for the cognitive impairment associated with Alzheimer’s disease, anxiety, obesity, autism, migraines, involuntary movement disorders, and obsessive-compulsive disorder (Aetna Clinical Policy Bulletins, 2006; Groves & Brown, 2005). The precise mechanism of action of VNS remains unknown (Salzman, 2006). III. History of Medicare Coverage CMS currently provides coverage for VNS for patients with medically refractory partial onset seizures, for whom surgery is not recommended or for whom surgery has failed. VNS is not covered for patients with other types of seizure disorders which are medically refractory and for whom surgery is not recommended or for whom surgery has failed (§160.18 of the Medicare National Coverage Determination Manual). Previously, Medicare did not have an NCD on VNS for treatment of resistant depression (TRD). In absence of an NCD, coverage was determined by local Medicare contractors. Current Request On July 26, 2006, CMS received a formal request for reconsideration from Cyberonics, Inc. The company proposed that CMS revise its current NCD to include coverage of VNS for TRD for patients who have been either (1) previously treated with or refused treatment with electroconvulsive therapy (ECT), or (2) have been previously hospitalized for depression. The specific indication requested for coverage is for the adjunctive long-term treatment of chronic or recurrent depression for patients over the age of 18 who are experiencing a major depressive episode and have not had an adequate response to four or more adequate depression treatments. Cyberonics, Inc. also requests the following to be considered as contraindications: The VNS Therapy System cannot be used in patients after a bilateral or left cervical vagotomy. Do not use short wave diathermy, microwave diathermy or therapeutic ultrasound diathermy on patients implanted with a VNS Therapy System. Diagnostic ultrasound is not included in this contraindication. Benefit Category For an item or service to be covered by the Medicare program, it must meet one of the statutorily defined benefit categories outlined in the Social Security Act. Vagus Nerve Stimulation, at a minimum, falls under the benefit categories set forth in sections §1861(s) (6) (durable medical equipment), 1861(s) (q) (physicians' services), and 1861(s) (2) (B), (hospital services "incident to" physicians' services rendered to outpatients). This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service. IV. Timeline of Recent Activities Date Action July 26, 2006 CMS received a formal request for reconsideration from Cyberonics, Inc. to include coverage of VNS for treatment of TRD. August 7, 2006 CMS formally opened an (NCD) as reconsideration to be made on VNS. The initial public comment period opened. September 6, 2006 The initial public comment period closed. October 30, 2006 Cyberonics, Inc. meeting with CMS. February 5, 2007 CMS released a proposed decision on VNS for TRD. CMS opened its final public comment period. March 7, 2007 Final public comment period closed. March 20, 2007 Cyberonics, Inc. meeting with CMS. May 4, 2007 CMS released a final decision on VNS for TRD. V. FDA Status FDA approval for the VNS Therapy System was received on July 15, 2005. This device is indicated for the adjunctive long-term treatment of chronic or recurrent depression for patients eighteen 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. VI. General Methodological Principles When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. The critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for patients. An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary. Methodological principles of study design that are used to assess the literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A. In general, features of clinical studies that improve quality and decrease bias include the selection of a clinically relevant cohort, the consistent use of a single good reference standard, and the blinding of readers of the index test, and reference test results. Public comment sometimes cites the published clinical evidence and gives CMS useful information. Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination. CMS uses the initial public comments to inform its proposed decision. CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum. VII. Evidence A. Introduction: The evidence provided by the sponsor included a randomized controlled trial for FDA PMA approval (D02), a case series study (D01), a company sponsored observational study (D02 observational), and a company sponsored trial of standard treatment for depression (D04) that was used as a comparison study for D02. The sponsor provided information in addition to the previously mentioned evidence which included: a booklet of sponsor commentary, a study of VNS in rats, abstracts, physiology studies, economic information including a cost analysis, investigator biographies, reviews of TRD, reviews of VNS, overview of MDD, STAR*D publications, an ECT trial, posters, and letters to insurance companies, an unpublished, confidential study, a reanalysis of previous data, data modeling, data relating to VNS in epilepsy, and coverage with evidence suggestions. Assessment of Outcome in Depression The use of outcomes measures attempts to follow what happens to a patient over time to quantify what is happening during the course of treatment. This is used for comparison purposes and to monitor a patient’s progress and treatment. The outcomes of interest for treatment with the VNS device for TRD are improvement in depression and implant-related adverse events. We can examine depressive symptoms, social and work functioning, quality of life, morbidity such as hospitalization, and mortality. Standardized outcome instruments commonly used involve a measurement of depressive symptoms in which patients’ subjective experience are translated into a numeric rating scale. Some of these symptom-only instruments include: the Hamilton Depression Rating scale (HDRS or HAM-D or HRSD), the Montgomery-Asberg Depression Rating Scale (MADRS), the Inventory of Depression Symptomatology Scale (IDS) (either clinician administered – CR, or self-administered –SR), and the Beck Depression Inventory (BDI). Depressive symptoms have been used to create items that make up scales, where the assumption is that the presence and absence of these symptoms and the patterns in which they occur define the illness—depression—and the outcome is the scale score from item answers. Mathematical operations on these numbers are assumed to reflect true patient changes (Bech 2006). A number of scales (hundreds) have been developed and are reliant on these assumptions (Veterans Administration, 2004). In 1979, Montgomery et al noted, “The large number of rating scales available to clinical investigators is a problem in psychiatric research (Pichot, 1972) and the comparability between scales is rarely known” (Montgomery and Asberg 1979). The purpose of using scales to measure depression can vary. Such measures may be used for screening or diagnosis, or as a tool for outcome assessment. To measure change brought about by treatment (outcome), the ability to detect small but clinically meaningful differences in severity is important (Nelson, Portera et al. 2006). Analysis of the scale as an outcome includes asking two questions: is the score meaningful and is the scale meaningful? It is important to use scales that are both reliable and valid. Reliability and validity determination is both an art and a science. Validity refers to the degree to which a test measures what it intends to measure. Reliability examines the consistency between two measures that evaluate the same thing, and is the ratio of the true variance to the total variance. There are several methods to assess reliability: examining internal consistency (how well do scale items measure a single characteristic); retest reliability (assesses to what degree multiple administrations of the scale produce the same results); and interrater reliability (the degree to which various raters produce the same result) (Bagby, Ryder et al. 2004). Reliability is a group-specific statistic, so if a narrowly defined population demonstrates small variance in the true score, the metric will be less reliable in a different population. Bagby et al have analyzed the psychometric properties of the most commonly used measure of depression, the original 17 item Hamilton Depression Rating Scale (Bagby, Ryder et al. 2004). Though it has been in use for 40 years, some suggest that the original 17-item version may be problematic from a reliability and validity standpoint (Bagby, Ryder et al. 2004; Licht, Qvitzau et al. 2005). Rehm et al report that this scale was developed not from a statistical or empirical process, but from logic (Rehm and O'Hara 1985). Bagby et al stated, “Finally, the Hamilton depression scale is measuring a conception of depression that is now several decades old and that is, at best, only partly related to the operationalization of depression in DSM-IV” and additionally, “In conclusion, we have been struck with the marked contrast between the effort and scientific sophistication involved in designing new antidepressants and the continued reliance on antiquated concepts and methods for assessing change in the severity of the depression that these very medications are intended to affect.” Some authors have noted that patients with equivalent total scores may have very different symptoms and thus, different meaning (Bech 2006; Nelson, Portera et al. 2006). The Hamilton items 18-21 are: diurnal variation, depersonalization, paranoid symptoms, and obsessive and compulsive symptoms. The 24-item scale adds hopelessness, worthlessness and helplessness (Nelson, Portera et al. 2006). In the review by Nelson, he stated of the 24-items, “These three items, however, have received much less attention in the literature and at this point do not have the empirical support that the other core symptoms have.” The MADRS (1979), the second most popular scale in antidepressant studies, was developed to be more sensitive to change, however, this scale was developed during the tricyclic antidepressant age (reflecting the symptom changes associated with this treatment) and many in this sample were inpatients (Nelson et al., 2006). Nevertheless, some suggest that the MADRS is superior to the HRSD 17 item for clinical trial outcomes (Carmody, Rush et al. 2006). The less frequently used IDS 28-item was published by Rush et al. in 1986 (Veterans Administration, 2004; (Nelson, Portera et al. 2006). In summation, it is not clear which items and which scales are most sensitive at measuring changes during a patient’s treatment for depression (Nelson et al., 2006). The Young Mania Rating Scale (YMRS) is the most frequently used scale for assessing mania severity in patients already diagnosed with mania. Instruments that are not depression-specific can also be used. The Global Assessment of Function (GAF) is a generic scale that evaluates both symptoms and functioning. It is not used much in the depression literature, but was a high ranking global instrument in Veterans Administration Technology Assessment Program (VATAP) report examining outcomes measurement in major depression to use in measuring the quality of treatment in Veterans Health Administration (VHA) mental health services. The SF-36 is a generic measure of perceived health status that also measures symptoms and function. The Clinical Global Impression (CGI) scale refers to the global impression of the patient, a single item response (normal to extremely ill). The VATAP has created a measures evaluation matrix of fifteen instruments that met certain criteria for depression treatment outcomes measurement (http://www.va.gov/vatap/pubs/Depressionfinal3-05.pdf). CMS generally accords more weight to outcomes with validated measures of patient functioning (social and work), quality of life, morbidity (such as hospitalization), and mortality. There is a lack of empirical evidence for endpoints in clinical studies of depression (Rush, Kraemer et al. 2006). Concepts of response, remission, recovery, relapse, and recurrence do not have standardized, empirical definitions (Rush, Kraemer et al. 2006). This makes study comparison very difficult. The recommended end point in the treatment of depression has become remission, but remission has been defined in a variety of ways, including: a score of 7 or less on the HAM-D 17- item, minimal or no symptoms of depression, failure to meet the DSM-IV diagnostic criteria for MDD, or return of normal function (both social and occupational) (Zajecka 2003). Rush et al 2006 noted, “Thus, use of different operational definitions of remission can lead to radically different descriptions of the course of illness, including both the number and duration of MDEs” (Rush, Kraemer et al. 2006). Rush et al. recommend that response criteria be met for 3 consecutive weeks “to take into account error in the assessment of symptomatology and unstable symptomatic fluctuations,” though this recommendation is not empirical (Rush, Kraemer et al. 2006). The association of symptom reduction with functional improvement is not well defined (Rush et al., 2006). Rush et al. recommend that remission refers only to the symptoms noted in DSM-IV, and that 3 consecutive weeks pass, during which each week was characterized by the absence of depressive symptoms (Rush et al., 2006). Symptoms can recur but may be insufficient in number, duration, or intensity to qualify for a relapse or recurrence; again, few studies have empirically evaluated these concepts (Rush et al., 2006). Rush et al. state, “Remission typically follows response by at least several weeks,” and recommended a 12-20 weeks trial duration, though in prolonged trials the chances of spontaneous remission increase, and some patients who remit will relapse (Rush et al., 2006). In general, more weight is given to conclusions of studies that have a scientifically derived endpoint of remission. Well-designed clinical trials are important for accurate outcome interpretation. Well constructed randomization protects against bias and inclusion of an appropriate comparator facilitates study interpretation. The placebo effect is a substantial, common consideration in trials of antidepressants. About one-half of randomized, double-blind placebo controlled antidepressant trials fail to show statistical superiority of widely used antidepressants in comparison to placebo (Khan, Khan et al. 2002). In 1999, a National Depressive and Manic-Depressive Association consensus statement on the use of placebo in clinical trials of mood disorders concluded that placebo has a role in mood disorder studies and new drugs found to be equivalent to standard treatment are not evidence of efficacy unless the new drug is significantly more effective than placebo (Kupfer and Frank 2002). The placebo effect appears to be a complex mental activity, having different mechanisms in different conditions, meaning there is not a single effect but many (Benedetti, Mayberg et al. 2005). In patients being treated with antidepressants, placebo response patients have been observed to have similar PET scan changes (Mayberg, Silva et al. 2002). Benedetti et al provide these comments: “The study of the placebo effect reflects a current neuroscientific thought that has as its central tenet the idea that ‘subjective’ constructs such as expectation and value have identifiable physiological bases, and that these bases are powerful modulators of basic perceptual, motor, and internal homeostatic processes,”; “ …the existence of placebo effects suggests that we must broaden our conception of the limits of endogenous human capability” (Benedetti, Mayberg et al. 2005). In the case of research in the area of depression, more weight will normally be accorded to studies that are designed to guard against the placebo effect. Adverse events are important medical outcomes. Patients need this information to make well-informed choices. For instance, invasive procedures such as the implantation of the VNS device in the carotid artery sheath could include events such as infection and tissue scarring. Serious injuries such as vocal cord paralysis, sleep apnea, shortness of breath, syncope, cardiac arrhythmias, and difficulty swallowing could be examples of potential adverse outcomes. Studies that provide an inclusive examination and explanation of adverse medical events are generally given more weight. B. Discussion of evidence reviewed 1. Question The development of an assessment in support of Medicare coverage decisions is based on the same general question for almost all requests: “Is the evidence sufficient to conclude that the application of the technology under study will improve health outcomes for Medicare patients?” For this NCD, the question of interest is: Is the evidence sufficient to conclude that, in the Medicare population, vagus nerve stimulation will improve health benefits for individuals with treatment resistant depression? 2. External technology assessments CMS did not commission an external technology assessment (TA); however, external assessments were identified on the topic of vagus nerve stimulation for treatment resistant depression. Blue Cross Blue Shield Technology Evaluation Center (TEC) In August 2005, the TEC published a TA titled, “Vagus Nerve Stimulation for Treatment-Resistant Depression”. Vagus nerve stimulation for treatment-resistant depression met only one of five of the TEC criteria. TEC determined, “…VNS therapy for the indication of treatment-resistant depression does not meet the TEC criteria.” The following TEC criteria were not met: 1) the scientific evidence must permit conclusions concerning the effect of the technology on health outcomes; 2) the technology must improve the net health outcome; 3) the technology must be as beneficial as any established alternatives; and, 4) the improvement must be attainable outside the investigational setting. These were some of the TEC concerns: “Overall, the evidence supporting efficacy of VNS is not strong. The single randomized clinical trial did not show statistically significant results in favor of VNS for the primary outcome. Treatment response in the randomized clinical trial was much lower than had been observed in case series studies, raising concerns about placebo effects and observer bias. The non-randomized observational study had numerous methodological problems. Alternative analyses showed diminished or no efficacy of VNS therapy. Although the FDA voted to approve VNS therapy, a poll of committee members showed that approval was based on the safety of VNS therapy rather than strong evidence of efficacy.” “Patient selection was a concern for all studies. VNS is intended for treatment-refractory depression, but the entry criteria of failure of 2 drugs and a 6-week trial of therapy may not be a strict enough definition of treatment resistance. Treatment-refractory depression should be defined by thorough state-of-the-art psychiatric evaluation and management before an invasive surgical procedure of limited efficacy is performed.” In summary, the TEC report stated the following: “…The available evidence is not sufficient to permit conclusions of the effect of VNS therapy on health outcomes.” The TEC updated its assessment in August 2006, with no change in TEC criteria determination. The TEC again concluded: “Since the last TEC Assessment, there have been no studies reporting clinical outcomes on any new or different patients. Data from the case series and clinical trials have been reanalyzed to show what proportions of patients who respond at one time are still responders at a subsequent time point. However, this information by itself does not provide evidence of the efficacy of VNS beyond that provided by the original observational comparison of VNS versus treatment as usual.” California Technology Assessment Forum (CTAF) In February 2006, the CTAF published a TA titled, “Vagus Nerve Stimulation for Treatment-Resistant Depression.” VNS for TRD met two of the five CTAF criteria. The two criteria met were: 1) the technology must have the appropriate regulatory approval; and 2) the scientific evidence must permit conclusions concerning the effectiveness of the technology regarding health outcomes. The following three CTAF criteria were not met: 1) the technology must improve the net health outcome; 2) the technology must be as beneficial as any established alternatives; and, 3) the improvement must be attainable outside the investigational settings. Based on the criteria, the CTAF panel approved the recommendation that “…VNS does not meet Technology Assessment Criterion 3, 4 or 5 for effectiveness and improvement in health outcomes for TRD.” In summary the TEC report stated the following. “… given the well-designed negative RCT and the fact that this is a single group of patients in an observational trial, it is early to conclude that the new technology of VNS improves the net health outcomes as much as or more than the established alternative of TAU with medications and/or electroconvulsive therapy.” 3. Internal technology assessments CMS performed a literature search utilizing PubMed evaluating the use of VNS for the treatment of depression and a review of end references. The literature search was limited to the English language and specific to the human population. Public access information from the FDA website was also used. Technical assessments using VNS for depression were searched for using Google. The primary evidence for VNS for the treatment of TRD comes from the randomized controlled trial for FDA PMA approval (D02), a case series study (D01), and a Cyberonics sponsored observational study (D02 observational). The evidence table is located in Appendix B. Evidence Summary VNS Pivotal Study D02 was a randomized, multi-center, placebo-sham trial with the objective of evaluating patients at 12 weeks post-implantation and during a 12 month follow-up period. The control-sham group received a functional VNS device, which was to be turned on after 12 weeks. Rush et al. state, “The sample size was powered to detect a difference in the HRSD 24 response rate of approximately 17%.” The 12 week trial (acute phase) was extended (long-term phase), with the control group’s devices activated. D02 Randomized Controlled Trial This 3 month double-blind trial randomized 235 outpatients with major depressive disorder (n = 210) or bipolar disorder, depressed phase (n = 25) to either active VNS treatment or inactive VNS treatment (sham control) at 21 sites. A third party assigned sequential numbers to all subjects and randomized the subjects 1:1. The device programmer had the randomization assignment for each participant so the active treatment devices could be activated (the programmer was not involved in care or clinical assessment, however, the programmer did collect information on all adverse events). Control patients with inactive devices had follow-up visits with the intent of device adjustment, and investigators were blinded to treatment. Inclusion and exclusion criteria based on Rush et al., 2005, George et al., 2005, and the FDA Clinical Memorandum are presented in Appendix C. Patients were randomized to either active VNS or inactive VNS. Patients had a 2 week recovery after implantation, followed by 2 weeks of electrical parameter adjustment and then 8 weeks of fixed electrical stimulation. For the adjustment of the electrical parameters, “…output current (mA setting) was increased progressively to the maximal level that could be comfortably tolerated by the participant” (Rush, Marangell et al. 2005). Initial electrical treatment parameters (frequency in hertz, pulse width in microseconds, on-off cycle in seconds and minutes, and output current in milliamps) were identical to those used for patients with epilepsy. Medication changes or ECT were not allowed other than the addition of the antidepressant trazodone (up to 300 mg/day). The primary efficacy endpoint was the proportion of subjects who had ≥ 50% decrease in the HAM-D 24 at visit 9 (12 weeks after implantation, 10 weeks of VNS therapy) as compared to the baseline value (FDA Clinical Memorandum). Protocol violators (“if they did not complete the acute phase, discontinued for reasons other than treatment-related adverse events or lack of efficacy, if implanted and had concomitant anti-depressant medication adjustments for at least 7 days during the acute phase, or received ECT during the acute phase”) were not considered in the efficacy analysis (FDA Clinical Memorandum). After the two week adjustment period, patients were seen weekly for two weeks then every other week over the following 6 weeks. Rush et al. states, “Efficacy and safety data were gathered at the two baseline visits and at post-implantation weeks 1 and 2 (recovery period), weeks 3 and 4 (stimulation adjustment period), and weeks 5, 6, 8, 10, and 12 (fixed-dose stimulation period).” Response measures were differentially evaluated (FDA Clinical Memorandum). HAM-D 28, MADRS, CGI, IDS-SR, and YMRS had 2 assessments during baseline (FDA Clinical Memorandum). HAM-D 28, MADRS, CGI, IDS-SR had 1 assessment during recovery and YMRS had 2 assessments during recovery (FDA Clinical Memorandum). During the remaining 10 weeks of the trial the measures were collected in the following manner: HAM-D 28 and MADRS had 4 assessments; CGI, 1 assessment at acute phase exit; IDS-SR and YMRS, 5 assessments. SF-36 was collected at baseline and acute phase end (FDA Clinical Memorandum). Rush et al. states, “Although the 28-item HRSD was administered to participants, the total of the first 24 questions was used to define the HRSD 24 total score.” Although multiple secondary outcomes were collected, no adjustments were made for multiple comparisons. Safety was assessed by evaluation of adverse events, serious adverse events (death, life-threatening event, in-patient hospitalization or prolonged existing hospitalization, persistent or significant disability/capacity), and physical and neurological examinations (FDA Clinical Memorandum). Table 1: D02 Acute Phase Enrollment (FDA Clinical Memorandum) Tracking Point Subject Number Target Enrollment 275 Actual Enrollment 266 Discontinued pre-implant 31 Implanted 235 Discontinued Acute Phase* 13 End of Acute Phase (evaluable subjects) 222 Randomized subjects 222 Treatment Group 112 Control Group 110 * 13 patients discontinued the 12 week acute phase: 4 did not meet visit 2 continuation criteria; 9 were protocol violators. Subjects were a mean age of 46.3 (N = 205); 74/205 (36%) were male; 198/205 (97%) were Caucasian (FDA Clinical Memorandum). Rush et al. stated, “Demographic data are reported on the 222 evaluable participants, and safety findings are reported on the total 235 implanted participants,” reporting 96% Caucasian, 63% female, mean age 46.5 years (SD 9.0), median 47.0 years (range 24-72). Concomitant treatments were supposed to remain stable, however 9 subjects (four treatment subjects and five control subjects) had changes in antidepressant, atypical antipsychotic, or anticonvulsant medications, and were therefore protocol violators (FDA Clinical Memorandum). Additionally, 3 subjects had increases in medication (FDA Clinical Memorandum). No ECT treatments were given. After 3 months, 15% (17/111) of patients in the active VNS group met the response criteria of a 50% reduction in HRSD-24, whereas 10% (11/110) met this criteria from the placebo-sham group (p = 0.238) (FDA Clinical Memorandum). A last observation carried forward (LOCF) analysis of responders also did not reveal statistical significant difference (FDA Clinical Memorandum). Of the 21 sites, Rush et al. stated, “Response rates were generally similar across sites, although some variation was seen (seven sites had < 10% response rate, four sites had ≥ 25% response rate).” Of the secondary measures (IDS-SR, CGI, MADRS, SF-36) only IDS-SR had a statistically significant difference in outcome, in favor of active VNS treatment (19/109 versus 8/106, p = 0.032) (FDA Clinical Memorandum). Rush et al. also found LOCF outcomes for IDS-SR response rates to be statistically significant (treatment group 17.0%, n = 112, control group 7.3%, n = 110; p= 0.032, reporting as a footnote that one patient in the control group did not have an IDS-SR assessment completed during the study), but no statistical difference for IDS-SR percent improvement from baseline (p = 0.158). It is noted that, “An exploratory analysis of this acute study found no relationship between output current and the percentage of change in the HRSD 24” (Rush, Marangell et al. 2005). Adverse events were categorized based on implantation related, stimulation related, serious adverse events, hypomanic/manic reactions, suicidal ideation, and death (FDA Clinical Memorandum). Implantation related adverse events reported at a ≥ 5% incidence among all implanted patients (N = 235) were incision pain, voice alteration, incision site reaction, device site pain, device site reaction, pharyngitis, dysphagia, hypesthesia, dyspnea, nausea, headache, neck pain, pain, paresthesia, and increased cough. (FDA Clinical Memorandum). Stimulation related adverse events reported at a ≥ 5% incidence among treatment patients (N=119) were asthenia, back pain, chest pain, device site pain, device site reaction, headache, incision pain, neck pain, pain, viral infection, wound infection, palpitation, constipation, diarrhea, dyspepsia, dysphagia, nausea, vomiting, depression, dizziness, hypesthesia, insomnia, paresthesia, cough increase, dyspnea, laryngismus, pharyngitis, rhinitis, voice alteration, and incision site reaction (FDA Clinical Memorandum). Twenty-seven patients reported 39 serious adverse events (events that required hospitalization or prolonged hospitalization, resulted in death, were considered life threatening that resulted in a persistent or significant disability or incapacity, or other) (FDA Clinical Memorandum). Rush et al. state, “Of 30 total serious adverse events (SAEs) involving 27 participants, 16 SAEs occurred in the active VNS group and 14 in the sham group. This total included 12 SAEs involving 11 participants of worsened depression that required hospitalization (seven participants in sham, four participants in active VNS, and one participant who had not yet received stimulation, but who was assigned to the active VNS group).” Thirty of these events occurred after implantation, with the most common event being worsening depression (N=12, 5 in the treatment group and 7 in the sham group), and included suicide, asystole, bradycardia, confusion, thinking abnormal, aspiration pneumonia, pneumonia, and renal failure (FDA Clinical Memorandum). Three subjects had adverse events of manic reaction in this acute phase (FDA Clinical Memorandum). “Two participants in the active VNS group (one of whom had a diagnosis of bipolar I disorder at baseline) met the threshold of significant hypomania, a score ≥15 on the YMRS, which was validated by DSM-IV criteria” (Rush et al., 2005). Suicidal ideation was evaluated by an increase of HAM-D item 3 of at least 2 points: 3/116 of the sham group and 2/119 of the treatment group met this criterion (FDA Clinical Memorandum). One death occurred before implantation (esophageal cancer) and one death from suicide occurred during the acute phase (treatment group). Three subjects left the study because of adverse events (Rush et al., 2005). The authors concluded, “This study did not yield definitive evidence of short-term efficacy in the context of this chronically ill, treatment-resistant, depressed population. This trial revealed that A) VNS was well tolerated; B) the adverse event profile and AE rates closely approximated those seen in patients with epilepsy; C) the modest difference in response rates to active VNS (15.2%), and sham VNS group (10.0%) was not statistically significant for the HRSD 24, the primary measure, and D) the secondary measure, the IDS-SR30 revealed a significant difference favoring VNS over sham (analyzed without correction for multiple tests).” D02 Observational Study Subjects at the exit of the 3 month (visit 9) acute phase study entered into the long-term phase study (FDA Clinical Memorandum). The FDA Clinical Memorandum states that, “the purpose of the long-term analysis is to examine adverse effects that occur after long-term exposure to VNS therapy.” Patients randomized to sham therapy in the acute phase were included only if the HRSD score was ≥ 18 at the two last assessments of the acute phase trial (average of the two assessments). Rush further stated, “they could elect to receive active VNS for humanitarian reasons.” Patients with sham devices who met this criterion had their devices activated at this time. While the baseline for the active treatment group remained the averaged ratings before implantation, the sham VNS group (the device being activated at entry into this phase of the study) had their baseline changed to the average of the 8 and 10 week rating (Rush, Sackeim et al. 2005). Medication changes and ECT were allowable. Device voltage adjustments and medication adjustments were allowed throughout this time period. Safety was assessed similar to the randomized acute phase trial (FDA Clinical Memorandum). In contrast with the randomized acute phase trial, protocol violators could be included in the efficacy analyses (FDA Clinical Memorandum). Table 2: D02 Enrollment (acute and long-term phase) (FDA Clinical Memorandum) Tracking Point Subject Number Target Enrollment 275 Actual Enrollment 266 Discontinued pre-implant 31 Implanted 235 Acute Phase 235 Discontinued Acute Phase 2 End of Acute Phase 233 Long-term phase* 233 Not evaluable** 28 Evaluable Subjects 205 Not 12 Month completers*** 28 12 month subjects who completed trial 177 * Two subjects did not meet acute phase continuation criteria because they only had continuation visits, thus 231 patients could be considered as intent-to-treat (ITT) subjects. ** Twenty-eight subjects were not evaluable. Four subjects (original treatment group) had no assessment data (no HAM-D scores post-acute phase) collected at any long-term visit. Three patients (original treatment group) did not meet acute phase continuation criteria. Twenty-one patients (sham-placebo group) had a 12 week exit score of HRSD