Home Use of Oxygen to Treat Cluster Headache

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CMS has determined that the evidence does not demonstrate that the home use of oxygen to treat cluster headache improves health outcomes in Medicare beneficiaries with cluster headache (CH). Therefore, we determine that home use of oxygen to treat CH is not reasonable and necessary under §1862(a)(1)(A) of the Social Security Act (the Act). However, we believe the available evidence suggests that the home use of oxygen to treat CH is promising and supports further research under §1862(a)(1)(E) of the Act through the Coverage with Study Participation (CSP) form of Coverage with Evidence Development (CED). Therefore, we are making the following decision: The home use of oxygen to treat CH is covered by Medicare only for beneficiaries with CH participating in an approved prospective clinical study comparing normobaric 100% oxygen (NBOT) with at least one clinically appropriate comparator for the treatment of CH. The clinical study must address one or more aspects of the following questions: Prospectively, compared to individuals with cluster headache who do not receive NBOT, do Medicare beneficiaries with CH who receive NBOT have improved outcomes as indicated by: Pain relief Time to pain relief Durability of pain relief Prospectively, among Medicare beneficiaries with cluster headache, which method of oxygen delivery provides the most benefit as indicated by: Pain relief Time to pain relief Durability of pain relief Prospectively, among Medicare beneficiaries with cluster headache, what other factors, if any, predict the patient’s response to 100% oxygen therapy as indicated by: Pain relief Time to pain relief Durability of pain relief Only those beneficiaries diagnosed with the condition of cluster headache are eligible for participation in a clinical study. CMS adopts the diagnostic criteria used by the International Headache Society to form a definitive diagnosis of CH. Therefore, the home use of oxygen to treat CH is covered by Medicare only when furnished to Medicare beneficiaries who have had at least five severe to very severe [1] unilateral headache attacks lasting 15-180 minutes when untreated. The headaches must be accompanied by at least one of the following findings: ipsilateral conjunctival injection and/or lacrimation; or ipsilateral nasal congestion and/or rhinorrhea; or ipsilateral eyelid edema; or ipsilateral forehead and facial sweating; or ipsilateral miosis and/or ptosis; or a sense of restlessness or agitation. The clinical study must adhere to the following standards of scientific integrity and relevance to the Medicare population: The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes. The research study is well supported by available scientific and medical information or it is intended to clarify or establish the health outcomes of interventions already in common clinical use. The research study does not unjustifiably duplicate existing studies. The research study design is appropriate to answer the research question being asked in the study. The research study is sponsored by an organization or individual capable of executing the proposed study successfully. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found at 45 CFR Part 46. If a study is regulated by the Food and Drug Administration (FDA), it must be in compliance with 21 CFR parts 50 and 56. All aspects of the research study are conducted according to appropriate standards of scientific integrity (see http://www.icmje.org). The research study has a written protocol that clearly addresses, or incorporates by reference, the standards listed here as Medicare requirements for CED coverage. The clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Trials of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard only if the disease or condition being studied is life threatening as defined in 21 CFR § 312.81(a) and the patient has no other viable treatment options. The clinical research study is registered on the ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. The research study protocol specifies the method and timing of public release of all prespecified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors (http://www.icmje.org). However a full report of the outcomes must be made public no later than three (3) years after the end of data collection. The research study protocol must explicitly discuss subpopulations affected by the treatment under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary. The research study protocol explicitly discusses how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the intervention. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility. Consistent with section 1142 of the Social Security Act, AHRQ supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions. This decision does not, aside from the use of home oxygen to treat cluster headache, modify the existing requirements for coverage of oxygen currently identified in Section 240.2 and Section 240.2.1. The scope of this decision does not include any consideration of normobaric oxygen under physician supervision in a health care facility that is not the beneficiary’s home. The scope of this decision does not include any consideration of hyperbaric oxygen (HBO) for any indication.

Decision Memo: TO: Administrative File: (CAG #00296R) Home Use of Oxygen to Treat Cluster Headache FROM: Louis Jacques, MD Director, Coverage and Analysis Group Tamara Syrek Jensen, JD Deputy Director, Coverage and Analysis Group James Rollins, MD, MSHA, PhD Director, Division of Items and Devices Jean Stiller, MA Lead Analyst Sarah Meisenberg Analyst Leslye Fitterman, PhD Epidemiologist Rosemarie Hakim, PhD Epidemiologist Ross Brechner, MD, MS (Stat), MPH Lead Medical Officer SUBJECT: Decision Memorandum for Home Use of Oxygen to Treat Cluster Headache (CAG-00296R) DATE: January 4, 2011 I. Decision CMS has determined that the evidence does not demonstrate that the home use of oxygen to treat cluster headache improves health outcomes in Medicare beneficiaries with cluster headache (CH). Therefore, we determine that home use of oxygen to treat CH is not reasonable and necessary under §1862(a)(1)(A) of the Social Security Act (the Act). However, we believe the available evidence suggests that the home use of oxygen to treat CH is promising and supports further research under §1862(a)(1)(E) of the Act through the Coverage with Study Participation (CSP) form of Coverage with Evidence Development (CED). Therefore, we are making the following decision: The home use of oxygen to treat CH is covered by Medicare only for beneficiaries with CH participating in an approved prospective clinical study comparing normobaric 100% oxygen (NBOT) with at least one clinically appropriate comparator for the treatment of CH. The clinical study must address one or more aspects of the following questions: Prospectively, compared to individuals with cluster headache who do not receive NBOT, do Medicare beneficiaries with CH who receive NBOT have improved outcomes as indicated by: Pain relief Time to pain relief Durability of pain relief Prospectively, among Medicare beneficiaries with cluster headache, which method of oxygen delivery provides the most benefit as indicated by: Pain relief Time to pain relief Durability of pain relief Prospectively, among Medicare beneficiaries with cluster headache, what other factors, if any, predict the patient’s response to 100% oxygen therapy as indicated by: Pain relief Time to pain relief Durability of pain relief Only those beneficiaries diagnosed with the condition of cluster headache are eligible for participation in a clinical study. CMS adopts the diagnostic criteria used by the International Headache Society to form a definitive diagnosis of CH. Therefore, the home use of oxygen to treat CH is covered by Medicare only when furnished to Medicare beneficiaries who have had at least five severe to very severe [1] unilateral headache attacks lasting 15-180 minutes when untreated. The headaches must be accompanied by at least one of the following findings: ipsilateral conjunctival injection and/or lacrimation; or ipsilateral nasal congestion and/or rhinorrhea; or ipsilateral eyelid edema; or ipsilateral forehead and facial sweating; or ipsilateral miosis and/or ptosis; or a sense of restlessness or agitation. The clinical study must adhere to the following standards of scientific integrity and relevance to the Medicare population: The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes. The research study is well supported by available scientific and medical information or it is intended to clarify or establish the health outcomes of interventions already in common clinical use. The research study does not unjustifiably duplicate existing studies. The research study design is appropriate to answer the research question being asked in the study. The research study is sponsored by an organization or individual capable of executing the proposed study successfully. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found at 45 CFR Part 46. If a study is regulated by the Food and Drug Administration (FDA), it must be in compliance with 21 CFR parts 50 and 56. All aspects of the research study are conducted according to appropriate standards of scientific integrity (see http://www.icmje.org). The research study has a written protocol that clearly addresses, or incorporates by reference, the standards listed here as Medicare requirements for CED coverage. The clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Trials of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard only if the disease or condition being studied is life threatening as defined in 21 CFR § 312.81(a) and the patient has no other viable treatment options. The clinical research study is registered on the ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. The research study protocol specifies the method and timing of public release of all prespecified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors (http://www.icmje.org). However a full report of the outcomes must be made public no later than three (3) years after the end of data collection. The research study protocol must explicitly discuss subpopulations affected by the treatment under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary. The research study protocol explicitly discusses how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the intervention. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility. Consistent with section 1142 of the Social Security Act, AHRQ supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions. This decision does not, aside from the use of home oxygen to treat cluster headache, modify the existing requirements for coverage of oxygen currently identified in Section 240.2 and Section 240.2.1. The scope of this decision does not include any consideration of normobaric oxygen under physician supervision in a health care facility that is not the beneficiary’s home. The scope of this decision does not include any consideration of hyperbaric oxygen (HBO) for any indication. II. Background Terminology For clarity, we note the meanings of the following terms used in this background section. Lacrimation refers to tearing up (crying) of the eyes; rhinorrhea is a runny nose; ptosis refers to eyelid droopiness; miosis is constriction (closing down) of the pupil in the eye. Ipsilateral means same sided, in contrast to contralateral which refers to opposite sided. Edema refers to fluid accumulation or swelling. Normobaric oxygen treatment means treatment at one atmosphere pressure (NBOT). Hyperbaric means treatment at more than one atmosphere pressure (HBOT). Introduction Cluster headache (CH), as described in Harrison’s Principles of Internal Medicine 16 th edition, is an episodic (most common), or chronic unilateral headache syndrome that begins with one to three short-lived headaches per day over many weeks followed by a period of remission. There may be a regular recurrence in the vast majority of attacks. When it becomes chronic, it is characterized by the absence of sustained periods of remission. Generally the cause is unknown but associations can occur with alcohol use which is the only known dietary trigger of CH. There are other triggers such as strong odors (mainly solvents and cigarette smoke) and napping. CH is also characterized by unilateral, excruciating pain principally in ocular, frontal and temporal areas, as well as ipsilateral lacrimation, conjunctival injection, photophobia and nasal stuffiness. Attacks may happen at precise hours, especially at night. During the attacks, patients tend to be restless. CH is associated with trigeminovascular activation [2] and neuroendocrine [3] and vegetative disturbances, [4] however, the precise causative mechanisms remain unknown. The hypothalamus is thought to be the site of activation for the disorder. Diagnosis is based on clinical findings and differential diagnosis includes other primary headache diseases such as migraine, paroxysmal hemicranias and SUNCT (short lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) syndrome. The disease course is unpredictable over a patient’s lifetime. Some patients have only one period of attacks, while in others the disease evolves from episodic to chronic form. Though there is no known cure for the syndrome, many patients experience spontaneous discontinuation of the headaches. Epidemiology CH affects young adults, predominantly males, with a seven to one male to female ratio. The disease is familial in about ten percent of cases. Genetic factors may play a role in CH susceptibility, and a causative role has been suggested for the hypocretin receptor gene. The table in Appendix A adapted from LeRoux et al. (2008), a review of CH prevalence studies from a number of specified countries, indicates a prevalence range from about 0.05 percent to 0.4 percent. Diagnostic criteria The following are the criteria used by the International Headache Society to make a definitive diagnosis: At least 5 attacks fulfilling criteria B-D Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15-180 minutes if untreated Headache is accompanied by at least one of the following: ipsilateral conjunctival injection and/or lacrimation ipsilateral nasal congestion and/or rhinorrhea ipsilateral eyelid edema ipsilateral forehead and facial sweating ipsilateral miosis and/or ptosis a sense of restlessness or agitation Attacks have a frequency from one every other day to 8 per day Not attributed to another disorder Treatment The medical literature includes anecdotal reports of the use of 100% normobaric and hyperbaric oxygen for the treatment of CH. Oxygen is an odorless, colorless gas at room temperature. It can be delivered in a chamber, by compressed air, via oxygen concentrator, or other method. Though often thought of as harmless, oxygen use has been noted to have adverse effects including blindness and pulmonary fibrosis. For patients who have advanced chronic obstructive lung disease, it can result in the suppression of the drive to breathe (Patel et al. 2003). Oxygen is also known to increase fire risk in certain environments. There are a number of drug treatments for CH, including but not limited to IV and sublingual sumatriptan. Effective prophylactic drugs include prednisone, lithium, methysergide, ergotamine, sodium valproate, and verapamil. At present, there is no curative treatment. The use of oxygen in supervised health care settings, e.g. emergency departments, is common practice. III. History of Medicare Coverage Medicare has a National Coverage Determination on the Home Use of Oxygen (NCD 240.2). The NCD states the home use of oxygen is reasonable and necessary for patients with significant hypoxemia, as evidenced by a blood gas study or a measurement of arterial oxygen saturation. In 2006, an internally generated NCD led to coverage with study participation for those beneficiaries who did not qualify for coverage based on the initial criteria for hypoxemia established in the earlier NCD (240.2.1). This expansion in coverage required that beneficiaries be enrolled subjects in clinical trials sponsored by the National Heart, Lung, and Blood Institute (NHLBI). Current national policy states that the home use of oxygen is reasonable and necessary only for those patients diagnosed with significant hypoxemia in conjunction with certain health conditions. Current Request CMS has received complete requests from Fred Sheftell, MD, President, American Headache Society and Robert C. Griggs, MD, FAAN, President, American Academy of Neurology. Benefit Category Medicare is a defined benefit program. An item or service must fall within a benefit category as a prerequisite to Medicare coverage, § 1812 (Scope of Part A); § 1832 (Scope of Part B) § 1861(s) (Definition of Medical and Other Health Services). Provided that all coverage requirements are met, Medicare covers home use of oxygen as a supply of durable medical equipment (DME), which is referenced in section 1861(s)(6) of the Social Security Act. Thus, the home use of oxygen falls within the DME benefit category. IV. Timeline of Recent Activities Date Action April 9, 2010 CMS posts a tracking sheet and opens a National Coverage Determination (NCD) reconsideration to determine if there is sufficient evidence to change the policy. Currently, CMS has a non-coverage policy for the Home Use of Oxygen when used to treat CH. The initial 30-day public comment period begins. May 9, 2010 Initial public comment period ended. CMS received a total of 65 comments. October 8, 2010 CMS posts the proposed decision memorandum for 30 days of public comment period. November 7, 2010 The public comment period on the proposed decision memo closes with five public comments received V. FDA Status Oxygen itself is a naturally occurring element, readily available commercially from a variety of industrial and other sources. While the FDA regulates the equipment and delivery systems required for providing oxygen therapy, it does not regulate the use of oxygen. VI. General Methodological Principles In general, when making NCDs under §1862(a)(1)(A), CMS evaluates relevant clinical evidence to determine whether or not the evidence supports 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 improves 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 Medicare beneficiaries. An improved health outcome is oneof several considerations in determining whether an item or service is reasonable and necessary under § 1862(a)(1)(A) of the Act. A detailed account of the methodological principles of study design that are used to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix B. 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, 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. VII. Evidence A. Introduction We are providing a summary of the evidence we considered during our review. The evidence reviewed to date in this NCD includes the published medical literature on pertinent clinical trials of home oxygen for treatment of CH. B. Discussion of Evidence Reviewed 1. Questions a. Is the evidence adequate to conclude that the home use of oxygen improves health outcomes in Medicare beneficiaries with cluster headache? b. If the answer to question a. is yes, what factors predict a favorable or unfavorable response to treatment? 2. External Technology Assessment: An external technology assessment was not commissioned for this review. 3. Internal Technology Assessment Systematic reviews are based on a comprehensive search of published studies to answer a clearly defined and specific set of clinical questions. A well-defined strategy or protocol (established before the results of the individual studies are known) guides this literature search. Thus, the process of identifying studies for potential inclusion and sources for finding such articles is explicitly documented at the start of the review. Finally, systematic reviews provide a detailed assessment of the studies included. Literature search methods We searched the MEDLINE database, the Cochrane Library, the National Guidelines Clearinghouse, and the International Network of Agencies for Health Technologies Assessment (INAHTA) database and performed a hand search of bibliographies included in the articles. Search criteria used the terms oxygen or O 2 , cluster headache, and identified those with and without RCT design. Of the 138 references found there were four articles that met methodologic criteria for further review. All four were systematic reviews or reports of randomized controlled trials (RCTs). The remaining papers often referred anecdotally to home oxygen use for CH, referred to one of the above four papers, or involved the use of specific medications for the treatment of CH. Systematic Review Bennett et al. Cochrane (2009): Normobaric and hyperbaric oxygen therapy for migraine and Cluster Headaches (Systematic review of RCTs). Country: Australia, Germany Disease studied: CH Study type: Systematic review of RCTs for treatment of CH N= 2 RCTs for NBOT Study focus: Oxygen treatment for migraine and CH Modalities compared: NBOT vs. sham, and NBOT vs. ergotamine Primary outcome measure(s): Termination of CH Age ≥ 65: Yes M:F: NA Race/Ethnicity reported/analyzed: No The purpose of this review was to assess the evidence of HBOT and NBOT for treating and preventing migraine and CHs. They included randomized trials comparing HBOT or NBOT with one another, other active therapies, placebo (sham) interventions or no treatment in patients with migraine or CH. Three reviewers independently evaluated study quality and extracted data. Only two small trials were found that evaluated NBOT for CH (Kudrow, Fogan, see below). NBOT was effective in terminating CH compared to sham (air) in a single small (N = 19) study, Fogan, (RR 7.88, 95% CI 1.13 to 54.66, P = 0.04) in which the systematic review reported that each participant had at least six headache episodes for both the oxygen and air treatments at 6L/mi (according to the table published with the review), but not superior to ergotamine administration in another small trial (RR 1.17, 95% CI 0.94 to 1.46, P = 0.16). Seventy-six per cent of patients responded to NBOT in these two trials, according to the review. No serious adverse effects of NBOT were reported. We note that in the original report of the Fogan study each participant actually had at most six headache episodes, not at least . Based on the authors’ findings they concluded that there was some evidence that oxygen was effective in the treatment of CH. Randomized Controlled Trials (RCTs) Cohen et al. (2009): High-Flow Oxygen for Treatment of Cluster Headaches: A Randomized Trial. Country: UK Disease studied: CH Study type: RCT - crossover N = 76 Study focus: Oxygen for CH Modalities compared: High flow oxygen (12L/min) vs. placebo (high flow air 12/L) Primary outcome measure(s): To render the patient pain free from CH at 15 minutes Age ≥ 65:Yes mean age = 39 (range 18-70 years). M:F: % Not given Race/Ethnicity reported/analyzed: No The purpose of this study was to ascertain whether high-flow inhaled oxygen was superior to high flow air (placebo) in the acute treatment of CH. They conducted a double-blind, randomized, placebo-controlled crossover trial of 109 adults (aged 18-70 years) with CH as defined by the International Headache Society. Patients were included in the study if they had episodic or chronic CH and experienced between one attack every other day to five a day and the duration of the attacks was between 45 minutes and three hours. Patients were treated for headache episodes with high flow inhaled oxygen or placebo. Then, during the crossover, they were treated with the alternative. Patients were selected from support groups across England. They were recruited and followed up between 2002 and 2007 at the National Hospital for Neurology and Neurosurgery, London, England. Randomization pertained to the order in which they received the active treatment or placebo and was described. The interventions were either 100% inhaled oxygen or high-flow air placebo at 12 L/min, delivered by face mask, for 15 minutes at the start of an attack of CH delivered alternately (first one unmarked tank as directed, then the other) for four attacks each intervention. The method of oxygen delivery was described including type and capacity of cylinder, compression of contents, regulator use for standardization, and face mask. In planning the study, and based on outcomes treatment by intranasal and subcutaneous sumatriptan in CH, the authors determined a 25% difference between placebo and active treatment would be clinically significant. They estimated that 55 patients were needed for a power of 80% with a type 1 error of 5%. A drop-out rate of 15% was allowed for, and therefore 70 patients were to be recruited. Outcome data were treated as binary, that is, success or failure in treating the CH. A total of 334 patients were assessed for eligibility (225 were excluded: 73 for previous oxygen treatment or chronic migraine; 58 stopped having CH; 37 declined participation; 31 diagnosis unclear; 22 receiving prevention; 4 for other reasons) and 109 were randomized between March 2003 and April 2007. Of these 109, 33 did not receive treatment for the following reasons: 17 stopped having CH; nine lost to follow-up; six withdrew from study; one died before receiving treatment. That left 76 subjects, 57 with episodic and 19 with chronic CH, all of whom were included in the analysis. Total time of the study was to be five years. The study was performed in the patient’s home with two gas containers labeled "treatment 1" and "treatment 2." Randomization of study-eligible patients was performed using opaque sealed envelopes, inside of which was a card labeled "A" or "B," which determined the order the patient received active treatment or placebo. Once the patients had treated four attacks each, they returned the diaries to the investigators and called the gas supplier to collect the cylinders from their homes. The primary end point was to "render the patient pain free", or in the absence of a diary to have adequate relief, at 15 minutes. For the primary end point the difference in outcome between oxygen, 78% (95% confidence interval, 71% - 85% for 150 attacks) and air, 20% (95% confidence interval, 14% -2 6%; for 148 attacks) was statistically significant (Wald test, Chi sq 5 df = 66.7, P < .001). There were no reported important adverse events. The authors concluded that treatment of patients with CH at symptom onset using inhaled high-flow 100% oxygen compared with 100% air (placebo) was more likely to result in being pain-free at 15 minutes. Fogan (1985): Treatment of Cluster Headaches A double-blind comparison of oxygen vs. air inhalation. Country: USA Disease studied: CH Study type: RCT crossover N= 19 Study focus: Oxygen for CH Modalities compared: 100% oxygen vs. air at 6L/min Primary outcome measure(s): The patients' subjective evaluation of CH pain relief Age ≥ 65: No - mean- age not given (range 20-50 years) M:F: 100:0% Race/Ethnicity reported/analyzed: No The author conducted an acute CH therapy cross-over RCT with allocation concealment and blinding of both patients and investigator. The cross-over was made after up to six episodes of CH were treated with the first assigned gas. Nineteen patients (20 to 50 years, all male) with a diagnosis of CH, according to the Ad Hoc Committee on Classification of Headache 1962, were selected. The stated intention was to do a double-blind crossover study comparing 100% oxygen and air inhalation at 6 L/min via nonrebreathing face masks for 15 minutes or less, for up to six headaches for each treatment. Eleven of the 19 were successfully crossed to receive both gases, but the remaining eight received only one of the gases (three air, five oxygen). Two were accidentally given the same gas both times, one oxygen and the other air. Patients scored their own degree of relief for each treatment as none, slight, substantial, or complete relief. The author aggregated all the data for each treatment into one group, despite the fact that 8 of 19 patients did not complete the study. Nine out of 16 patients (56%) who used oxygen reported a complete or substantial relief in 80% or more of their cluster attacks compared with only one of 14 patients (7%) who used air. Six of the patients’ CH syndrome disappeared before the end of the trial. The average (± SE) relief score for all oxygen-treated patients was 1.93 ± 0.22 out of a possible total score of 3.0, and for air the treatment relief score was 0.77 ± 0.23. This difference was reported to be highly statistically significant using an analysis-of-variance F test. The author concluded that his results document that patients with CH can benefit from oxygen inhalation during acute attacks. Kudrow (1981): Response of Cluster Headaches attacks to oxygen inhalation. Country: USA Disease studied: CH Study type: RCT N = 100 Study focus: Oxygen for CH Modalities compared: Oxygen, ergotamine Primary outcome measure(s): Complete or almost complete response and time to success Age ≥ 65: Not given - mean age = 48.5 M:F: 84:16% Race/Ethnicity Reported/Analyzed: No The purpose of this study was to compare treatment of CH with 100% oxygen to sublingual ergotamine tablet by performing a randomized control trial. Fifty persons were randomly selected for a cross-over trial where 25 (Group1) received oxygen at 7L/minute for 10 consecutive CHs and 25 (Group2) received sublingual ergotamine (up to three tablets 15 minutes apart) for 10 consecutive CHs. Then the groups crossed over and reversed treatment for another 10 consecutive CHs (Group2 received oxygen on crossover and Group1 received ergotamine). Successful response for either oxygen or ergotamine was defined as almost complete, or complete cessation of head pain within 15 minutes, for at least seven of 10 attacks. Regardless of order of treatment and lack of classification of CH into chronic or episodic, 100% oxygen had an 82% success rate compared to 70% for sublingual ergotamine. The average time to success with NBOT was shorter, about six minutes as compared to 12 for sublingual ergotamine. The findings were not found to be statistically significant. When comparing episodic CH patient treatment with oxygen as compared to sumatriptan, there was no statistically significant success difference (77.7% vs. 71.4%) but there was one comparison in favor of oxygen (86.1% vs. 50%) when comparing treatment of chronic CH. Rapidity of CH relief was similar for oxygen versus ergotamine given a 15 minute time period, but 46% of oxygen treated patients had relief at six minutes as compared to 40% having relief at 12 minutes for ergotamine. The author concluded that 100% oxygen at 7L/min was effective in treating CH. The author further commented that contraindications and/or side effects to oxygen are rare and concluded that oxygen is an excellent way to treat CH. 4. MEDCAC A Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) meeting was not convened on this issue. 5. Evidence Based Guidelines We searched for evidence-based guidelines that discussed oxygen to abort or prevent cluster headache. Relevant parts are included below. The online National Guideline Clearinghouse database was searched using the term "cluster headache." One guideline was found, developed by the European Federation of Neurological Societies (EFNS). The guideline was published in the European Journal of Neurology in 2006. The International Headache Society has since adopted the EFNS guideline. The website for the National Headache Foundation, the American Academy of Neurology, and the Institute for Clinical Systems Improvement (ICSI) were searched using the terms "cluster headache" and "cluster headache guidelines." Guidelines were found on and taken from each organization’s website. The website for the American Neurological Association, American Headache Society, National Institute of Neurological Disorders and Stroke, the American Medical Association, the American Academy of Family Physicians, and the American Society of Internal Medicine were searched using the terms "cluster headache" and "cluster headache guidelines." No guidelines were found. The European Federation of Neurological Societies (EFNS) Guideline The guideline prepared by the European Federation of Neurological Societies (EFNS) considers treatment and prevention efforts for cluster headaches. The EFNS taskforce based their guideline on hand searches of published literature and searches of electronic databases. The evidence was graded on a rating scheme where classes range between I and IV, with Class I indicating the strongest evidence and Class IV the weakest. Class I includes a sufficiently powered prospective, randomized, controlled clinical trial with blinded outcome assessment in a representative population, or a sufficiently powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. Class II represents a prospective matched-group cohort study in a representative population with masked outcome assessment that meets the criteria in Class I, or a controlled trial in a representative population that lacks a criterion stated in Class I. Class III includes all other controlled trials in a representative population, where outcome assessment is independent of patient treatment. Class IV is evidence from uncontrolled studies, case series, case reports, or expert opinion. The evidence from the studies was evaluated in accordance with EFNS recommendations. Findings were given a level A, B, or C recommendation. Level A rating means the recommendation is effective, ineffective, or harmful, and is based on at least one influential Class I study or at least two consistent Class II studies. Level B rating means the recommendation is probably effective, ineffective, or harmful and requires at least one convincing Class II study or overwhelming Class III evidence. Level C rating means the recommendation is possibly effective, ineffective, or harmful and requires at least two convincing Class III studies. According to the guidelines, the first choice for the treatment (Level A) of an acute attack should be inhalation of 100% oxygen with at least seven liters per minute over a 15 minute period or with the subcutaneous injection of six mg sumatriptan. Nasal sumatriptan or oral zolmitriptan are alternatives; however they take longer to become effective. Prevention of cluster headache should first employ verapamil at a daily dose of at least 240 mg. Steroid use of at least 100 mg methylprednisone given orally or up to 500 mg intravenously per day over five days is recommended and effective, although no Class I or Class II trials are available. Level B recommendations include intranasal lidocaine and subcutaneous octreotide when level A medication is ineffective or contraindicated. Methysergide and lithium are next in line if lidocaine and subcutaneous octreotide are ineffective or contraindicated. Corticosteroids, topiramate, melatonin and ergotamine tartrate are recommended in certain doses and based on tolerance and individual cases. Pizotifen and intranasal capsaicin have side effects and therefore should rarely be used. National Headache Foundation The guideline prepared by the National Headache Foundation considers treatment, prevention, and maintenance efforts for cluster headaches. The guideline is based on searches of electronic databases and the consensus of an advisory panel of practitioners chosen for their expertise. Guidelines are also based on experience in clinical settings. Oxygen inhalation is the customary treatment for cluster headaches. Inhalation of 100% oxygen at a flow rate of 7-10 liters per minute for 15 minutes is the standard. In most patients, oxygen use is effective, however, in some patients, pain returns and is not completely eliminated. Sumatriptan administered subcutaneously at six mg is most effective for patients who experience one or two cluster attacks per day. Zolmitriptan, dihydroergotamine, nasal lidocaine, and capsaicin are all used for relief, and some are more effective for different patients. Preventive treatment, meant to repress attacks and to maintain relief through the cluster period, includes the use of corticosteroids and ergotamine derivatives. Maintenance therapy includes verapamil, methysergide maleate, lithium carbonate, valproic acid, topiramate, and melatonin. American Academy of Neurology The "Headaches: Practical Management" guideline developed by the American Academy of Neurology (AAN) lists treatments and prevention options. For symptomatic treatment of cluster headache, the AAN recommends oxygen inhalation. The patient should receive 100% oxygen at seven or more liters per minute with a facemask. The drug DHE-45 preceded by an antiemetic may also provide relief. Subcutaneous injection of sumatriptan is also effective, but the patient must be monitored for risk factors for coronary artery disease because it is a contraindication to use of sumatriptan. Transnasal butorphanol is another alternative. For preventive treatment, the authors suggest prednisone for quick control of the episode, but they caution its use because it causes immediate bone loss. Therefore, Vitamin D should be taken as a supplement. Methysergide, verapamil, valproic acid, and lithium are also useful for prevention, but lithium must be monitored for toxicity. For refractory cases, gabapentin, and topiramate might be useful, and combinations of verapamil and lithium, or verapamil and valproic acid may be effective when individual drugs are not effective. When all other options are exhausted, surgical treatment might be appropriate. Current practice is percutaneous radiofrequency lesions directed against the trigeminal ganglion. Institute for Clinical Systems Improvement The ICSI health care guideline for the diagnosis and treatment of headache was updated in March 2009 and is intended as a guideline to help clinicians diagnose and treat patients. This document included treatment of cluster headache. The Committee for Evidence-based Practice comprises a group of 6-12 members including physicians, nurses, pharmacists, other healthcare professionals relevant to the topic, and an ICSI staff facilitator. The group conducts a literature search to identify important clinical trials, meta-analyses, systematic reviews, or regulatory statements, as well as other professional guidelines. Then a critical review process allows the clinicians to thoroughly review the science and make changes to the guideline or approve what is proposed. Literature is also graded based on design type and quality of the research report. A grade I conclusion is supported by good evidence and consistent results from strong studies in which results are clinically important and consistent, there are no significant threats to internal and external validity, few to no flaws in design, and adequate statistical power. A Grade II conclusion is supported by fair evidence consisting of studies of strong design but withuncertainty due to inconsistencies among results, minor threats to internal and external validity, research design flaws, or inadequacy of sample size. Grade III studies feature strong design for answering the question addressed, but include substantial uncertainty in results because of serious threats to internal and external validity, research design flaws, or inadequacy of sample size. The ICSI guideline for the diagnosis and treatment of cluster headache states that oxygen inhalation is highly effective at 7-15 liters per minute via a face mask. Drugs to treat the acute attack may be hard to attain in proper quantities. Subcutaneous sumatriptan is the most effective self-administered medication for pain relief, but is not effective when used prophylactically. Dihydroergotamine mesylate (DHE) also provides relief. For bridging treatment of cluster headache, ICSI recommends corticosteroids, ergotamine, or occipital nerve block. For first line maintenance treatment, ICSI recommends verapamil. Other maintenance treatments include avoiding alcohol, taking verapamil in high doses, corticosteroids, lithium, divalproex sodium, or topiramate. Though the guidelines indicate that all treatments for cluster headache should be used under the direction of a physician familiar with cluster headache, they do not specifically address the unsupervised use of oxygen at home. For example, the EFNS guideline did not reference location of treatment. The National Headache Foundation states that treatments of cluster headache should be used under the direction of a physician familiar with cluster headaches, but does not provide information about treatment setting. The American Academy of Neurology guideline supports physician supervision, but does not specifically mention a place of service for treatment. The Institute for Clinical Systems Improvement implies physician supervision, but does not specifically mention place of service. None of the guidelines provide any information about unsupervised treatment. 6. Professional Society Position Statements During the initial comment period, the American Academy of Neurology (AAN) expressed strong support for the use of oxygen to treat cluster headaches. The AAN, a requester of the national coverage determination, recommended that oxygen therapy to treat cluster headache should be used because it can be administered more than once per day, is very effective in eliminating pain, and has minimal to no adverse side effects for the majority of those who are affected. Oxygen is also convenient for the patient because it is easily transported. The AAN recommends oxygen use to abort or reverse an individual attack of cluster headache, especially under the following circumstances: when preventive or abortive therapies are less than entirely effective and breakthrough headaches occur, when preventive or abortive medications are contraindicated or produce adverse effects, when multiple attacks occur during a 24-hour period, making other abortive treatments unacceptable, and in the elderly population where breakthrough attacks must be treated quickly and other potential therapies or medications are unsafe or inappropriate. 7. Expert Opinion Except for communications with the NCD requestor and the professional society comments noted below, CMS received no formal expert opinion statements from the medical or scientific community regarding this issue. 8. Public Comments CMS uses the initial public comments to inform its proposed decision. 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. Public comments that contain personal health information are not made available to the public. CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum. A. Initial Comment Period 4/9/2010 - 5/9/10 CMS received 65 comments during the initial 30-day public comment period. Comments that were submitted via the CMS coverage website may be viewed using the following link: http://www.cms.gov/mcd/viewpubliccomments.asp?ncd_ID=244. The summary of those comments can be found in our proposed decision memorandum which is published on the CMS website at http://www.cms.gov/mcd/viewdraftdecisionmemo.asp?id=244. Initial Comment Period 4/9/2010 – 5/9/10 CMS received a total of 65 comments during the initial 30 day public comment period. Commenters self-identified as organizations, suppliers, physicians, other clinicians and patients. Many comments, 31 in all, were submitted by patients with CH or their advocates. Four comments were submitted by industry, one by a physician professional organization, one by a physician, one by a nurse, and 27 others who did not identify an affiliation. The American Academy of Neurology (AAN) was the only Physician Professional Organization to submit a formal comment. The AAN urged CMS to allow for the home use of oxygen to treat CH especially for those patients who are treatment resistant, have contraindications to existing therapies, or suffer with breakthrough attacks. Some stakeholders came in for face-to-face meetings with CMS staff members to express their support for the home use of oxygen to treat CHs. CMS met with representatives from the American Headache Society on July 27, 2010. Two practicing neurologists and their representatives provided us with information on the diagnosis and treatment of cluster headache. These materials included three pages from a textbook entitled, "Wolff’s Headache and Other Head Pain" that describes the use of normobaric oxygen to treat cluster headache. All comments submitted were in favor of Medicare coverage - no one who wrote to CMS opposed coverage. Many comments stated that oxygen has no known adverse events associated with its use in treatment of CH. Others state that treatment with oxygen is especially useful for patients with contraindication to prescription medications. One physician and one nurse wrote in support of coverage based on their experience in administering oxygen for CH in a clinical setting. Industry comments favored the use of hyperbaric oxygen to treat CH, even though the use of hyperbaric oxygen is not considered in this NCD. B. Public Comment Period 10/8/2010 - 11/7/2010 Five commenters wrote to CMS in response to our proposed decision. Multiple concerns were presented, which will be discussed below. All were opposed to the proposed decision and advocated for national coverage of oxygen to treat cluster headache (CH). Three comments from patient advocates stated that oxygen is a safe and effective CH treatment. The other two comments were from an academic medical center, and a professional society of health care providers who specialize in CH treatment. These institutions pointed out the ethical and practical challenges of conducting clinical trials, stated that current evidence is adequate to support oxygen as a CH treatment, and referenced guidelines and established clinical practice in which oxygen treatment is standard. We also received additional published materials from commenters (see below) that had not been initially reviewed in the proposed decision. Comment All five commenters state that CMS should provide national coverage of oxygen for patients diagnosed with cluster headache. Response We disagree. The evidence is not sufficient to recommend national coverage for home use of oxygen therapy for cluster headache under section 1862(a)(1)(A) of the act. The evidence base specific to home use is lacking in several important ways. For example, in the study by Kudrow (1981), the definition of cluster headache was not in agreement with current definitions, the method of patient selection was not stated, and the mean age was not typical of Medicare beneficiaries. In the Fogan (1985) study, eight of the 19 enrollees did not receive both air and oxygen during the crossover, an inappropriate statistical test was used to analyze the data, and the study had a small number of participants. In the third and last randomized control trial by Cohen (2009), episodic and chronic cluster headache patients were not analyzed separately and there was selection bias. The above methodological flaws made the evidence insufficient to support national coverage. We believe coverage with evidence development (CED) is a means to provide limited coverage under 1862(a)(1)(E) of the act. CED allows for coverage by providing support for well-designed well-executed clinical studies to obtain additional evidence and to establish the value of promising, if unproven, treatments. Comment Several commenters focused on the medications used to treat cluster headache. Two comments state that cluster headaches reach maximum intensity rapidly, within five to 15 minutes, too fast for an oral medication to take effect. Two commenters wrote that the two most commonly prescribed drugs used to treat cluster headache are dangerous when used by patients with vascular disease. Another commenter provided the package insert on sumatriptan, which states that this drug is not recommended for use in the elderly. Three commenters wrote that treatment of cluster headache with vasoconstrictive agents, such as sumatriptan or dihydroergotamine injections, results in treatment that costs substantially more than oxygen. Response We agree that currently available medications have limitations. However medications, in contrast to home oxygen delivery systems, are readily available to patients who are not necessarily at home at the onset of headache. Portable oxygen systems are cumbersome for patients who are not chronically hypoxic and thus likely to be more physically active. In contrast with chronic hypoxia, cluster headache patients are asymptomatic between attacks. We believe it is unclear from the current evidence whether the potential real world effectiveness of home oxygen for cluster headache will be realized in actual use. CMS generally does not consider costs in making national coverage decisions. Comment One commenter opposes the use of placebo-controlled trials for cluster headache given the severity of attacks. This commenter states that the severity of pain associated with cluster headache makes it unethical for study participants to be assigned to the placebo arm where treatment is not provided. Another commenter disputes the use of FDA-approved drugs for a comparator because the FDA package insert does not recommend the use of those prescriptions in the aged population. Response We did not propose to require placebo-controlled trials. All study designs must be reviewed and approved by an Institutional Review Board (IRB), which includes consideration of the ethical implications of the study. An IRB must ensure that the following safeguards are instituted to minimize harm: participants at increased risk of harm from nonresponse are excluded; the placebo period is limited to the minimum required for scientific validity; subjects will be carefully monitored, with inpatient observation when appropriate; rescue medications will be administered if serious symptoms develop; and there are explicit and specific criteria for the withdrawal of subjects who have adverse events (Emanuel and Miller). The concern about FDA status is not unique to the comparator arm. We also note that while FDA approves or clears various apparatus for the delivery of oxygen, oxygen itself does not have FDA approval or clearance for any indication. Thus both the oxygen and the various medications might in some study protocols be furnished for unlabeled use. Comment One commenter argues that oxygen inhalation has been the standard of care for the symptomatic relief of cluster headache for over 50 years. They point to the clinical guidelines from The American Academy of Neurology and other medical professional societies and maintain that such guidelines qualify as scientific evidence. Response We remind the reader that the scope of this NCA is specifically focused on the unsupervised home use of high flow oxygen by patients whose primary diagnosis is cluster headache, rather than the more common use of low flow oxygen, customarily 2L/min, by patients whose primary diagnosis is hypoxia, generally secondary to chronic obstructive pulmonary disease. High flow oxygen is generally not used in the latter patients, particularly in unsupervised settings, due to the risk of suppression of the hypoxic drive to breathe. We note that various guidelines on cluster headache recommend oxygen flow rates of 7L/min to 15L/min. We are concerned that some Medicare beneficiaries with cluster headache may have underlying hypoxic disease related to chronic tobacco smoke exposure with advanced age. Tobacco use is believed to trigger cluster headache via nicotine exposure, and tobacco users are also advised to refrain due to the interference of nicotine with medications. In our review of the evidence we did not find evidence that hypoxia assessment is routinely performed prior to the administration of high flow oxygen. Commenters have correctly pointed to considerable physician experience with the administration of high flow oxygen to abort cluster headache in patients who present to health care facilities. In such settings, professional staff is readily available to monitor the patient’s response and overall status. This is clearly not the case in a beneficiary’s home, where the oxygen would be administered by the distressed patient himself or by a family member or caregiver. In addition, the prospective clinical study of home use of oxygen must include safety criteria for