Medical Policy: 02.01.45
Original Effective Date: July 2011
Reviewed: February 2017
Revised: November 2017
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Asthma, a chronic lung disease, affects approximately 7.6% of adults and 8.4% of children in the United States. Asthma symptoms include episodic shortness of breath that is generally associated with other symptoms such as wheezing, chest tightness and coughing. There is substantial heterogeneity in the inflammatory features of patients diagnosed with asthma, and this biologic diversity is responsible, at least in part, for the variable response to treatment in the asthma population. Most patients with asthma have mild to moderate disease and can be easily controlled by regular use of inhaled corticosteroids (ICS) combined with short acting inhaled B2 agonists for relief of symptoms. However, some patients asthma continues to be poorly controlled in terms of ongoing symptoms, frequent exacerbations, persistent and variable airway obstruction, and frequent requirements for B2 agonists despite aggressive treatment.
The goal of the treatment of asthma is to achieve and maintain clinical control by eliminating symptoms during both the day and night, to normalize measures of lung function, and to reduce the risk of exacerbations.
Management of asthma consists of environmental control, patient education, management of comorbidities, and regular follow up for all affected patients, as well as a stepped approach to medication treatment. Despite this multidimensional approach, many patients continue to experience considerable morbidity. In addition to ongoing efforts to optimally implement standard approaches to asthma treatment, new therapies are being developed. One recently developed therapy is bronchial thermoplasty and is a potential treatment option for patients with severe persistent asthma.
Bronchial thermoplasty is based on the premise that patients with asthma have an increased amount of smooth muscle in the airway and that contraction of this smooth muscle is a major cause of airway constriction. The thermal energy delivered via bronchial thermoplasty aims to reduce the amount of smooth muscle and thereby decrease muscle mediated bronchoconstriction with the ultimate goal of reducing asthma-related morbidity. Bronchial thermoplasty is intended as a supplemental treatment for patients with severe persistent asthma.
During the procedure a standard flexible bronchoscope is placed through the patient’s mouth or nose into the distal targeted airway and a catheter is inserted into the working channel of the bronchoscope. After placement, the electrode array in the top of the catheter is expanded, and radiofrequency energy is delivered from a proprietary controller used to heat tissue to 65 degrees Celsius over a 5 mm area. The positioning of the catheter and application of thermal energy is repeated several times in contiguous areas along the accessible length of the airway. At the end of the treatment session, the catheter and bronchoscope are removed.
After the first treatment session, previously treated airways are evaluated by bronchoscopy before proceeding with further treatment. A course of treatment consists of 3 separate procedures in different regions of the lung scheduled about 3 weeks apart. The procedure is performed on an outpatient basis with conscious sedation and requires approximately 1 hour to complete.
Three industry sponsored randomized controlled trials (RCTs) on bronchial thermoplasty have been published (AIR, RISA, AIR2) for the treatment of asthma. The largest RCT with the most rigorous methodology was the AIR2 trial. This was the only published trial that was double blinded and sham controlled, and also the only published RTC with sites in the United States.
AIR2 was an RCT evaluating the efficacy of bronchial thermoplasty at 30 sites in 6 countries (including the United States); findings were published in 2010 by Castro et al. Unlike the other 2 RCTs, the control condition was a sham intervention, and the trial was double-blind. Eligibility criteria were similar to those in the AIR trial; key differences were that a higher initial dose of ICSs was required (equivalent to at least 1000 μg beclomethasone), and patients were required to have experienced at least 2 days of asthma symptoms during the 4-week baseline period and have a baseline score on the Asthma Quality of Life Questionnaire (AQLQ) of no more than 6.25. (The possible range of the AQLQ score is 1 to 7, with a higher number representing a better QOL.) Also different from the AIR trial, patients were not required to experience symptom worsening during a period of abstinence from LABAs. Patients were stable on their asthma medication and continued their regimens during the study. The primary outcome was the difference between groups in the change from baseline in the AQLQ score, with scores from the 6-, 9-, and 12-month follow-ups averaged (integrated AQLQ score). A related outcome was the proportion of patients who achieved a change in their AQLQ score of 0.5 or greater, generally considered the minimally important difference for this scale. Bayesian analysis was used. The target posterior probability of superiority (PPS) of bronchial thermoplasty over sham was 95%, except for the primary AQLQ end point; there the target was 96.4% to adjust for 2 interim looks at the data.
A total of 297 patients were randomized, 196 to a bronchial thermoplasty group and 101 to a sham control group. The intervention for all participants consisted of 3 bronchoscopy procedures, performed 3 weeks apart. Participants and outcome assessment was blinded, but the intervention team was unblinded. The sham intervention was identical to the active treatment, except that no radiofrequency energy was delivered. Nine participants withdrew consent before beginning treatment, and 288 underwent bronchoscopy and were included in the intention-to-treat (ITT) population. One hundred eighty-five participants in the treatment group and 97 in the sham control group underwent the second bronchoscopy, and the same numbers of patients had the third bronchoscopy (it is not clear whether they were exactly the same patients). A total of 278 (94%) of the 297 enrolled patients completed the 12-month visit, 181 in the treatment group and 97 in the sham control group.
The superiority of bronchial thermoplasty was not achieved in the ITT population for the primary effectiveness outcome, mean change in the integrated AQLQ score. Mean (SD) change was 1.35 (1.10) in the bronchial thermoplasty group and 1.16 (1.23) in the sham control group. Using Bayesian analysis, the PPS was 96%. This did not surpass the target PPS of 96.4%. However, superiority of bronchial thermoplasty on a related outcome was achieved. In the ITT population, the percentage of patients achieving an AQLQ score change of 0.5 or greater (ie, at least the minimally important difference) was 79% in the bronchial thermoplasty group and 64% in the control group. The PPS at 99.6% surpassed the target probability for secondary outcomes of 95%. Additional analysis of data from the active treatment group suggested that responders (defined as a change in AQLQ score of at least 0.5) were more likely to have a lower baseline score than non-responders (mean, 4.1 vs 5.1, respectively).
Several secondary outcomes favored bronchial thermoplasty over the sham control group. They include a reduction in the proportion of patients reporting asthma worsening during follow-up (27.3% vs 42.9%, respectively; PPS=99.7%) and a reduction in the number of emergency department visits (0.07 vs 0.43 visits per person per year, respectively; PPS=99.9%). Moreover, there was a reduction in severe exacerbations of 0.47 per person per year in the bronchial thermoplasty group compared with 0.70 per person per year in the control group (PPS=95.5%). There were no significant differences between groups in other secondary efficacy outcomes, including morning peak expiratory flow, number of symptom-free days, symptom score, and rescue medication use.
For safety outcomes, during the treatment phase, there was a higher rate of respiratory adverse events in the active treatment group (85% of participants; mean, 1.0 events per bronchoscopy) compared with the sham group (76% of participants; mean, 0.7 events per bronchoscopy). A total of 16 (8.4%) patients in the active treatment group required 19 hospitalizations for respiratory symptoms during the treatment phase compared with 2 (2%) patients in the sham group, who required 1 hospitalization each. However,
during the posttreatment period, 70% of patients in the bronchial thermoplasty group and 80% of patients in the sham group reported adverse respiratory events. During this phase of the trial, 5 (2.6%) patients in the bronchial thermoplasty group had a total of 6 hospitalizations for respiratory symptoms, and 4 (4.1%) patients in the sham group had 12 hospitalizations (1 patient had 9 hospitalizations).
In the AIR2 trial, the sham group had a relatively high rate of response (eg, 64% experienced a clinically significant increase in the AQLQ score). Blinding appeared to be initially successful and remained so for the sham group. Participants in both groups were unable to correctly guess their treatment group after the first bronchoscopy. During subsequent assessments, this continued among patients in the sham group, whereas in the bronchial thermoplasty group, a larger proportion guessed correctly.
Two- and 5-year follow-up data on patients in the treatment group of the AIR2 trial have been published. In 2011, Castro et al reported 2-year data on 166 (87%) of 190 patients randomized to the bronchial thermoplasty group. In the second year after treatment, the proportion of participants who experienced severe exacerbations was 23.0% (95% confidence interval [CI], 16.6% to 29.5%). This compares with a 30.9% (95% CI, 24.2% to 37.7%) rate of exacerbations during year 1. The proportion who experienced asthma adverse events was 28.7% (95% CI, 22.1% to 35.3%) in year 1 and 26.5% (95% CI, 19.8 to 33.2) in year 2. In 2013, Wechsler et al reported 5-year data on 162 patients in the AIR2 trial (85% of those randomized to the treatment group).10 In a matched-pair analysis including the 162 study completers and the same group in previous years, the rate of severe exacerbations in years 1, 2, 3, 4, and 5 were 30.9%, 23.5%, 34.0%, 36.4%, and 21.6%, respectively. The proportion of patients experiencing severe exacerbations in years 2, 3, 4, and 5 did not differ significantly from the number of exacerbations in year 1. The proportion of patients who experienced asthma adverse events (at least > 2 asthma symptoms occurring at the same time) were 28.7%, 27.9%, 29.6%, 31.4%, and 24.7%, respectively. The proportion of patients with at least 1 hospitalization for respiratory adverse events these same years was 3.3%, 4.2%, 6.2%, 5.7%, and 1.9%, respectively. In the 12 months before bronchial thermoplasty, the rate of hospitalization for respiratory symptoms in this group was 4.2%. These follow-up studies are limited in that follow-up data were not collected on patients randomized to the sham group, and therefore outcomes (eg, rate of exacerbations, rate of hospitalizations) cannot be compared in patients who did and did not receive bronchial thermoplasty.
The results of the AIR-2 trial have generated enormous interest, controversy, and confusion regarding the true efficacy of bronchial thermoplasty for severe asthma. The FDA approved bronchial thermoplasty for the treatment of adults with severe asthma and this approval was based on the results of the AIR-2 trial. Current marketing of bronchial thermoplasty highlights its use for adult patients with severe and persistent asthma, which is interpreted by most clinicians as meaning oral corticosteroid dependence, frequent exacerbations, or a significantly reduced FEV1 with poor quality of life (QOL). However, these types of patients were specifically excluded from the AIR-2 trial which raises questions about the efficacy of bronchial thermoplasty.
Several pooled analyses of the 3 published RCTs were identified. Most recently, in 2016, Zhou et al published a systematic review of the published RCTs and extension studies, focusing on the durability and long-term responses for treated patients. Reviewers pooled data on long-term effects in bronchial thermoplasty treated patients only (i.e. not in comparison groups). In an analysis of 216 patients with 5 years of follow-up, there was no significant decline in spirometry-detected prebronchodilator FEV1 (percent predicted) compared with 1-year findings (weighted mean difference [WMD], 0.75; 95% CI, -3.36 to 1.85; p=0.57 ; I2=0%). Similarly, there was no significant decline in postbronchodilator FEV1 (WMD=0.62; 95% CI, -3.32 to 2.08; p=0.65; I2=0%). In terms of adverse events over time, the rates of respiratory adverse events, emergency department visits for adverse events, and hospitalizations did not differ significantly after the 1- and 5-year follow-ups.
In 2014, a Blue Cross Blue Shield Association TEC Assessment was published on bronchial thermoplasty for treatment of inadequately controlled severe persistent asthma. The Assessment included the 3 published RCTs (AIR, RISA, AIR2) and concluded, “the evidence is insufficient to determine whether potential improvements in some outcomes, but not others defining the net health outcome, outweigh the potential harms” and that the technology did not meet TEC criteria.
In 2014, a Cochrane review of RCTs was published by Torrego et. al. reviewers included the 3 RCTs. Potential trial limitations identified by reviewers were lack of blinding in 2 of the 3 trials and lack of a sham control in 2 trials. Pooled analyses were not conducted for asthma exacerbation outcomes. A meta-analysis of the 3 trials found significantly greater improvement in AQLQ scores at 12 months in the bronchial thermoplasty groups than in the control groups (mean difference [MD], 0.28; 95% CI, 0.07 to 0.40). However, at 12 months, the proportion of patients using rescue medication did not differ significantly between groups (MD = -0.68; 95% CI, -3.63 to 2.28). In terms of adverse events, a significantly higher number of patients were admitted to the hospital for respiratory events during the treatment period (relative risk [RR], 3.50; 95% CI, 1.26 to 9.68). There was no significant difference between groups in the proportion of patients admitted to the hospital for respiratory events in the posttreatment period (RR=1.12; 95% CI, 0.44 to 2.85).
In 2011, Wu et. al. published a meta-analysis of the findings of the 3 published RCTs. Pooled analyses of them found greater mean improvement in asthma QOL in the bronchial thermoplasty groups than in the control groups (WMD=0.63; 95% CI, 0.10 to 1.15) and greater improvement in the peak expiratory flow with bronchial thermoplasty treatment than with the control treatment (WMD=21.78; 95% CI, 8.06 to 35.50). During the treatment period (beginning on the day of the first treatment session and lasting 6 weeks after the last session), there were more respiratory adverse events in the bronchial thermoplasty groups (1113 events in 257 patients) than in the control groups (369 events in 164 patients) (p value not reported). Also during the treatment period, there was a significantly higher risk of hospitalization with bronchial thermoplasty than with control (RR=3.78; 95% CI, 1.39 to 10.24). In the posttreatment period (end of treatment to the 12-month follow-up visit), there was no significant difference between groups in the risk of hospitalization (RR=1.15; 95% CI, 0.47 to 2.79).
After publication of the 3 RCTs (AIR, RISA, AIR2), several case series have described outcomes in clinical practice. They generally had small sample sizes (eg, N=7,14 N=10,15 and N=2016). In addition, a rigorous U.K. registry study was published by Burn et al (2016), which focused on safety outcomes. The study combined data from 2 sources, the U.K. Difficult Asthma Registry and the Hospital Episode Statistics warehouse, and included patients treated with bronchial thermoplasty in the U.K. between June 2011 and January 2015. Eighty-three patients were identified in the Difficult Asthma Registry and 85 in the Hospital Episode Statistics database. For 59 patients, data in the 2 databases could be matched. Most patients had a course of 3 bronchial thermoplasty treatment sessions. Data from the matched cohort were used to calculate event rates for 4 binary safety outcomes. Procedural complications were reported in 17 (11%) of 152 procedures in 13 (22%) patients; emergency department readmissions within 30 days of the initial hospitalization were reported for 15 (11.8%) patients; and accident and emergency visits (i.e. emergency department) visits for any reason were reported for 13 (8.6%) patients. For the fourth binary outcome (post-procedure overnight stay), 70 (46.1%) of 152 procedures were followed by an overnight stay. In total, 20.4% of procedures in the matched cohort were associated with at least 1 of the 4 safety issues. The authors noted that the relatively high rate of safety events might be related to older patients with more severe disease being treated in clinical practice compared with patients included in clinical trials.
Three RCTs have evaluated bronchial thermoplasty for the treatment of asthma. The AIR2 trial is the largest of the 3 published RCTs, and the only one double-blinded and sham-controlled, with sites in the United States. Over 1 year, bronchial thermoplasty was not found to be superior to sham treatment on the investigator-designed primary efficacy outcome of mean change in quality of life (QOL) score, but was found to be superior on a related outcome, improvement in quality of life of at least 0.5 points on the Asthma Quality of Life Questionnaire (AQLQ). There was a high response rate in the sham group of the AIR2 trial, which suggests a large placebo effect, particularly for subjective outcomes such as quality of life. On the secondary outcomes, bronchial thermoplasty provided greater benefit than sham treatment on some, but not all, outcomes. In the AIR and RISA trials, there were improvements in quality of life (QOL) for the bronchial thermoplasty group compared to the medical management group. However, given the lack of benefit in the AIR2 trial, it is possible that the difference in quality of life (QOL) for these 2 trials were due at least in part to a placebo effect. There are no long-term sham-controlled efficacy data. Findings on adverse events from the 3 trials have suggested that bronchial thermoplasty is associated with a relatively high rate of adverse events, including hospitalizations during the treatment period, but not in the post treatment period. Safety data from a U.K. registry study, published in 2016, found that 20% of bronchial thermoplasty procedures were associated with a safety event (i.e. procedural complications, emergency respiratory readmissions, emergency department visits, and/or post-procedure overnight stays).
Conclusions cannot be drawn about the effect of bronchial thermoplasty on the net health outcome due to the limited amount of sham controlled data (1 RTC) on short term efficacy, and also the uncertain degree of treatment benefit in that single sham-controlled trial, the lack of long-term sham-controlled data in the face of high initial placebo response and the presence of substantial adverse events. In addition, there is a lack of data on patient selection factors for this procedure and, as a result, it is not possible to determine whether there are patient subgroups that might benefit. Support by professional societies/organizations in the form of published consensus statements is variable. The European Respiratory Society (ERS) and the American Thoracic Society (ATS) guideline on the definition, evaluation and treatment of severe asthma is based on systematic review of the literature and their recommendation states “bronchial thermoplasty performed in adults with severe asthma should only be in the context of an Institutional Review Board approved independent systemic registry of a clinical study.” There is insufficient and low quality evidence regarding the use of bronchial theramoplasty in patients with severe asthma who are resistant to standard therapies. Additional well-designed studies are needed to identify long term safety and efficacy of bronchial thermoplasty for the treatment of severe asthma. The evidence is insufficient to determine the effects of bronchial thermoplasty on net health outcomes.
In a 2015 statement on bronchial thermoplasty the ACAAI notes: “Bronchial thermoplasty is a well-studied treatment for patients with very severe asthma who continue to be symptomatic despite maximal medical treatment including steroids, long-acting beta agonists (LABAs), long-acting muscarinic agents (LAMAs), leukotriene antagonists and biologics. The device to deliver this therapy is FDA approved. The scientific literature supports bronchial thermoplasty as a therapeutic consideration for some carefully chosen patients with severe asthma. Carefully selected patients with severe persistent asthma who have persistent burden of disease, asthma exacerbations, emergency department visits or hospitalizations despite maximal medical treatment may benefit from this procedure. Therefore, ACAAI recommends that insurers provide coverage for bronchial thermoplasty for those adult patients who meet the stringent requirements.”
In 2012 NICE published a guideline IPG419 bronchial thermoplasty for severe asthma. The guideline notes that evidence on the efficacy of bronchial thermoplasty for severe asthma shows improvement in symptoms and quality of life, and reduced exacerbations and admission to hospital. Evidence on safety is adequate in the short and medium term. More evidence is required on the safety of the procedure in the long term. Therefore, ths procedure should only be used with special arrangements for clinical governance, consent and audit for research. NICE encourages further research into bronchial thermoplasty for severe asthma. Research outcomes should include objective measurements of lung function, symptom control, medication requirements and quality of life. Long-term safety and efficacy outcomes are particularly important.
In 2015 NICE published Individual Research Recommendation Details regarding IPG419 that notes: NICE encourages further research into bronchial thermoplasty for severe asthma. Research outcomes should include objective measurements of lung function, symptom control, medication requirements and quality of life. Long-term safety and efficacy outcomes are particularly important.
Evidence on the efficacy of bronchial thermoplasty for severe asthma shows improvement in symptoms and quality of life, and reduced exacerbations and admission to hospital. Evidence on safety is adequate in the short and medium term. More evidence is required on the safety of the procedure in the long term. Therefore, ths procedure should only be used with special arrangements for clinical governance, consent and audit for research.
GINA is an international network of organizations and professionals with expertise in asthma. The group has been updating a report entitled Global Strategy for Asthma Management and Prevention annually since 2002, the most recent update was issued in 2017. GINA recommends stepped care for the treatment of asthma. Step 1 consists of reliever inhaler use on an as needed basis. Step 2 involves low dose controller medication plus as needed reliever medication. Step 3 includes one or two controllers plus as needed reliever medication. Step 4 is two or more controllers plus as needed reliever medication. Step 5 involves higher level of care and/or add-on treatment.
According to the GINA document, options for add-on treatment include bronchial thermoplasty for some adults with severe asthma (Evidence B). The document also notes the following:
In May 2014, ACCP posted a position statement on Coverage and Payment for Bronchial Thermoplasty for Severe Persistent Asthma. The document states in part,
“CHEST believes that based on the strength of the clinical evidence, bronchial thermoplasty offers an important treatment option for adult patients with severe asthma who continue to be symptomatic despite maximal medical treatment and, therefore should not be considered experimental. Randomized controlled trials of bronchial thermoplasty for severe asthma have shown a reduction in the rate of severe exacerbations, emergency department visits, and days lost from school or work. Additionally, data published in December 2013 demonstrates the persistence of reduction in asthma symptoms achieved by bronchial thermoplasty for at least 5 years…”
In 2014, a joint task force of the European Respiratory Society and American Thoracic Society published guidelines on the definition, evaluation and treatment of severe asthma. The guideline was based on a systematic review of the literature. It includes the statements:
In 2016, the British Thoracic Society and the Scottish Intercollegiate Guidelines Network published a revised national guideline on management of asthma. The guideline states:
In April 2010, the Alair® Bronchial Thermoplasty System (Asthmatx, Inc. Sunnyvale, CA, now part of Boston Scientific Corp.) was approved by the U.S. Food and Drug Administration (FDA) through the premarket approval (PMA) process for the use in adults with severe and persistent asthma whose symptoms are not adequately controlled with inhaled corticosteroids and long acting beta agonists. The labeling also lists the following contraindications:
Patients with the following conditions should not be treated:
Patients should not be treated while the following conditions are present:
Bronchial thermoplasty is considered investigational for the treatment of asthma and other indications.
For individuals who have asthma refractory to standard treatment who receive bronchial thermoplasty, the evidence includes 3 randomized controlled trials (RCTs) and systematic reviews of these RCTs. Conclusions cannot be drawn about the effect of bronchial thermoplasty on the net health outcome due to the limited amount of sham controlled data (1 RTC) on short term efficacy, and also the uncertain degree of treatment benefit in that single sham-controlled trial, the lack of long-term sham-controlled data in the face of high initial placebo response and the presence of substantial adverse events. In addition, there is a lack of data on patient selection factors for this procedure and, as a result, it is not possible to determine whether there are patient subgroups that might benefit. Support by professional societies/organizations in the form of published consensus statements is variable. The European Respiratory Society (ERS) and the American Thoracic Society (ATS) guideline on the definition, evaluation and treatment of severe asthma is based on systematic review of the literature and their recommendation states “bronchial thermoplasty performed in adults with severe asthma should only be in the context of an Institutional Review Board approved independent systemic registry of a clinical study.” There is insufficient and low quality evidence regarding the use of bronchial theramoplasty in patients with severe asthma who are resistant to standard therapies. Additional well-designed studies are needed to identify long term safety and efficacy of bronchial thermoplasty for the treatment of severe asthma. The evidence is insufficient to determine the effects bronchial thermoplasty on net health outcomes.
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