Background

Asthma

Asthma, a chronic lung disease, affects approximately 7.7% of adults and 7.5% of children in the U. S. and, in 2018, accounted for approximately 1.6 million emergency department visits and 3564 deaths.^1, Asthma symptoms include episodic shortness of breath that is generally associated with other symptoms such as wheezing, coughing, and chest tightness. Objective clinical features include bronchial hyperresponsiveness, airway inflammation, and reversible airflow obstruction (at least 12% improvement in forced expiratory volume in 1-second post-bronchodilator, with a minimum of 200 mL improvement). However, 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.

Management

Management of asthma consists of environmental control, patient education, management of comorbidities, and regular follow-up for affected patients, as well as a stepped approach to medication treatment. Guidelines from the National Heart, Lung and Blood Institute have defined 6 pharmacologic steps: step 1 for intermittent asthma and steps 2 through 6 for persistent asthma.^2,The preferred daily medications: step 1: short-acting b-agonists as-needed; step 2: low-dose inhaled corticosteroids (ICS); step 3: ICS and long-acting b-agonists (LABA) or medium-dose ICS; step 4: medium-dose ICS and LABA; step 5: high-dose ICS and LABA; and step 6: high-dose ICS and LABA, and oral corticosteroids.

Despite this multidimensional approach, many patients continue to experience considerable morbidity. In addition to ongoing efforts to implement optimally standard approaches to asthma treatment, new therapies are being developed. One recently developed therapy is bronchial thermoplasty, the controlled delivery of radiofrequency energy to heat tissues in the distal airways. 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. A typical full course of treatment consists of 3, one hour sessions, given 3 weeks apart under moderate sedation. All accessible airways distal to the main stem bronchus that are 3 to 10 mm in diameter are treated once, except those in the right middle lobe; the lower lobes are treated first followed by the upper lung. Bronchial thermoplasty is intended as a supplemental treatment for patients with severe persistent asthma (ie, steps 5 and 6 in the stepwise approach to care).

Regulatory Status

In April 2010, the Alair® Bronchial Thermoplasty System (Asthmatx, now Boston Scientific) was approved by the U.S. Food and Drug Administration (FDA) through the premarket approval process (P080032) for use in adults with severe and persistent asthma whose symptoms are not adequately controlled with low-dose ICS and LABA. Use of the treatment is contraindicated in patients with implantable devices and those with sensitivities to lidocaine, atropine, or benzodiazepines. It should also not be used while patients are experiencing an asthma exacerbation, active respiratory infection, bleeding disorder, or within 2 weeks of making changes in their corticosteroid regimen. The same area of the lung should not be treated more than once with bronchial thermoplasty. FDA product code: OOY.

Related Policies

• None

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Bronchial Thermoplasty for the Treatment of Asthma
Clinical Context and Test Purpose

The purpose of bronchial thermoplasty in patients who have asthma refractory to standard treatment is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does bronchial thermoplasty improve health outcomes in patients with treatment-refractory asthma?

The following PICO was used to select literature to inform this review.

Patients

The relevant population of interest is individuals with persistent and severe asthma whose symptoms are not adequately controlled with low-dose inhaled corticosteroids and long-acting b-agonists (LABAs). Asthma symptoms can vary between individuals but may include bronchial hyperresponsiveness, airway inflammation, and reversible airflow obstruction.

Interventions

The therapy being considered is bronchial thermoplasty as an add-on treatment in patients whose asthma is not adequately controlled with medical management.

Bronchial thermoplasty procedures are performed on an outpatient basis, and each session lasts approximately 1 hour. During the procedure, a standard flexible bronchoscope is placed through the patient's mouth or nose into the most 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 and used to heat tissue to 65°C 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. A course of treatment consists of 3 separate procedures in different regions of the lung scheduled about 3 weeks apart.

Comparators

Currently, clinical response to continued medical management is being used to make decisions about the use of bronchial thermoplasty for treatment-refractory asthma. Continued medical management of asthma consists of environmental control, patient education, management of comorbidities, and regular follow-up for affected patients, as well as a stepped approach to medication treatment.

Outcomes

Beneficial outcomes are symptom relief, improvement in QOL, reductions in medication adverse events and hospitalizations, and treatment-related morbidity. Instruments such as the Asthma Quality of Life Questionnaire (AQLQ) score and the Asthma Control Questionnaire (ACQ) may be used to assess improvements in asthma symptoms. A clinically significant change in the AQLQ is considered to be 0.05 from baseline.^4,

Potential harms include periprocedural risk and risk for exacerbation of asthma during the treatment phase.

Short-term results are evaluated from weeks posttreatment to 12 months. Long-term follow-up studies have evaluated patients receiving bronchial thermoplasty up to 5 years posttreatment.

Study Selection Criteria

We selected methodologically credible studies, following these principles.

• To assess efficacy outcomes, we sought comparative controlled prospective trials, with preference for randomized controlled trials.
• To assess longer term outcomes and adverse effects, we sought single-arm studies that capture longer periods of follow up and/or larger populations.
• Within each category of study design, we preferred larger sample size studies and longer duration studies.
• We excluded studies with duplicative or overlapping populations.

Review of Evidence
Randomized Controlled Trials

There are 3 industry-sponsored RCTs that have evaluated the efficacy and safety of bronchial thermoplasty. The study characteristics and results are summarized in Tables 1 and 2.

Research in Severe Asthma Trial

Pavord et al (2007) published the initial results of the Research in Severe Asthma (RISA) trial.^5, Participants met multiple criteria for severe uncontrolled asthma. After a 2 week run-in period, participants were randomized to a control group that received continued medical management alone or to medical management plus treatment with the Alair Bronchial Thermoplasty System.

The primary objective of RISA was to determine the safety of bronchial thermoplasty. The rates of the procedure and postprocedure respiratory adverse events as well as more serious adverse events (defined as any event that was fatal, required prolonged hospitalization, caused substantial immediate risk of death, resulted in permanent impairment, or required intervention to prevent permanent impairment). No overall statistical analysis was done that compared serious adverse events in the 2 groups.

Secondary objectives included an evaluation of the effect of bronchial thermoplasty on asthma symptoms and daily medication requirements as an indication of efficacy. At 52 weeks, bronchial thermoplasty patients had a significantly greater improvement in b-agonist use than control patients (decrease of 26 puffs per week vs6 puffs per week, respectively, p<0.05). There were no significant differences between groups in other efficacy variables including morning and evening peak expiratory flow, symptom scores, number of symptom-free days, percent predicted improvement in forced expiratory volume in 1-second (FEV₁) and QOL measures. The small sample size limited the power to detect differences in the efficacy outcomes.

Pavord et al (2013) published 5-year safety data on 14 (82%) of the 17 patients randomized to bronchial thermoplasty in the RISA trial.^6, All 14 patients completed the 3-year evaluation, and 12 patients completed evaluations at 4 and 5 years. As previously described, safety outcomes were the primary outcomes of RISA. In year 1, each asthma symptom was considered an adverse event and, in subsequent years, multiple asthma symptoms were considered to be a single adverse event. Among those with follow-up data available, the number of patients with asthma adverse events in years 2, 3, 4, and 5 were 5 (36%), 7 (50%), 2 (17%), and 5 (42%), respectively. Also, during years 2 to 5, there were 11 respiratory-related hospitalizations in 5 patients. The number of patients with data available was too small to draw reliable conclusions about long-term safety, and there were no long-term data available on patients in the control group.

Asthma Intervention Research Trial

Cox et al (2007) published findings of the Asthma Intervention Research (AIR) trial, which was designed to evaluate symptom control and adverse events following bronchial thermoplasty in patients with moderate-to-severe persistent asthma.^7, Participants were randomized to medical management with inhaled corticosteroids and LABA or to the same medical management strategy plus bronchial thermoplasty. At the end of the follow-up visits at 3, 6, and 12 months, there was a 2-week period of abstinence from LABA, during which data on exacerbations were collected. Between data collection periods, patients could use all maintenance therapies.

The primary outcome was the difference between groups in the rate of mild exacerbations from the baseline 2 week abstinence period. An exacerbation was defined as the occurrence on 2 consecutive days of a reduction in the morning peak expiratory flow of at least 20% below the average value (recorded during the week before the abstinence period), the need for more than 3 additional puffs of rescue medication compared with the week before the abstinence period, or nocturnal awakening caused by asthma symptoms. The trial was powered to detect a difference between groups of 8 mild exacerbations per person per year. Data were available at 3 months for 100 (89%) of 112 patients and at 12 months for 101 (90%) patients; all patients were included in the safety analysis.

The rate of adverse events was higher in the bronchial thermoplasty group during the active treatment period, but the proportion of adverse events was similar in the 2 groups in the posttreatment period. Posttreatment, 3 patients in the bronchial thermoplasty group required hospitalization and 2 patients in the control group required a total of 3 hospitalizations. A trial limitation is the lack of a sham intervention and, consequently, an inability to blind patients to the treatment group.

Thomson et al (2011) published 5-year data from the AIR trial.^8, All trial participants who completed the 1-year follow-up visit were invited to participate in the extension study; 45 (87%) of 52 in the bronchial thermoplasty group and 24 (49%) of 49 in the control group opted to participate. Follow-up was done on an annual basis. Patients in the control group were followed for 2 additional years, and patients in the bronchial thermoplasty group were followed for 5 years. Twenty-one (88%) of 24 patients in the control group and 42 (93%) of 45 in the bronchial thermoplasty group completed the final follow-up. No instances of pneumothorax, intubation, mechanical ventilation, cardiac arrhythmias, or death were reported during the extension study. In the first year (year 2 of the study), the rate of hospitalizations was 3 (7%) of 45 in the bronchial thermoplasty group and 0 in the control group (p=0.55). In year 3, the rate of hospitalizations in the bronchial thermoplasty group was again 3 (7%) of 45, and 1 (5%) of 21 patients in the control group (p=1.00). Rates of emergency department visits in year 2 were 3 (7%) and 3 (12.5%) in the bronchial thermoplasty and control groups, respectively (p=0.41); in year 3, rates were 3 (5%) and 3 (5%), respectively (p=1.00). There was 1 hospitalization each of years 4 and 5 in the bronchial thermoplasty group.

In the extension study of the AIR trial, unlike the initial follow-up period, respiratory adverse events with multiple symptoms were recorded as a single adverse event. This could give a misleading impression of the total number of adverse events or relative number in the 2 groups. The incidence of respiratory adverse events during year 2 was 24 (53%) of 45 in the bronchial thermoplasty group and 13 (54%) of 24 in the control group. During year 3, the incidence was 24 (56%) of 43 in the bronchial thermoplasty group and 12 (57%) of 21 in the control group; differences between groups were not statistically significant in year 2 or 3. The incidence of respiratory adverse events in the bronchial thermoplasty group was similar in subsequent years; rates were 23 (53%) of 43 in year 4 and 22 (52%) of 42 in year 5.

The Thomson et al (2011) study also reported on 2 measures of lung function: post-bronchodilator FEV₁ and forced vital capacity. Exact numbers were not reported, but post-bronchodilator FEV₁ did not go below 80% of predicted in either group during years 2 to 5. The group comparisons of safety and efficacy in this follow-up trial were limited by the differential rate of follow-up between the 2 groups, with a lower percentage of patients in the control group agreeing to participate in the follow-up study.

Asthma Intervention Research 2 Trial

The Asthma Intervention Research 2 (AIR2) Trial was an RCT evaluating the efficacy of bronchial thermoplasty at 30 sites in 6 countries (including the U.S.); findings were published by Castro et al (2010). 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 inhaled corticosteroids 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 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 endpoint; there the target was 96.4% to adjust for 2 interim looks at the data. The prior for the analysis was not reported in the article.

Participants and outcome assessments were 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 population. One hundred eighty-five participants in the treatment group and 97 in the sham control group underwent the second bronchoscopy, and the same number of patients had the third bronchoscopy (it is not clear whether they were the same patients).

The superiority of bronchial thermoplasty was not achieved in the intention-to-treat population for the primary effectiveness outcome, mean change in the integrated AQLQ score. Mean standard deviation (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, the superiority of bronchial thermoplasty on a related outcome was achieved. In the intention-to-treat 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 nonresponders (mean, 4.1 vs 5.1, respectively).

Several secondary outcomes favored bronchial thermoplasty over the sham control group. They included 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, the 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 response rate (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. Castro et al (2011) reported on 2-year data on 166 (87%) of 190 patients randomized to the bronchial thermoplasty group.^9, 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. Wechsler et al (2013) reported on 5-year data for 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 adverse asthma events (at least ³2 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, the rate of exacerbations, the rate of hospitalizations) cannot be compared in patients who did and did not receive bronchial thermoplasty.

Table 1. Summary of Key RCT Characteristics

Study; Trial	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Pavord et al (2007)5,;RISA	U.K., Brazil, Canada	8	2004-2006	≥18 y with uncontrolled asthma refractory to high-dose ICSa and LABAb FEV1≥50% predicted Airway hyperresponsivenessc Abstinence from smoking for 1 y Smoking history ≤0 pack-years	17 medical management and BT Weeks 0-6: 3 treatments at least 3 wk apart Weeks 6-22: steroid stable Weeks 22-36: protocol defined steroid wean Weeks 36-52: investigator-led steroid reduction	17 medical management alone ICS dose tapered in 3 stages by 20%-25% of baseline dose every 4 wk to minimal dose of fluticasone propionate 100-600 mg/d or equivalent
Cox et al (2007)7,;AIR	U.K., Brazil, Canada, Denmark	11	2002-2005	18-65 y with moderate-to-severe persistent asthma requiring daily ICSd and LABAb FEV1 60%-80% of predicted Airway hyperresponsiveness Stable asthma 6 wk prior to enrollment No current or recent respiratory infectione	56 medical management and BT (3 treatments at least 3 wk apart) Follow-up at 3, 6, and 12 mo,f then 2-wk LABA abstinence	56 medical management alone Follow-up at 3, 6, and 12 mo,f then 2-wk LABA abstinence
Castro et al (2010)11,;AIR2	U.S., EU, Canada, Australia	30	2000-2015	≥2 d asthma symptoms during 4-wk baseline required high initial dosage of ICSg Baseline AQLQ score ≤6.25	196 received BT (3 treatments at least 3 wk apart)	101 received sham procedure

AIR: Asthma Intervention Research Trial, AQLQ: Asthma Quality of Life Questionnaire; BT: bronchial thermoplasty, FEV1: forced expiratory volume at 1 minute, ICS: inhaled corticosteroids, LABA: long-acting b-agonist, RCT: randomized controlled trial, RISA: Research in Severe Asthma.

a Treatment of fluticasone propionate ≥750 μg/d or equivalent.
b Treatment of salmeterol ≥100 μg/d or equivalent.
c Demonstrated by challenge with methacholine or reversible bronchoconstriction during prior 12 mo.
e No more than 2 respiratory infections requiring treatment in past year and required to undergo a 2-wk baseline test period without LABAs; eligibility depended on worsening asthma control during that time.
^f Between data collection periods, patients could use all maintenance therapies
^g Treatment of beclomethasone ≥1000 μg or equivalent.

Study	Respiratory AE(No. of Events)	Serious AE  (Hospitalization)b	Reduction in SABA (puffs per 7 days)c	% Reduction in OCS Dosed	% Reduction in ICS Dosed
Pavord et al (2007)5,;RISA
BT (n=15)a	136	7	-26.6 (40.1)	63.6 (45.4)	28.6 (30.4)
MM (n=17)	57	0	-1.5 (11.7)	26.2 (40.7)	20 (32.9)
Effect (95% CI); p			NR (NR); <0.05`	NR (NR); 0.12	NR (NR); 0.059
	Change in Rate of Exacerbationse
Cox et al (2007)7,;AIR
BT (n=52)f
Baseline	0.35 (0.32)
12 months	0.18 (0.31)
MM (n=49)f
Baseline	0.28 (0.31)
12 months	0.31 (0.41)
Effect (95% CI); p	NR (NR); 0.03
	Change in AQLQh
Castro et al (2010)11,;AIR2
BT (n=190)g
Baseline	4.30 (1.17)
12 months	5.66 (1.06)
Mean change	1.35 (1.10)
BT sham (n=98)g
Baseline	4.31 (1.21)
12 months	5.48 (1.15)
Mean change	1.16 (1.23)

^a There were 2 withdrawals from BT group prior to first treatment.
^b There were no deaths or serious AEs other than hospitalization related to respiratory events in either group.
^c Results at 22 wks.
^d Results at 52 wks.
^e Change from baseline in mean number of mild exacerbations per subject per week at 12 mo.
^f Analyses based on participants available for evaluation at 12 mo.
^g Intention-to-treat analyses based on participants who underwent at least 1 bronchoscopy procedure in either arm.
^h Change from baseline in integrated AQLQ score at 12 months with higher score (0-7) indicating better quality of life. A score change of ≥0.5 defines minimal important difference.

Chupp et al (2017) compared 3-year follow-up results from 190 patients in the AIR2 trial with a subgroup (n=190) from a prospective nonrandomized clinical study (Post-U.S. Food and Drug Administration Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma [PAS2]).^12, PAS2 is an ongoing open-label trial of the Alair system required for post premarket approval. Of those enrolled, 168 patients from PAS2 reached 3 years of follow-up and were compared with 165 patients from AIR2 who also had 3 years of follow-up. The primary outcome was comparing the incidence of severe exacerbation in each trial. In the 12 months before treatment, 74.2% of patients from PAS2 experienced severe exacerbations, which decreased significantly during the third year of follow-up to 39.9% (p<0.001). A similar reduction was observed in AIR2 patients, with the incidence of severe exacerbations decreasing 36.8%. Similar decreases in emergency department visits occurred in both groups when year 3 was compared with the 12 months before treatment (PAS2, 55% reduction; AIR2, 72.3% reduction; p<0.001); the incidence of hospitalization also decreased for both groups. In the first and second years after treatment, the incidence of hospitalization in PAS2 decreased to 14.4% and 12.7%, respectively; the incidence of emergency department visits decreased to 18.3% in the first year and 13.5% in the second year after treatment. Overall, patients from PAS2 showed improved results comparable to those observed in AIR2; however, there were a number of differences between the trials that limited conclusions. At baseline, patients enrolled in AIR2 had better asthma control than those in PAS2; PAS2 was restricted to North America, and different definitions of severe exacerbations were used in each trial.

A TEC Assessment (2014) assessed bronchial thermoplasty as a treatment for inadequately controlled severe asthma.^3, The Assessment included the 3 published RCTs discussed 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.

Registries

Reports from the U.K. Severe Asthma Registry (UKSAR) are described in Tables 3 and 4. All UK centers performing bronchial thermoplasty provide data to the registry.

Burn et al (2017) reported on safety outcomes of bronchial thermoplasty outcomes in the U.K.^13, The analysis combined data from 2 sources, UKSAR and the Hospital Episode Statistics warehouse. For 59 patients, data in the 2 databases could be matched and 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 (ie, emergency department) for any reason were reported for 13 (8.6%) patients. For the fourth outcome (postprocedure 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 have been related to older patients with more severe disease being treated in clinical practice compared with patients included in clinical trials.

Efficacy and Safety data from the UKSAR registry were subsequently reported by Burn et al (2019).^4, Efficacy data were available for 86 patients with at least 1 follow-up visit. Safety data were available for 131 patients, including the 59 in the previous report. Follow-up data up to 60 mo were recorded with counts of adverse events annualized to compare rates before and after bronchial thermoplasty. Comparison of the first year post-treatment with pre-procedure baseline showed a statistically and clinically significant improvement in the AQLQ of 0.75 (P<.001) and EuroQoL-5D, but there was no significant improvement in other outcome measures when adjusted for multiple comparisons. There were trends for a decrease in unscheduled healthcare visits (-0.93, P=.050) and in hospital admissions in the year after bronchial thermoplasty (-2.0, P=.056). There was no significant change in mean forced expiratory volume (FEV₁) at 12 or 24 mos. Because of the strong placebo effects noted in the controlled trials, interpretation of subjective quality of life measures is limited.

Table 3. Summary of Registry Study Characteristics

Study	Study Type	Registry	Dates	Participants	Treatment	Treatment2	Follow-Up
Burn et al (2017) 13,	Registry	UKSAR and Hospital Episode Statistics warehouse	2011-2015	59 patients who received bronchial thermoplasty and had data in both UKSAR and the Hospital Episode Statistics database	3 bronchial thermoplasty sessions		30 days
Burn et al (2019)4,	Registry	UKSAR	2011-2016	133 patients who received bronchial thermoplasty and consented to be in the UKSAR Registry	At least 1 bronchial thermoplasty session		6 mo to 5 yr

UKSAR: U.K. Severe Asthma Registry

Table 4. Summary of Registry Study Results

Study	AQLQ	ACQ	EQ-5D	Rescue Steroid (P)	Procedural Complications	Overnight Stay	Unscheduled or Emergency Department Visits	Hospital admissions
Burn et al (2017)13,					17 (11%) of procedures	70 (46.1%) of procedures	13 (8.6%) of patients	15 (11%) of patients
Burn et al (20194,
Change from baseline (P)	0.75 (<.001)	-0.43 (p=.083)	.008 (.909)	-0.26 (.307)			-0.93 (.050)	-2.0 (.056)

AQLQ: Asthma Quality of Life Questionnaire; ACQ: Asthma Control Questionnaire; EQ-5D: EuroQol-5D

Summary of Evidence

For individuals who have asthma refractory to standard treatment who receive bronchial thermoplasty added to medical management, the evidence includes 3 RCTs and observational studies. Relevant outcomes are symptoms, QOL, hospitalizations, and treatment-related morbidity. Early studies (RISA, AIR) investigated safety outcomes, finding similar rates of adverse events and exacerbations between the bronchial thermoplasty and control groups. These trials were limited by their lack of sham control. The AIR2 trial is the largest of the 3 published RCTs, and the only 1 double-blinded and sham-controlled, with sites in the U. S. Over 1 year, bronchial thermoplasty was not found to be superior to sham treatment on the investigator-designated primary efficacy outcome of mean change in the QOL score but was found to be superior on a related outcome, improvement in the QOL of at least 0.5 points on the AQLQ. There was a high response rate in the sham group of the AIR2 trial, suggesting a large placebo effect, particularly for subjective outcomes such as QOL. 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 posttreatment period. Safety data up to 5 years have been reported in the RCTs for patients treated with bronchial thermoplasty but not for control patients. Data from a U.K. registry showed that 20% of bronchial thermoplasty procedures were associated with a safety event (ie, procedural complications, emergency respiratory readmissions, emergency department visits, and/or postprocedure overnight stays), with uncertain benefit. 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 RCT) on short-term efficacy, the uncertain degree of treatment benefit in that single sham-controlled trial, the lack of long-term sham-controlled data in the face of a high initial placebo response, and the presence of substantial adverse events. Also, 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. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION
Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 1 physician specialty society and 4 academic medical centers while this policy was under review in 2014. Input was mixed on whether bronchial thermoplasty is considered investigational for the treatment of asthma; 3 reviewers agreed with this statement and 2 reviewers disagreed. Reviewers who disagreed tended to use bronchial thermoplasty in patients who had not responded to other treatments and who did not think there were treatment alternatives.

Practice Guidelines and Position Statements
Global Initiative for Asthma

Global Initiative for Asthma 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 2019.^14, The organization has recommended stepped care for treatment of asthma. Options for add-on treatment in step 5 include bronchial thermoplasty for some adults with severe asthma, anti-immunoglobulin E, sputum-guided treatment, add-on low-dose oral corticosteroids, and tiotropium. The document noted that evidence on bronchial thermoplasty is limited and long-term treatment effects are unknown (level of evidence B).

American College of Chest Physicians

In May 2014, the American College of Chest Physicians posted a position statement on coverage and payment for bronchial thermoplasty.^15,The document stated in part:

"…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 clinical 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 the reduction in asthma symptoms achieved by bronchial thermoplasty for at least 5 years…."

National Institute for Health and Care Excellence

The National Institute for Health and Care Excellence (2018) published guidance on bronchial thermoplasty for severe asthma.^16, The guidance stated: "Current evidence on the safety and efficacy on bronchial thermoplasty for severe asthma is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit." It was also noted that "further research should report details of patient selection and long-term safety and efficacy outcomes."

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 3.

Table 3. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT03765307a	Safety and Efficacy of the SyMap Bronchial Ablation System for Treatment of Severe Asthma: A Prospective, Multicenter, Randomized Controlled Clinical Trial (Bronchial Ablation for Treatment of Asthma (BATA) Trial)	160	Feb 2021
NCT01185275	A Prospective Observational Study of Biopredictors of Bronchial Thermoplasty Response in Patients With Severe Refractory Asthma (BTR Study)	133	Dec 2021
NCT02464995	Bronchial Thermoplasty in Severe Asthma With Frequent Exacerbations (THERMASCORT)	34	Nov 2022
NCT03435237	Phenotyping Asthma for Bronchial Thermoplasty: Airway Smooth Muscle Structure and Function	50	Dec 2022
NCT02975284	TASMA Extension Study: Long Term Efficacy and Safety of Bronchial Thermoplasty in Severe Asthma	40	Sep 2024
NCT04077528	Research on Severe Asthma	2000	Jun 2025
Unpublished
NCT02104856a	Bronchial Thermoplasty Global Registry (BT Registry)	158	Jun 2019

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Bronchial Thermoplasty
Thermoplasty, Bronchial
Alair Bronchial Thermoplasty System
Bronchial Thermoplasty System

References:
1. Centers for Disease Control & Prevention, National Center for Health Statistics. Asthma. 2018; https://www.cdc.gov/nchs/fastats/asthma.htm. Accessed May 28, 2020.

2. National Heart Lung and Blood Institute. Guidelines for the Diagnosis and Management of Asthma (EPR-3). 2012; https://www.nhlbi.nih.gov/health-topics/guidelines-for-diagnosis-management-of-asthma. Accessed May 28, 2020.

3. Grant MD. Bronchial thermoplasty for treatment of inadequately controlled severe asthma. Technol Eval Cent Assess Program Exec Summ. Mar 2015; 29(12): 1-5. PMID 25962190

4. Burn J, Sims AJ, Patrick H, et al. Efficacy and safety of bronchial thermoplasty in clinical practice: a prospective, longitudinal, cohort study using evidence from the UK Severe Asthma Registry. BMJ Open. Jun 19 2019; 9(6): e026742. PMID 31221880

5. Pavord ID, Cox G, Thomson NC, et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med. Dec 15 2007; 176(12): 1185-91. PMID 17901415

6. Pavord ID, Thomson NC, Niven RM, et al. Safety of bronchial thermoplasty in patients with severe refractory asthma. Ann Allergy Asthma Immunol. Nov 2013; 111(5): 402-7. PMID 24125149

7. Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med. Mar 29 2007; 356(13): 1327-37. PMID 17392302

8. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med. Feb 11 2011; 11: 8. PMID 21314924

9. Castro M, Rubin A, Laviolette M, et al. Persistence of effectiveness of bronchial thermoplasty in patients with severe asthma. Ann Allergy Asthma Immunol. Jul 2011; 107(1): 65-70. PMID 21704887

10. Wechsler ME, Laviolette M, Rubin AS, et al. Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol. Dec 2013; 132(6): 1295-302. PMID 23998657

11. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med. Jan 15 2010; 181(2): 116-24. PMID 19815809

12. Chupp G, Laviolette M, Cohn L, et al. Long-term outcomes of bronchial thermoplasty in subjects with severe asthma: a comparison of 3-year follow-up results from two prospective multicentre studies. Eur Respir J. Aug 2017; 50(2). PMID 28860266

13. Burn J, Sims AJ, Keltie K, et al. Procedural and short-term safety of bronchial thermoplasty in clinical practice: evidence from a national registry and Hospital Episode Statistics. J Asthma. Oct 2017; 54(8): 872-879. PMID 27905828

14. Global Initiative for Asthma. Asthma Management and Prevention for Adults and Children Older than 5 Years. https://ginasthma.org/wp-content/uploads/2019/04/GINA-2019-main-Pocket-Guide-wms.pdf. Accessed May 28, 2020

15. American College of Chest Physicians (ACCP). Position Statement for Coverage and Payment for Bronchial Thermoplasty. 2014; http://www.chestnet.org/News/CHEST-News/2014/05/Position-Statement-for-Coverage- and-Payment-for-Bronchial-Thermoplasty. Accessed May 28, 2020.

16. National Institute for Health and Care Excellence. Bronchial thermoplasty for severe asthma. Interventional procedures guidance [IPG635]. 2018 https://www.nice.org.uk/guidance/ipg635. Accessed May 28, 2020.

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