Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2010032
Category:	Surgery
Initiated:	June 2010
Last Review:	December 2023

Bronchial Thermoplasty

Description:

Thermoplasty is a potential treatment option for patients with severe persistent asthma. It consists of radiofrequency energy delivered to the distal airways with the aim of decreasing smooth muscle mass believed to be associated with airway inflammation.

Background

Asthma, a chronic lung disease, affects approximately 8.4% of adults and 5.8% of children in the United States (CDC, 2022). As of 2018, 14.3% of Black children under 18 in the U.S. had asthma, followed by 8% of Hispanic children, 5.6% of White children, and 3.6% of Asian children (NCHS, 2019). In the U.S., the burden of asthma falls disproportionately on Black, Hispanic, and American Indian/Alaska Native individuals; these groups have the highest rates, deaths, and hospitalizations (AAFA, 2020). Compared to White Americans, Black Americans are 1.5 times more likely to have asthma, and Puerto Rican Americans are almost 2 times more likely to have asthma. In 2018 and 2020, asthma exacerbations accounted for approximately 1.6 million emergency department visits and 4145 deaths overall, respectively (CDC, 2022).,Black Americans are 5 times more likely than White Americans to visit the emergency department for asthma and 3 times more likely to die from asthma (AAFA, 2020). 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 [FEV-1] post-bronchodilator, with a minimum of 200 mL improvement). However, there is substantial heterogeneity in the inflammatory features of patients who are diagnosed with asthma and this biological diversity is responsible, at least in part, for the variable response to treatment in the asthma population.

Management of asthma consists of environmental control, patient education, management of comorbidities and regular follow-up for all affected individuals, as well as a stepped approach to medication treatment. Guidelines from the National Heart, Lung and Blood Institute (NHLBI) define 6 pharmacologic steps: step 1 for intermittent asthma, and steps 2-6 for persistent asthma (NHLBI, 2012). The preferred daily medications: step 1: short-acting beta-agonists as needed; step 2: low-dose inhaled corticosteroids (ICS); step 3: ICS and long-acting beta-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. A focused update in 2020 addressed the use of add-on long-acting antimuscarinic agents (LAMA), immunotherapy, and bronchial thermoplasty (GINA, 2021).

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, 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 (i.e., 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 FDA through the premarket approval (PMA) process for use in adults with severe and persistent asthma whose symptoms are not adequately controlled with inhaled corticosteroids and long-acting beta agonists. 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.

Coding

There are specific category I CPT codes for this procedure:

31660 Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with bronchial thermoplasty, 1 lobe

31661 with bronchial thermoplasty, 2 or more lobes

Between 2012 and 2013, there were specific category III CPT codes for this procedure:

0276T Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with bronchial thermoplasty, 1 lobe

0277T with bronchial thermoplasty, 2 or more lobes

Prior to 2012, there was no specific CPT code for this procedure. The company recommended that the unlisted code

31899 (unlisted procedure, trachea, bronchi) be used at that time.

Policy/
Coverage:

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Bronchial thermoplasty for the treatment of asthma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

For members with contracts without primary coverage criteria, bronchial thermoplasty for the treatment of asthma is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

The policy was created with a literature review using MEDLINE through April 2010. In addition to small case series, three randomized controlled trials (RCTs) evaluating the safety and efficacy of bronchial thermoplasty have been published. All of the RCTs were supported by Asthmatx, the manufacturer of the Alair system.

Research in Severe Asthma (RISA) trial: This study, published by Pavod and colleagues in 2007, was conducted at 8 centers in the U.K., Brazil and Canada (Pavord, 2007). Eligibility criteria included age 18 or older; asthma diagnosis; uncontrolled symptoms despite treatment with high-dose inhaled corticosteroids (at least 750 ug fluticasone propionate per day or equivalent) and long-acting beta agonists (at least 100 ug salmeterol per day or equivalent), with or without other medications including oral prednisone or leukotriene modifiers; FEV-1 at least 50% of predicted; demonstrated airway hyperresponsiveness by challenge with methacholine or reversible bronchoconstriction during the prior 12 months; abstinence from smoking for at least 1 year and a past smoking history of less than 10 pack-years. After a 2-week run-in period, participants were randomized to a control group (n=17) that received continued medical management alone or medical management plus treatment with the Alair Bronchial Thermoplasty System (n=17). The bronchial thermoplasty group received 3 procedures at least 3 weeks apart (weeks 0-6). During weeks 6-22, all participants remained on a stable dose of steroids and then during weeks 22-36, in attempt was made to reduce the dose of oral corciosteroids (or inhaled corticosteroids for patients not taking the oral medication). Between weeks 36 to 52, patients took the reduced dose of steroids. The primary outcomes of the study were the rate of adverse events and serious adverse events (defined as any event that was fatal, required or prolonged hospitalization, caused substantial immediate risk of death, resulted in permanent impairment or required intervention to prevent permanent impairment). A total of 32 of the 34 participants (94%) completed the study. In the initial treatment period, 4 patients in the bronchial thermoplasty group experienced 7 serious adverse events requiring hospitalization and none occurred in the control group. During the remainder of the study, 3 patients in the bronchial thermoplasty group experienced 5 serious adverse events and 1 patient in the control group experienced 4 serious adverse events; all of these events required hospitalization. There were an additional 5 severe adverse events in 2 bronchial thermoplasty group patients and 1 event in a control group patient that were medically treated without hospitalization (the authors did not report whether or not these were the same patients who were hospitalized). No overall statistical analysis was done comparing serious adverse events in the two groups. The authors also reported a number of efficacy variables as secondary outcomes. At the end of the study at 52 weeks, bronchial thermoplasty patients had a significantly greater improvement in beta-agonist use than control patients (decrease of 26 puffs versus 6 puffs per week, p<0.05) and there was no significant difference between groups in other efficacy variables including morning and evening peak expiratory flow, symptom scores, number of symptom-free days, improvement in FEV-1 predicted and several quality of life measures. The study was limited in its ability to accurately evaluate safety by a small sample size.

Asthma Intervention Research (AIR) trial: Cox and colleagues published findings of the AIR trial in 2007; patients were recruited from the same 3 countries as the RISA study plus Denmark (Cox, 2007). The eligibility criteria included age 18-65 with moderate to severe persistent asthma requiring daily therapy with inhaledcorticosteroids (equivalent to at least 200 ug beclomethasone) and long-acting beta-agonists (at least 100ug salmeterol or equivalent). Also required for study entry were an FEV-1 of 60-85% predicted, airway hyperresponsiveness and stable asthma in the 6 weeks before enrollment, no current respiratory infection and not more than 2 lower respiratory infections requiring treatment in the past year. An additional criterion was worsening asthma control during a 2-week baseline test period during which time LABA were withheld. A total of 112 individuals met eligibility following the baseline test phase and were randomized to receive medical management with inhaled corticosteroids and long-acting beta-agonists (n=56) or the same medical management strategy plus bronchial thermoplasty 3 sessions approximately 3 weeks apart, (n=56). After follow-up visits at 3, 6 and 12 months, there was a 2-week period of abstinence from long-acting beta-agonists, during which time data on exacerbations were collected. Between data collection periods, patients could use all maintenance therapies. The primary outcome was the difference between groups in change in 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 to the week before the abstinence period or nocturnal awakening caused by asthma symptoms. The study was powered to detect a difference between groups of 8 mild exacerbations per person per year. Data were available at 3-months for 100 of 112 patients (89%) and at 12 months for 101 patients (90%); all patients were included in the safety analysis.

The mean number of mild exacerbations per person per week in the bronchial thermoplasty group was 0.35 during the baseline test period and 18 per person per week at 12 months (a decrease of 0.17 per person per week). In the control group, the mean number of mild exacerbations per person per week was 0.28 at baseline and 0.31 at 12 months (an increase of 0.03 per person per week). Compared to the control group, the bronchial thermoplasty group had a significantly greater reduction in mild exacerbations at the 12 month follow-up. Overall, the average number of exacerbations during the 2-week data collection periods at 3, 6 and 12 months decreased in the bronchial thermoplasty group, a mean decrease of 0.16 per person per week but not in the control group which had a mean increase of 0.04 mild exacerbations. This resulted in a mean difference of a mean of .20 mild exacerbations per week or about 10 per year. In contrast, there was not a significant difference between in the number of severe exacerbations at any time point, compared to baseline but the study may not have had sufficient statistical power for this outcome. At the 12-month follow-up, the mean number of severe exacerbations in the bronchial thermoplasty group was 0.01 per person per week compared to 0.07 at baseline. The number of severe exacerbations in the control group was 0.06 per person per week compared to 0.09 at baseline. 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 two groups in the post-treatment period. Post-treatment, 3 individuals in the bronchial thermoplasty group required hospitalization and 2 patients in the control group required a total of 3 hospitalizations. A limitation of the study is the lack of a sham intervention and consequently, an inability to blind patients to treatment group.

Asthma Intervention Research 2 (AIR2) Trial: The AIR2 trial was conducted at 30 sites in 6 countries including the United States; findings were published in 2010 by Castro and colleagues (Castro, 2010). Unlike the other two 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 1000ug 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 quality of life.) Also different from the AIR trial, patients were not required to experience symptom worsening during a period of abstinence from long-acting beta agonists. Patients were stable on their asthma medication and continued their medication regimen 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. In an unpublished FDA document reporting minutes from an advisory panel meeting, one of the study authors stated that they used a non-informative prior (Cox, 2007).

A total of 297 individuals 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 and eight-five participants in the treatment group and ninety-seven in the sham control group attended the second bronchoscopy and the same numbers of individuals had the third bronchoscopy (it is not clear whether these were exactly the same patients). A total of 278 out of the 297 enrolled patients (94%) completed the 12-month visit, 181 in the treatment group and 97 in the sham control group. In the intention to treat population, the mean change in the integrated AQLQ score, the primary effectiveness outcome, was 1.35 in the bronchial thermoplasty group and 1.16 in the sham control group. Using Bayesian analysis, the posterior probability of superiority was 96%. This did not surpass the target PPS of 96.4%. However, in the ITT population, the percentage of patients achieving an AQLQ score change of 0.5 or greater (i.e., at least the minimal important difference) was 79% in the bronchial thermoplasty group and 64% in the control group. The posterior probability of superiority was 99.6% surpassed the target probability for secondary outcomes of 95%. Additional analysis of data from the active treatment group suggests 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 of 4.1 vs. 5.1, respectively).

Several secondary outcomes favored bronchial thermoplasty over the sham control group. These include a reduction in the proportion of patients reporting asthma worsening during follow-up (27.3% vs. 42.9%, respectively, posterior probability of superiority 99.7%) and a reduction in the number of emergency room 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 to 0.70 per person per year in the control group (the PPS was 95.5%). There was no significant difference between groups in other secondary efficacy outcomes including morning peak expiratory flow, number of symptom-free days, symptom score and rescue medication use.

Regarding safety outcomes, during the treatment phase, there was a higher rate of respiratory adverse events in the active treatment group (85% of participants mean of 1.0 events per bronchoscopy) compared to the sham group (76% of participants, mean of 0.7 events per bronchoscopy). A total of 16 patients (8.4%) in the active treatment group required 19 hospitalizations for respiratory symptoms during the treatment phase compared to 2 patients (2%) in the sham group who required 1 hospitalization each. However, during the post-treatment 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 study, 5 patients (2.6%) in the bronchial thermoplasty group had a total of 6 hospitalizations for respiratory symptoms and 4 patients (4.1%) in the sham group had 12 hospitalizations (1 patient had 9 hospitalizations).

In the AIR2 study, the sham group had a relatively high rate of response e.g. 69% experienced a clinically significant increase in the AQLQ. Blinding appeared to be initially successful and remained so for the sham group. After the first bronchoscopy, 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.

Long-term safety and effectiveness

All 3 of the randomized controlled trials followed patients for 1 year. Long-term safety and effectiveness data have not been published. However, an unpublished FDA document reports some long-term followup data from extensions of the RISA and AIR trials. Fourteen of the 17 patients assigned to bronchial thermoplasty in the RISA trial have been followed through year 3, and follow-up will continue through year 5. Respiratory adverse events decreased from 8.4 per patient at year 1 to 0.9 at year 2 and 1.1 at year 3. Patients in the control group were not followed beyond 1 year. Seventy of the 112 (63%) patients from the AIR trial, 46 in the bronchial thermoplasty group and 24 controls, were followed through 3 years. During this time, the proportion of respiratory adverse events and the number of respiratory adverse events per person decreased in both groups and there were no significant differences between the groups. Patients in the bronchial thermoplasty group continue to be followed through year 5.

As part of the device approval process, the FDA has required a five-year post-approval study of the Alair bronchial thermoplasty device. Asthmatx will conduct the study which will include patients from the AIR2 trial as well as 300 additional patients. A search of the National Institutes of Health Clinicaltrials.gov database did not identify any additional trials evaluating bronchial thermoplasty that are planned or underway.

Summary

Three RCTs on bronchial thermoplasty have been published, including one double-blind sham-controlled study (AIR2). The high rate of response in the sham group of the AIR2 suggests a large placebo effect with novel asthma treatments, particularly for subjective outcomes such as quality of life; this calls into question conclusions about efficacy in the earlier trials that did not have a sham control. In the AIR2 trial, bronchial thermoplasty provided benefit in terms of quality of life and some, but not all, secondary outcomes. It is unclear, however, which patients are most likely to respond. Data from the AIR2 suggests that those with more severe asthma may experience the greatest improvement. Also of concern, there are insufficient safety data; no published safety data beyond 1 year have been published and the potential long-term adverse effects of bronchial thermoplasty are not known. Additional randomized trials using sham controls are needed to confirm the findings of the AIR2 study. In addition, long-term follow-up is needed to understand potential adverse complications.

Technology Assessments, Guidelines and Position Statements

National Heart, Lung and Blood Institute: Their most recent guidelines on the diagnosis and management of asthma, developed by an expert panel, were published in 2007 and did not mention bronchial thermoplasty.

2012 Update

A search of the MEDLINE database through September 2012 did not reveal any new information that would prompt a change in the coverage statement. The following is a summary of the key identified literature.

In 2011, Thomson and colleagues published 5-year data from the AIR trial (Thomson, 2011). All study participants who completed the 1-year follow-up visit were invited to participate in the extension study; 45 of 52 (87%) in the bronchial thermoplasty group and 24 of 49 (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 of 24 (88%) patients in the control group and 42 of 45 (93%) in the bronchial thermoplasty group completed the final follow-up. No instances of pneumothorax, intubation, mechanical ventilation, cardiac arrhythmias or death were reported over the course of the extension study. As previously stated, data were collected on both treatment groups during the first 2 years of the extension study. In the first year (Year 2 of the study), the rate of hospitalizations was 3 of 45 (7%) 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 of 45 (7%), and 1 of 21 (5%) patients in the control group was hospitalized (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, and in Year 3 rates were 3 (5%) and 3 (5%), respectively (p=1.00). There was one hospitalization each year in the bronchial thermoplasty group in Years 4 and 5.

In the extension study, 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 two groups. The incidence of respiratory adverse events during Year 2 was 24 of 45 (53%) in the bronchial thermoplasty group and 13 of 24 (54%) in the control group. During Year 3, incidence was 24 of 43 (56%) in the bronchial thermoplasty group and 12 of 21 (57%) 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 of 43 (53%) in Year 4 and 22 of 42 (52%) in Year 5.

The Thompson et al. study also reported two measures of lung function, post-bronchodilator FEV-1 and forced vital capacity (FVC). Exact numbers were not reported, but post-bronchodilator FEV-1 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 was limited by the differential rate of follow-up between the two groups, with a lower percent of patients in the control group agreeing to participate in the follow-up study.

Two-year follow-up data on patients in the bronchial thermoplasty group of AIR2 study were published in 2011 by Castro and colleagues (Castro, 2011). A total of 166 of 190 (87%) individuals randomized to the bronchial thermoplasty group completed the two-year evaluation. 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 to a 30.9% (95% CI=24.2 to 37.7%) rate of exacerbations during Year 1. The proportion who experienced asthma adverse events in Year 2 was 26.5% (95% CI: 19.8- 33.2). The rate in Year 1 was 28.7 (95% CI=22.1 to 35.3%). The follow-up study is limited in that follow-up data are not being collected on patients randomized to the sham group and therefore outcomes such as rate of exacerbations and hospitalizations cannot be compared in patients who did and did not receive bronchial thermoplasty.

In 2011, Wu and colleagues published a meta-analysis of safety and efficacy findings of the 3 published RCTs (Wu, 2011). In all analyses reported here, data from the 3 trials were pooled. A pooled analysis found greater mean improvement in asthma quality of life in the bronchial thermoplasty compared to control groups (weighted mean difference [WMD]: 0.63, 95% CI: 0.10 to 1.15). The authors did not discuss a possible placebo effect that might impact quality of life reporting in the medication trials. In addition, there was significantly greater improvement in the peak expiratory flow with bronchial thermoplasty treatment compared to control (WMD: 21.78, 95% CI: 8.06 to 35.50). Adverse events were also reported. 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) compared with the control groups (369 event in 164 patients) (p-value not reported). Also during the treatment period, there was a significantly higher risk of hospitalization with bronchial thermoplasty than control (risk ratio [RR] 3.78, 95% CI=1.39 to 10.24). In the post-treatment period (end of treatment to the 12-month follow-up visit), there was not a significant difference between groups in the risk of hospitalization between groups (RR=1.15, 95% CI=0.47 to 2.79). The authors also noted that there were no patient deaths and no permanent disability in any study participant.

Ongoing Clinical Trials

The following trials were identified on the clinicaltrials.gov website.

RISA Extension Study (NCT00401986): The purpose of this study is to follow patients who were treated with the Alair device in the RISA study for an additional 4 years to identify any long-term safety issues. This study is sponsored by Asthmatx.

AIR2 Extension study (NCT01350414): This study is following patients who were treated with the Alair device in the AIR2 study for an additional 4 years to determine the long-term efficacy of the device. The primary outcome is the rate of asthma exacerbations in Years 2-5 compared to Year 1 (the initial AIR2 study). The expected date of completion is July 2012. This study is sponsored by Asthmatx. (12) Two-year data were published in 2011.

Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) (NCT01350336): This study is being conducted as part of the conditions of the pre-market approval for the Alair system. Asthmatx, the study sponsor, is required by the FDA to evaluate the long-term safety and efficacy of the system in the intended use population in the United States. The study is being conducted at 3 U.S. sites and is including adults with asthma who are taking regular maintenance medication with pre-bronchodilator FEV-1 at least 60% of predicted. The estimated study completion date is April 2018.

A Prospective Observational Study of Biopredictors of Bronchial Thermoplasty Response in Patients With Severe Refractory Asthma (BTR Study) (NCT01185275): This is a prospective observational study of adults with asthma who have been taking regular maintenance medication for the past 12 months. Additional eligibility includes prebronchodilator FEV-1 at least 50% of predicted and asthma symptoms on at least 2 days or 1 night per week over the past 2 weeks. The study will assess the relationship between baseline clinical, physiologic, biologic, and imaging markers and response to bronchial thermoplasty. The expected study completion date is August 2014. This study is sponsored by the Washington University School of Medicine.

Summary

Three industry-sponsored RCTs on bronchial thermoplasty have been published. The largest RCT with the most rigorous methodology was the AIR2 trial. This was the only published trial that was double-blind and sham-controlled, and also the only published RCT with sites in the United States. Over one year, bronchial thermoplasty was not found to be superior to sham treatment on the investigator-designated primary efficacy outcome, mean change in quality of life score, but was found to be superior on a related outcome, improvement in quality of life of at least 0.5 points on the AQLQ scale. There was a high rate of response 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, of the outcomes. In the AIR trial and RISA trial, there were improvements in quality of life for the bronchial thermoplasty group. However, given the lack of benefit in the AIR2 trial, it is possible that the differences in quality of life for these other trials were due to placebo effect.

There are longer-term (3-year) comparative published data from the AIR trial. Rates of hospitalizations and respiratory adverse events did not differ significantly in the groups that received bronchial thermoplasty versus medication in Years 2 and 3. Data up to 5 years in the bronchial thermoplasty group did not suggest delayed complications. For the sham-controlled AIR2 trial, two-year follow-up data are available only for bronchial thermoplasty group. In Year 2, patients did not experience an increase in severe exacerbations or asthma adverse events compared to Year 1.

Findings on adverse events from the three trials suggest 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. Additional safety data on patients from published RCTs who were treated with bronchial thermoplasty are being collected in extension studies.

The uncertain degree of benefit and the presence of substantial adverse events leave a large degree of uncertainty about the impact of bronchial thermoplasty on the net health outcome. 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 which patients receive the most benefit.

2013 Update

A search of the MEDLINE database through August 2013 did not reveal any new literature that would prompt a change in the coverage statement.

2013 Literature Review

AIR2 trial (Weschsler, 2013): in the initial study bronchial thermoplasty was not found to be superior to sham treatment on the investigator-designated primary efficacy outcome, mean change in quality-of-life 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) scale. There was a high rate of response 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, of the outcomes. In the AIR trial and RISA trial, there were improvements in quality of life for the bronchial thermoplasty group. However, given the lack of benefit in the AIR2 trial, it is possible that the differences in quality of life for these other trials were due to placebo effect. While the absence of delayed complications and some improvement in severe exacerbations persist (compared to year 1 when adverse events were increased), there is no data relative to the follow-up experience of the sham control group. It is important to note that in the initial trial experience, there were no differences in the secondary outcomes of changes in asthma control, symptom-free days, peak expiratory flow, FEV1, and use of rescue medication.

For the second cited trial (Cox, 2007), bronchial thermoplasty reduced the frequency of mild exacerbations in patients with moderate to severe persistent asthma, although there was no effect on the rate of severe exacerbations. In the RISA paper, trial size is small and again there is no long term follow-up of the control group (Pavord, 2013).

The high rates of adverse effects in the initial treatment phase, uncertainty of benefits, and the absence of a reliable means of identifying those who will benefit (phenotype or biomarker) leave significant questions about the impact on net health outcomes. Current literature does not support a change in policy at this time.

2014 Update

A literature search conducted through November 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

In 2013, Pavord and colleagues published 5-year safety data on 14 of the 17 patients (82%) randomized to the bronchial thermoplasty group in the RISA study (Pavord, 2013). All 14 individuals completed the 3 year evaluation and 12 patients completed evaluations at 4-year and 5-years. As described above, safety outcomes were the primary outcomes in the RISA study. In Year 1 of the study, 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. In addition, during Years 2-5, there were a total of 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.

In 2013, Wechsler and colleagues reported 5-year data on 162 patients in the AIR2 study (85% of those randomized to the treatment group) (Wechsler, 2013). 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 individuals 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 of more 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 were 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%.

Two pooled analyses of findings of the 3 RCTs were identified. In 2014, a Cochrane systematic review of RCTs was published by Torrego and colleagues (Torrego, 2014). The investigators included the 3 published RCTs in their review. Potential study limitations identified by the authors was lack of blinding in 2 of the 3 trials and lack of a sham control in 2 trials. Pooled analyses were not conducted on asthma exacerbation outcomes. A meta-analysis of the 3 studies found significantly greater improvement in AQLQ scores at 12 months in the bronchial thermoplasty versus 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, there was a significantly higher number of patients admitted to the hospital due to respiratory events during the treatment period (RR [risk ratio]: 3.50, 95% CI: 1.26 to 9.68). There was not a significant difference between groups in the proportion of patients admitted to the hospital due to respiratory events in the posttreatment period (RR: 1.12, 95% CI: 0.44 to 2.85).

2015 Update

A literature search conducted through November 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this policy are listed below:

(NCT02464995) Bronchial Thermoplasty in Severe Asthma With Frequent Exacerbations (THERMASCORT); planned enrollment 40; completion date November 2018.

(NCT022253925) an industry sponsored or cosponsored trial. Unravelling Targets of Therapy in Bronchial Thermoplasty in Severe Asthma (TASMA); planned enrollment 40; completion date April 2018.

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 the short-term efficacy of bronchial thermoplasty, the uncertain degree of 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. 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 which patients might receive the most benefit.

British Thoracic Society/Scottish Intercollegiate Guidelines Network

In 2014, the British Thoracic Society and the Scottish Intercollegiate Guidelines Network published a revised national guideline on management of asthma (SIGN. 2014). The guideline states: “Bronchial thermoplasty may be considered for the treatment of adult patients who have poorly controlled asthma despite optimal therapy.” The guideline includes a summary of recommended stepwise management of asthma in adults. Bronchial thermoplasty is not specifically mentioned in the stepwise management summary, but step 5 includes recommendations to consider other treatments to minimize the use of steroid tablets and to refer patients for specialty care.

2016 Update

A literature search conducted through November 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

Zhou and colleagues published a meta-analysis of the published RCTs and extension studies, focusing on the durability and long-term responses for treated patients (Zhou, 2016). The authors pooled data on long-term effects in bronchial thermoplasty-treated patients only (ie. not in comparison groups). In an analysis of 216 patients with 5 years of follow-up, there was no significant decline in spirometry-detected pre-bronchodilator 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 post-bronchodilator 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.

2017 Update

A literature search conducted through November 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

Several case series have been published describing outcomes in clinical practice. These generally had small sample sizes (eg, N=7, [Arrigo, 2016] N=10, [Bicknell, 2015] and N=20, [Langton, 2017]). In addition, a rigorous U.K. registry study was published by Burn and colleagues which focused on safety outcomes (Burn, 2016). 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 readmissions within 30 days of the initial hospitalization were reported for 15 (11.8%) patients; and accident and emergency visits (ie, emergency department) visits for any reason were reported for 13 (8.6%) patients. For the fourth binary 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 be related to older patients with more severe disease being treated in clinical practice compared with patients included in clinical trials.

Safety data from a U.K. registry study, published in 2016, found that 20% of bronchial thermoplasty procedures were associated with at least 1 of 4 safety events (ie, procedural complications, emergency respiratory readmissions, emergency department visits, and/or postprocedure overnight stays).

National Institute for Health and Care Excellence

In 2012, the National Institute for Health and Care Excellence (NICE) published guidance on bronchial thermoplasty for severe asthma (NICE, 2012). The guidance stated: “Evidence on the efficacy of bronchial thermoplasty for severe asthma shows some 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, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. “

2018 Update

A literature search was conducted through November 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

BRONCHIAL THERMOPLASTY FOR THE TREATMENT OF ASTHMA

Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma

Chupp et al 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-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma [PAS2]) (Chupp, 2017). 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<001); 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.

Observational and Nonrandomized Studies

Langton et al (2017) published a single-center, observational study of 24 patients who had severe uncontrolled asthma and were treated with bronchial thermoplasty. 13 Primary response was measured by change in 5-item Asthma Control Questionnaire (ACQ-5) scores at 6 months after treatment. The mean ACQ-5 score of the group was 3.3 (SD=1.1) at baseline, which improved to 1.5 (SD=1.1) at 6 months (p<001). For 21 patients, the change achieved the minimal clinically significant improvement (defined as an ACQ-5 improvement ≥0.5). Authors also reported deterioration in postbronchodilator FEV1: 24 hours after treatment, FEV1 decreased by a mean of 166 mL (95% CI, 102 to 224 mL; p<001). The predictors of acute change in FEV1 were age (p=0.02) and a number of activations (ie, more activations predicted worsened FEV1 postprocedure; p=0.01). Patients deemed responders according to ACQ-5 improvement had a mean of 221 (SD=45) activations, while those clinically deemed nonresponders had a mean of 13 (SD=11) activations (p<0.01). There were significantly more activations applied to upper lobe (78.8) than in the with the right (40.1) or left (42.8; p<0.001) lower lobes, which aligns with the significant deterioration in FEV1 (≥15%) in 60% of patients treated in upper lobe (p=0.009). Patients whose right or left lower lobes were treated were quicker to return to baseline FEV1 levels by day seven postprocedure compared with those whose upper lobes were treated. While the study was limited by its small size and observational nature, it provides data on the aggravating effect radiofrequency activations may have on FEV1, especially on upper lobes.

D’Hooghe et al published results from the prospective imaging Unravelling Targets of Therapy in Bronchial Thermoplasty in Severe Asthma trial, which assessed 12 patients who underwent 36 bronchial thermoplasty procedures and had chest x-ray (n=34) or ultra-low-dose computed tomography (n=16) (D’Hooghe, 2017). The primary outcome was radiologic abnormalities following bronchial thermoplasty, and a large percentage of the cohort showed 1 of 4 abnormalities: peribronchial consolidations and ground glass opacities (94%), atelectasis (38%), partial bronchial occlusions (63%), or bronchial dilatations (19%). There was no clear association between abnormal x-ray results and asthma exacerbation (55% experienced both) compared with the incidence of asthma exacerbations in those who had normal radiologic images (roughly 2 of every 3 patients). Seventy-three percent of abnormal results resolved within 6 weeks, and 100% resolved 6 months postprocedure.

2019 Update

Annual policy review completed with a literature search using the MEDLINE database through November 2019. No new literature was identified that would prompt a change in the coverage statement.

2020 Update

Annual policy review completed with a literature search using the MEDLINE database through November 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Efficacy and Safety data from the UKSAR registry were subsequently reported by Burn et al (Burn, 2019). Efficacy data was available for 86 patients with at least 1 follow-up visit. Safety data was available for 131 patients, including the 59 in the previous report. Follow-up data up to 60 mo was 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.

2021 Update

Annual policy review completed with a literature search using the MEDLINE database through November 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Chaudhuri et al reported 10-year safety and efficacy results for patients enrolled in the AIR, RISA, and AIR2 trials, including 136 (52%) patients who had received bronchial thermoplasty and 56 (33%) sham or control patients (Chaudhuri, 2021). Eighteen patients in the sham/control group received bronchial thermoplasty after participation in the original trials. Median patient follow-up was 12.1 years post-treatment (range, 10.8 to 15.6 years). The primary study effectiveness endpoint was the durability of treatment effect, described as the proportion of participants with severe exacerbations during years 1 and 5 compared to the proportion of patients who experienced severe exacerbations in the 12 months preceding the 10+ year visit. No formal hypothesis testing was planned. Severe exacerbations were defined as a self-reported worsening of symptoms requiring the use of systemic corticosteroids or increased dose of systemic corticosteroids. The primary safety endpoint was the absence of clinically significant respiratory changes, including bronchiectasis or bronchial, as confirmed by CT imaging. In the year preceding the 10+ year visit, 34/136 (24%, 95% CI, 18.0 to 33.1) patients treated with bronchial thermoplasty experienced severe exacerbations, which were similar to the year 5 (22%, 95% CI, 14.8 to 29.6) and year 1 (24%, 95% CI, 17.5 to 32.6) proportions. The number of severe exacerbations per patient were significantly higher compared to year 5 (p =.044), but not significantly different compared to year 1 (p =.43). In the year preceding the 10+ year visit, severe exacerbations were experienced in 14/38 (37%, 95% CI, 21.8 to 54.0) sham or control patients compared to 12/38 (32%, 95% CI, 17.5 to 48.7) in year 1. There was no change in the rate of severe exacerbations over time in the 24 sham participants from the AIR2 trial who had baseline, 1 year, and 10 year data. Both treated and non-treated groups experienced a reduction in emergency department visits. Six (7%) AIR2 patients treated with bronchial thermoplasty developed new cases of asymptomatic bronchiectasis compared to 0 cases in the sham group at the 10 year visit. Improvements in AQLQ and ACQ scores were sustained in patients treated with bronchial thermoplasty. However, these scores were not reported for sham/control patients. Interpretation of study results is limited by recall bias and low enrollment of sham-treated patients. While bronchial thermoplasty is only recommended for use in patients with severe asthma, 26% of participants did not fulfill these criteria. Additionally, the long-term effects of treatment on clinically significant respiratory changes requires further elucidation.

2022 Update

Annual policy review completed with a literature search using the MEDLINE database through November 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

The 5-year follow-up results for the full PAS2 cohort are described in a study by Chupp et al (Chupp, 2022). Of the 284 individuals enrolled in PAS2, 227 (81%) completed 5 years of follow up; 84% of individuals included were White, 9% Black or African heritage, 3% Hispanic or Latino, 1.4% Asian, 1% American Indian or Alaska native, and 1.6% from other racial or ethnic groups that were not described by investigators. Of note, a larger proportion of the 52 individuals who were not followed for 5 years experienced severe exacerbations (92.3% vs. 74.4%), emergency department visits (51.9% vs. 24.2%), and hospitalizations (30.8% vs. 12.8%) during the 12 months before bronchial thermoplasty compared with the 227 individuals followed for 5 years, indicating that those who dropped out of PAS2 may have had more serious disease and were not included in the analysis. By year 5 posttreatment, the proportion of individuals with severe exacerbations was significantly lower at 42.7%, compared with 77.8% in the 12 months prior to treatment (p<.001). There was also a significant reduction in severe exacerbations from baseline (1.61 exacerbations/individual) to 5 years posttreatment (0.72 exacerbations/individual; p<.001). Emergency department visits and hospitalizations were also significantly decreased by 5 years compared to 12 months prior to treatment, from a rate of 29.4% to 7.9% (p<.001) and 16.1% to 4.8% (p=.0003), respectively. At year 5 after bronchial thermoplasty, annual hospitalization rates fell from 0.22 hospitalizations per individual at baseline to 0.06 hospitalizations per individual (p=.0012). Bronchial thermoplasty did not alter spirometric parameters as reported in previous studies but did reduce asthma maintenance medication use. The mean daily dose of inhaled corticosteroids (beclomethasone or equivalent) was reduced from 2272 microg/d at baseline to 1928 microg/d by year 5. The number of individuals on maintenance oral corticosteroids decreased from 19.4% at baseline to 9.7% at 5 years. Clinical improvement was statistically significant across all subgroup analyses, regardless of baseline eosinophil and neutrophil counts. These results are limited by the lack of a comparator arm, increased drop-out rates of those with more severe asthma, lack of long term QOL scores, and lack of response comparison between bronchial thermoplasty and standard of care medications.

The BTGR is a prospective, open-label, multicenter study across 18 centers in Spain, Italy, Germany, the UK, the Netherlands, the Czech Republic, South Africa, and Australia that enrolls adults indicated for and treated with bronchial thermoplasty. Torrego et al reported on the 2-year outcomes from the BTGR (Torrego, 2021). One hundred fifty-seven adults were included in the registry at 2 years. Racial and ethnic demographics of participants were not described. A comparison of the proportion of individuals experiencing asthma events during the 12 months prior to bronchial thermoplasty to the 2-year follow-up showed a reduction in severe exacerbations requiring corticosteroids (90.3% vs. 56.1%; p<.0001), emergency department visits (53.8% vs. 25.5%; p<.0001), and hospitalizations (42.9% vs. 23.5%; p=.0019). Asthma Control Questionnaire and AQLQ scores improved from 11.18 and 3.26 at baseline to 15.54 and 4.39 at 2 years, respectively (p<.0001 for both). The registry results were limited by a lack of a comparator arm, a high attrition rate, with approximately one-third of individuals dropping out, and variation in investigator experience with bronchial thermoplasty between clinical sites.

Global Initiative for Asthma (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 2022 (GINA, 2022). The organization has recommended stepped care for treatment of asthma. Step 5 options for patients with uncontrolled symptoms and/or exacerbations include referral for phenotypic investigation and potential add-on treatment. Bronchial thermoplasty may be considered as an add-on treatment in adults with severe asthma that remains uncontrolled despite optimization of asthma therapy and referral to a severe asthma specialty center. GINA notes that bronchial thermoplasty should only be administered in the context of a systematic registry or a clinical study, as the evidence for efficacy and long-term safety is limited.

A guide for the diagnosis and management of difficult-to-treat and severe asthma was first published in 2019, with a goal to update annually (GINA, 2019).,The updated guidance has not yet been released to the public (GINA, 2022).,For patients whose asthma remains uncontrolled despite GINA step 4 or 5 treatment with no evidence of type 2 inflammation (i.e., medium- or high-dose inhaled corticosteroids and long-acting ß-agonists), treatment options include a trial of tiotropium or macrolide if not already tried, low-dose oral corticosteroids, and consideration of bronchial thermoplasty with registry enrollment. Bronchial thermoplasty with registry enrollment may also be considered for patients who do not respond to type 2-targeted biologic therapy. The guidance notes that the evidence for the efficacy and long-term safety of bronchial thermoplasty is limited.

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:

References:

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