TITLE: Bronchial Thermoplasty for Severe Asthma: A Review ... · Bronchial Thermoplasty for Severe Asthma 5 to September 2014,1 and from an unspecified date to October 2014.4 The

Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners’ own terms and conditions.

TITLE: Bronchial Thermoplasty for Severe Asthma: A Review of the Clinical and Cost-Effectiveness, and Guidelines

DATE: 27 August 2015 CONTEXT AND POLICY ISSUES Severe asthma is a chronic condition in which patients experience airway inflammation and airway muscle contraction leading to symptoms of breathlessness, wheezing, coughing, and chest tightness. It is one of the most common chronic conditions with an estimated 235 million people affected worldwide, an increasing global prevalence, and a lifetime of impacts on healthcare systems.1,2 Exacerbations of this condition can be serious, negatively impact patient quality of life, require hospitalization and emergency department (ED) services.3 The standard approach to care employs regular maintenance medications, usually inhaled corticosteroids (ICS) and a long-acting β2-agonist (LABA), while other medications may also be used including omalizumab and oral corticosteroids.1,2 Bronchial thermoplasty (BT) is an endoscopic therapy, the first nonpharmacologic intervention approved by Health Canada for the treatment of severe asthma.1 BT employs radiofrequency energy pulses to selectively reduce the thicker airway smooth muscle found in asthmatic patients. This selective ablation is thought to reduce airway hyper-responsiveness, airway obstruction, and asthma symptoms.3 Further research is required to help more clearly determine the mechanisms of action of bronchial thermoplasty.3-5 Limitations of the technique include the inability to treat distal symptomatic airways due to their small diameter, and contraindications for patients with implanted medical devices.3,5 This report is an update to a previous Canadian Agency for Drugs and Technologies in Health (CADTH) Rapid Response Report published in March 2014 that provided a summary of abstracts on bronchial thermoplasty.6 The purpose of this report is to retrieve and review the current evidence from full text articles of clinical efficacy, safety, and cost-effectiveness of BT. In addition this report aims to retrieve and review existing guidelines on the use of BT for the treatment of severe asthma.

Bronchial Thermoplasty for Severe Asthma 2

RESEARCH QUESTIONS 1. What is the clinical effectiveness of bronchial thermoplasty for patients with severe

asthma?

2. What is the cost-effectiveness of bronchial thermoplasty for patients with severe asthma?

3. What are the evidence-based guidelines regarding the use of bronchial thermoplasty for

patients with severe asthma? KEY FINDINGS Three randomized clinical trials, two that demonstrated evidence of performance bias, provided the evidence basis for the systematic review, two health technology assessments, two economic studies and four guidelines on bronchial thermoplasty identified and reviewed in this report. For patients with poorly controlled, severe asthma limited evidence suggested a marginal improvement in quality of life for some patients who received bronchial thermoplasty. One randomized controlled trial reported decreased emergency department visits following the bronchial thermoplasty treatment period as compared to a sham control. During the bronchial thermoplasty treatment period, consistent evidence was identified for an increased incidence of respiratory related adverse events requiring hospitalization in the treatment group. This increase did not extend past the treatment period or in five years of follow-up of treated patients. Other outcomes, including asthma control, respiratory related hospitalizations, frequency of severe exacerbations, and pulmonary function outcomes were either not improved or the evidence was mixed. One economic analysis found that when decreased emergency department visits and hospitalizations followed bronchial thermoplasty an increase in cost-effectiveness was realized, while another found that this decreased resource use may provide savings within five years when introduced into an asthmatic cohort of patients. No clear recommendations on which patient populations would benefit most from bronchial thermoplasty were provided, however three of the four identified guidelines conditionally recommended bronchial thermoplasty as a potential treatment option for poorly controlled, severely asthmatic patients already on optimal pharmacological therapy. METHODS Literature Search Strategy This report makes use of a literature search conducted for a previous CADTH report. The original literature search was conducted in February 2014 on key resources including PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit retrieval by study type. Where possible, retrieval was limited to the human population. The initial search was also limited to English-language documents published between January 1, 2009 and March 18, 2014. For the current report, database searches were rerun on July 27, 2015 to capture any articles published since the initial search date. The search of major health technology agencies was also updated to include documents published since March 2014.


Selection Criteria and Methods One reviewer screened titles and abstracts from the original (March 2014) literature search for inclusion in the previous CADTH report.6 A second reviewer screened titles and abstracts identified by the updated literature search strategy which were screened for retrieval of full-text articles. Full-text articles from the original CADTH report and the updated search satisfying the criteria presented in Table 1 were included in the final selection for this report.

Table 1: Selection Criteria

Population

Patients with severe asthma

Intervention

Bronchial Thermoplasty

Comparator

Q1 and Q2: Standard of care, medical management, sham intervention, no treatment, and/or no comparator Q3: No comparator

Outcomes

Q1: Clinical benefit (e.g. alleviate need for medication, decreased medication dosage) Q2: Cost-effectiveness Q3: Guidelines and Recommendations

Study Designs

Health Technology Assessments (HTA)/Systematic review (SR)/Meta-analysis (MA); Randomized controlled trials (RCTs); Non-randomized studies; Economic evaluations; and Evidence-based Guidelines

Exclusion Criteria Studies that did not meet the selection criteria, were already included in at least one selected systematic review (SR) or health technology assessment (HTA), were published in a language other than English, or were published prior to 2009 were excluded. Critical Appraisal of Individual Studies The quality of the included SR and HTAs were assessed using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool.7 The quality of the economic studies included in this report were evaluated using Drummond’s Checklist.8 Critical appraisal of the included guidelines used the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument.9 All critical appraisals described the strengths and limitations narratively instead of assigning a numerical score. SUMMARY OF EVIDENCE Quantity of Research Available The literature search strategy identified 46 citations, 31 of which were excluded based upon available titles and abstracts. An additional 19 potentially relevant reports were retrieved from grey literature resulting in 34 potentially relevant reports. The 11 potentially relevant reports from the previous CADTH Summary of Abstracts were included for a total of 45 potentially relevant reports. Following retrieval and screening of these full-text articles, 36 reports were


excluded. Nine relevant articles were included in this report; one SR,3 two HTAs,1,4 two economic studies,10,11 and four guidelines containing relevant recommendations met the selection criteria.2,12,13 A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart14 describes the selection procedure of the included studies of this review and is included in Appendix 1. The 36 excluded articles consisted of one study examining an irrelevant outcome (airway smooth muscle mass)15, one was the original CADTH report for which this report is an update and whose articles were considered for inclusion, ten were narrative reviews, six were duplicates of included articles, six were already included in at least one selected SR or HTA, one was unavailable for review,16 two were available as conference abstracts only,17,18 two were press releases, three were insurance benefit policies, one was a case study, and three were correspondence. Summary of Study Characteristics The same three randomized controlled trials (RCTs) were examined in the identified SR and HTAs included in this report.1,3,4,19-21 Additional follow-up trial data published separately on the AIR trial,22 the RISA trial,23 and the AIR2 trial24,25 was also included in the SRs and HTAs.1,3,4 Results of a meta-analysis (MA)26 that included the three RCTs was already included in the most recently published HTA.4 The most recently published of these trials, the AIR2 trial, was utilized as the source for clinical efficacy and adverse event data in the included economic studies.10,11,21 Of the included guidelines, Scottish Intercollegiate Guidelines Network (SIGN) and the British Thoracic Society based recommendations on these three RCTs,13,27 another based BT recommendations only on the most recent RCT and SIGN guidelines,2,13,21 and one guideline was unclear as to what evidence recommendations were based upon and did not cite these RCTs.12 It is not clear how independent guidelines from SIGN and the British Thoracic Society are as the latter was also involved in the development of the SIGN guidelines.13,27 This report therefore presents articles that base clinical effectiveness, cost-effectiveness, safety, and guidelines upon the overlapping clinical data. SR and HTAs The SR and HTAs included in this report all specifically examine the evidence on clinical efficacy and safety of BT.1,3,4 The SR, published by the Cochrane collaboration, examined BT data from three RCTs, that were identified in an electronic literature search from an unspecified date up to January 2014.3,19-21 The defined population was adult patients with asthma. The review compared data on standard care (SC) with BT treatment to SC or sham intervention without BT. Reported outcomes were Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Questionnaire (ACQ), the number of asthma exacerbations, the use of rescue medications, and adverse events. Original trial data with a follow-up of 12 months was included in the analysis of the SR.3 While there were some differences in definitions of included patients, interventions, and comparators, the two included HTAs also identified and included the same three RCTs as the SR,1,3,4,19-21 however the HTAs both included additional published trial data on adverse events during five year follow-ups of trial participants.1,4 Electronic literature searches were from 1996


to September 2014,1 and from an unspecified date to October 2014.4 The search criteria for both HTAs specified evidence from RCTs.1,4 Clinical effectiveness outcomes reported in the HTAs from the RCTs were AQLQ,1,4 ACQ,1,4 number of exacerbations,1,4 medication use,1,4 forced expiratory volume in one second (FEV1),

4 and percentage of symptom free days.1,4 Outcomes categorized as adverse events and reported in the included HTAs were hospitalizations,1,4 adverse events categorized by severity,1 respiratory adverse events,4 and long-term adverse events/patient/year.1 It was possible that categorization of number of exacerbations as clinical effectiveness, and hospitalizations for respiratory adverse events in the post treatment period as adverse events could have been interpreted differently.1,3,4 In this report, all outcomes involving hospitalization were categorized as adverse events. Characteristics of the included SR and HTAs are tabulated in Appendix 2, Table A2.1. Economic Studies The identified economic evaluations included a cost-effectiveness study and a budget impact analysis.10,11 The cost-effectiveness analysis perspective was from a private, commercial payer perspective in the United States,10 and the budget impact analysis examined the impact of implementing BT from an regional Italian healthcare service perspective.11 Both economic studies used the same published data from the AIR2 trial.10,11,21 The patients in the AIR2 trial had an AQLQ score of 6.25 or lower, prebronchodilator FEV1 less than or equal to 60%, at least 2 days of asthma symptoms during the 4-week baseline period in spite standard maintenance treatment, non-smokers for at least one year, and a history of less than 10 pack-years.10 The cost-effectiveness study examined a population of poorly controlled, severe, persistent asthma patients where the entire population was suited to BT treatment.10 Additional clinical inputs for the rate of exacerbations and patient quality of life were estimated from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) population. This population had severe or difficult-to-treat asthma for at least one year, had two or more asthma related unscheduled healthcare visits, and/or high medication use for asthma.10 The budget impact analysis examined a hypothetical heterogeneous cohort of severe, uncontrolled asthma patients and the impact of introducing BT to a subset of these patients who are nonresponsive to omalizumab (OMAL), or are contraindicated for OMAL and nonresponsive to standard care. This analysis was the only evidence included in this report where OMAL was part of SC in the control group. The mix of treatments followed clinical indications of the Global Initiative for Asthma (GINA) guidelines.2 The analysis used a reference population data from Istituto nazionale di STATistica.11 Outcomes for both studies included itemized costs of asthma therapy, and cumulative costs over five years.10,11 The cost-effectiveness study also modelled BT impacts on five year quality adjusted life years (QALYs) and incremental cost-effectiveness ratios in US$/QALY. The analysis assumed the Markov property and that the use of maintenance medications was equivalent in BT patients and SC patients.10 The budget impact analysis also assumed that BT and OMAL treatment would not decrease the use of maintenance medication.11 Additionally both economic analyses assumed three BT treatment sessions three weeks apart per patient all in the first year (as per the AIR2 trial). The budget impact analysis evaluated the case where 75% of OMAL patients received one injection/month and 25% received two injections/month. Many costs in this analysis were estimated using local data including SC, OMAL treatment, BT procedure, ER visits, and specialist costs.11 A summary of the characteristics of the included economic studies in included in Appendix 2, Table A2.2.


Guidelines The most recent identified guidelines, published in May 2015, are from the Global Initiative for Asthma (GINA).2 Two identified guidelines, published in 2014, were from the Scottish Intercollegiate Guidelines Network (SIGN),13 and the European Respiratory Society/American Thoracic Society (ERS/ATS),12 both published in 2014. The oldest identified guidelines were from the British Thoracic Society published in 2011. Three guidelines focused broadly on recommendations for many different populations of patients with asthma.2,12,13 The British Thoracic Society recommendations focused on guidelines for diagnostics and therapeutic procedures for bronchoscopy in adults.27 Guidelines relevant to BT from GINA were for highly selected adult patients with uncontrolled, severe asthma despite use of recommended therapeutic regimens. Severe asthma was defined in these guidelines as requiring high-dose inhaled corticosteroids and long-acting β2-agonists (ICS/LABA) to prevent an ―uncontrolled‖ condition, or asthma that remains ―uncontrolled‖ despite this treatment.2 SIGN had BT recommendations for adult patients, aged 18 to 65 years, with poorly controlled moderate to severe asthma despite ―maximal‖ therapy (maximal therapy was not explicitly defined). These guidelines did not provide a definitions for asthma severity apart from acute conditions.13 The recommendations for BT in the ETS/ATS guidelines were for adult patients with severe asthma where severe asthma was defined as asthma that requires treatment with high dose ICS, and a second controller and/or systemic corticosteroids to prevent the condition from being ―uncontrolled‖ or remains ―uncontrolled‖ despite this therapy.12 The British Thoracic Society guidelines for BT were for patients with severe persistent asthma on maximal therapy.27 All four guidelines provided evidence levels that support the recommendations,2,12,13 and three of these also provide a grade for recommendations.12,13,27 Recommendations from GINA are intended for health professionals and policy makers.2 The target audience for the recommendations from SIGN were reported as healthcare professionals involved in the care of asthma patients, asthma patients, parents/caregivers and those who interact with people with asthma, and those planning healthcare service delivery to these patients in England, Wales, Ireland, and Scotland.13 Guidelines from ERS/ATS are intended for specialists in respiratory medicine, allergy managing adults and children with severe asthma, general internists, paediatricians, primary care physicians, other healthcare professionals, and policy makers.12 The target audience of the guidelines from the British Thoracic Society was health professionals in the UK.27 Further detail on the evidence levels and the grades of recommendations used, along with a summary of characteristics of the included guidelines, are provided in Appendix 2, Table A2.3. Summary of Critical Appraisal SR and HTAs The included SR and HTAs all included methodology on a systematic literature search, and predefined criteria for inclusion and exclusion of studies. In one SR two independent reviewers screened and selected studies, and also extracted data from included studies. A third reviewer was used in the case of disagreements.3 One HTA used a single reviewer for study selection and data extraction,4 while in the other HTA the number of authors contributing to study selection and data extraction was unclear.1 Additional methodology provided by the three articles included a defined research objective, a defined patient population, and a description of the statistical methods used. All three also assessed the quality of included studies, reported potential conflict of interests (COIs), provided tabulated study characteristics, and examined reported adverse events.1,3,4 None of these articles provided an examination of publication bias, however the SR reported that the small number studies identified was prohibitive for such


analysis and that publication bias would be explored in the future when ten or more studies have been published.3 The SR included a meta-analysis (MA) of the data from the three identified RCTs which facilitated reporting of quantified conclusions and statistical heterogeneity of the studies. In some cases the SR referred to findings as significant without providing details.3 The HTAs did not provide a COI statement, however an examination of the regulatory status, guidelines, and ongoing clinical trials for BT was included.1,4 The SR and one HTA presented a PRISMA flowchart describing the article selection process and included methodology on data extraction.3,4 One HTA provided a brief examination of the cost-effectiveness of BT,1 citing the budget impact analysis included in this report.11 The other HTA also provided some analysis of existing evidence gaps providing some opportunities for future research.4 The major source of bias identified by the SR and HTAs of the RCT data was the open design of two of the trials which compared BT to medical management only.1,3,4 Quality of the unblinded trials was rated as moderate by one HTA,1 and poor by the other,4 due to the lack of a sham control. The SR rated the unblinded trials at high risk of performance bias, and at low risk for other biases.3 The latest RCT, AIR2,21 was blinded and contained a sham BT control. This RCT was rated as good by one HTA. The identified limitations were partial blinding (a sham control was used and envelopes were used for randomization) and an unclear analytical approach for correlated events.4 The other HTA in this report did not identify limitations of the allocation methods, mentioned the low attrition up to one-year follow-up, noted that the bronchoscopy team was unblinded and rated the quality of the conduct and reporting of AIR2 as high.1 The SR determined that allocation methods were inadequately described and therefore the AIR2 trial was at an unknown risk of selection bias.3 Additionally the SR noted that the RISA trial had baseline patient differences between treatment arms.3,20 Economic Studies The two economic studies analyzed the impact of BT on costs using different methods, however the analyses share some strengths including an explicit objective, relevant comparators, sensitivity analyses, well-described methodology, looked at costs over five years, and accounted for costs of adverse events.10,11 The cost-effectiveness analysis of Cangelosi et al.10 used costs from published sources except for the costs associated with the BT procedure. The authors provided a discussion on the reasoning behind assumptions of the clinical effectiveness outcomes in a subset of patients for which no clinical data was available. The authors argued that similar AQLQ results in patients with more poorly controlled asthma from the RISA trial is suggestive of similar BT effectiveness in the modelled patient population that required hospitalization. If BT had different clinical effectiveness in these patients it would impact cost-effectiveness.10 Menzella et al.11 used only local cost estimations for costs of standard care, OMAL treatment, BT procedure costs, ER visit costs, and specialist visits. The use of this data for cost estimates may make conclusions of limited generalizability to other healthcare settings. Additionally the budget impact analysis, by design, did not include any information about cost-effectiveness in terms of QALYs.11 Both economic analyses have potential COIs.10,11 Guidelines Three identified guidelines that provided some evidence-based recommendations on BT had a broad focus on many different asthma interventions for many different asthmatic patient populations.2,12,13 One guideline focused on bronchoscopy procedures.27 Three guidelines provided sufficient details on the development methods for the recommendations,2,13,27 however none of the guidelines provided specific literature search methodology for BT.2,12,13,27 Three of


the guidelines provided a general description of an electronic literature search methodology,2,13,27 the selection of literature was also outlined generally.2,13,27 GINA described the selection process as the judgement of the reviewers,2 whereas SIGN and the British Thoracic Society mentioned a more systematic method.13,27 These three guidelines also used two reviewers for the selection process.2,13,27 Guidelines from ERS/ATS did not provide any details of an electronic search strategy or study selection.12 All four guidelines assessed the level of evidence that supported the recommendations,2,12,13,27 and three of these also graded the strength of the recommendations.12,13,27 The patient population for which the recommendations apply was well described in three of the selected guidelines,12,13,27 but not in guidelines from GINA.2 Additionally the GINA guidelines used the SIGN guidelines as the source of evidence for BT recommendations.2,13 The guidelines from ERS/ATS had several additional limitations including vague evidence levels and grades of recommendations, supporting evidence for the recommendations was unclear, limited guideline implementation information, limited discussion on the limitations of the guidelines, and unclear methods for updating the guidelines. These guidelines did provide a good description of the methods used to avoid potential COIs in the guideline development committee.12 Guidelines from SIGN and GINA both provided potential COIs of guideline development groups in a separate source.2,13 Potential COIs of guideline committee from the British Thoracic Society were available.27 Three identified guidelines had limited stakeholder representation in guideline development groups and consisted of researchers, clinicians, and specialists.2,12,13 The guidelines from the British Thoracic Society specifically mention inclusion of various stakeholders in the development of the guidelines.27 Summary of Findings The findings are summarized below and more detailed quantification is presented in Appendix 4, Table A4.1. What is the clinical effectiveness of bronchial thermoplasty for patients with severe asthma? SR and HTAs - clinical effectiveness The SR and the two HTAs included in this report examine clinical effectiveness data from three RCTs.1,3,4,19-21 The SR included an MA of data from these three clinical trials.3 Statistically significant improvements in AQLQ were identified when results from the three RCTs were pooled.3 No significant difference in symptomatic control, as measured by ACQ, or the use of rescue medication was observed in the pooled data.3 Another MA, included in one HTA, also found statistically significant improvements in AQLQ when RCT results were pooled.4 The most recent RCT (AIR2)21 included a sham control, whereas the previous RCTs19,20 used SC as a comparator. When compared to SC, BT produced statistically significant improvements in these three clinical effectiveness outcomes. Results of the AIR2 trial, using a sham control, did not demonstrate statistically significant improvements in AQLQ, ACQ, or use of rescue medication.1,3,4 The SR and HTAs reported that the results of this RCT suggested a large placebo effect of the control treatment as improvements in the subjective measures of AQLQ were observed in both BT and sham control groups.1,3,4 However, the SR and one HTA also reported that significantly more participants in the BT group of the AIR2 trial showed a minimal clinically important difference (MCID) in AQLQ improvement (0.5 or greater) as compared to the sham control.3,4 The AIR2 trial also found that 21% of the BT treatment arm patients did not achieve clinically meaningful improvements in quality of life, which perhaps reflected unknown heterogeneity in the patient population.3 The included HTAs reported statistically significant


improvements in AQLQ, ACQ, and rescue medication use when compared to SC in the AIR and RISA RCTs.1,4 The HTAs, like the SR, also reported that these differences were not significant in the sham controlled RCT.1,3,4 The SR referred to the reduction of severe exacerbations per year per patient as statistically significant as well as the proportion of patients that experienced severe exacerbations during the 12 months study.3 The HTA from ECRI also reported a statistically significant difference in the rate of severe exacerbations per week in the 12 month follow-up of 0.22 (95% confidence interval [CI]: 0.20 to 0.24).1 The difference was not reported as statistically significant in the other HTA using the statistical analysis criteria of the AIR2 trial.4,21 The HTAs also reported no statistically significant differences in prebronchodilator FEV1,

4 postbronchodilator FEV1,4 or percent symptom free days in the included RCTs.1,4

SR and HTAs - adverse events Analysis of the pooled trial data from the three RCTs identified a statistically significant increased number of hospitalizations for respiratory adverse events in the BT treatment arm during the treatment period.3 The treatment period was defined as the time between the first BT treatment and six weeks after the last treatment, a total of twelve weeks. The definition of treatment period was unclear in some cases and was also reported as six weeks.1,3 When RCT data was pooled, the SR found that 6% of BT patients (95%CI: 1 to 21) required hospitalization during the treatment period due to respiratory adverse events. The MA included in one HTA also found that when RCT results were pooled the relative risk (RR) for hospitalization was greater for BT patients during the treatment period (RR 3.8, (95% CI 1.4 to 10.2).4 Adverse events from the RCTs, as reported by the included HTAs greater frequency of hospitalization due to respiratory adverse events in the BT treatment arm during the treatment period in the AIR2 trial,1,4,21 and RISA trial.1,20 Evidence of statistical significance of this finding was provided by the ECRI HTA.1 The ECRI HTA also included adverse events categorized by severity and reported a greater percentage of severe adverse events during the BT treatment period in all three RCTs. The severe adverse events associated with BT included severe exacerbation of asthma, partial collapse of a lung lobe, pleurisy, chest infection, shortness of breath, segmental atelectasis, lower respiratory infection, hemoptysis, and aspirated prosthetic tooth.1 Moderate adverse events were also reportedly greater during BT treatment in the AIR2 trial. An analysis of the significance of this data was not presented. The HTA from the ECRI institute provided some data on the type of adverse events observed during the treatment period, some of the data was provided by the manufacturer, Boston Scientific (Marlborough, MA, USA). It was not clear if this data was available to the authors of the other studies included in this report. Dyspnea, wheezing, cough, chest discomfort, night awakenings, productive cough, and discoloured sputum were significantly more common in the BT treatment group during the treatment period in the AIR trial. Wheezing, cough, chest discomfort and discoloured sputum were significantly more common in the RISA trial, while cough and chest discomfort were significantly more common in the AIR2 trial in the BT treatment group during the treatment period. Night awakenings were not reported in the RISA trial or the AIR2 trial, and discoloured sputum was not reported in the AIR2 trial.1 There was no statistically significant difference in the risk of hospitalization after the treatment period between treatment groups when results of the three RCTs were pooled.3,4 In the AIR2 trial a decreased rate of respiratory related hospitalizations experienced by the BT treatment group after the treatment period was statistically significant.1 The proportion of patients requiring Emergency Department (ED) services reported in the AIR2 trial in the 12 month post-treatment period was significantly greater in the sham group than the


BT treatment group (15.3% vs 8.4%).3 The ECRI HTA reported this outcome as ED visits/patient/year. The BT treatment group had 0.07 ED visits/patient/year whereas the control had 0.43 visits/patient/year and was a statistically significant difference using the criteria of the RCT.1,21 ED visits were not statistically significantly different between treatment groups in one SC controlled trial.1,3 Five year follow-up data did not include data from the control group except for the first three years of the AIR trial. The AIR trial follow-up data did not identify large differences between groups in this timeframe beside an increased number of patient ED visits in the control group (12.5% vs 6.7%) during the second year after BT treatment. This result was not statistically significant.4,22 Follow-up data from the RISA trial did not include control group data, however a decreased frequency of ED visits for respiratory symptoms was maintained for 5 years as compared to the year before treatment. Again, this difference was not statistically significant. The data demonstrated no increase in respiratory related adverse events in any of the following five years.1,3,4,23 Five year follow-up data on the AIR2 trial also demonstrated no increased adverse events.1,3,4,24 Also, the data compared the severe exacerbation rate in years two to five with the first year of BT treatment, with a predetermined noninferiority margin of 20%, and demonstrated a durable decrease in the severe exacerbation in all four years.4,24 What is the cost-effectiveness of bronchial thermoplasty for patients with severe asthma?

Economic studies The cost-effectiveness study reported an ICER of US$5 495 per QALY of BT compared to SC in a patient population with poorly controlled severe, persistent asthma that required at least one ED visit in the past 12 months. If the requirement for an ED visit in the past 12 months is not used for poorly controlled, severe persistent asthma patients the cost per QALY increases to US$62 922. Therefore the ICER of BT in this study depended upon decreased ED visits. The Markov model developed in this study also demonstrated sensitivity to the cost of the BT procedure and the rate of hospitalizations. Probabilistic sensitivity analyses found that BT reduced costs and increased QALYs in 21.5% of iterations. These analyses also demonstrated an ICER of less than US$50 000/QALY in 45% of iterations. The authors conclude that using BT in patients who had one or more hospitalizations within a year would be cost-effective at US$5 500/QALY.10 The budget impact analysis found that in a mixed cohort of asthma patients that required different treatment for different asthma indications, savings could be realized by introducing BT to OMAL non-responders and patients on SC who were contraindicated for OMAL. These savings were realized in three or four years after BT introduction depending upon the proportion of patients treated with BT and the cost of the BT procedure. Five years after the introduction of BT to the study setting of with 18 146 patients €19 920 849 in savings was estimated. Rates of resource consumption did not greatly impact the estimated savings in this analysis.11 What are the evidence-based guidelines regarding the use of bronchial thermoplasty for patients with severe asthma?


Guidelines Refer to Appendix 4, Table A4.3 for BT guidelines quoted from the guideline development groups. For evidence levels and grades of recommendations used below refer to Appendix 2, Table A2.3. Guidelines from GINA were for highly-selected patients who have uncontrolled asthma despite recommended therapeutic regimens and referral to as asthma specialty center. Highly-selected patients in these recommendations were not further defined. The evidence supporting the recommendation for use of BT in patients satisfying this criteria was assigned an Evidence Level B. These guidelines had a global perspective and mentioned in this recommendation that BT is only available in some countries. The guidelines also recommend caution in patient selection because of the limited data available on BT and assigned this recommendation an Evidence D.2 The SIGN guidelines included a grade A recommendation for use of BT treatment in adult patients with poorly controlled asthma despite optimal therapy. Supporting evidence statements were provided and assigned a level of evidence. The statement that BT has been shown to reduce the frequency of severe asthma attacks, ED visits and days lost from school or work in the year after treatment, cited the AIR2 trial and was assigned a level of evidence of 1++. The statement that BT results in a modest improvement in asthma quality of life in the year after treatment was assigned a level of evidence of 1++. The statement that BT produces no consistent improvement in asthma symptoms or FEV1, and at best a very small increase in peak expiratory flow were assigned a level of evidence of 1++ and 1+, respectively. The statement that BT results in increases in asthma-related symptoms and hospital admissions during the treatment period, and despite this there is no overall increased rate of hospital admission with BT at one year was assigned a level of evidence of 1++. The statement that there is some evidence for the long-term safety of BT for up to five years post-treatment was assigned a level of evidence of 1+. Four additional recommendations graded Good Practice Points accompanied the grade A recommendation. These recommendations are in regard to what centres are suitable to use BT, that patients should be aware of risks and benefits of the procedure, that longer term follow-up of BT patients should be conducted, and that further research is required to precisely determine the indications that would most benefit from BT.13 The strong recommendation from the ERS/ATS is that BT is only suitable for adult patients with severe asthma in the context of an Institutional Review Board approved independent systematic registry or clinical study. This recommendation was graded as strong but supported by a very low quality of evidence as determined by ERS/ATS. The recommendation was accompanied by a values and preferences statement that a higher value was placed on avoiding adverse effects, avoiding increased resource use, and the lack of understanding on which patients would benefit most from BT. The values and preferences also stated that a lower value was placed on the ―uncertain improvement in symptoms and quality of life.‖ The ERS/ATS guidelines also remark on low confidence in the currently available estimates of BT effects in severe asthmatic patients, and remark that long-term consequences are unknown. It was remarked that further research is encouraged and that it will likely have an important impact on the recommendation from ERS/ATS.12 One recommendation for the use of BT was formulated in the British Thoracic Society guidelines along with one good practice point. The recommendation was assigned the highest grade and stated that BT is a possible treatment option for selected patients with severe


persistent asthma that are already on maximal therapy. The recommendation acknowledged that the place of BT in the treatment of asthma remains to be established, and the good practice point continues to acknowledge that long-term safety and efficacy remains unclear. The good practice point also recommends, based upon expert opinion, that BT be limited to specialist centers and carefully selected patients. Long-term follow-up of BT patients is also an expert opinion recommendation from the British Thoracic Society.27 Limitations Identified evidence included in this report is derived from the same three RCTs, therefore results are not exclusive and the overall quantity of evidence should not be overestimated. These RCTs were funded by the manufacturer and had potential for conflict of interest. Two RCTs did not have any methods of blinding for assessment or for trial participants and a significant placebo effect was identified in the blinded trial. Results of the unblinded trials were therefore prone to performance bias. The included economic analyses may have had limited applicability to a Canadian healthcare setting due to differences in costs and perspective.10,11 The guidelines may also have had limited Canadian applicability due to differences in the availability of BT and qualified personnel. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING The evidence for the clinical effectiveness of BT in patients with severe asthma identified in this report is based upon three RCTs, two published in 2007 and one published in 2010, and the continued follow-up of BT patients from these trials.19-21,23-25 Analysis of these RCTs and follow-up studies was identified in one SR and two HTAs included in this report.1,3,4 The SR had very few important limitations, however it referred to findings as significant without providing a statistical analysis.3 The HTAs were also well conducted but did not provide any information on potential COIs.1,4 The data was presented and analyzed differently in these three articles. Quality of life, as measured by AQLQ, demonstrated a large placebo effect and a difference above the MCID was not detected.5 The evidence suggested a modest benefit of BT, when post-hoc analysis found a statistically significant greater proportion of BT patients achieving an MCID benefit by AQLQ.3,4 A large percentage of BT patients (21%) did not achieve any meaningful quality of life improvements, which suggested the potential for improved patient selection for this intervention.1,3,4 ACQ and the use of rescue medication did not demonstrate consistent improvements in the BT treatment group between trials or in pooled data.1,3,4 The evidence for statistically significant reductions in the number of severe exacerbations per severe asthma patient treated with BT per year was also inconsistent.1,3,4,19,21 The trials also did not identify significant improvements in pulmonary function parameters.1,4 There was some consensus in the identified evidence of a statistically significant increased risk of respiratory related adverse events requiring hospitalization for BT patients during the treatment period.1,3,4 The majority of these adverse events were mild or moderate.1,3,4 The RCT data suggested that during the first year there was no difference in the rate of hospitalizations for respiratory adverse events for BT patients as compared to controls when the treatment period is included.3 Evidence for a statistically significant reduction in these adverse events was observed in the 12 month follow-up period when the treatment period was excluded was mixed.1,3,4 ED visits after the treatment period were reduced in patients that received BT treatment as compared to sham control,1,3,4 but not when compared to SC in one trial.1,3 One HTA noted that one sham patient had nine hospitalizations after the treatment period, and it was


not clear how much this patient may have also contributed to ED visits, or severe exacerbations.1 Long-term data of BT patients five years after treatment from one trial was limited due to loss to follow-up, 47% of controls were followed for three years in the AIR trial, and suggest similar rates of adverse events. No comparative data was available for the other two trials, however the adverse event rates support long term safety of BT.1,4 Together the analyses suggest a tradeoff for BT treatment for adult patients with severe asthma. Mostly mild to moderate adverse events experienced during the treatment period may have resulted in decreased ED visits and severe exacerbations in the post treatment period. The decreased exacerbations and use of ED resources observed in the AIR2 trial was a key driver in the industry funded cost-effectiveness study. The modelled cost-effectiveness of BT relied on decreasing resource use associated with exacerbations, ED visits, and selection of BT for patients who would use these resources. If patients who would have used these resources were selected, the ICER of BT as compared to SC was US$5 495/QALY while less selective use of BT results in an ICER of US$62 922/QALY when compared to SC, according to the model. This study was well described and provided sources for most utility values and costs.10 The cost-effectiveness analysis found that BT costs over 5 years are greater than that of SC, while the budget impact analysis found that savings could be realized over this same time period by introduction of BT in a mixed population of severe, uncontrolled asthma patients. Costs of the BT procedure and the percentage of patients selected for BT were the most significant contributors to costs in the budget impact analysis. This analysis also had a potential COI, and was possibly limited in generalizability due to sources for estimated costs and the specific healthcare setting.11 The guidelines for BT were unclear with regard to specific indications for BT treatment.2,12,13,27 Two of the four identified guidelines provided statements that further research may improve BT patient selection.2,13 Two sets of guidelines, with few important limitations, strongly recommended considering BT in adult patients with poorly controlled asthma despite optimal therapy.13,27 One of these guidelines qualified by this recommendation by stating that expert opinion supported BT in a few specialist centres in carefully selected patients due to unclear long-term safety and efficacy.27 Another set of guidelines, with more important limitations, strongly recommended that BT only be used in a clinical study, or in an approved independent systematic registry.12 Three of four guidelines identified in this report provided conditional recommendations for the use of BT in adult patients with poorly controlled asthma despite optimal conventional therapy.2,13,27 All recommendations all acknowledge that further research is required to better establish which patients would benefit most from BT.2,12,13 PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca

http://www.cadth.ca/


ABREVIATIONS ACQ Asthma Control Questionnaire AQLQ Asthma Quality of Life Questionnaire BT bronchial thermoplasty ED emergency department FEV1 forced expiratory volume in the first second FU follow-up GINA Global Initiative for Asthma HTA health technology assessment ICER incremental cost-effectiveness ratio ICS inhaled corticosteroids LABA long-acting β2-agonists MA meta-analysis MCID minimal clinically important difference MD mean difference NR not reported NS not statistically significant OMAL omalizumab pr posterior probability of superiority PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses QALY quality adjusted life year QoL quality of life RCT randomized controlled trial RR relative risk SC standard care SD standard deviation SR systematic review UK United Kingdom


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10. Cangelosi MJ, Ortendahl JD, Meckley LM, Bentley TG, Anene AM, Shriner KM, et al. Cost-effectiveness of bronchial thermoplasty in commercially-insured patients with poorly controlled, severe, persistent asthma. Expert Rev Pharmacoecon Outcomes Res. 2015 Apr;15(2):357-64.

11. Menzella F, Zucchi L, Piro R, Galeone C, Castagnetti C, Facciolongo N. A budget impact analysis of bronchial thermoplasty for severe asthma in clinical practice. Adv Ther. 2014 Jul;31(7):751-61.

12. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J [Internet]. 2014 Feb [cited 2015 Jul 31];43(2):343-73. Available from: http://erj.ersjournals.com/content/43/2/343.full.pdf+html

13. Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. A national clinical guideline [Internet]. Edinburgh, Scotland: SIGN; 2014 Oct. [cited 2015 Jul 31]. (SIGN 141). Available from: http://www.sign.ac.uk/pdf/SIGN141.pdf

14. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol [Internet]. 2009 [cited 2015 Aug 7];62(10):e1-e34. Available from: http://ac.els-cdn.com/S0895435609001802/1-s2.0-S0895435609001802-main.pdf?_tid=2c251712-3d34-11e5-8cba-00000aab0f01&acdnat=1438973179_fe277816dd89bbfbb0dbc037bc459f08

15. Pretolani M, Dombret MC, Thabut G, Knap D, Hamidi F, Debray MP, et al. Reduction of airway smooth muscle mass by bronchial thermoplasty in patients with severe asthma. Am J Respir Crit Care Med. 2014 Dec 15;190(12):1452-4.

16. Bronchial thermoplasty for treatment of asthma. Lansdale (PA): Hayes; 2014. Available from: http://www.hayesinc.com/hayes/htareports/directory/alair-bronchial-thermoplasty-system-for-treatment-of-asthma/

17. Saint Jacques A. Spirometric response to bronchial thermoplasty in patients with severe asthma [Internet]. Fort Washington (PA): MDLinx; 2014 Oct 29. [cited 2015 Aug 10]. (Conference reports. CHEST 2014: American College of Chest Physicians Annual Meeting, Austin TX). Available from: http://www.mdlinx.com/pulmonology/conference-abstract.cfm/30081/?conf_id=50069&searchstring=&coverage_day=0&nonus=0&page=6

18. Kiran S, Ajay S, Tammy K, Kozlowski J, Wilson B, Schechtman K, et al. Predictors of bronchial thermoplasty response in patients with severe refractory asthma. Am J Respir Crit Care Med [abstract on the Internet]. 2014 May 1 [cited 2015 Aug 10];189(2014):A2429. Available from: http://dx.doi.org/10.1164/ajrccm-conference.2014.189.1_MeetingAbstracts.A2429 (Presented at American Thoracic Society International Conference).

http://erj.ersjournals.com/content/43/2/343.full.pdf+htmlhttp://www.sign.ac.uk/pdf/SIGN141.pdfhttp://ac.els-cdn.com/S0895435609001802/1-s2.0-S0895435609001802-main.pdf?_tid=2c251712-3d34-11e5-8cba-00000aab0f01&acdnat=1438973179_fe277816dd89bbfbb0dbc037bc459f08http://ac.els-cdn.com/S0895435609001802/1-s2.0-S0895435609001802-main.pdf?_tid=2c251712-3d34-11e5-8cba-00000aab0f01&acdnat=1438973179_fe277816dd89bbfbb0dbc037bc459f08http://ac.els-cdn.com/S0895435609001802/1-s2.0-S0895435609001802-main.pdf?_tid=2c251712-3d34-11e5-8cba-00000aab0f01&acdnat=1438973179_fe277816dd89bbfbb0dbc037bc459f08http://ac.els-cdn.com/S0895435609001802/1-s2.0-S0895435609001802-main.pdf?_tid=2c251712-3d34-11e5-8cba-00000aab0f01&acdnat=1438973179_fe277816dd89bbfbb0dbc037bc459f08http://www.hayesinc.com/hayes/htareports/directory/alair-bronchial-thermoplasty-system-for-treatment-of-asthma/http://www.hayesinc.com/hayes/htareports/directory/alair-bronchial-thermoplasty-system-for-treatment-of-asthma/http://www.mdlinx.com/pulmonology/conference-abstract.cfm/30081/?conf_id=50069&searchstring=&coverage_day=0&nonus=0&page=6http://www.mdlinx.com/pulmonology/conference-abstract.cfm/30081/?conf_id=50069&searchstring=&coverage_day=0&nonus=0&page=6http://dx.doi.org/10.1164/ajrccm-conference.2014.189.1_MeetingAbstracts.A2429http://dx.doi.org/10.1164/ajrccm-conference.2014.189.1_MeetingAbstracts.A2429


19. Cox G, Thomson NC, Rubin AS, Niven RM, Corris PA, Siersted HC, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med [Internet]. 2007 Mar 29 [cited 2015 Aug 12];356(13):1327-37. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa064707

20. Pavord ID, Cox G, Thomson NC, Rubin AS, Corris PA, Niven RM, et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med. 2007 Dec 15;176(12):1185-91.

21. Castro M, Rubin AS, Laviolette M, Fiterman J, De Andrade LM, Shah PL, 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 [Internet]. 2010 Jan 15 [cited 2015 Aug 18];181(2):116-24. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269231

22. Thomson NC, Rubin AS, Niven RM, Corris PA, Siersted HC, Olivenstein R, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med [Internet]. 2011 [cited 2015 Aug 19];11:8. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3045390

23. Pavord ID, Thomson NC, Niven RM, Corris PA, Chung KF, Cox G, et al. Safety of bronchial thermoplasty in patients with severe refractory asthma. Ann Allergy Asthma Immunol. 2013 Nov;111(5):402-7.

24. Wechsler ME, Laviolette M, Rubin AS, Fiterman J, Lapa e Silva JR, Shah PL, et al. Bronchial thermoplasty: long-term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol [Internet]. 2013 Dec [cited 2015 Aug 18];132(6):1295-302. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4114404

25. Castro M, Rubin A, Laviolette M, Hanania NA, Armstrong B, Cox G, et al. Persistence of effectiveness of bronchial thermoplasty in patients with severe asthma. Ann Allergy Asthma Immunol. 2011 Jul;107(1):65-70.

26. Wu Q, Xing Y, Zhou X, Wang D. Meta-analysis of the efficacy and safety of bronchial thermoplasty in patients with moderate-to-severe persistent asthma. J Int Med Res. 2011;39(1):10-22.

27. Du Rand IA, Barber PV, Goldring J, Lewis RA, Mandal S, Munavvar M, et al. British Thoracic Society guideline for advanced diagnostic and therapeutic flexible bronchoscopy in adults. Thorax. 2011;66(Suppl 3):iii1-21.

http://www.nejm.org/doi/full/10.1056/NEJMoa064707http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269231http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3045390http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4114404


APPENDIX 1: Selection of Included Studies

31 citations excluded

15 potentially relevant articles retrieved for scrutiny (full text, if

available)

19 potentially relevant reports retrieved from other sources (grey

literature, hand search)

34 potentially relevant reports and 11 potentially relevant reports from Summary of

Abstracts

36 reports excluded: -irrelevant outcomes (1) -original CADTH report (1) -reviews (10) -duplicates (6) -unavailable (3) -press releases (2) -insurance benefit rationales (3) -case study (1) -correspondence (3) -already included in at least one of the selected systematic reviews (6)

9 reports included in review

46 citations identified from electronic literature search and screened


APPENDIX 2: Summary of Study Characteristics

Table A2.1: Summary of Study Characteristics of Included SR, and HTAs Study Design Population

(sample size) Intervention Comparator(s) Outcomes

Systematic Review

Torrego et al., 20143

SR: (3 RCTs) FU: 12 months

Adult patients with asthma (n = 429)

BT and SC Any active control (standard of care medical management or sham intervention)

• AQLQ • ACQ • Medication use • Adverse events -hospitalizations

Health Technology Assessments

Grant et al., 20154

HTA: (1MA, 3 RCTs) FU: 5 years

Adult patients with inadequately controlled severe persistent asthma (n = 429)

BT and best medical care

Best medical care

• AQLQ • ACQ • Number of exacerbations • Medication use • FEV1 • Percentage symptom-free days • Adverse events -hospitalizations -respiratory adverse events

ECRI Institute, 20141

HTA: (3 RCTs) FU: 5 years

Adult patients with severe symptomatic asthma (n = 429)

BT and SC • SC • SC with OMAL • Standard care with oral corticosteroids

• AQLQ • ACQ • Number of exacerbations • Medication use • Percentage symptom-free days • Adverse events -hospitalizations -severe, moderate, and mild adverse events -long-term adverse events/patient/year

ACQ=Asthma Control Questionnaire; AQLQ= Asthma Quality of Life Questionnaire; BT=bronchial thermoplasty; FEV1=forced expiratory volume in the first second; FU=follow-up; HTA=health technology assessment; ICS=inhaled corticosteroids; LABA=long-acting β2-agonists; MA=meta-analysis; OMAL=omalizumab; QoL=quality of life; RCT=randomized controlled trial; SC=standard care; SR=systematic review;


Table A2.2: Summary of Study Characteristics of Included Cost-Effectiveness Studies

Type of

Economic

Evaluation,

Perspective,

Time

Patient Population Comparison Outcomes Assumptions

Cangelosi et al., 201510

Cost-

effectiveness

study

Private,

commercial

payer

perspective in

USA

FU: 5 years

Poorly controlled,

severe, persistent

asthma patients

treated with BT and

SC (ICS and LABA

with additional

controller

medications as

necessary (e.g.,

leukotriene

modifiers)

Poorly controlled,

severe, persistent

asthma patients

treated with SC

(ICS and LABA

with additional

controller

medications as

necessary (e.g.,

leukotriene

modifiers)

• Costs

-treatment

-physician visits

-hospitalizations

-ER visits

-medications

-adverse events

• 5 year cost

• 5 year QALY

• ICER

($US/QALY)

• Assumed a

subgroup of

patients requiring

prior

hospitalization will

have equivalent

clinical outcomes

as entire patient

cohort of RCT

• Markov model of

hypothetical

cohort

• Use of

maintenance

medication use

equivalent across

treatment arms

Menzella et al., 201411

Budget impact

analysis

Italian regional

healthcare

service

perspective

FU: 5 years

Severe, uncontrolled

asthma patients with

40% non-respondent

OMAL patients using

BT and 5% of SC

patients using BT.

Severe,

uncontrolled

asthma patients

treated with

OMAL and SC

(20%), and SC

alone (80%).

• Costs

-treatment

-physician visits

-hospitalizations

-ER visits

-medications

-severe adverse

event costs

• 5 year costs

• BT or OMAL

treatment would

not decrease

maintenance

medications

• Three BT

sessions per

patient all in the

first year

• OMAL 75%

receive one

injections/month,

25% receive two

injections/month

• BT, SC,

specialist visit

costs estimated

BT=bronchial thermoplasty; FU=follow-up; ICER=incremental cost-effectiveness ratio; ICS=inhaled corticosteroids; LABA=long-

acting β2-agonists; OMAL=omalizumab; QALY=quality adjusted life year; RCT=randomized clinical trial; SC=standard care;


Table A2.3: Summary of Study Characteristics of Included Guidelines

Origin,

Publication

Date

Interventions of

Interest

Evidence Levels and

Recommendation Grading

Target

Population

FitzGerald et al., 20152

Global

Initiative for

Asthma

(GINA)

May 19, 2015

A very broad focus on

interventions for

asthma in many

different patient

populations.

Recommendations for

BT are for highly-

selected adult patients

with uncontrolled,

severe asthma despite

use of recommended

therapeutic regimens.

Evidence Levels:

A: Consistent evidence from RCTs and

MAs involving a substantial number of

participants

B: Limited evidence from RCTs and

MAs

C: Evidence is from non-randomized

controlled trials and/or observational

studies

D: Panel consensus judgement

Health

professionals and

policy makers.

SIGN, 201413

Scottish

Intercollegiate

Guidelines

Network

Revised in

2014

A very broad focus on

interventions for

asthma in many

different patient

populations.

Recommendations for

BT are for selected

adult patients with

moderate to severe

asthma (aged 18–65

years) who have

poorly controlled

asthma despite

maximal therapy.

Levels of Evidence: 1++: High quality MAs, systematic reviews of RCTs or RCTs with very low bias risk 1+: Well conducted MAs, systematic reviews of RCTs or RCTs with low bias risk 1-: MAs, systematic review of RCTs or RCTs with high bias risk 2++: High quality systematic reviews of case control or cohort studies with very low bias risk 2+: Well conducted case control or cohort studies with low bias risk 2-: Case control or cohort studies with high bias risk and/or significant risk that relationship is not causal 3: non-analytic studies 4: expert opinion Grades of Recommendation: A: At least one MA, systematic review of RCTs or RCT rated as 1++, consistent evidence rated as 1+ B: Evidence overall consistent studies of 2++, or extrapolated evidence from 1++ or 1+ C:Evidence overall consistent studies of 2+, or extrapolated evidence from 2++ D: Evidence 3 or 4, or extrapolated evidence from 2+ Good practice point: Expert opinion

Healthcare

professionals

involved in the

care of patients

with asthma,

people with

asthma,

parents/carers

and those who

interact with

people with

asthma (e.g.,

teachers), those

planning

delivery of

healthcare

services to

patients with

asthma in

England, Wales,

Northern Ireland

and Scotland.



Origin,

Publication

Date

Interventions of

Interest

Evidence Levels and


Target

Population

Chung et al., 201412

European

Respiratory

Society

(ERS)/Americ

an Thoracic

Society (ATS)

April 2014

A broad focus on

interventions for

asthma in many

different patient

populations.

Recommendations are

for adult patients with

severe asthma

Quality of Evidence:

High: RCTs or very high quality,

consistent observational studies

Moderate: RCTs with limitations or high

quality observational studies

Low: RCTs with significant limitations or

observational studies

Very Low: RCTs with very significant

limitations or observational studies with

limitations or case series/case reports

Grades of Recommendation: Strong: Patients would want

recommended course of action.

Clinicians adherence to

recommendation could be used as a

quality criterion or performance

indicator. Policy makers the

recommendation can be adopted as

policy in most situations

Conditional: Patients majority would

want suggested course of action but

many would not. Clinicians’ difference

choices are appropriate for individual

patients. Decision aids may be useful.

Policy makers requires substantial

debate and involvement of various

stakeholders.

Specialists in

respiratory

medicine, allergy

managing adults

and children with

severe asthma,

general internists,

paediatricians,

primary care

physicians, other

healthcare

professionals, and

policy makers.

British Thoracic Society, 201127

National

Guideline

Clearinghouse

,

British

Thoracic

Society

November

2011

Focused on guidelines

for diagnostics and

therapeutic procedures

for bronchoscopy in

adults

1++: High quality MAs, systematic reviews of RCTs or RCTs with very low bias risk 1+: Well conducted MAs, systematic reviews of RCTs or RCTs with low bias risk 1-: MAs, systematic review of RCTs or RCTs with high bias risk 2++: High quality systematic reviews of case control or cohort studies with very low bias risk 2+: Well conducted case control or cohort studies with low bias risk

Intended

information for

health

professionals in

the UK to share

with patients



Origin,

Publication

Date

Interventions of

Interest

Evidence Levels and


Target

Population

2-: Case control or cohort studies with high bias risk and/or significant risk that relationship is not causal 3: non-analytic studies 4: expert opinion Grades of Recommendation: A: At least one MA, systematic review of RCTs or RCT rated as 1++, consistent evidence rated as 1+ B: Evidence overall consistent studies of 2++, or extrapolated evidence from 1++ or 1+ C:Evidence overall consistent studies of 2+, or extrapolated evidence from 2++ D: Evidence 3 or 4, or extrapolated evidence from 2+ Good practice point: Expert opinion

BT=bronchial thermoplasty; GINA=Global Initiative for Asthma; MA=meta-analysis; RCT=randomized clinical trial; UK=United

Kingdom;


APPENDIX 3: Summary of Critical Appraisal

Table A3.1: Critical Appraisal Summary for SR/HTAs using AMSTAR tool7

Strengths Limitations

Systematic Review


• Literature search, inclusion, exclusion methodology provided • Data extraction methodology provided • Study selection and data extraction done in duplicate by independent reviewers • PRISMA flowchart of study inclusion and exclusion • Assessment of included study quality and

funding sources

• Research objective and patient population defined • Tabulated study characteristics • Examined reported adverse events

• Statistical methods reported

• Quantified conclusions

• Analyzed pooled results - meta-analyses

• Examined study heterogeneity

• Statement of no financial COI

• Publication bias assessment and sensitivity

analysis not conducted - due to number of studies

available

• Statistical significance of some findings unclear


Grant et al., 20154

• Literature search, inclusion, exclusion methodology provided • Data extraction methodology provided • PRISMA flowchart of study inclusion and exclusion • Assessment of included study quality and

potential COIs

• Research objective and patient population defined • Tabulated study characteristics • Examined reported adverse events


• Examined regulatory status, guidelines, and ongoing registered clinical trials • Identified evidence gaps for potential future research

• Results not pooled • Study selection and data extraction by a single reviewer • No mention of publication bias • No COI statement


• Literature search, inclusion, exclusion methodology provided • Assessment of included study quality and

potential COIs

• Research objective and patient population defined • Tabulated study characteristics

• No data extraction methodology provided • Unclear if study selection or data extraction was duplicated independently • No flowchart of study inclusion and exclusion • Results not pooled • No mention of publication bias • No COI statement


Table A3.1: Critical Appraisal Summary for SR/HTAs using AMSTAR tool7


• Examined reported adverse events


• Examined regulatory status, guidelines, and ongoing registered clinical trials • Examined cost-effectiveness

COI=conflict of interest; PRISMA=Preferred Reporting Items for Systematic Reviews and Meta-Analyses;

Table A3.2: Critical Appraisal Summary for Included Economic Studies using

Drummond’s Checklist8


Cost-Effectiveness

Cangelosi et al., 201510

• Explicit objective

• Relevant comparator (standard care w/o

omalizumab)

• Most costs available from published sources

• Sensitivity analyses performed

• Well described methodology

• Modelled costs over five years

• Incremental cost data

• Utility values from published source

• Accounted for costs of adverse events

• Clinical outcomes for model based upon single

RCT without selection criteria

• Analyzed a subgroup of patients for which clinical

outcome data was unavailable

• Omalizumab intervention not included in analysis

• Costs of BT, including physician and procedure

costs, from unpublished sources

• Manufacturer funded study

Menzella et al., 201411

• Explicit objective • Assesses budget impact of BT implementation on a patient population • Relevant comparators (standard care and

standard care with omalizumab)

• Sensitivity analyses performed

• Well described methodology

• Costs over five years

• Accounted for costs of adverse events

• No citations, only estimates from a single center,

given for costs of standard care, OMAL treatment,

BT procedure, ED visits, or specialist visits

• Costs may have limited generalizability outside

Italian regional setting

• No cost-effectiveness analysis only examined

budget impact of BT implementation

• Acknowledged COI

BT=bronchial thermoplasty; ED=ED; COI=conflict of interest


Table A3.3: Critical Appraisal Summary for Included Guidelines using AGREE II tool9


Guidelines

FitzGerald et al., 20152

• Guideline development methodology

described

• Literature search methods described

• Two reviewers used for study selection

• Recommendations linked to a level of

evidence

• Guideline update process outlined

• Guideline implementation strategies provided

• Target audience described

• Limitations of recommendations described

• Broad focus on asthma and global patient

population

• Literature search methodology lacked specificity to

BT

• Study selection methods lacked objectivity

• Cited source for evidence level of BT

recommendations was SIGN guidelines,13

although

the AIR2 trial is in bibliography

• Unclear patient population in BT recommendations

• Potential COIs of committee members only

available in separate source

• Limited stakeholder representation

SIGN, 201413

• Guideline development outlined

• Literature search and selection methods

described


• Well described and established levels of

evidence and grades of recommendations

• Grades of recommendations linked to a level

of evidence

• Patient population for BT recommendations

described

• Supporting evidence for recommendations

clear

• Target audience well described

• Guideline update process outlined

• Guideline implementation strategies provided

• Limitations of recommendations described

• Broad focus on asthma


BT

• Potential COIs of committee members only

available in separate source


Chung et al., 201412


of evidence

• Patient population for BT recommendations

described


• Methods used to avoid COIs outlined

• Broad focus on asthma

• Vague evidence levels and grade of

recommendations

• Literature search methodology available only in a

separate source

• Supporting evidence for recommendations unclear

• Lacks details on guideline development

methodology

• Guideline implementation, updating and limitations

vague



Table A3.3: Critical Appraisal Summary for Included Guidelines using AGREE II tool9


British Thoracic Society, 201127

• Guideline development outlined

• Literature search and selection methods

described


• Well described and established levels of

evidence and grades of recommendations


of evidence


of evidence

• Supporting evidence for recommendations

clear


• Formulation of guidelines included consultation

with various stakeholders

• Unclear patient population for BT

recommendations

• Potential COIs of committee members

acknowledged

• Guideline implementation strategies, updating and

discussion of limitations not provided


BT

BT=bronchial thermoplasty; COI=conflict of interest;


APPENDIX 4: Summary of Findings

Table A4.4: Summary of Main Findings and Author’s Conclusions of the Included

SR/HTAs

Main Findings Author’s Conclusions

Systematic Review


Clinical Effectiveness

AQLQ

BT vs control at 12 months follow-up (3 RCTs)19-21

MD (95% CI): 0.28 (0.07, 0.50) (I2=0.0%)

MD>0 favours BT

BT vs medical management at 12 months follow-up (2

RCTs)19,20

MD (95% CI): 0.44 (0.10, 0.79) (I2=0.0%)

MD>0 favours BT

BT vs sham BT at 12 months follow-up (1 RCT)21

MD (95% CI): 0.18 (-0.09, 0.45)

MD>0 favours BT

AQLQ > 0.5

BT vs sham BT at 12 months follow-up (1RCT) (pr = 0.979)* 21

BT 78.9%

Sham 64.3%

ACQ

BT vs control at 12 months follow-up (3 RCTs)19-21

MD (95% CI): -0.15 (-0.40, 0.10) (I2=0.0%)

MD



SR/HTAs


BT vs medical management at 12 months follow-up (2

RCTs)19,20

MD (95% CI): -2.65 (-11.24, 5.95) (I2=0.0%)

MD1 favours control

ED visits/patient/y after treatment period

BT Control/sham

AIR221

8.4% 15.3%

referred to as significant



SR/HTAs


ED visits/patient/y five year follow-up

Before BT Follow-up BT

RISA20,23

(p = NS) 0.36 0.12

* statistically significant when pr > 0.964 (2 interim analyses)


Grant et al., 20154


AQLQ score change (mean (SD))

BT Control/sham

AIR19

(p = 0.01) 1.3 (1.0) 1.1 (0.6)

RISA20

(p = 0.001) 1.53 (0.79) 0.42 (0.82)

AIR221

(pr = 0.960)* 1.35 (1.10) 1.16 (1.23)

AQLQ score change (mean (SD))

BT vs control at 12 months follow-up (1 MA)26

MD (95% CI): 0.63 (0.10, 1.15) (I2=1.0%)

MD>0 favours BT

AQLQ score improvement > 0.5 (mean (SD))

BT Control/sham

AIR221

(pr = 0.979)* 79% 64%

ACQ score (or change Δ) (mean (SD))

BT Control/sham

AIR19

(p = 0.001) 1.3(0.9) 1.7(0.4)

AIR221

(pr = 0.638)* Δ0.82(0.95) Δ0.77(1.08)

Severe exacerbations/year (SD)

BT Control/sham

AIR19

(NS) 0.01 (0.08) 0.06 (0.24)

AIR221

(pr = 0.955)* 0.48 (0.07) 0.70 (0.12)

Severe exacerbations per patient

AIR220,24

BT Sham

Year 1 (pr = 0.955)* 0.48 0.70

Year 2 0.41 NR

Year 3 0.55 NR

Year 4 0.56 NR

Year 5 0.31 NR

Using a noninferiority margin of 20%, the decreased

exacerbations was determined to be durable.


―Evidence from the 3 trials of BT

applicable to individuals with severe

persistent and inadequately

controlled asthma—a single trial

incorporated a sham control—is

accompanied by uncertainty

concerning the net health outcome.‖

―The substantial response observed

following a sham procedure in AIR2

emphasizes the necessity of a

sham control to estimate treatment

effects. Although a number of

outcomes in the AIR2 trial favored

BT, others did not, and for those

that did effect magnitudes could be

interpreted as modest.‖ (pp. 3)

Adverse Events

―BT is accompanied by a risk of

adverse events during the treatment

phase that may require

hospitalization—a tradeoff for

potential future benefit. Although

under conditions of controlled trials

and careful patient selection, the

morbidity from adverse events was

not described as concerning,

adoption outside those settings

where patient selection may be less

strict and providers less

experienced with the device could

be accompanied by a different

adverse event profile.‖(pp.3)



SR/HTAs


Rescue β2-agonist puff/week (or change Δ) (mean(SD))

BT Control/sham

AIR19

(p = 0.04) 11.0 (15.1) 15.0 (22)

RISA20

(p < 0.05) Δ -25.6 (31.2) Δ -6.1 (12.4)

AIR221

(pr = 0.813)* 7.4 (15.0) 7.5 (12.6)

FEV1 prebronchodilator (SD)

BT Control/sham

AIR19

(NS)

AIR221

(pr = 0.241)* 76.6% (17.7) 79.1% (16.0)

FEV1 postbronchodilator (SD)

BT Control/sham

AIR221

(pr = 0.371)* 83.4% (16.4) 83.4% (16.4)

Percent symptom-free days (% or change Δ(SD))

AIR19

(p = NR) 40.6% (39.7) 17.0% (37.9)

RISA20

(NS) Δ -21.6% (30.6) Δ -17.9% (43.4)

AIR221

(pr = 0.776)* 40.8% (38.2) 37.9% (37.0)

Adverse Events

Hospitalizations for respiratory adverse during treatment

period

BT Control/sham

AIR19

7.3%

RISA20

26.6%

AIR221

** 8.4% 2.0%

Hospitalizations for respiratory adverse events during

treatment period

BT vs control (1 MA)26

RR (95% CI): 3.8 (1.4, 10.2) (I2=0.0%)

RR>1 favours control

** one sham subject had nine hospitalizations

Hospitalizations for respiratory adverse events during post-

treatment period

BT vs control (1 MA)26

RR (95% CI): 1.2 (0.47, 2.8) (I2=0.0%)

RR>1 favours control

ED visits/patient/y after treatment period

BT Sham

AIR221

(pr = 0.999) 0.07 0.43



SR/HTAs


Respiratory adverse events/patient during follow-up

AIR19,22

BT Control

Year 1 4.5 3.1

Year 2 1.2 1.2

Year 3 1.3 1.3

Year 4 1.2

Year 5 1.1

RISA20,23

BT

Year 1

Year 2 1.4

Year 3 2.4

Year 4 1.7

Year 5 2.4

* statistically significant when pr > 0.964 (2 interim analyses)



AQLQ

BT vs control/sham at 12 months follow-up (MD (95% CI))

AIR19

0.70 (0.28, 1.12)

RISA20

1.11 (0.55, 1.67)

AIR221

0.21 (-0.025, 0.445)

MD>0 favours BT

ACQ

BT vs control/sham at 12 months follow-up (MD (95% CI))

AIR19

0.71 (0.31, 1.11)

RISA20

0.77 (0.21, 1.33)

AIR221

0.05 (-0.19, 0.29)

MD>0 favours BT

Rate of severe exacerbations per week

BT vs control sham at 12 months follow-up (MD (95% CI)

AIR19

0.03 (-0.06, 0.12)

RISA20

NR

AIR221

0.22 (0.20, 0.24)

MD>0 favours BT

Mean change in rescue medication use (doses/week)

BT vs control sham at 12 months follow-up (MD (95% CI)

AIR19

7.7 (0.4, 15.0)

RISA20

19.5 (3.4, 35.6)


―… only one of the trials blinded

patients to their treatment (i.e.,

AIR2), and both the treated and

sham control groups reported

clinically significant improvements in

these scores, suggesting a placebo

effect. Nonetheless, the AIR2 trial

results suggest a marginal

improvement in QOL for patients

receiving BT compared with sham

treatment.‖ (pp. 27)

Adverse Events

Documents

TITLE: Bronchial Thermoplasty for Severe Asthma: A Review ... · Bronchial Thermoplasty for Severe Asthma 5 to September 2014,1 and from an unspecified date to October 2014.4 The