Chest
Volume 146, Issue 1, July 2014, Pages 17-21
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Commentary
Bronchial Thermoplasty: Reappraising the Evidence (or Lack Thereof)

https://doi.org/10.1378/chest.14-0536Get rights and content

Bronchial thermoplasty (BT) involves the application of radiofrequency energy to visible proximal airways to selectively ablate airway smooth muscle. BT is the first nonpharmacologic interventional therapy approved by the US Food and Drug Administration (FDA) for severe asthma. This approval was based on the results of the pivotal Asthma Intervention Research (AIR)-2 trial, which is the only randomized, double-blind, sham-controlled trial of BT. The primary end point of the AIR-2 trial was improvement in the Asthma Quality of Life Questionnaire (AQLQ). The results of the AIR-2 trial have generated enormous interest, controversy, and confusion regarding the true efficacy of BT for severe asthma. Current marketing of BT highlights its use for patients with “severe” asthma, which is interpreted by most practicing clinicians as meaning oral corticosteroid dependence, frequent exacerbations, or a significantly reduced FEV1 with a poor quality of life. Did the AIR-2 trial include patients with a low FEV1, oral steroid dependence, or frequent exacerbations? Did the trial show efficacy for any of the primary or secondary end points? The FDA approved the device based on the reduction in severe asthma exacerbations. However, were the rates of asthma exacerbations, ED visits, or hospitalizations truly different between the two groups, and was this type of analysis even justified given the original study design? This commentary is designed to specifically answer these questions and help the practicing clinician navigate the thermoplasty literature with confidence and clarity. We carefully dissect the design, conduct, and results of the AIR-2 trial and raise serious questions about the efficacy of bronchial thermoplasty.

Section snippets

A Brief Overview of Airway Smooth Muscles and Thermoplasty

Thermoplasty involves applying radiofrequency energy to selectively ablate airway smooth muscle (ASM) in visible proximal airways (typically up to the subsegmental level). Early animal studies documented selective loss of ASM without significant fibrosis, epithelial injury, or structuring.3 The distal airways (< 2-3 mm in diameter) account for about 10% of the total airway resistance in a normal person. However, in asthma, there exists a continuum of inflammation all the way from the proximal

AIR-2 Trial Design

The AIR-2 trial was a high-quality multicenter (multinational) double-blind sham-controlled study that randomized patients with severe asthma on a 2:1 basis to bronchial thermoplasty vs sham thermoplasty. A total of 288 patients were analyzed, of which 190 subjects underwent bronchial thermoplasty and 98 subjects underwent sham thermoplasty (2:1 randomization). It is important to note that the sham procedure was elaborate and mimicked the actual thermoplasty procedure in every way except for

AIR-2 Trial Results: Primary and Secondary End Points

The primary end point of the AIR-2 trial was the change in the Asthma Quality of Life Questionnaire (AQLQ) from baseline to 12 months. The AQLQ has 32 items in four domains: activities (12 items), asthma symptoms (11 items), emotional function (five items), and environmental exposure (four items). The minimal clinically important difference for the AQLQ is determined to be 0.5 (range, 0.42-0.58), with higher scores (a greater positive change) indicating improved asthma-related quality of life

AIR-2 Trial Results: Unplanned Analysis of Health-care Use

The AIR-2 trial also reported on some other end points that had not been prospectively included in their planned analysis. These included unscheduled physician office visits, ED visits, and hospitalizations (Table 1). A quick look at Table 1 would make one realize that these three outcomes are interlinked. For example, a patient who was hospitalized was also likely to have visited the ED and also to be simultaneously classified as having had a severe asthma episode. This is a very important

Clinical vs Statistical Significance

How are we to interpret the AIR-2 results? As noted above, if one were to use routine frequentist statistical methods (eg, a t test), the AQLQ difference of 0.19 between the two groups would not reach statistical significance (P = .2).15 In fact, even in the AIR-2 trial, this primary end point did not reach statistical significance. The AIR-2 trial used Bayesian statistics to analyze the primary and secondary end points. The concept of posterior probability of success (PPS) was used their

Editorial Controversy

The original AIR-2 trial had an accompanying editorial that did point out flaws in the trial design (lack of run-in period) and results (statistical but lack of clinical significance regarding the AQLQ difference between groups).13 Very surprisingly, exactly 1 year after the original editorial, the same authors wrote an unsolicited letter to the editor sharply criticizing the AIR-2 trial design and reporting methodology.15 They rightfully pointed out that the outcomes based on which the FDA

Problems With the AIR-2 Postapproval Follow-up Studies

A number of post-approval safety and efficacy studies have been published, and we now have 5-year postthermoplasty safety and efficacy data.17, 18 The biggest criticism regarding these studies is the absence of any information regarding outcomes in the sham group. One must again recall the large improvement in AQLQ of 1.16 in the sham group. This beneficial effect was likely a result of the more diligent and protocol-driven asthma care they received as part of the AIR-2 trial. These benefits

Critical Importance of Having a Sham-Controlled Arm in Asthma Trials

Asthma is a poorly defined entity with vast intersubject variability in disease perception, disease severity, and quality of life. The power of the placebo has been long recognized (and skillfully exploited) in medicine.20 Several sham-controlled trials of arthroscopy, vertebroplasty, and so forth have all upended decades of conventional wisdom regarding the usefulness of those procedures.21, 22 The placebo effect is particularly well recognized in asthma, and this aspect was elegantly

FDA Device Approval Process

Bronchial thermoplasty was approved by the FDA in 2010 based on a single pivotal trial. This process is based on the 1997 FDA modernization act (aka FDAMA), which allowed for “one or more clinical investigations” to be the new standard for device approval, replacing the previous standard, which required that clinical investigations be required prior to a new device approval. This innocuous-sounding change in the approval process allowed for medical device approval based on just one positive

Conclusions

Current marketing of thermoplasty highlights its use for patients with severe asthma, which is interpreted by most clinicians as meaning oral corticosteroid dependence, frequent exacerbations, or a significantly reduced FEV1 with a poor QOL. These types of patients were specifically excluded from the AIR-2 trial. We all care for patients with severe asthma for whom existing treatment options appear ineffective. We owe it to these patients to accept only the highest standards for efficacy,

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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  • Cited by (35)

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      No intubations or pneumothoraces were reported.5,25 Another consideration in the 5-year follow-up study for the AIR-2 trial is that the information regarding outcomes in the sham group was not reported, which produces difficulty in interpreting the actual benefits of thermoplasty.27 One factor that makes the evaluation of the efficacy of BT in treating patients with asthma difficult is the lack of consistency throughout most of the clinical trials.

    • Guidelines for severe uncontrolled asthma

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      A recent study, with a 5-year follow-up, showed a sustained improvement in disease control (reduction in number of severe exacerbations and visits to the emergency room) and confirmed the safety of the procedure51 (evidence B-R2). It is currently recommended only in experienced units and in the research setting1,52 (evidence D-R2)53 (evidence B-R2). Although no controlled trials have been performed in severe asthma, theophylline as a single agent has relatively weak anti-inflammatory activity, but at low doses it can markedly enhance the action of corticosteroids on the expression of inflammatory genes54 (evidence D-R2).

    • Response

      2015, Chest
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      This is not true. Given the importance of the subject matter, we made sure that the manuscript underwent careful and close scrutiny before publication.1 Our reasons for going ahead with publishing the Commentary are well reflected by the response of Drs Iyer and Lim.3

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