Evidence review

Advice

Clinical and technical evidence
Costs and resource consequences
Strengths and limitations of the evidence

Evidence review

Clinical and technical evidence

Regulatory bodies

A search of the Medicines and Healthcare Products Regulatory Agency website revealed no manufacturer Field Safety Notices or Medical Device Alerts for this device.

A search for 'Alair' in the 'brand name' field of the US Food and Drug Administration (FDA) database: Manufacturer and User Device Facility Experience (MAUDE) identified 237 records between 1 January 2008 and 31 October 2015.

Reported event types included:

Injury (232 records): including asthma exacerbation, atelectasis, pneumonia upper respiratory tract infection, bronchitis, haemoptysis and chest pain.
Malfunction (3 records): 5 mm black marker bands wearing off the catheter (with no manufacturer response).
Death (2 records): 1 cardiac‑related death (unrelated to the procedure) and 1 death in a patient with end‑stage renal failure (a patient subgroup in whom safety had not been determined in the existing trials).

The manufacturer's responses and conclusions to the adverse event reports were as follows:

product not returned; no device failure analysis conducted (132 records)
known risk (86 records)
not reported (7 records)
operational context (3 records)
inconclusive (2 records)
patients with condition not studied; safety not determined in patient group (2 records)
no longer a reportable event (1 record)
product returned; analysis ongoing (1 record)
report withdrawn by user (1 record)
user did not follow procedure medication guidelines (1 record)
device passed testing; event reported is a known risk (1 record).

Of the total 237 records, 77 (33%) were reported for a first BT procedure, 61 (26%) for a second, 77 (33%) for a third and 1 (0.4%) for a fourth. The frequency of BT procedure was not reported in the other 22 records.

It should be noted that the MAUDE database is a passive surveillance system and potentially includes incomplete, inaccurate, untimely, unverified or biased data. The incidence of an event cannot be determined from this reporting system alone due to potential under‑reporting of events and lack of information about frequency of device used.

Clinical evidence

Of the papers reviewed, 12 met the criteria for inclusion in this briefing. Three were systematic reviews: 2 (Torrego et al. 2014, Wu et al. 2011) presented meta‑analyses of data from 3 randomised controlled trials (Cox et al. 2007, Pavord et al. 2007, Castro et al. 2010) and 1 compared data at 1‑ and 5‑year follow‑up after BT for intervention group patients (but not for controls) from the same 3 randomised controlled trials (Zhou et al. 2015). Three were randomised controlled trials (Cox et al. 2007, Pavord et al. 2007, Castro et al. 2010) and 4 reported on follow‑up studies (Thomson et al. 2011, Pavord et al. 2013, Castro et al. 2011, Wechsler et al. 2013) from the same 3 trials. The remaining 2 papers were economic analyses (Zein et al. 2015, Zafari et al. 2016).

The randomised controlled trials and follow‑up studies are not discussed separately in this briefing because they were included in the systematic reviews.

A Cochrane review (Torrego et al. 2014) of randomised controlled trials comparing BT to any active control in adults with moderate or severe difficult to treat asthma included the 3 randomised controlled trials described above (n=429). Results were pooled and it was found that quality of life scores (Asthma Quality of Life Questionnaire [AQLQ]) were significantly better after BT (weighted mean difference [WMD] 0.28, p=0.01) but the size of the difference was not clinically significant. BT increased the risk of hospitalisation for adverse events during the treatment period (BT: 9.2% [24/260], control: 2.4% [4/169]; relative risk 3.50, p=0.016). Most adverse events resolved within 1 week. The risk of hospitalisation after the treatment period was similar in the 2 groups (BT: 4.2% [11/260], control: 4.1% [7/169]), as was use of rescue medication at 1 year (WMD −0.68, p=0.65). There was no significant difference in Asthma Control Questionnaire (ACQ) scores over 1 year (pooled WMD from the 3 trials −0.15, p=0.23).

For some outcomes in the Torrego et al. (2014) review, results from the 3 trials could not be pooled and so the studies were presented individually. The largest study (Castro et al. 2010) found that BT was associated with a reduction in the proportion of people experiencing severe exacerbations at 1 year (26% of patients in the BT arm compared with 40% in the control arm). The follow‑up study from this trial (Wechsler, 2013) reported that this reduction in severe exacerbations was maintained after 5 years (30.9% of patients in the BT arm compared with 51.6% in the BT group in the year before to BT therapy). In the Cox et al. (2007) study, there was no statistically significant differences between groups in terms of number of severe exacerbations per patient, with patients in both groups having fewer severe exacerbations at 12 months. Castro et al. (2010) showed a significant reduction in proportion of patients visiting the emergency department for respiratory symptoms over 12 months following BT (BT: 8.4%, sham treatment: 15.3%).

An earlier systematic review by Wu et al. (2011) included randomised controlled trials that compared BT with any active control in adults with moderate or severe persistent asthma, and included the same 3 randomised controlled trials. Results were reported for AQLQ and hospitalisations for respiratory adverse events, which were similar to those reported in the Cochrane review by Torrego et al. (2014). The authors calculated the number needed to harm and reported that there would be 1 extra hospitalisation per year for respiratory adverse events during treatment for every 15 patients having BT. The pooled results from the 3 randomised controlled trials showed that BT had a significant benefit on morning peak expiratory flow at 1 year (WMD 21.78 l/min; p=0.002).

A third systematic review (Zhou et al. 2015) included randomised controlled trials of adults with moderate to severe persistent asthma who had BT at least once using Alair system, and included and pooled data from the 3 randomised controlled trials from patients having BT (n=249) who had data at 5‑year follow‑up (n=216) compared with data at 1 year (not compared with the original the control group). There was no significant decline over time in pre‑bronchodilator forced expiratory volume in 1 second (FEV_1;WMD −0.75, p=0.57) or post‑bronchodilator FEV₁ (WMD −0.62, p=0.65). The number of emergency room visits for adverse respiratory events remained unchanged (relative risk 1.06, p=0.71) and there was no significant increase in the incidence of hospitalisation for respiratory adverse events (relative risk 1.47, p=0.32).

These 3 systematic reviews are summarised in the appendix.

A specialist commentator identified a recent audit (published in December 2015, after the search cut‑off date) comparing safety and efficacy outcomes, 12 months after BT, in 10 clinic patients and 15 patients recruited to clinical trials at the same UK centre. Baseline asthma severity was greater in the clinic group. Clinical improvements occurred in 50% of the clinic patients compared with 73% of the research patients (Bicknell et al. 2015).

Recent and ongoing studies

Eleven ongoing or in‑development trials on BT using the Alair system for severe asthma were identified in the preparation of this briefing (see table 1).

Table 1 Recent and ongoing studies of the Alair system

Study name	Design	Inclusion criteria	Outcomes	Estimated completion	Notes
Bronchial thermoplasty for severe asthma (BTS difficult asthma registry)	Prospective, open‑label, single‑arm using patients from British Thoracic Society difficult asthma registry	Adults scheduled to have BT at a UK centre	Respiratory adverse events, lung function, AQLQ scores, unscheduled healthcare use, hospital admissions for respiratory cause, rescue medication use and days lost from normal activities	March 2017	Designed to assess long‑term safety and efficacy
Bronchial Thermoplasty Global Registry	Prospective, open‑label, single‑arm, observational registry. to collect outcome data and clinical and demographic characteristics of patients having BT	Adults scheduled to have BT at a UK centre	Primary: proportion of patients with severe exacerbations at 1 and 2 years after BT. Secondary: AQLQ and ACT scores, emergency department visits, unscheduled office visits and hospitalisations for asthma symptoms and pre‑ and post‑bronchodilator FEV₁ at 2 years	December 2018	Will be done at up to 80 sites globally and enrol up to 500 patients
Bronchial Thermoplasty in Severe Persistent Asthma (PAS2)	Phase IV open‑label, single‑arm study, 284 patients, 27 centres in the US with 5‑year follow‑up	Adults with severe persistent asthma having BT	Severe exacerbations. Secondary: respiratory adverse events, emergency room visits, hospitalisations and FEV₁	December 2019	The FDA required the manufacturer to provide data to assess the durability of the BT treatment effect as well as safety data in the intended use population in the US
Bronchial Thermoplasty: Effect on Neuronal and Chemosensitive Component of the Bronchial Mucosa	Open‑label, single‑arm study, 12 patients in Italy	Patients with severe persistent uncontrolled asthma	Analysis of the risk and benefit profile with ACT and AQLQ questionnaires at 1 year	December 2015. (See Facciolongo et al. [2015])	–
Unravelling Targets of Therapy in Bronchial Thermoplasty in Severe Asthma	Randomised controlled trial, comparing immediate BT treatment with BT treatment delayed to week 25. 40 patients, 3 European centres	Adults with asthma having maintenance medication including systemic corticosteroids	Primary: change in ASM mass. Secondary: FEV_1, ACQ and AQLQ; healthcare utilisation and rescue medication use	April 2018
Study of Physiopathological Mechanisms and Results of Treatment With Bronchial Thermoplasty in Severe Asthma	Open‑label, single‑group biological study, 15 patients, 1 Spanish centre	Adults with severe persistent asthma	Primary: change from baseline in bronchial smooth muscle at 6 months post‑treatment. Secondary: AQLQ, ACT, number of exacerbations, number of hospitalisations, respiratory function, radiological findings (thorax HRCT scan) and biological inflammatory markers at 6 months	September 2016
Bicentric Prospective Study, Evaluating Bronchial Thermoplasty in a Patient Presenting Severe Uncontrolled Asthma	Prospective, 80 patients in 2 centres in France	Adults with severe difficult to control asthma	Primary: reduction in smooth muscle surface area. Secondary: AQLQ and ACQ, severe exacerbations, respiratory function, use of rescue medication, emergency room visits and hospitalisations	November 2015 (see Pretolani et al. [2014])	The primary objective is to identify patients who will benefit most from BT. Designed to evaluate BT in patients with severe uncontrolled asthma and significant bronchial smooth muscle mass
A Prospective Observational Study of Biopredictors of Bronchial Thermoplasty Response in Patients With Severe Refractory Asthma (BTR Study)	Prospective, 1‑year, observational study. 70 patients, 7 US centres	Adults with severe difficult to control asthma	Primary: relationship between baseline clinical, physiologic, biologic and imaging markers and response to BT, defined as improvement in asthma quality of life. Secondary: baseline predictors of severe exacerbations, healthcare utilisation, safety, and predictive models of response to BT	August 2018
Efficacy of Bronchial Thermoplasty in Korean	Open‑label single‑group treatment study. 9 patients at 1 Korean centre	Patients with severe difficult to control asthma	Primary: Quality of Life Questionnaire for Adult Korean Asthmatics at 3 months. Secondary: the same measure at 6 months and acute exacerbations at 3 and 6 months	February 2015
Bronchial Thermoplasty for Severe Asthma With Dynamic Hyperinflation	Open‑label single‑group study. 15 patients in 1 French centre	Adults with severe difficult to control asthma	Primary: evolution of dynamic hyperinflation at 3 months. Secondary: description of the structural modification of the bronchial wall induced by BT, ACQ and AQLQ	December 2018
Bronchial Thermoplasty in Severe Asthma With Frequent Exacerbations	Randomised controlled trial. 34 patients with severe difficult to control asthma in 1 French centre	–	Primary: severe exacerbation rate. Secondary: FEV₁, ACQ and AQLQ, structural airway remodelling and inflammatory cells and markers in induced sputum	The estimated study completion date is November 2018	Patients will be randomised 1:1 to either BT and medical management or medical management only
Abbreviations: ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test; AQLQ, Asthma Quality of Life Questionnaire; BT, bronchial thermoplasty; FEV₁, forced expiratory volume in 1 second; GRCT, high‑resolution computed tomography.

Costs and resource consequences

Two economic analyses were identified, both set in the US. Zein et al. (2015) assessed the 10‑year cost effectiveness of BT compared with usual care for a hypothetical cohort of 41‑year old patients with severe, uncontrolled asthma. The authors used: efficacy and safety data from the trial by Castro et al. (2010), which was done in multiple countries; a US healthcare payer perspective; average Medicare reimbursement rates; and 2013 price levels. Compared with usual care, BT resulted in more quality‑adjusted life years (6.40 compared with 6.21) and a higher cost ($7,512 [£5,067] compared with $2,054 [£1,385]) per patient. The incremental cost‑effectiveness ratio (ICER) for BT at 10 years was $29,821 (£20,114) per quality‑adjusted life year gained. The authors concluded that in the US, BT is a cost‑effective treatment for severe asthma in people at high risk of exacerbations (at least 0.63 per year), if the 3 BT procedures in total cost no more than $10,384 (around £7,000). The study was funded by Federal grants and no conflicts of interest were declared.

Zafari et al. (2016) evaluated the 5‑year cost effectiveness of standard therapy, BT and omalizumab for moderate to severe uncontrolled asthma. The perspective was the healthcare system and costs were 2013 US dollars. The ICER for BT compared with standard therapy was US $78,700 (£53,083) per quality-adjusted life year. The ICER for omalizumab compared with BT was US $3.86 million (£2.60 million) per quality-adjusted life year.

Strengths and limitations of the evidence

One high‑quality Cochrane systematic review (Torrego et al. 2014) and another moderate quality systematic review (Wu et al. 2011) compared BT and control group data from the same 3 randomised controlled trials (Cox et al. 2007, Pavord et al. 2007 and Castro et al. 2010). The 3 trials included patients with different severities of asthma, were limited in size, underpowered to examine important outcomes and 2 (Cox et al. 2007 and Pavord et al. 2007) had no sham intervention. Unpublished studies were not included. A third systematic review of moderate quality (Zhou et al. 2015) compared data for thermoplasty patients at 1 and 5 years after the procedure, with no data from the control patients. In this review, the authors used a denominator of '1,715' to compare the number of adverse events, but it is unclear what this denominator represents. We did not find any high‑quality long‑term comparative evidence.