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Background
Asthma is one of the most common chronic diseases in the United States, and its prevalence has been increasing since 1980. In 2000, asthma was responsible for 4,487 deaths, about 0.5 million hospitalizations, 1.8 million visits to the emergency room, and 10.4 million visits to the physician office among individuals of all ages. The Behavioral Risk Factor Surveillance System (BRFSS) collects data each year from the 50 states, the District of Columbia, and 3 United States territories to provide prevalence data for state and local health department asthma programs. Findings from BRFSS indicated that approximately 7.2 % of adults in the United States have current asthma (CDC, 2003). According to the National Heart, Lung and Blood Institute's (2002) global strategy for asthma management and prevention, the preferred therapy for patients with moderate persistent asthma is regular treatment with a combination of inhaled corticosteroids and a long-acting inhaled beta 2-agonist twice-daily. For patients with severe persistent asthma, the primary therapy includes inhaled corticosteroid at higher doses plus a long-acting inhaled beta 2-agonist twice-daily.
Bronchial thermoplasty (BT) is a bronchoscopic procedure that employs radiofrequency ablation to reduce the mass of airway smooth muscle (ASM), thus attenuating bronchoconstriction. It is being studied as a minimally invasive method to improve asthma control. Bronchial thermoplasty is performed on an outpatient basis with conscious sedation (i.e., no general anesthesia is needed), and it usually takes approximately one hour to complete. There are 2 assumptions that underlie the development of this procedure: (i) ASM is a vestigial tissue; and (ii) treatment directed at ASM alone will provide sustained symptomatic and physiological improvement in patients with asthma.
Mitzner (2006) discussed the potential of BT in preventing serious consequences resulting from asthma. The most important factor in minimizing an asthmatic attack is limiting the degree of smooth muscle shortening. The premise that ASM can be either inactivated or obliterated without any long-term alteration of other lung tissues, and that airway function will remain normal, albeit with reduced bronchial constriction, has been demonstrated in dogs, a subset of normal subjects, as well as mild asthmatics. Bronchial thermoplasty may thus develop into a useful clinical procedure to effectively impair the ability for ASM to reach the levels of pathological narrowing that characterizes an asthma attack. It may also enable more successful treatment of asthma patients who are unresponsive to more conventional therapies. Whether this will remain stable for the lifetime of the patient still remains to be determined, but at the present time, there are no indications that the smooth muscle contractility will return. The authors concluded that this preliminary experience showing that BT could be safely performed in patients with asthma has led to an ongoing clinical trial at a number of sites in Europe and North America designed to examine the effectiveness of this procedure in subjects with moderately severe asthma.
In a prospective study, Miller et al (2005) evaluated the feasibility and safety of BT in the human airway, and determined if the reduction in ASM observed in animal studies could be replicated. A total of 9 patients scheduled to undergo lung resection for suspected or proven lung cancer received BT during routine preoperative bronchoscopy up to 3 weeks prior to pre-scheduled lung resection. Treatment was limited to areas of the segmental bronchi within the lobe that was to be removed. Treated airways were inspected via bronchoscopy at the time of thoracotomy, and were examined histologically following surgical resection. There were no adverse clinical effects of the procedure, including no new symptoms and no unscheduled visits for medical care. Treated sites exhibited slight redness and edema of the mucosa within 2 weeks of treatment, and appeared normal at later time points. There was narrowing (visually estimated at 25 to 50%) in four airways in 2 subjects examined at 5 days and 13 days after treatment, with excess mucus in two of these airways. There was no bronchoscopic evidence of scarring in any of the airways examined. Histological examination showed a reduction in ASM, and the extent of the treatment effect was confined to the airway wall and the immediate peri-bronchial region. The authors concluded that BT to the human airway appears to be well-tolerated, and treatment resulted in significant reduction of smooth muscle mass in the airways. They noted that BT may provide therapeutic benefit in disease states such as asthma.
Cox et al (2006) examined the safety and impact on lung function and airway responsiveness of BT over 2 years in 16 subjects with mild-to-moderate asthma. Baseline and 12-week post-treatment measurements included spirometry, methacholine challenge, daily diary recordings of peak flow, symptoms, and medication usage. Subjects completed follow-up evaluations at 12 weeks, 1 year, and 2 years. The procedure was well-tolerated; side effects were transient and typical of what is commonly observed after bronchoscopy. All subjects reported improvement in airway responsiveness. The mean PC(20) increased by 2.37 +/- 1.72 (p < 0.001), 2.77 +/- 1.53 (p = 0.007), and 2.64 +/- 1.52 doublings (p < 0.001), at 12 weeks, 1 year, and 2 years post-procedure, respectively. Data from daily diaries collected for 12 weeks indicated significant improvements over baseline in symptom-free days (p = 0.015), morning peak flow (p = 0.01), and evening peak flow (p < or = 0.007). Spirometry measurements remained stable throughout the study period. The authors concluded that BT is well-tolerated in patients with asthma and results in decreased airway hyper-responsiveness that persists for at least 2 years. Limitations of this case series includes its small size, lack of comparison group, and limited duration of followup. In an editorial that accompanied the afore-mentioned article, Bel (2006) noted that "[w]hether bronchial thermoplasty will earn a place in the treatment of asthma remains to be determined. However, this study shows the potential for a completely new approach of treating asthma and stimulates the development of new hypotheses".
Cox and colleagues (2007) examined the effect of BT on the control of moderate or severe persistent asthma. These researchers randomly assigned 112 subjects who had been treated with inhaled corticosteroids and long-acting beta 2-adrenergic agonists (LABA) and in whom asthma control was impaired when the LABA were withdrawn to either BT or a control group. The primary outcome was the frequency of mild exacerbations, calculated during 3 scheduled 2-week periods of abstinence from LABA at 3, 6, and 12 months. Airflow, airway responsiveness, asthma symptoms, the number of symptom-free days, use of rescue medication, and scores on the Asthma Quality of Life Questionnaire (AQLQ) and the Asthma Control Questionnaire (ACQ) were also assessed. The mean rate of mild exacerbations, as compared with baseline, was reduced in the BT group but was unchanged in the control group (change in frequency per subject per week, -0.16 +/- 0.37 versus 0.04 +/- 0.29; p = 0.005). At 12 months, there were significantly greater improvements in the BT group than in the control group in the morning peak expiratory flow (39.3 +/- 48.7 versus 8.5 +/- 44.2 L/min), scores on the AQLQ (1.3 +/- 1.0 versus 0.6 +/- 1.1) and ACQ (reduction, 1.2 +/- 1.0 versus 0.5 +/- 1.0), the percentage of symptom-free days (40.6 +/- 39.7 versus 17.0 +/- 37.9), and symptom scores (reduction, 1.9 +/- 2.1 versus 0.7 +/- 2.5) while fewer puffs of rescue medication were required. Values for airway responsiveness and forced expiratory volume in 1 second did not differ significantly between the 2 groups. Adverse events immediately after treatment were more common in the BT group than in the control group but were similar during the period from 6 weeks to 12 months after treatment. The authors concluded that BT in subjects with moderate or severe asthma results in an improvement in asthma control. Limitations of the study included the lack of blinding, raising the criticism that the improvement in symptoms among people getting BT was purely due to a placebo effect after undergoing an invasive procedure. In addition, the primary study outcomes of bronchial thermoplasty occured during a period of withdrawal of LABA per study protocol, which does not reflect how asthma is managed in standard clinical practice. The small increment in improvement quality of life with BT compared to the control group was of questionable clinical significance. The rate of severe adverse reactions where higher (3 percent) in the BT group compared to the control group (1 percent). The BT group also had more hospitalizations for respiratory causes (9) than the control group (5). In an editorial that accompanied the afore-mentioned article, Solway and Irvin (2007) stated that "[b]ronchial thermoplasty represents a novel approach to targeting airway smooth muscle, but it ablates airway myocytes only in bronchi 3 mm or larger in diameter, which can be treated directly. For this reason, and because of the considerable effort involved (three separate bronchoscopic procedures, each with a small but significant risk of complications), notable adverse effects (in the short term, at least), and likely expense, bronchial thermoplasty will probably need further refinement if it is to emerge as a widely applicable, practical treatment for moderate or severe asthma. Nonetheless, the results reported by Cox and colleagues suggest that we should now contemplate other approaches to targeting airway smooth muscle that might prove to be less invasive, more practical, and more amenable to application throughout the airways".
In a subsequent publication (Thomson et al, 2011a), the investigators continued to follow the BT group for a total of five years and the control group for a total of three years. Patients enrolled in the AIR Trial were on inhaled corticosteroids greater than or equal to 200 μg beclomethasone or equivalent plus long-acting-beta2-agonists and demonstrated worsening of asthma on long-acting-β2-agonist withdrawal. Following initial evaluation at 1 year, subjects were invited to participate in a 4-year safety study. Adverse events and spirometry data were used to assess long-term safety out to 5 years post-BT. A total of 45 of 52 treated and 24 of 49 control group subjects participated in long-term follow-up of 5 years and 3 years, respectively. The rate of respiratory AEs per subject was stable in years 2 to 5 following BT (1.2, 1.3, 1.2, and 1.1, respectively). There was no increase in hospitalizations or emergency room visits for respiratory symptoms in years 2, 3, 4, and 5 compared to year 1. The forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) values showed no deterioration over the 5-year period in the BT group. Similar results were obtained for the control group. The authors concluded that absence of clinical complications (based on AE reporting) and the maintenance of stable lung function (no deterioration of forced vital capacity and FEV(1) over a 5-year period post-BT in this group of patients with moderate-to-severe asthma support the long-term safety of the procedure out to 5 years. However, it is interesting to note that similar results were obtained in the control group. During the three years of long-term follow-up with data comparing the two groups there were no differences in the clinically relevant outcomes: hospitalizations, emergency room visits, and oral steroids to treat respiratory exacerbations. Although the outcomes of this study suggest that the benefits of BT persist and no unexpected respiratory pathologies develop, the sample size was small, so considerable uncertainty remains.
Pavord et al (2007) examined the safety and effectiveness of BT in patients with symptomatic, severe asthma. Adults who were symptomatic despite treatment with fluticasone or equivalent at more than 750 mug/day and other medications, which could include 30 mg or less of oral prednisolone/day, were randomized to BT or to a control group. After treatment, subjects entered a 16-week steroid stable phase (weeks 6 to 22), a 14-week steroid wean phase (weeks 22 to 36), and a 16-week reduced steroid phase (weeks 36 to 52). Bronchial thermoplasty resulted in a transient worsening of asthma symptoms. Seven hospitalizations for respiratory symptoms occurred in 4 of 15 patients who received BT during the treatment period. Five hospitalizations were within 3 days of treatment. Two subjects had segmental collapse involving the most recently treated lobe; 1 required bronchoscopy and aspiration of a mucus plug. There were no hospitalizations during this period in the 17 control subjects. The rate of hospitalizations was similar in both groups in the post-treatment period. At 22 weeks, patients who received BT had significant improvements versus control subjects in rescue medication use (-26.6 +/- 40.1 versus -1.5 +/- 11.7 puffs/7 day, p < 0.05), pre-bronchodilator forced expiratory volume in 1 second [FEV(1)] % predicted (14.9 +/- 17.4 versus -0.94 +/- 22.3 %, p = 0.04), and Asthma Control Questionnaire scores (-1.04 +/- 1.03 versus -0.13 +/- 1.00, p = 0.02). Improvements in rescue medication use and ACQ scores remained significantly different from those of controls at 52 weeks. The authors concluded that BT is associated with an excess of hospitalizations and a short-term increase in asthma-related morbidity. However, there is preliminary evidence of long-lasting improvement in asthma control. However, the results of this study may be biased because it was a small trial with large imbalances in important participant characteristics at baseline.The study is also limited because of lack of blinding.
Wechsler (2008) noted that BT holds promise in the management of patients with asthma. Herth (2008) stated that a short-term increase in morbidity due to bronchoscopy is to be expected with BT. The author noted that further trials are needed to investigate the value of this method, particularly with regard to long-term effects. Jesudason (2009) stated that BT is a new treatment for refractory asthma. However, the mechanism of its effects is unclear.
In a review on BT for the treatment of asthma, Martin and Pavord (2009) concluded that applying thermal energy to the airway in the form of BT results in the selective destruction of ASM; this is replaced by fibrous connective tissue. In early animal and human studies, this was associated with a reduction in objective measurements of asthma control, such as airway hyper-responsiveness (AHR). However, in the 2 published randomized controlled trials (RCTs) on this technique, there has been a failure to show improvements in AHR, although there have been significant improvements in more subjective measurements of asthma control. Neither trial was blinded, and concern remains about a significant placebo effect of the treatment. The Asthma Intervention Research 2 (AIR2) Trial, which is randomized and blinded with a sham treatment arm, has been designed to try to address these issues in more detail.
In randomized sham-controlled clinical study of BT in patients with refractory asthma (AIR2 study), Castro et al (2010) reported a significant improvement in Asthma Quality of Life scores in patients treated with bronchial thermoplasty. However, subjects assigned to a sham procedure also experienced a significant improvement from baseline, such that the difference between subjects treated with BT versus subjects treated with a sham procedure was of questionable clinical significance. In this study funded by Asthmatx, Castro et al (2010) evaluated the effectiveness and safety of BT versus sham procedure in subjects with severe asthma who remain symptomatic despite treatment with high-dose inhaled corticosteroids and long-acting beta 2-agonists. In this study, 288 adult subjects were randomized to BT or sham control underwent three bronchoscopy procedures. Primary outcome was the difference in a Asthma Quality of Life Questionnaire (AQLQ) scores from baseline to average of 6, 9, and 12 months (integrated AQLQ). The AQLQ is a 7-point Likert scale, where a 0.5 change in score is considered the minimally important difference. Subjects assigned to BT had an average 1.35 +/- 1.10 improvement over baseline in integrated AQLQ score. However, subjects assigned to a sham procedure had an average 1.16 +/- 1.23 improvement over baseline. The 0.19 point difference between the BT and sham control group fell short of the cutoff of 0.5 points for a minimally important difference in the AQLQ. There were more respiratory adverse events in the BT group during the initial treatment period including an excess of hospitalizations. After the initial treatment period, there was a reduction in ER visits, but not in hospitalizations for the BT group compared to the sham group.
An editorial that accompanied the afore-mentioned study by Castro et al, Bel (2010) noted that "[t]he trial demonstrated that 6 to 12 months after the procedure, bronchial thermoplasty had a small, but significantly greater mean positive effect on the asthma-related quality of life score than did the sham procedure. The mean difference in score was 0.19, which was statistically significant but substantially smaller than the minimum clinically important difference of 0.5. Remarkably, not one of the secondary outcomes showed a difference between bronchial thermoplasty and sham procedure. Additional outcomes that were collected to assess safety showed that during the post-treatment period there were less severe exacerbations and emergency room visits in the bronchial thermoplasty group compared with the sham control group, but over the entire study period there was no difference in outcomes between the groups". Furthermore, Bel (2010) stated that "[t]he overall net effect of bronchial thermoplasty in the AIR2 trial is somewhat disappointing. Although airway hyperresponsiveness as a most relevant outcome of bronchial thermoplasty is difficult to measure in patients with severe asthma, one would have hoped to see at least an effect on asthma control, use of rescue medication, or pre/post-bronchodilator FEV1. This was not the case. Instead, the authors observed a reduction in the rate of severe exacerbations and emergency department visits in the post-treatment period. This safety outcome was completely unexpected and was not considered in the rationale and hypothesis of the study. How can this be explained in the absence of any improvement in asthma control? Does it suggest that bronchial thermoplasty has more effects than just inactivating the airway smooth muscle? Does it suggest that the procedure might alter the inflammatory or neurogenic responses to viral infection or other triggers of asthma exacerbations?" On the question of whether BT should be offered to patients with severe asthma, Bel (2010) stated that "[f]or patients with uncontrolled asthma who have not been submitted to a rigorous treatment protocol, the answer is no. For the remaining patients, the AIR2 results might offer some hope. Bronchial thermoplasty appears to have a benefit on the quality of life and severe exacerbations. Importantly, severe asthma has many phenotypes, and at present we have no clue which phenotype will benefit the most. It is inevitable that phenotypic targeting will be essential for this invasive procedure. Moreover, we need to know how durable the benefit will be to ensure that the benefits outweigh the risks and burden of the procedure. Therefore, long-term clinical and morphological research in various severe-asthma phenotypes is still needed to obtain the required information for clinical decisions".
Commenting on the AIR2 trial, Wahidi & Kraft (2012) noted that patients treated with bronchial thermoplasty had a slight 0.19 point improvement in AQLQ scores (1.35 vs. 1.16 with sham procedure), falling well short of the cutoff of 0.5 points for a “clinically meaningful” improvement in the AQLQ over the sham group. Moreover, both the sham and bronchial thermoplasty groups experienced a clinically meaningful improvement in AQLQ, again raising the question of whether it was the experience of undergoing an invasive procedure that led to the patient-perceived benefits. The authors noted that no differences were noted between the groups in FEV1, peak flow, or rescue medication use. However, the patients treated with bronchial thermoplasty had significantly fewer emergency room visits, severe exacerbations, and days missed from school or work. These benefits persisted on follow-up studies at 2 years, although the sham group was not followed for comparison. The authors noted that the AIR2 trial was also criticized because of its approach to patient selection: the average FEV1 was ~78% predicted, although less than 60% is considered representative of severe asthma by the National Asthma Education and Prevention Program. Patients with more severe asthma (low FEV1, greater than 2 exacerbations or pneumonias in the previous year, or greater than 3 oral steroid bursts in the previous year) were excluded, opening questions about extrapolations of any benefits of bronchial thermoplasty to these patients.
In an editorial, Michaud and Ernst (2011) commented on the selection of quality of life as the primary endpoint of AIR2 because that endpoint can be affected by unintentional unmasking of treatment assignment. "The selection of a soft primary end point, a quality-of-life measure, is concerning because a significant proportion of patients in the intervention group accurately determined their study assignment at the time of their second bronchoscopy (thermoplasty, 0.011; control, 0.342)." They also faulted the study for failing to assess whether bronchial thermoplasty resulted in a clinically important change in medication use.
Torrego Fernandez (2010) stated that despite the numerous guidelines and treatments available for asthma, the disease remains poorly controlled in some patients, who remain symptomatic, are a considerable burden on the health system, and account for most of the hospitalizations due to asthma. Bronchial thermoplasty is a novel experimental therapeutic option that consists of delivering radiofrequency-generated heat to the airways via a catheter inserted in the bronchial tree through a flexible bronchoscope to reduce smooth muscle quantity and contractility. The first investigations were conducted using an animal model. Subsequently, 2 RCTs designed to evaluate the safety and efficacy of BT in patients with moderate-to-severe asthma with a 1-year follow-up period showed the procedure to be safe, with mostly transient adverse affects and several clinical benefits. The authors stated that, although results from ongoing clinical trials are still awaited, BT may become an innovative therapeutic approach to asthma.
In a review, Cox (2010) noted that asthma can be provoked by a wide range of stimuli that include infectious, allergic, and environmental agents. Bronchoconstriction determines much of the short-term variability in airflow that characterizes asthma. Current treatments do not redress the excess smooth muscle mass that is present in the re-modeled airway in chronic asthma. Thus, it is intriguing to consider the potential contribution of BT as a treatment for poorly controlled asthma.
In April 2010, the Food and Drug Administration (FDA) approved the Alair Bronchial Thermoplasty System (Asthmatx Inc., Sunnyvale, CA) for the treatment of patients aged 18 and older whose severe and persistent asthma is not well-controlled with inhaled corticosteroids and long-acting beta agonist medications. The FDA based its approval on data from AIR2, a clinical trial of 297 patients with severe and persistent asthma. The trial showed a reduction of severe asthma attacks with use of the Alair system. Moreover, the FDA is requiring a 5-year post-approval study of the device to study its long-term safety and effectiveness. Asthmatx will follow many of the patients who were enrolled in the clinical trial and enroll 300 new patients at several medical centers across the United States.
According to the product labeling, possible side effects during the course of treatment may include anxiety, asthma attacks, atelectasis, chest tightness or pain, headaches, hemoptysis, nausea, and wheezing. While the Alair system is designed to reduce the number of severe asthma attacks on a long-term basis, there is a risk of immediate asthma attacks during the course of the treatment. Furthermore, the Alair system is not for use in asthma patients with a pacemaker, internal defibrillator, or other implantable electronic device. Also, those patients with known sensitivities to lidocaine, atropine, or benzodiazepines should not use the device. Alair has not been studied for success in re-treatment of the same area of the lung. Currently, patients should not be re-treated with the Alair system in the same area of the lung. In addition, asthma patients considering the Alair system should not be treated while the following conditions are present: an active respiratory infection, asthma exacerbations, coagulopathy, or if they have had changes to their corticosteroid regimen 14 days before the proposed treatment.
Castro and colleagues (2011) examine the persistence of effectiveness of BT 2 years post-treatment in subjects with severe asthma. Subjects participating in the long-term safety follow-up phase of the AIR2 Trial were evaluated by comparing the proportion of subjects who experienced exacerbations, adverse events (AEs), or healthcare utilization during the first year (year 1) after BT with the proportion of subjects who experienced the same during the subsequent 12 months (year 2). Severe exacerbations, respiratory AEs, emergency department visits for respiratory symptoms, and hospitalizations for respiratory symptoms (proportion of subjects experiencing and rates of events), and stability of pre- and post-bronchodilator FEV(1), were comparable between years 1 and 2. The proportion of subjects experiencing severe exacerbations in year 2 after BT was 23.0 %, compared with 30.9 % in year 1. The authors concluded that reduction in the proportion of subjects experiencing severe exacerbations after BT is maintained for at least 2 years.
It is also interesting to note in a recent review by Thomson et al (2011b), BT is listed as one of the emerging therapeutic option for severe asthma. This is in agreement with Colice (2011) who also listed BT as an emerging therapy for asthma. Colice concluded that although more studies are needed to examine the safety and effectiveness of both pharmacological and non-pharmacological approaches including BT, there is future promise for therapeutic advances in severe, persistent asthma. Furthermore, Oliveinstein et al (2011) reviewed alternative therapeutic strategies in the management of severe asthma including macrolide antibiotics, biologic agents, modulators of signal transduction pathways and BT. The authors noted that the challenge remains to determine the appropriate phenotype for each therapeutic strategy in view of the heterogeneity of severe asthma.
Wu and associates (2011) performed a meta-analysis of the safety and effectiveness of BT in patients with moderate-to-severe persistent asthma. An electronic literature search identified 3 RCTs of BT that recruited a total of 421 patients. Outcomes of interest were the Asthma Quality of Life Questionnaire (AQLQ) score, morning peak expiratory flow (PEF), tolerability and safety. Compared with standard medications and sham-bronchial thermoplasty, BT significantly improved AQLQ scores and PEF from baseline to the end of the trials. There were more respiratory AEs and hospitalizations for adverse respiratory events with BT than with medications or sham-treatment during the treatment period, but most events resolved, on average, within 1 week. This effect of BT was not seen during the post-treatment period. The authors concluded that additional long-term RCT are needed to confirm whether BT provides benefit to patients with moderate-to-severe persistent asthma.
The National Horizon Scanning Centre (2011) has stated: "Further longer-term safety data and data on the effect of bronchial thermoplasty on long term health outcomes such as hospitalisation rates, GP consultation rates, medication use and quality of life are awaited. Research into the exact mechanism through which the device may work and in predicting which patients are most likely to respond to this treatment is required"
The Institute for Clinical Systems Improvement's practice guideline on diagnosis and management of asthma (ICSI, 2010) does not mention the use of BT.
The California Technology Assessment Forum (Tice, 2011) concluded that use of bronchial thermoplasty for the treatment of severe, refractory asthma meets CTAF TA Criterion 1 through 5 for safety, effectiveness and improvement in net health outcomes. The CTAF assessment noted that the most important trial of BT to consider is the AIR2 trial, because it was the only trial that used a sham control to blind patients and they also ensured that staff assessing patient outcomes remained blinded to patient allocation. The CTAF assessment found a slightly greater improvement in quality of life in the BT group compared to the sham group in the AIR2 trial, but it did not meet the pre-specified criteria for statistical or clinical significance. However, the CTAF panel felt that the net improvements were sufficient in this patient population with few options. The CTAF assessment concluded that there remain some concerns about the long-term sequelae of BT, as the number of patients followed out for five years and longer is relatively small, so there may be some uncommon long-term harms that have yet to be identified.
The National Institue for Health and Clinical Excellence (NICE, 2012) issued guidance on BT for severe asthma, which states that evidence on the safety of BT is adequate in the short- and medium-term, although patients may experience exacerbation of symptoms after the procedure. The guidance states that more evidence is required on the safety of the procedure in the long-term. The guidance notes that, with regard to efficacy, there is some evidence of improvement in symptoms and quality of life but objective evidence of improved lung function is inadequate. NICE recommends, therefore, that this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Specialist Advisors to NICE stated that improvement in symptoms and quality of life, and reductions in exacerbations and in the need for admission to hospital were more relevant efficacy outcomes than the results of lung function tests.The NICE Committee noted that many patients are young and it is therefore particularly important to monitor them for any possible long-term adverse effects such as development of bronchial stenosis.
In a review on the future of chronic obstructive pulmonary disease (COPD) treatment, Martinez and colleagues (2011) listed several novel non-pharmacotherapies including creation of arterio-venous fistulas, endobronchial glue, endobronchial thermal vapor, insertion of endobronchial valves, non-invasive mechanical ventilation, and transcutaneous electrical stimulation. Bronchial thermoplasty is not mentioned as a possible therapeutic option. Furthermore, the Institute for Clinical Systems Improvement's practice guideline on diagnosis and management of COPD (ICSI, 2011) does not mention the use of BT.
James and Gupta (2011) stated that even with the use of maximum pharmacological treatment, asthma still remains uncontrolled in some cases. For such cases of uncontrolled asthma, a novel therapy, BT, has shown some promising results over the past few years. Three major trials of BT showed that it does not cause any improvement in FEV1. However, BT improved the quality of life and decreased the future exacerbations and emergency hospital visits due to asthma. But the benefit observed was too small to be clinically significant. Follow-up (2 to 5 years) results of these BT trials did not show any significant long-term adverse event related to BT. However, further independent large RCTs and results of application of BT in real hospital settings are needed to define its role in asthma management.
On behalf of the British Thoracic Society, Du Rand and colleagues (2011) published a guideline for advanced diagnostic and therapeutic flexible bronchoscopy in adults. Regarding the use of BT the guideline noted that it is a possible treatment option in selected patients with severe persistent asthma already on maximal therapy, although its place in the treatment of asthma remains to be established. The authors also noted that the long-term safety and effectiveness of this procedure remain unclear. Hence treatment should be limited to a few specialized centers in carefully selected patients. They stated that longer-term follow-up of treated patients is needed.
Boulet and Laviolette (2012) stated that BT has been shown to reduce asthma exacerbations, and improve asthma control and quality of life over a 3-year period without significant complications up to a 5-year period. It could be considered as another option in the treatment of selected patients requiring oral and/or high doses of inhaled corticosteroids to control asthma. It should, however, be performed in specialized centers in patients who understand the potential benefits and side-effects of this technique. The response to this treatment varies from one patient to another. The authors concluded that further studies are needed to better-define the role of this option in the treatment of asthma.
Wahidi and Kraft (2012) stated that RCTs of BT in severe asthma have not been able to show a reduction in airway hyper-responsiveness or change in FEV(1), but have suggested an improvement in quality of life, as well as a reduction in the rate of severe exacerbations, emergency department visits, and days lost from school or work. Strict inclusion and exclusion criteria of these trials resulted in the elimination of patients with severe asthma who experienced more than 3 exacerbations per year. Therefore, the generalizability of this treatment to the broader severe asthma population still needs to be determined. The short-term adverse events consist primarily of airway inflammation and occasionally more severe events requiring hospitalization. Long-term safety data are evolving and have shown thus far clinical and functional stability up to 5 years after BT treatment. The authors concluded that additional studies on BT are needed to establish accurate phenotyping of positive responders, durability of effect, and long-term safety.
In a review on "Severe asthma: Future treatments" O'Byrne et al (2012) stated that BT may provide benefit in improving control and reducing exacerbations in selected patients. The addition of the muscarinic antagonist, tiotropium also improves airflow obstruction, but its benefit on exacerbation risk is not yet established. Other developments being evaluated in severe refractory asthma are CXCR2 antagonists in patients with a persisting neutrophilic airway inflammation, and CRTh2 antagonists, both of which are small molecule antagonists, and hMabs against IL4 and IL-13. Finally, other approaches to reduce receptor numbers, using inhaled anti-sense, has shown to reduce allergen-induced airway eosinophilia, and combining different anti-sense against different targets may become a feasible treatment option. A variety of new treatment options are being investigated to help improve overall asthma control in patients with severe refractory asthma. These include medications to optimize lung function; BT to reduce airway smooth muscle in central airways; and those which target specific inflammatory cells or receptors of inflammatory mediators.
Mathew et al (2012) stated that as the overall prevalence of asthma has escalated in the past decades, so has the population of patients with severe asthma. This condition is often difficult to manage due to the relative limitation of effective therapeutic options for the physician and the social and economic burden of the disease on the patient. Management should include an evaluation and elimination of modifiable risk factors such as smoking, allergen exposure, obesity and non-adherence, as well as therapy for co-morbidities like gastro-esophageal reflux disease and obstructive sleep apnea. Current treatment options include conventional agents such as ICSs, LABAs, leukotriene antagonists, and oral corticosteroids. Less conventional treatment options include immunotherapy with methotrexate, cyclosporine and tacrolimus, biological drugs like monoclonal antibodies, tumor necrosis factor-α blockers and oligonucleotides, phosphodiesterase inhibitors, anti-microbials and BT.
Silvestri et al (2012) noted that over the past 15 years, patients with a myriad of pulmonary conditions have been diagnosed and treated with new technologies developed for the pulmonary community. Advanced diagnostic and therapeutic procedures once performed in an operating theater under general anesthesia are now routinely performed in a bronchoscopy suite under moderate sedation with clinically meaningful improvements in outcome. With the miniaturization of scopes and instruments, improvements in optics, and creative engineers, a host of new devices has become available for clinical testing and use. A growing community of pulmonologists is doing comparative effectiveness trials that test new technologies against the current standard of care. While more research is needed, it seems reasonable to provide an overview of pulmonary procedures that are in various stages of development, testing, and practice at this time. Five areas are covered: (i) navigational bronchoscopy, (ii) endobronchial ultrasound, (iii) endoscopic lung volume reduction, (iv) BT, and (v) pleural procedure. Appropriate training for clinicians who wish to provide these services will become an area of intense scrutiny as new skills will need to be acquired to ensure patient safety and a good clinical result.
Cayetano et al (2012) noted that BT is a novel treatment modality that employs radiofrequency energy to alter the smooth muscles of the airways. This therapy represents a radical change in the treatment paradigm from daily repetitive dosing of medications to a truly long-term and potentially permanent attenuation of perhaps the most feared component of asthma -- smooth muscle-induced bronchospasm. A large, multi-centered, double-blinded, RCT employed the unprecedented (but now industry standard for bronchoscopic studies) approach of using sham bronchoscopy as a control. It demonstrated that BT is safe, improved quality of life, and decreased frequency of severe exacerbations in the treatment group compared to the control group. Although the mechanism of action of BT is not currently completely understood, it should be considered as a valid and potentially valuable option for patients who have severe persistent asthma and who remain symptomatic despite inhaled corticosteroids and long-acting beta-2 agonists. Such patients should however be carefully evaluated at centers with expertise in managing severe asthma patients and with physicians who have experience with this promising new treatment modality.
The GINA’s practice guideline on Global Strategy for Asthma Management and Prevention (2012) stated that “For adult patients whose asthma remains uncontrolled despite application of this therapeutic paradigm, and referral to an asthma specialty center, bronchial thermoplasty is now a possible option in some countries. In this bronchoscopic treatment, airways are treated on three occasions with a localized radiofrequency pulse. The treatment, which itself is associated with asthma exacerbations in the months post-bronchoscopy, results in a subsequent decrease in exacerbations. There are no significant effects on lung function or asthma symptoms. Extended follow-up on a small number of patients has provided some additional support for long-term safety of bronchial thermoplasty. However, longer-term follow-up of larger number of control and active patients is needed to assess effectiveness and caution should be used in selecting patients for this procedure”. The Global Initiative for Asthma (GINA) was launched in conjunction with the World Health Organization and the National Heart, Lung and Blood Institute.
A Horizon Scan prepared by the ECRI Institute for the Federal Agency for Healthcare Research and Quality (ECRI, 2012) stated that experts commenting on BT were cautiously optimistic about its potential to offer an option for some patients with severe asthma that does not respond to medical therapies. However, experts also cited the small evidence base, lack of long-term data, serious risks associated with BT, required investment in equipment and training, and relatively small number of qualified bronchoscopists as barriers to widespread diffusion
Doeing et al (2013a) performed BT in 8 patients with severe asthma as defined by Expert Panel Report 3 (EPR-3) guidelines who were poorly controlled despite step 5 therapy. Data were available on each subject for 1 year prior to and 15 to 72 weeks following BT. The mean (+/- SEM) pre-bronchodilator FEV1 prior to BT was 51.8 +/- 8.6 % of predicted, and the mean (+/- SEM) number of hospitalizations for asthma in the year prior to BT was 2.9 +/- 1.2. No subject had an unexpected severe adverse event due to BT. Among the 8 patients with follow-up of at least 15 weeks, there was no significant decline in FEV1 (p = 0.4). The authors concluded that these findings suggested that BT may be safe for asthma patients with severe airflow obstruction and higher hospitalization rates than previously reported.
Doeing et al (2013b) stated that BT is an emerging therapy for patients with severe persistent asthma who remain poorly controlled despite standard maximal medical therapy. Thermoplasty elicits asthma control over time by applying thermal radiofrequency energy to airways to ablate underlying smooth muscle. While this therapy is suggested to eliminate such smooth muscle permanently, no human studies have examined the possibility of treatment failure. These researchers presented the case of a 62-year old female with severe, refractory asthma symptoms who underwent BT without apparent complications. However, severe symptoms including multiple clinical exacerbations persisted despite BT treatment. Repeat endobronchial biopsy done 6 months after BT treatment demonstrated persistent smooth muscle hyperplasia in multiple airways that previously had been treated. The patient continued to have uncontrolled, refractory asthma despite multiple therapies. The authors concluded that this case is the first to describe a failure of BT to reduce or eliminate airway smooth muscle in a patient with severe persistent asthma. It suggested the potential for treatment failure in the management of these patients after BT and highlighted the need for further study of potential BT-refractory patients.
Wechsler et al (2013) evaluated the safety and effectiveness of BT in asthmatic patients 5 years after therapy. Subjects treated with BT from the Asthma Intervention Research 2 trial were evaluated annually for 5 years to assess the long-term safety of BT and the durability of its treatment effect. Outcomes assessed after BT included severe exacerbations, adverse events, health care use, spirometric data, and high-resolution computed tomographic scans. A total of 162 (85.3 %) of 190 BT-treated subjects from the Asthma Intervention Research 2 trial completed 5 years of follow-up. The proportion of subjects experiencing severe exacerbations and emergency department (ED) visits and the rates of events in each of years 1 to 5 remained low and were less than those observed in the 12 months before BT treatment (average 5-year reduction in proportions: 44 % for exacerbations and 78 % for ED visits). Respiratory AEs and respiratory-related hospitalizations remained unchanged in years 2 through 5 compared with the first year after BT. Pre-bronchodilator FEV1 values remained stable between years 1 and 5 after BT, despite a 18 % reduction in average daily inhaled corticosteroid dose. High-resolution computed tomographic scans from baseline to 5 years after BT showed no structural abnormalities that could be attributed to BT. The authors concluded that these findings demonstrated the 5-year durability of the benefits of BT with regard to both asthma control (based on maintained reduction in severe exacerbations and ED visits for respiratory symptoms) and safety. They stated that BT has become an important addition to the treatment armamentarium and should be considered for patients with severe persistent asthma who remain symptomatic despite taking inhaled corticosteroids and long-acting β2-agonists. Whether BT is a disease-modifying therapy will depend on the results of future appropriately designed clinical studies. The main drawback of this study was the lack of a sham control group beyond 1 year.
Pavord et al (2013) evaluated the long-term safety of BT for 5 years. Patients with asthma aged 18 to 65 years requiring high-dose inhaled corticosteroids (ICSs) (greater than 750 mg/day of fluticasone propionate or equivalent) and LABAs (at least 100 mg/day of salmeterol or equivalent), with or without oral prednisone (less than or equal to 30 mg/day), leukotriene modifiers, theophylline, or other asthma controller medications were enrolled in the Research in Severe Asthma (RISA) Trial. Patients had a pre-bronchodilator FEV1 of 50 % or more of predicted, demonstrated methacholine airway hyper-responsiveness, had uncontrolled symptoms despite taking maintenance medication, abstained from smoking for 1 year or greater, and had a smoking history of less than 10 pack-years. A total of 14 patients (of the 15 who received active treatment in the RISA Trial) participated in the long-term follow-up study for 5 years. The rate of respiratory adverse events (AEs per patient per year) was 1.4, 2.4, 1.7, and 2.4, respectively, in years 2 to 5 after BT. There was a decrease in hospitalizations and emergency department visits for respiratory symptoms in each of years 1, 2, 3, 4, and 5 compared with the year before BT treatment. Measures of lung function showed no deterioration for 5 years. The authors concluded that these findings suggested that BT is safe for 5 years after BT in patients with severe refractory asthma. The major drawbacks of this study were the absence of a control group during the longer-term follow-up as well as the small sample size (n = 14).
An UpToDate review on “Alternative and experimental agents for the treatment of asthma” (Martin, 2013) states that “The Food and Drug Administration has approved marketing of Alair Bronchial Thermoplasty System for the treatment of adult patients (greater than or equal to 18 years old) with severe asthma not well-controlled with inhaled glucocorticoids and long-acting beta agonists. Due to the risk of the procedure and modest degree of improvement, additional data are needed regarding long-term effects and morphologic changes in the airways prior to determining when to use BT”.
The Work Loss Data Institute’s guideline on “Asthma. In: Pulmonary (acute & chronic)” (2013) stated that “Bronchial thermoplasty, utilizes heat to decrease the smooth muscle mass/function in the larger bronchial airways. It is still to be considered an experimental approach until more data can be presented. It has been used in individuals with severe asthma who fail traditional, aggressive forms of therapy. These individuals may not always be identified clinically or by physiologic parameters”.
In a Cochrane review, Torrego et al (2014) examined the safety and effectiveness of BT in adults with bronchial asthma. These investigators searched the Cochrane Airways Group Specialized Register of Trials (CAGR) up to January 2014. They included RCTs that compared BT versus any active control in adults with moderate or severe persistent asthma. The primary outcomes were quality of life, asthma exacerbations and adverse events. Two review authors independently extracted data and assessed risk of bias. These researchers included 3 trials (429 participants) with differences regarding their design (2 trials compared BT versus medical management and the other compared BT versus a sham intervention) and participant characteristics; 1 of the studies included participants with more symptomatic asthma compared with the others. The pooled analysis showed improvement in quality of life at 12 months in participants who received BT that did not reach the threshold for clinical significance (3 trials, 429 participants; mean difference (MD) in Asthma Quality of Life Questionnaire (AQLQ) scores 0.28, 95 % confidence interval (CI) 0.07 to 0.50; moderate-quality evidence). Measures of symptom control showed no significant differences (3 trials, 429 participants; MD in Asthma Control Questionnaire (ACQ) scores -0.15, 95 % CI: -0.40 to 0.10; moderate-quality evidence). The risk of bias for these outcomes was high because 2 of the studies did not have a sham intervention for the control group. The results from 2 trials showed a lower rate of exacerbation after 12 months of treatment for participants who underwent BT. The trial with sham intervention showed a significant reduction in the proportion of participants visiting the emergency department for respiratory symptoms, from 15.3 % on sham treatment to 8.4 % over 12 months following BT. The trials showed no significant improvement in pulmonary function parameters (with the exception of a greater increase in morning PEF in 1 trial). Treated participants who underwent BT had a greater risk of hospitalization for respiratory adverse events during the treatment period (3 trials, 429 participants; risk ratio 3.50, 95 % CI: 1.26 to 9.68; high-quality evidence), which represents an absolute increase from 2 % to 8 % (95 % CI: 3 % to 23 %) over the treatment period. This meant that 6 of 100 participants treated with BT (95 % CI: 1 to 21) would require an additional hospitalization over the treatment period. No significant difference in the risk of hospitalization was noted at the end of the treatment period. Bronchial thermoplasty was associated with an increase in respiratory adverse events, mainly during the treatment period. Most of these events were mild or moderate, appeared in the 24-hour post-treatment period, and were resolved within a week. The authors concluded that BT for patients with moderate to severe asthma provides a modest clinical benefit in quality of life and lower rates of asthma exacerbation, but no significant difference in asthma control scores. The quality of life findings were at risk of bias, as the main benefits were seen in the 2 studies that did not include a sham treatment arm. This procedure increases the risk of adverse events during treatment but has a reasonable safety profile after completion of the bronchoscopies. The overall quality of evidence regarding this procedure is moderate. For clinical practice, it would be advisable to collect data from patients systematically in independent clinical registries. Moreover, they stated that further research should provide better understanding of the mechanisms of action of BT, as well as its effect in different asthma phenotypes or in patients with worse lung function.
Kaukel et al (2014) stated that BT is a new treatment option for patients with severe bronchial asthma who remain symptomatic despite maximal medical therapy. The aim of this interventional therapy option is the reduction of smooth muscle in the central and peripheral airways in order to reduce symptomatic broncho-constriction via the application of heat. A full treatment with BT is divided into 3 bronchoscopies. Randomized, controlled clinical trials have shown an increase in quality of life, a reduction in severe exacerbations, and decreases in ED visits as well as days lost from school or work. The trials did not show a reduction in hyper-responsiveness or improvement in FEV1. Short-term adverse effects include an increase in exacerbation rate, an increase in respiratory infections and an increase in hospitalizations. In the 5-year follow-up of the studies available there was evidence of clinical and functional stability of the treated patients. Moreover, the authors concluded that further studies are needed to identify an asthma phenotype that responds well to this treatment.
Iyer and Lim (2014) noted that BT involves the application of radiofrequency energy to visible proximal airways to selectively ablate airway smooth muscle. Bronchial thermoplasty is the first non-pharmacologic interventional therapy approved by the 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 AQLQ. The results of the AIR-2 trial have generated enormous interest, controversy, and confusion regarding the true effectiveness 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 2 groups, and was this type of analysis even justified given the original study design? This commentary was designed to specifically answer these questions and help the practicing clinician navigate the thermoplasty literature with confidence and clarity. The authors carefully dissected the design, conduct, and results of the AIR-2 trial and raised serious questions about the effectiveness of BT.
Bezzi et al (2014) stated that BT is a new modality for treating asthma. It targets ASM by delivering a controlled specific amount of thermal energy (radiofrequency ablation) to the airway wall through a dedicated catheter. The use of BT has been widely discussed for its potential in the treatment of asthma, since it seems to be able to reduce the symptoms of asthma. The definitive study for BT (AIR2 trial) employed a randomized, double-blind, sham-controlled design and enrolled 288 subjects with severe persistent asthma from 30 U.S. and international centers. The results of the AIR2 trial demonstrated clinically significant benefits of BT compared with the sham group at 1 year post-treatment, including an improvement in asthma-related quality of life, 32 % reduction in severe exacerbations, 84 % reduction in ED visits for asthma symptoms, and a 66 % reduction in time lost from work/school/other daily activities because of asthma symptoms. Pre-clinical work showed that ASM is reduced after BT by at least 3 years after treatment. The recent article from the ARI2 trial study group analyzed the long-term safety and effectiveness of BT in patients with severe persistent asthma and demonstrated the 5-year durability of the benefits of BT in the control of symptoms and safety. It supports the evidence that reduction in asthma attacks, ER visits, and hospitalizations for respiratory symptoms are maintained for at least 5 years. The authors concluded that there is a pressing need to understand the underlying mechanism(s) of BT and how the delivered heat is translated into clinical benefit. This necessitates additional investigation to identify disease and patient characteristics that would enable accurate phenotyping of positive responders to avoid unnecessary procedures and risks.
Guidelines from the American Thoracic Society and the European Respiratory Society (Chung et al, 2014) stated that “we recommend that bronchial thermoplasty is performed in adults with severe asthma only in the context of an Institutional Review Board approved independent systematic registry, or a clinical study”. This is a strong recommendation, based upon very low quality of evidence.
Furthermore, guidelines from the Global Initiative for Asthma (GINA, 2014) stated that “for highly selected adult patients with uncontrolled asthma despite use of recommended therapeutic regimens and referral to an asthma specialty center (Step 5), bronchial thermoplasty is a potential treatment option in some countries”. The guidelines stated that “evidence is limited and in selected patients” and that “the long-term effects are not known”. The guidelines stated that “caution should be used in selecting patients for this procedure, as the number of studies is small, and people with chronic sinus disease, frequent chest infections or FEV1 less than 60 percent predicted were excluded”. The guidelines also stated that “more studies are needed to identify its efficacy and long-term safety in broader severe asthma populations”. The guidelines explain that “carefully controlled trials are important as a large placebo effect has been seen in studies to date”.
In summary, although available data are promising, more research is needed to ascertain what role, if any, BT should play in the treatment of patients with asthma. Furthermore, there is a lack of evidence regarding the effectiveness of BT in the management of patients with chronic obstructive pulmonary disease.
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