Published ahead of print on September 27, 2007, doi:10.1164/rccm.200704-571OC
© 2007 American Thoracic Society doi: 10.1164/rccm.200704-571OC
Safety and Efficacy of Bronchial Thermoplasty in Symptomatic, Severe Asthma1 Glenfield General Hospital, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom; 2 St. Joseph's Healthcare–McMaster University, Hamilton, Canada; 3 Gartnavel General Hospital, University of Glasgow, Glasgow, United Kingdom; 4 Irmandade Santa Casa de Misericórdia, Porto Alegre, Brazil; 5 Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, United Kingdom; 6 Wythenshawe Hospital, University of Manchester, Manchester, United Kingdom; 7 National Heart and Lung Institute, Imperial College, London, United Kingdom; and 8 Laval Hospital, Laval University, Quebec, Canada Correspondence and requests for reprints should be addressed to Ian D. Pavord, M.D., Glenfield General Hospital, University Hospitals of Leicester NHS Trust, Groby Road, Leicester LE3 9QP, United Kingdom. E-mail: ian.pavord{at}uhl-tr.nhs.uk
Rationale: Bronchial thermoplasty (BT) is designed to reduce airway smooth muscle and improve asthma control. Objectives: This study was conducted to determine the safety and efficacy of this procedure in subjects with symptomatic, severe asthma. Methods: Adults who were symptomatic despite treatment with fluticasone or equivalent at more than 750 µg/day, a long-acting β2-agonist, 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 6–22), a 14-week steroid wean phase (Weeks 22–36), and a 16-week reduced steroid phase (Weeks 36–52). Measurements and Main Results: BT resulted in a transient worsening of asthma symptoms. Seven hospitalizations for respiratory symptoms occurred in 4 of 15 BT subjects during the treatment period. Five hospitalizations were within 3 days of treatment. Two subjects had segmental collapse involving the most recently treated lobe; one 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, BT subjects had significant improvements versus control subjects in rescue medication use (–26.6 ± 40.1 vs. –1.5 ± 11.7 puffs/7 d, P < 0.05), prebronchodilator FEV1% predicted (14.9 ± 17.4 vs. –0.94 ± 22.3%, P = 0.04), and Asthma Control Questionnaire scores (–1.04 ± 1.03 vs. –0.13 ± 1.00, P = 0.02). Improvements in rescue medication use and Asthma Control Questionnaire scores remained significantly different from those of controls at 52 weeks. Conclusions: BT is associated with a short-term increase in asthma-related morbidity. However, there is preliminary evidence of long-lasting improvement in asthma control. Clinical trial registered with www.clinicaltrials.gov (NCT 00214539).
Key Words: bronchial thermoplasty • asthma • bronchoscopy • airway smooth muscle • radiofrequency energy
Asthma is an increasingly prevalent disease that adversely impacts the lives of millions of subjects and caregivers. Much of the morbidity, mortality, and health care expense attributed to asthma occur in patients with more severe disease, and the need for better therapeutic options in this important group of patients is widely acknowledged (1–6). Some of the variable symptoms of asthma are due to airway smooth muscle (ASM) contraction, which results from a variety of stimuli (7). The application of bronchial thermoplasty (BT) to the airways is an innovative treatment approach to reduce the bronchoconstrictor response in asthma. Preclinical studies have shown that BT results in reduction of ASM (8, 9). Animal studies have shown that this is associated with a long-lasting reduction in airway responsiveness to methacholine (8). In a feasibility study to determine the safety of BT in subjects with mild to moderate asthma (n = 16), there were no severe adverse events in the 2-year study period (10). Although the study was not powered to evaluate efficacy, BT resulted in significant improvements in symptom-free days and PEF at 3 months, and a reduction in airway hyperresponsiveness that persisted for at least 2 years (10). In the Asthma Intervention Research (AIR) trial, which evaluated the effects of BT in subjects with moderate to severe asthma, treatment significantly reduced mild exacerbations and use of rescue medication. It also improved morning PEF, Asthma Quality-of-Life Questionnaire (AQLQ) scores, Asthma Control Questionnaire (ACQ) scores, and symptom scores compared with the control group (11). A post hoc analysis suggested that the benefits of treatment were particularly marked in subjects with more severe disease. The primary objective of this study, the Research in Severe Asthma (RISA) trial, was to determine the safety of BT in subjects with symptomatic, severe asthma. Secondary objectives included evaluation of the effect of BT on asthma symptoms and daily medication requirements. Some of the results of this study have been previously reported in the form of abstracts (12, 13).
Subject Selection Key inclusion criteria were as follows: subjects with asthma aged 18 to 65 years; requirement of high-dose inhaled corticosteroid (ICS) (>750 µg fluticasone propionate per day or equivalent) and long-acting β2-agonist (LABA) (at least 100 µg salmeterol per day or equivalent), with or without oral prednisone (  30 mg/d), leukotriene modifiers, or theophylline; prebronchodilator FEV1  50% of predicted; demonstrable airway hyperresponsiveness by challenge with methacholine (methacholine challenge not performed in subjects with prebronchodilator FEV1 < 60% predicted or FEV1 less than the lower limit defined by individual hospital protocol) or reversible bronchoconstriction during prior 12 months as demonstrated by an increase in FEV1 of at least 12% 30 minutes after four puffs of a short-acting β2-agonist; uncontrolled symptoms despite taking maintenance medication (demonstrated by the use of rescue medication on at least 8 of the 14 days before enrollment, or daytime symptoms on at least 10 of the 14 days before enrollment); and abstinence from smoking for 1 year or greater and past smoking history of less than 10 pack-years.
Study Design and Intervention After a 2-week run-in period, subjects were randomized either to the control group or to treatment (BT group) with the Alair Bronchial Thermoplasty System (Asthmatx, Inc., Mountain View, CA) using randomization envelopes based on a computer-generated code (blocks of 4 per site). BT group subjects underwent three procedures at least 3 weeks apart (11). All subjects maintained baseline asthma medications. After the treatment period, subjects entered a 16-week steroid stable phase (Weeks 6–22), followed by a 14-week steroid wean phase (Weeks 22–36), and a 16-week reduced steroid phase (Weeks 36–52) (Figure 1). During the steroid wean phase, investigators attempted to wean subjects, following a prospectively defined protocol, from oral corticosteroids (OCS) or ICS. OCS dose was reduced by 20 to 25% of the baseline dose in steps of 2 weeks each. For subjects successfully weaned to OCS daily doses of 5–7.5 mg, further attempts to reduce the OCS dose were per investigator discretion. For subjects taking only ICS+LABA, the ICS dose was tapered in three stages by 20 to 25% of the baseline dose every 4 weeks to a minimal dose of 100–600 µg/day of fluticasone propionate or equivalent (12). Investigators were not blinded to treatment.
The weaning process was stopped and medications were adjusted to the previous tolerable dose if a subject experienced a mild exacerbation (lasting more than 7 d), or experienced a severe exacerbation, or if the investigator determined that a deterioration in asthma control required a change in asthma medication. Mild and severe exacerbation definitions were as previously described (11). During the reduced steroid phase, subjects continued those medications prescribed at the end of the steroid wean phase for as long as possible.
Measurements
In addition, an adverse event could also be classified as a serious adverse event. According to protocol, a serious adverse event was predefined as any event that was fatal, required or prolonged hospitalization, caused substantial risk of dying at the time of the event, resulted in permanent or significant disability/incapacity, or required intervention to prevent permanent impairment. Additional endpoints included change in OCS and ICS, use of rescue medication, morning and evening PEF, FEV1, PC20 (provocative concentration causing a 20% fall in FEV1), asthma symptom score, symptom-free days (11), or AQLQ (15) and ACQ scores (16). Further details of the outcome measures are supplied in the online supplement.
Statistical Analyses
Thirty-two subjects completed this study (15 in the BT group, 17 in the control group) (Figure 1); all subjects met the Global Initiative for Asthma (GINA) criteria for severe persistent asthma (17) and all but one (one subject had one major but only one minor criterion) met the American Thoracic Society (ATS) criteria for refractory asthma (1). The mean FEV1 percent predicted was 63% in the BT group and 66% in the control group. Approximately half of the subjects in each group were taking OCS in addition to their ICS+LABA. Baseline parameters were similar between groups except for symptom score (5.6 for the BT group and 3.4 for controls, P = 0.02; Table 1). In the 12 months before study entry, the BT group reported more hospitalizations for respiratory adverse events than the control group, although the difference in the proportion of subjects reporting a hospitalization was not statistically significant (10 in 6 subjects vs. 5 in 2 subjects, respectively; P = 0.11; Table 1).
Safety All adverse events were recorded for safety analysis. After BT, there was an increase in respiratory adverse events in the treatment period (Table 2), but there was no increase in the frequency of adverse events with successive treatments. There was no difference between groups during the post-treatment period (Table 2). The most frequently observed respiratory adverse events in the treatment period for BT subjects were wheezing, cough, chest discomfort, dyspnea, productive cough, and discolored sputum (Table 2). Most of these adverse events occurred within 1 day of the bronchoscopy procedure and resolved on average within a week.
During the treatment period, the BT group had 136 respiratory adverse events: 49% were mild, 41% were moderate, and 10% were severe. The control group had 57 respiratory adverse events: 49% were mild, 47% were moderate, and 4% were severe. There were no subject deaths and no permanent or significant disability/incapacity in any patient in the study. All of the respiratory adverse events that met the definition of serious adverse events involved a hospitalization and are described in Table 3.
During the treatment period, there were seven hospitalizations for respiratory adverse events involving four subjects in the BT group and none in the control group (Table 3). Five of the seven hospitalizations in the BT group were for exacerbations of asthma and two were for partial collapse of a lower lobe of the lung. In one case, a left lower lobe segment collapsed 2 days after treatment of the same area and the lung segment reinflated after physiotherapy plus standard medical therapy. In the other case, the lung segment collapse occurred the day after treatment of the area, and was due to a mucus plug; aspiration of the mucus plug resulted in reinflation of the lung segment. The median length of stay for the hospitalizations in the BT group during this period was 2 days. In addition, two subjects in the BT group had five severe respiratory adverse events (chest infection, increased wheeze, cough, shortness of breath on exertion) and two subjects in the control group had two severe respiratory adverse events (dyspnea, chest infection) that were medically treated and did not result in hospitalization. In the post-treatment period, five hospitalizations occurred in three subjects in the BT group and four hospitalizations occurred in one subject in the control group (Table 3). This difference was not statistically significant (P = 0.32). No BT subjects required intubation or treatment in the intensive care unit (ICU); one control subject had an exacerbation on Day 42 that resulted in management in the ICU (respiratory failure). In addition, in the post-treatment period, two subjects in the BT group had five severe respiratory adverse events (increased wheeze, chest tightness, increased breathlessness, nocturnal wheeze, and chest infection) and one subject in the control group had one severe respiratory adverse event (flulike syndrome), all of which were medically treated and did not result in hospitalization.
Efficacy
There were no significant differences in morning or evening PEF, symptom-free days, symptom scores, or methacholine PC20 (see the online supplement).
Reduced steroid phase (Weeks 36–52). After the reduced steroid phase at 52 weeks, BT subjects compared with control subjects continued to show a significantly better improvement in short-acting β2-agonist use (–25.6 ± 31.2 vs. –6.1 ± 12.4 puffs/7 d, P < 0.05; Figure 2A, right panel), AQLQ (1.53 ± 0.79 vs. 0.42 ± 0.82, P = 0.001; Figure 2C, right panel), and ACQ (–0.99 ± 0.83 vs. –0.22 ± 0.78, P = 0.01; Figure 2D, right panel). There were no significant differences between groups in the change from baseline and the end of this reduced steroid phase in the other efficacy measures.
Post hoc analysis of covariance.
This is the first randomized clinical trial to evaluate BT in the treatment of symptomatic, severe asthma. All subjects met the GINA criteria for severe persistent asthma, and all but one subject met the criteria established by the ATS Workshop on Refractory Asthma, indicating a severe patient population that is not well controlled by current therapy (1). We found that, in this population, BT was associated with a short-term increase in asthma-related morbidity around the time of treatment but showed a potential for a longer term improvement in rescue medication use, lung function, asthma control, and quality of life. Consistent with previous observations, treatment with BT was associated with adverse events, some requiring hospitalization, that were primarily related to worsening of asthma symptoms in the period immediately after treatment (10, 11). Subjects in the AIR study were less symptomatic than subjects in the current study, and had a mean FEV1% predicted of 73% and a mean daily beclomethasone equivalent inhaled steroid dose of approximately 1,350 µg. In that study, there were six hospitalizations in 4 subjects out of 55 treated subjects during the treatment period; there were no hospitalizations in the 18 BT subjects with mild–moderate asthma and relatively normal lung function studied by Cox and colleagues (10, 11). Thus, as has been shown before for bronchoscopy and bronchial biopsy in asthma, the severity and frequency of the adverse events appear to be greater in subjects with severe asthma compared with those with less severe asthma (18–20). In keeping with the AIR study, respiratory adverse events were similar between 6 weeks and 12 months in BT-treated subjects and control subjects, suggesting that longer term adverse effects related to BT do not occur and that subjects with more severe asthma are not at increased risk for these effects. However, longer and larger studies of subjects with different asthma severity are required before we can be sure that there are not delayed adverse effects. The adverse events that were reported after BT included episodes of lobar segmental collapse in two subjects, one of whom required a bronchoscopy with aspiration of a mucus plug. A partial lobar collapse occurred 2 days after treatment in the AIR study (11). All reported cases have involved the most recently treated lobe, suggesting that BT was at least partly responsible for the complication. Further work is required to determine whether there is an increase in lobar segmental collapse associated with BT. If so, a better understanding of the mechanism and risk factors for this complication may allow the development of effective preventive strategies. In considering the potential long-term role for BT in the treatment of severe asthma, the increased short-term risk of procedure-related adverse events needs to be weighed against the preliminary evidence of improvement in a range of measures of asthma control. In the stable steroid phase of this study (6–22 wk), treated subjects had clinically and statistically significant improvements over baseline in rescue medication use, prebronchodilator FEV1% predicted, and AQLQ and ACQ scores. Given the increase in hospitalizations in the treatment period, we considered whether the timing of the last OCS dose resulting from these hospitalizations could have influenced the 22-week evaluation. One BT subject completed his/her OCS dose 25 days before the 22-week evaluation, and all other subjects completed their OCS dose more than 2 months before the 22-week evaluation. Therefore, it is unlikely that the increased steroid use due to hospitalization contributed to the outcomes observed. The net improvement in FEV1 of 16% seen in our study was larger than that seen in the AIR trial (11), perhaps because the effect of BT is more readily observed in a more severe patient population because of greater room for improvement. The changes from baseline compared with the control group in the questionnaire scores (+1.1 and –0.9 for AQLQ and ACQ, respectively) were significantly higher than the reported clinically important differences in these measures, and the reduction in puffs per week equates to almost seven fewer canisters of rescue medication per year (21, 22). Changes in bronchodilator use, AQLQ, and ACQ remained statistically significant at 52 weeks, after an attempt had been made to reduce corticosteroid treatment, providing further evidence of a sustained beneficial effect of BT (11). The changes in corticosteroid requirements were not statistically significant, but the power of the study to demonstrate such an effect was low. Future appropriately powered studies should address this important question. Our results show that most subjects with symptomatic, severe asthma were able to safely tolerate BT. There were seven short-term hospitalizations for respiratory adverse events involving four subjects in the BT group during the treatment period. In the post-treatment period, treated subjects had an adverse event profile similar to their baseline and the control group, but with improvements in their rescue medication use, lung function, asthma control, and quality of life. Some caution is required in interpreting these results as this was a small study with a high potential for placebo effect and there were differences in baseline values, which although not statistically significant, could have influenced the response to treatment. However, a post hoc analysis of covariance suggests that the baseline differences did not account for the improvements observed with the exception of one measure. The magnitude of the positive effects, their persistence to 52 weeks, the similar findings in the AIR study (11), and the significant improvements observed in measures like FEV1, which are less susceptible to bias, provide further reassurance that the results are real. However, appropriately powered studies with blinded sham treatment are critical. Only then will it be possible to interpret the real risk–benefit balance of this novel procedure.
The authors are indebted to Alan Leff, M.D. (University of Chicago, Chicago, IL), Louis-Philippe Boulet (Laval University, Quebec, Canada), Ratko Djukanovic (University of Southampton, Southampton, UK), Nizar Jarjour, M.D. (University of Wisconsin, Madison, WI), Elliot Israel, M.D. (Brigham and Women's Hospital, Boston, MA), Monica Kraft, M.D. (Duke University, Durham, NC), Mario Castro, M.D. (Washington University, St. Louis, MO), for their valuable contributions to the design and interpretation of this study, and to Michael D. Laufer, M.D., who pioneered the method of treating airway smooth muscle physically to ameliorate asthma. The data and safety monitoring board comprised William Busse, M.D., Robert Schellenberg, M.D., and Arthur S. Slutsky, M.D. (chair).
The RISA Trial was funded by Asthmatx, Inc. All authors were investigators in the Research in Severe Asthma (RISA) trial. This is the first clinical study to evaluate the effects of bronchial thermoplasty in symptomatic severe asthma.
* A list of the participants in the RISA Trial Study Group may be found at the end of this article. This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Originally Published in Press as DOI: 10.1164/rccm.200704-571OC on September 27, 2007 Conflict of Interest Statement: I.D.P. received $2,000 from GlaxoSmithKline and $5,000 from AstraZeneca in lecture fees, and received a $250,000 grant from GlaxoSmithKline for a study on severe asthma. G.C. received $1,000 in speaker fees in 2005 from Asthmatx, Inc., and received $108,000 in 2006 and $58,000 in 2007 in operating grant support from Asthmatx, Inc., for clinical trials of bronchial thermoplasty in asthma. N.C.T. received grants from AstraZeneca ($30,000 in 2006), Asthmatx ($77,000 in 2004, $36,000 in 2005, $28,000 in 2006, $75,000 in 2007), and GlaxoSmithKline ($111,540 in 2004, $165,000 in 2005, $112,500 in 2006) for participating in clinical trials. A.S.R.'s institution, Santa Casa de Porto Alegre, received $98,000 in 2004, $248,000 in 2005, $281,000 in 2006, and $60,000 in 2007 from Asthmatx in research grants for participating in multicenter clinical trials. P.A.C.'s institution, Freeman Hospital, received $20,000 in 2004, $171,000 in 2005, and $68,000 in 2007 in reimbursement for expenses related to clinical trials of bronchial thermoplasty. The funding was placed in a research account for the Department of Respiratory Medicine. R.M.N. participated in three clinical trials of bronchial thermoplasty over 4 years and will receive approximately £220,000 in research payments for the trials as a principal investigator. K.F.C. received $1,000 in 2006 from GlaxoSmithKline, $700 in 2005 from AstraZeneca, and $2,000 in 2005 and 2006 from Novartis for participation in advisory board meetings; received unrestricted educational grants from Novartis, Altana, and Boehringer Ingelheim; and participated in the current RISA trials supported by Asthmatx, Inc. M.L. participated in clinical trials for Altana, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Bayer, Merck, Asthmatx, and Topigen. M.L.'s institution, Laval Hospital, received $182,000 in 2004, $115,000 in 2005, $151,000 in 2006, and $169,000 in 2007 for the reimbursement of expenses related to clinical trials of bronchial thermoplasty; gave lectures sponsored by Altana, AstraZeneca, 3M, GlaxoSmithKline, Merck, and Asthmatx; and received a $50,000 medical research grant from Merck Frost in 2004. The RISA Trial Study Group comprised the following investigators, coinvestigators, and study coordinators who contributed to this study: Mike Berry, M.D., Dominick Shaw, M.D., Nicola Sheldon (Glenfield General Hospital, University of Leicester, UK); John Miller, M.D., Parameswaran Nair, M.D., Sarah Goodwin, Kathleen Currie (St. Joseph's Healthcare, McMaster University, ON, Canada); Rekha Chaudhuri, M.D., Steve Bicknell, M.D., Eric Livingston, M.D., Jane Lafferty, R.N. (Gartnavel General Hospital, University of Glasgow, UK); Paulo Guerreiro Cardoso, M.D., P.h.D., Patricia Ristori Dias Soares (Irmandade Santa Casa de Misericórdia, Porto Alegre, Brazil); Bernard Higgins, M.D., Therese Small, R.N., Barbara Foggo, R.N. (Institute of Cellular Medicine, Newcastle University, UK); Curig Prys-Picard, M.D., Gill Fletcher (Wythenshawe Hospital, University of Manchester, UK); Pallav Shah, M.D., Mun Lim, R.N., Sally Meah, R.N. (National Heart and Lung Institute, Imperial College, London, UK); Simon Martel, M.D., Louis-Philippe Boulet, M.D., Lucie Morel, Luce Trépanier (Laval Hospital, Laval University, Quebec, Canada). Received in original form April 12, 2007; accepted in final form September 25, 2007
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