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Background Bronchial thermoplasty is a bronchoscopic procedure to reduce the mass of airway smooth muscle and attenuate bronchoconstriction. We examined the effect of bronchial thermoplasty on the control of moderate or severe persistent asthma.
Methods We randomly assigned 112 subjects who had been treated with inhaled corticosteroids and long-acting
Results The mean rate of mild exacerbations, as compared with baseline, was reduced in the bronchial-thermoplasty group but was unchanged in the control group (change in frequency per subject per week, –0.16±0.37 vs. 0.04±0.29; P=0.005). At 12 months, there were significantly greater improvements in the bronchial-thermoplasty group than in the control group in the morning peak expiratory flow (39.3±48.7 vs. 8.5±44.2 liters per minute), scores on the AQLQ (1.3±1.0 vs. 0.6±1.1) and ACQ (reduction, 1.2±1.0 vs. 0.5±1.0), the percentage of symptom-free days (40.6±39.7 vs. 17.0±37.9), and symptom scores (reduction, 1.9±2.1 vs. 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 two groups. Adverse events immediately after treatment were more common in the bronchial-thermoplasty group than in the control group but were similar during the period from 6 weeks to 12 months after treatment.
Conclusions Bronchial thermoplasty in subjects with moderate or severe asthma results in an improvement in asthma control. (ClinicalTrials.gov number, NCT00214526
[ClinicalTrials.gov]
.)
2-adrenergic agonists (LABA) and in whom asthma control was impaired when the LABA were withdrawn to either bronchial thermoplasty or a control group. The primary outcome was the frequency of mild exacerbations, calculated during three 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.
Methods
Subjects
Persons 18 to 65 years of age were eligible for enrollment if they had moderate or severe persistent asthma, defined according to the guidelines of the Global Initiative for Asthma,9 requiring daily therapy with inhaled corticosteroids equivalent to a dose of 200 µg or more of beclomethasone and long-acting 2-adrenergic agonists (LABA), at a dose of 100 µg or more of salmeterol (Serevent, GlaxoSmithKline) or the equivalent, to maintain reasonable asthma control. Inclusion criteria were airflow obstruction, assessed as a prebronchodilator forced expiratory volume in 1 second (FEV1) of 60 to 85% of the predicted value, and airway hyperresponsiveness, defined by a provocative concentration of methacholine required to lower the FEV1 by 20% (PC20) of less than 8 mg per milliliter, as well as stable asthma during the 6 weeks before enrollment. Stable asthma was defined as an absence of unscheduled physician visits for asthma care, unchanged use of asthma medication for maintenance therapy, and stable use of rescue medication (4 puffs or fewer of a short-acting bronchodilator at a dose of 100 µg per puff delivered by a metered-dose inhaler [albuterol or the equivalent]) during 24 hours for symptom relief.
One other criterion in addition to fulfilling the definition of moderate or severe asthma was worsening asthma control after abstention from LABA at baseline for 2 weeks, documented by either an increase of at least 0.5 in the score on the Asthma Control Questionnaire (ACQ)10 (on a scale of 0 to 6, with higher numbers indicating worse control), or a decline of 5% in the average morning peak expiratory flow (PEF) during the second week of abstinence, as compared with the mean morning PEF during the week immediately before LABA therapy was withdrawn. Subjects were excluded if they had had three or more lower respiratory tract infections requiring antibiotics during the previous 12 months or a respiratory tract infection within the previous 6 weeks.
Study Design
This randomized, controlled trial was conducted at 11 centers in four countries. During the 4-week baseline period, subjects continued to receive maintenance therapy with inhaled corticosteroids and LABA for the first 2 weeks, and LABA were then withheld for the next 2 weeks. Therapy with inhaled corticosteroids and LABA was resumed for the treatment period, which lasted for at least 6 weeks and usually no more than 9 weeks, with a subsequent 12-month follow-up period. The study design is shown in Figure 1. All subjects were seen in follow-up at 3 months while receiving treatment with inhaled corticosteroids and LABA. They were asked to refrain from using LABA after this point, unless they had a severe exacerbation (an event requiring treatment with oral corticosteroids, as judged by the investigator, or a decrease in the morning PEF, for 1 or more days, of more than 30% below the average baseline morning PEF recorded during the week immediately preceding withdrawal from LABA therapy), or if they were judged by the investigator to have poor asthma control that required the resumption of LABA. For those subjects whose asthma could be controlled without LABA, evaluations were performed after 6 and 12 months of treatment with inhaled corticosteroids alone. Subjects who needed to resume LABA therapy before the visits at 6 and 12 months were evaluated at those assessment points after withdrawal from LABA therapy for 2 weeks.
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Randomization
Eligible subjects were assigned to treatment with inhaled corticosteroids plus LABA (control group) or to treatment with bronchial thermoplasty in addition to inhaled corticosteroids and LABA (bronchial-thermoplasty group) in blocks of four at each center. The randomization code was computer-generated centrally and provided to the study sites in separate envelopes. Investigators were unaware of the block size.
Treatment Period
Subjects assigned to the bronchial-thermoplasty group underwent three bronchoscopy procedures performed with the use of the Alair system (Asthmatx) at intervals of approximately 3 weeks. During the procedure, they were under either general anesthesia or conscious sedation, as previously described.5,8 A video showing part of an actual procedure is in the Supplementary Appendix, available with the full text of this article at www.nejm.org. Control subjects had three treatment visits at intervals of 3 weeks for clinical review and spirometric assessment and received a systemic corticosteroid similar to that administered to subjects in the bronchial-thermoplasty group.
Follow-up Period
All subjects in the two groups were seen 2 weeks after each treatment visit. After the last treatment visit (designated as time 0), clinic visits were scheduled at 6 weeks and at 3, 6, and 12 months. Subjects were contacted by telephone on days 1 and 7 after each treatment visit and monthly after the visit at month 3.
Outcome Measures
The primary outcome was the difference between the two groups in the change in the rate of mild exacerbations between baseline and later time points. Exacerbations, ascertained from daily diaries in which subjects recorded events, were defined as at least one of the following occurrences on 2 consecutive days: a reduction in the morning PEF of at least 20% below the average value (based on the PEF recorded during the week immediately preceding the withdrawal of LABA at baseline), the need for more than three additional puffs of rescue medication exceeding the average use during the week immediately preceding the withdrawal of LABA at baseline, or nocturnal awakening caused by asthma symptoms.11 Only events occurring during the 2-week periods of abstinence from LABA, according to the study protocol, at 3, 6, and 12 months were used to calculate the rates of mild and severe exacerbations.
All subjects kept a daily diary from the beginning of the baseline period to the visit at month 6, and for a 4-week period before the visit at month 12. The data recorded in the diaries were used to assess changes in the PEF, the use of rescue medication, the number of symptom-free days, and the symptom score. The symptom score was the total of the individual scores (on a scale of 0 to 3, with higher numbers indicating more frequent or more severe symptoms or both) for nighttime wheezing and cough and daytime wheezing, cough, breathlessness, and sputum production. These six individual scores were summed to yield a maximum possible score of 18. A symptom-free day was defined as a day during which the symptom score was 0 and there was no nighttime awakening. The ACQ consists of six questions and the measurement of prebronchodilator FEV1, and responses are scored on a scale of 0 to 6, with lower numbers indicating better asthma control. The minimal important change in the score is thought to be 0.5.12 The Asthma Quality of Life Questionnaire (AQLQ) consists of 32 items covering asthma-related symptoms and limitations during the 2 weeks preceding administration of the questionnaire, and responses are scored on a scale of 1 to 7, with higher numbers indicating a better quality of life. The minimal important change in the score is thought to be 0.5.13 For details of the outcome measures, see the Supplementary Appendix.
Monitoring Adverse Events
At each visit and during each telephone call, subjects were asked by research staff about potential adverse events, and their daily diaries were examined by study personnel to ensure complete reporting of events. Adverse events were classified as respiratory or nonrespiratory events and were reported at baseline and for the treatment period and the post-treatment period.
Statistical Analysis
The statistical analysis was performed on an intention-to-treat basis and included those subjects who completed at least one bronchoscopy session or treatment visit. The study was powered to detect differences between the two groups in the change from baseline to later time points. There was no imputation of missing data. Frequencies of adverse events were compared with the use of Fisher's exact test. For continuous variables, statistical significance was determined with the use of Student's t-test, and for categorical variables, statistical significance was determined with the use of the Cochran–Mantel–Haenszel test. P values of less than 0.05 were considered to indicate statistical significance. Data are reported as means (±SD), and all reported P values are two-sided, unless otherwise indicated.
The study was designed with more than 90% power to detect a difference of eight mild exacerbations per subject per year between the two groups with the use of a two-tailed t-test. Exacerbation rates and secondary outcomes were analyzed on the basis of the change from the baseline period (the 2-week period during which the subjects were treated with inhaled corticosteroids alone) to the 2-week periods at 3, 6, and 12 months during which they were treated with inhaled corticosteroids alone (Figure 1). For the analysis of the effects of bronchial thermoplasty in addition to usual care, at 3 months, the relevant baseline was treatment with inhaled corticosteroids plus LABA. Data for all subjects were included in the safety analyses.
The protocol was designed by a committee of academic authors and employees of the sponsor, with comment in specific areas from an advisory board. The database was managed and all analyses requested by the investigators were performed by QST Consultations. The manuscript was written by the corresponding author, with contributions from all coauthors and selected employees of the sponsor, and was reviewed by the external advisory board. The final manuscript was prepared by the corresponding author, without limitation by the sponsor. All the authors vouch for the accuracy and completeness of the reported data.
Results
Baseline Characteristics of the Subjects
Of 240 subjects who underwent screening, 68 did not fulfill all the entry criteria on assessment during the run-in period and 60 did not complete the phase of withdrawal from LABA (i.e., could not tolerate withdrawal, did not have deterioration, or withdrew consent). The remaining 112 subjects underwent randomization, and 56 subjects were assigned to each of the two study groups (Figure 1). Outcomes for the effect of bronchial thermoplasty in addition to usual care were assessed at 3 months for 52 subjects in the bronchial-thermoplasty group and 48 control subjects; complete data after 12 months of follow-up were available for 52 subjects in the bronchial-thermoplasty group and 49 in the control group (Figure 1). The baseline demographic characteristics of the two groups were similar (Table 1). For the statistical comparisons, baseline means were calculated only for subjects for whom follow-up data were available.
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Twelve months after the last study treatment, the mean number of mild exacerbations in the bronchial-thermoplasty group was 0.18±0.31 per subject per week, as compared with 0.35±0.32 at baseline. The number of mild exacerbations in the control group was 0.31±0.46 per subject per week, as compared with 0.28±0.31 at baseline. The difference between the two groups in the change from baseline was significant at 3 months and at 12 months (P=0.03 for both comparisons) but not at 6 months (Figure 2). As compared with baseline, the average number of exacerbations during the 2-week periods at 3, 6, and 12 months when subjects in the two groups were treated with inhaled corticosteroids alone was reduced in the bronchial-thermoplasty group but was not significantly changed in the control group (–0.16±0.37 vs. 0.04±0.29 per subject per week, P=0.005 for the comparison between the groups). Analysis with the use of the Wilcoxon rank-sum method also showed a significant difference between the groups (P=0.01). This finding can be extrapolated to approximately 10 fewer mild exacerbations per subject per year in the bronchial-thermoplasty group.
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Changes in the secondary outcomes (airflow, airway hyperresponsiveness, use of rescue medication, asthma symptoms, and scores on the AQLQ and ACQ) in the subjects receiving usual care at 3 months and when LABA were withdrawn at 3, 6, and 12 months are shown in Figure 3. For further data on secondary outcomes, see the Supplementary Appendix.
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In a post hoc analysis, data for a subgroup of subjects requiring high maintenance doses of inhaled corticosteroids (>1000 µg of beclomethasone or the equivalent) at baseline were analyzed separately and showed greater differences between the control group and the bronchial-thermoplasty group. Data on this analysis are in the Supplementary Appendix.
Adverse Events
There was an increase in adverse respiratory events in subjects undergoing bronchial thermoplasty immediately after the procedure, with a return to baseline values during the post-treatment period. During the treatment period, there were 407 adverse respiratory events, of which 69% were mild, 28% were moderate, and 3% were severe. In the control group there were 106 adverse respiratory events, of which 69% were mild, 30% were moderate, and 1% were severe. The most frequently observed adverse events during the treatment period are listed in Table 2. In the bronchial-thermoplasty group, the majority of the adverse events occurred within 1 day after the procedure and resolved an average of 7 days after the onset of the event.
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During the post-treatment period, the proportion of subjects with adverse respiratory events was similar in the two groups (Table 2). The rate of hospitalization for respiratory events was low during this period and did not differ significantly between the two groups: three subjects in the bronchial-thermoplasty group required hospitalization — one for chest infection and two for asthma exacerbation — and two subjects in the control group required a total of three hospitalizations for increased asthma symptoms. There were no deaths during the study.
Although there were variations among the study centers in the size of the treatment effect and the number of adverse events, there was no obvious relationship between the investigators' experience with bronchial thermoplasty or the numbers of subjects treated and the outcomes or adverse events. One additional hospitalization for an adverse respiratory event occurred 14 months after bronchial thermoplasty in a subject who had undergone the procedure uneventfully and had completed the trial with normal spirometric values and good asthma control (score on the ACQ, 0.2; symptom score, 0), but who subsequently underwent resection for an abscess in a left upper lobe. Histologic examination did not reveal obstruction or any other potentially contributory abnormality in the airways as a result of thermoplasty. (For information on the follow-up in the bronchial-thermoplasty group after completion of the study, see the Supplementary Appendix.)
Discussion
This randomized, controlled study examined the efficacy and safety of bronchial thermoplasty in subjects with moderate or severe persistent asthma. The study design was based on the hypothesis that if bronchial thermoplasty were beneficial, then in subjects treated with bronchial thermoplasty, as compared with control subjects, asthma control would be improved when treatment with LABA was discontinued. Although the benefits of bronchial thermoplasty were obvious when LABA were withdrawn, they were also observed at 3 months, when all subjects in the two study groups were still receiving LABA (Figure 3). Among subjects treated with inhaled corticosteroids alone, bronchial thermoplasty reduced the frequency of mild exacerbations at a rate equivalent to 10 exacerbations per subject per year and provided 86 additional symptom-free days per subject per year. These improvements were achieved during a period in which the use of rescue medication was reduced in the bronchial-thermoplasty group, as compared with the control group.
The effect of bronchial thermoplasty was evident 3 months after the procedure. The improvements in objective and subject-centered outcomes did not diminish over the course of the study, and the outcomes assessed at 1 year showed the same degree of improvement as at 3 months. In a preliminary, nonrandomized study, we found that the benefits of bronchial thermoplasty persisted at 2 years.8 Thus, although the duration of the effect of bronchial thermoplasty remains uncertain, in this study the benefit appeared to persist at 1 year.
Treatment with bronchial thermoplasty was associated with adverse events related primarily to worsening of asthma symptoms during the period immediately after treatment. Although the frequency of adverse events was similar in the two groups at 6 weeks to 1 year after bronchial thermoplasty, studies of larger numbers of patients and with a longer follow-up will be needed to rule out less common adverse events than those identified in this study.
The interpretation of our results is confounded by the nonblinded study design; this limitation is important, given that bronchial thermoplasty is a procedure that may increase the potential for a strong placebo effect.14,15,16 However, the magnitude and persistence of the effects of the intervention observed are probably greater than what could be attributed to placebo alone. For example, a within-group change of 0.5 in scores on the AQLQ is considered clinically significant,13 and we found a between-group difference of 0.69 at 12 months. Of the outcomes reported, perhaps the two that are least susceptible to bias are the morning PEF, since it was measured daily for most of the study period, and the number of mild exacerbations per subject per week, since these were counted after the study had ended by a statistician who reviewed the data in the daily diaries, according to predetermined criteria. The increase in the morning PEF value of 39 liters per minute from baseline to 12 months among subjects treated with bronchial thermoplasty (between-group difference, 31 liters per minute) exceeded the change seen in placebo groups in other trials involving patients with asthma (range, –22 to 17 liters per minute).17,18,19,20,21 Our data showing potential beneficial effects of bronchial thermoplasty provide the basis for mounting a placebo-controlled trial involving the use of sham bronchial thermoplasty.
Supported by Asthmatx.
All authors received financial support from Asthmatx for the completion of this study. Dr. Cox reports receiving lecture fees from Novartis, Merck Frosst, Asthmatx, GlaxoSmithKline, and AstraZeneca, fees for serving on advisory boards from GlaxoSmithKline and AstraZeneca, and grant support from AstraZeneca and GlaxoSmithKline; Dr. Thomson, grant support from AstraZeneca and GlaxoSmithKline; Dr. Siersted, lecture fees from GlaxoSmithKline, consulting fees from GlaxoSmithKline and Novartis, and grant support from GlaxoSmithKline; Dr. Laviolette, lecture fees from 3M, GlaxoSmithKline, and Merck Frosst and grant support from GlaxoSmithKline; Dr. Pavord, lecture fees from GlaxoSmithKline and AstraZeneca and grant support from GlaxoSmithKline; and Dr. Niven, lecture fees from Altana, Novartis, GlaxoSmithKline, and AstraZeneca and grant support from Wyeth. No other potential conflict of interest relevant to this article was reported.
We thank Alan Leff (University of Chicago, Chicago), Nizar Jarjour (University of Wisconsin, Madison), Elliot Israel (Brigham and Women's Hospital, Boston), Monica Kraft (Duke University, Durham, NC), Louis-Philippe Boulet (Laval University, Quebec, QC), and Mario Castro (Washington University, St. Louis) for their valuable contributions to the design and interpretation of this study; and Michael Laufer, who pioneered the concept of bronchial thermoplasty for the treatment of asthma.
Source Information
From St. Joseph's Healthcare, McMaster University, Hamilton, ON, Canada (G.C., J.D.M.); Gartnavel General Hospital, University of Glasgow, Glasgow, United Kingdom (N.C.T., R.C.); Irmandade Santa Casa de Misericórdia, Porto Alegre, Brazil (A.S.R.); Wythenshawe Hospital, University of Manchester, Manchester, United Kingdom (R.M.N.); Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, United Kingdom (P.A.C.); Odense University Hospital, Odense, Denmark (H.C.S.); Montreal Chest Institute, Montreal (R.O.); Glenfield General Hospital, University Hospitals of Leicester National Health Service Trust, Leicester, United Kingdom (I.D.P.); London Health Science Centre, London, ON, Canada (D.M.); and Laval Hospital, Laval University, Quebec, QC, Canada (M.L.).
Address reprint requests to Dr. Cox at the Firestone Institute for Respiratory Health, St. Joseph's Healthcare and McMaster University, 50 Charlton Ave. E., Rm. T2123, Hamilton, ON L8N 4A6, Canada, or at coxp{at}mcmaster.ca.
References
Members of the AIR Trial Study Group were as follows: data and safety monitoring board — W. Busse, R. Schellenberg, A.S. Slutsky (chair); coinvestigators and study coordinators — Canada: McMaster University: P. Nair, S. Goodwin, K. Currie; Montreal Chest Institute: J. Bourbeau, F. Houghton; London Health Science Centre: N. Patterson, S. Metha, J. Howard, L. MacBean; Laval University: S. Martel, L.-P. Boulet, L. Morel, L. Trépanier; United Kingdom: University of Glasgow: S. Bicknell, E. Livingston, J. Lafferty; University of Manchester: C. Prys-Picard, G. Fletcher; Newcastle University: B. Higgins, T. Small, B. Foggo; University of Leicester: M. Berry, D. Shaw, N. Sheldon; London Chest Hospital: N. Barnes (investigator), D. Watson; Brazil: Santa Casa: P.G. Cardoso, P.R.D. Soares; Denmark: Odense University Hospital: F. Rasmussen, H.M. Christensen, M. Olsen.
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Related Letters:
Bronchial Thermoplasty
Macklem P. T., Medford A. R.L., Agrawal A., Cox G., Thomson N. C., Laviolette M.
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N Engl J Med 2007;
356:2744-2745, Jun 28, 2007.
Correspondence
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