Title: Point: Efficacy of Bronchial Thermoplasty for Patients With Severe Asthma. Is There Sufficient Evidence? Yes
Abstract: Asthma Intervention Research last observation carried forward The overall burden of severe asthma on individuals and society is substantial because patients with severe asthma often experience disabling symptoms and account for a disproportionately high amount of asthma-care expenditures.1Antonicelli L Bucca C Neri M et al.Asthma severity and medical resource utilisation.Eur Respir J. 2004; 23: 723-729Crossref PubMed Scopus (251) Google Scholar Asthma is associated with persistent and progressive decline in lung function2Brown PJ Greville HW Finucane KE Asthma and irreversible airflow obstruction.Thorax. 1984; 39: 131-136Crossref PubMed Scopus (261) Google Scholar that is not modified by currently available therapeutic approaches, including inhaled bronchodilators and corticosteroids.3Strunk RC Sternberg AL Szefler SJ Zeiger RS Bender B Tonascia J. Childhood Asthma Management Program (CAMP) Research Group Long-term budesonide or nedocromil treatment, once discontinued, does not alter the course of mild to moderate asthma in children and adolescents.J Pediatr. 2009; 154: 682-687Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar The majority of patients with severe asthma require three to four medications and take long-term oral corticosteroids or frequent bursts.4Dolan CM Fraher KE Bleecker ER TENOR Study Group et al.Design and baseline characteristics of the epidemiology and natural history of asthma: Outcomes and Treatment Regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma.Ann Allergy Asthma Immunol. 2004; 92: 32-39Abstract Full Text PDF PubMed Scopus (267) Google Scholar Despite these expensive therapies, patients with severe asthma are responsible for a disproportionately high share of asthma-associated morbidity and mortality5Cisternas MG Blanc PD Yen IH et al.A comprehensive study of the direct and indirect costs of adult asthma.J Allergy Clin Immunol. 2003; 111: 1212-1218Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar and continue to experience repeated symptoms, including exacerbations that are potentially life threatening. In the Severe Asthma Research Program, we have demonstrated that almost one-half of these patients have sought emergency care in the past 12 months.6Moore WC Bleecker ER Curran-Everett D National Heart, Lung, Blood Institute's Severe Asthma Research Program et al.Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program.J Allergy Clin Immunol. 2007; 119: 405-413Abstract Full Text Full Text PDF PubMed Scopus (771) Google Scholar Therefore, a substantial proportion of patients with severe asthma lack effective therapy to control their symptoms and to minimize impairment. The evidence basis for add-on medications for patients with severe asthma who take high-dose inhaled corticosteroids and long-acting β-agonists is minimal. Currently, the National Asthma and Education and Prevention Program Expert Panel Report 37National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Institutes of Health. National Heart, Lung, and Blood Institute, 2007Google Scholar recommends add-on therapy with long-acting β-agonists, leukotriene modifiers, theophylline, and omalizumab (anti-IgE monoclonal antibody) for patients with uncontrolled asthma who take inhaled corticosteroids. Only omalizumab is recommended as an add-on therapy in those patients with severe asthma who are allergic and uncontrolled on inhaled or oral corticosteroids (corresponding to steps 5 and 6 therapy).7National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Institutes of Health. National Heart, Lung, and Blood Institute, 2007Google Scholar Omalizumab was approved by the US Food and Drug Administration based on pivotal studies demonstrating efficacy in patients with moderate to severe persistent allergic asthma uncontrolled on high-dose inhaled corticosteroids alone.8Busse W Corren J Lanier BQ et al.Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma.J Allergy Clin Immunol. 2001; 108: 184-190Abstract Full Text Full Text PDF PubMed Scopus (1098) Google Scholar, 9Solèr M Matz J Townley R et al.The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics.Eur Respir J. 2001; 18: 254-261Crossref PubMed Scopus (783) Google Scholar A subsequent study performed in patients with severe asthma uncontrolled on combination therapy with high-dose inhaled corticosteroids and long-acting β-agonists did not demonstrate efficacy.10Holgate ST Chuchalin AG Hébert J Omalizumab 011 International Study Group et al.Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma.Clin Exp Allergy. 2004; 34: 632-638Crossref PubMed Scopus (480) Google Scholar In the subset of patients with severe asthma who qualified for omalizumab, the reported response varied, with an average risk reduction for exacerbations of 45%.11Rodrigo GJ Neffen H Castro-Rodriguez JA Efficacy and safety of subcutaneous omalizumab vs placebo as add-on therapy to corticosteroids for children and adults with asthma: a systematic review.Chest. 2011; 139: 28-35Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar Furthermore, when measuring the impact of available therapies for patients with severe asthma on patient-centered outcome, such as asthma-specific quality of life, a similar magnitude of improvement of the active treatment over placebo was noted across these therapies, as shown in Figure 1. This figure also demonstrates that the improvement in quality of life must be interpreted with caution because the underlying therapy that these patients with severe asthma received (as-needed β-agonists, inhaled corticosteroids alone, or combination therapy) varied considerably across studies. Finally, many of these add-on medications are expensive, have substantial side effects, and require adherence to daily medications or monthly or biweekly injections. Therefore, an alternative therapy with efficacy in this patient population is needed. Bronchial thermoplasty provides a novel solution to this unmet need. Bronchial thermoplasty is performed with the Alair Bronchial Thermoplasty System (Asthmatx, Inc; Sunnyvale, California), which is designed to deliver a specific amount of radiofrequency (thermal) energy through a dedicated catheter. Treatments occur in three separate sessions, with careful preprocedure and postprocedure monitoring to address respiratory complications that can occur in patients with severe asthma. This controlled heating of the airway wall causes a decrease in the amount of airway smooth muscle.12Cox PG Miller J Mitzner W Leff AR Radiofrequency ablation of airway smooth muscle for sustained treatment of asthma: preliminary investigations.Eur Respir J. 2004; 24: 659-663Crossref PubMed Scopus (130) Google Scholar Bronchial thermoplasty reduces the ability of the airway to bronchoconstrict in response to agonists, such as methacholine.13Miller JD Cox G Vincic L Lombard CM Loomas BE Danek CJ A prospective feasibility study of bronchial thermoplasty in the human airway.Chest. 2005; 127: 1999-2006Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar Bronchial thermoplasty has been evaluated for both efficacy and safety in three controlled clinical trials14Castro M Rubin A Laviolette M et al.Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled trial.Am J Respir Crit Care Med. 2010; 181: 116-124Crossref PubMed Scopus (579) Google Scholar, 15Cox G Thomson NC Rubin AS AIR Trial Study Group et al.Asthma control during the year after bronchial thermoplasty.N Engl J Med. 2007; 356: 1327-1337Crossref PubMed Scopus (486) Google Scholar, 16Pavord ID Cox G Thomson NC RISA Trial Study Group et al.Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma.Am J Respir Crit Care Med. 2007; 176: 1185-1191Crossref PubMed Scopus (360) Google Scholar in >275 patients treated with bronchial thermoplasty—an unparalleled series of studies for a respiratory medical device. The first multicenter prospective randomized controlled trial of bronchial thermoplasty in patients with moderate to severe asthma taking inhaled corticosteroids and long-acting β-agonists was the Asthma Intervention Research (AIR) trial.15Cox G Thomson NC Rubin AS AIR Trial Study Group et al.Asthma control during the year after bronchial thermoplasty.N Engl J Med. 2007; 356: 1327-1337Crossref PubMed Scopus (486) Google Scholar The AIR trial at 1 year demonstrated that patients receiving bronchial thermoplasty showed improved asthma symptoms, and there was an encouraging reduction in mild exacerbations. The second multicenter prospective randomized controlled trial, Research in Severe Asthma, evaluated patients with more severe asthma than those in the AIR trial.16Pavord ID Cox G Thomson NC RISA Trial Study Group et al.Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma.Am J Respir Crit Care Med. 2007; 176: 1185-1191Crossref PubMed Scopus (360) Google Scholar Major improvements in various measures of asthma, including FEV1, quality of life, asthma control, and use of rescue medications, were seen in the bronchial thermoplasty group compared with the control group. A trend to greater overall reduction in oral corticosteroid dose was observed in the bronchial thermoplasty group compared with the control group at 1 year. The largest randomized study of bronchial thermoplasty, the AIR2 trial, contained a sham control group, allowing this to be a truly double-blinded trial.14Castro M Rubin A Laviolette M et al.Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled trial.Am J Respir Crit Care Med. 2010; 181: 116-124Crossref PubMed Scopus (579) Google Scholar Results showed a significant improvement in asthma quality of life from baseline to 1 year in those treated with bronchial thermoplasty compared with sham bronchoscopy (Fig 2). Among the patients treated with bronchial thermoplasty in the posttreatment period (>6 weeks after treatment), there was a significant decrease in severe exacerbations, emergency department visits, and days lost from work or school compared with the sham group. In these controlled trials, bronchial thermoplasty has demonstrated persistent efficacy in reducing exacerbations, health-care utilization, days lost from school or work, and results in improved quality of life and asthma symptoms. Recent data from the AIR2 trial provide evidence that this improvement persists now beyond 2 years in patients receiving bronchial thermoplasty.17Castro M Rubin A Laviolette M et al.Two-year persistence of effect of bronchial thermoplasty (BT) in patients with severe asthma: AIR2 trial [abstract].Chest. 2010; 138: 768AAbstract Full Text Full Text PDF Google Scholar Bronchial thermoplasty provides a treatment that pulmonologists can deliver safely and effectively. The most common respiratory-related adverse events during the treatment period are breathlessness, wheeze, cough, chest discomfort, night awakenings, and productive cough. The majority of these adverse events occur within 1 day of the procedure and resolve in an average of 7 days after the onset of the event with standard therapy (bronchodilators, corticosteroids).18Castro M Musani AI Mayse ML Shargill NS Bronchial thermoplasty: a novel technique in the treatment of severe asthma.Ther Adv Respir Dis. 2010; 4: 101-116Crossref PubMed Scopus (30) Google Scholar CT scanning of the chest was performed in the first 100 patients in the bronchial thermoplasty-treated group and the first 50 patients in the sham group. Analysis of these CT scans showed no evidence of airway or parenchymal injury related to bronchial thermoplasty at 1 year in the AIR2 trial,19Gupta SS Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma.Am J Respir Crit Care Med. 2010; 182: 1565-1567Crossref PubMed Scopus (2) Google Scholar and this finding has been confirmed in additional long-term (5-year) studies of bronchial thermoplasty-treated patients.20Cox G Laviolette M Rubin A et al.Long term safety of bronchial thermoplasty (BT): 3 year data from multiple studies [abstract].Am J Respir Crit Care. 2009; 179: A2780Google Scholar Since obtaining approval from the Food and Drug Administration in 2010, bronchial thermoplasty has been implemented in clinical practice at >55 sites globally (N. Shargill, PhD, written communication, Asthmatx, Inc, July 20, 2011). Not treating a patient with severe asthma who qualifies for bronchial thermoplasty and who is experiencing substantial morbidity from asthma and its treatment (especially from corticosteroids) poses a significant dilemma for the clinician. Patients with difficult-to-treat asthma should be evaluated systematically to confirm the diagnosis of asthma, exclude an alternative diagnosis, identify comorbidities, assess treatment compliance, and evaluate for treatment-induced side effects. A systematic evaluation of patients referred to specialized centers for asthma has identified that only ∼50% of these patients have asthma that is truly difficult to control.21Heaney LG Conway E Kelly C et al.Predictors of therapy resistant asthma: outcome of a systematic evaluation protocol.Thorax. 2003; 58: 561-566Crossref PubMed Scopus (162) Google Scholar Therefore, bronchial thermoplasty should be reserved for these patients as add-on step 5 or 6 therapy (Fig 3). With appropriate patient selection, management, and follow-up, bronchial thermoplasty provides a treatment that pulmonologists can deliver both safely and effectively. /cms/asset/e2f0b1b2-a102-47a0-a4a9-9da40b1d79e9/mmc1.mp3Loading ... Download .mp3 (17.14 MB) Help with .mp3 files Supplementary audioBronchial Thermoplasty for Patients With Severe AsthmaDuration: 27:26 minModerator: D. Kyle Hogarth, MD, FCCP, Podcast Editor, CHESTParticipants: Mario Castro, MD, FCCP; Gaetane Michaud, MD, FCCP