BACKGROUNDMost guidelines recommend either a long-acting beta-agonist (LABA) plus an inhaled glucocorticoid or a long-acting muscarinic antagonist (LAMA) as the firstchoice treatment for patients with chronic obstructive pulmonary disease (COPD) who have a high risk of exacerbations. The role of treatment with a LABA-LAMA regimen in these patients is unclear. METHODSWe conducted a 52-week, randomized, double-blind, double-dummy, noninferiority trial. Patients who had COPD with a history of at least one exacerbation during the previous year were randomly assigned to receive, by inhalation, either the LABA indacaterol (110 μg) plus the LAMA glycopyrronium (50 μg) once daily or the LABA salmeterol (50 μg) plus the inhaled glucocorticoid fluticasone (500 μg) twice daily. The primary outcome was the annual rate of all COPD exacerbations. RESULTSA total of 1680 patients were assigned to the indacaterol-glycopyrronium group, and 1682 to the salmeterol-fluticasone group. Indacaterol-glycopyrronium showed not only noninferiority but also superiority to salmeterol-fluticasone in reducing the annual rate of all COPD exacerbations; the rate was 11% lower in the indacaterolglycopyrronium group than in the salmeterol-fluticasone group (3.59 vs. 4.03; rate ratio, 0.89; 95% confidence interval [CI], 0.83 to 0.96; P = 0.003). The indacaterolglycopyrronium group had a longer time to the first exacerbation than did the salmeterol-fluticasone group (71 days [95% CI, 60 to 82] vs. 51 days [95% CI, 46 to 57]; hazard ratio, 0.84 [95% CI, 0.78 to 0.91], representing a 16% lower risk; P<0.001). The annual rate of moderate or severe exacerbations was lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (0.98 vs. 1.19; rate ratio, 0.83; 95% CI, 0.75 to 0.91; P<0.001), and the time to the first moderate or severe exacerbation was longer in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (hazard ratio, 0.78; 95% CI, 0.70 to 0.86; P<0.001), as was the time to the first severe exacerbation (hazard ratio, 0.81; 95% CI, 0.66 to 1.00; P = 0.046). The effect of indacaterol-glycopyrronium versus salmeterolfluticasone on the rate of COPD exacerbations was independent of the baseline blood eosinophil count. The incidence of adverse events and deaths was similar in the two groups. The incidence of pneumonia was 3.2% in the indacaterol-glycopyrronium group and 4.8% in the salmeterol-fluticasone group (P = 0.02). CONCLUSIONSIndacaterol-glycopyrronium was more effective than salmeterol-fluticasone in preventing COPD exacerbations in patients with a history of exacerbation during the previous year. (Funded by Novartis; FLAME ClinicalTrials.gov number, NCT01782326.)

Obstructive sleep apnea is an important disorder because of both its prevalence and its cardiovascular and neurocognitive sequelae. Despite the fact that male sex is a major risk factor for this disorder, the mechanisms underlying this predisposition are unclear. To understand the pathophysiologic basis of the male predisposition for pharyngeal collapse, we performed a detailed analysis of the anatomic and physiologic features of the upper airway in a cohort of normal and near-normal subjects (equal number of men and women). Although no important physiologic (genioglossal electromyogram, airflow resistance) differences were observed between sexes, a number of anatomic differences were apparent. The pharyngeal airway length was substantially longer in men compared with women. There was also an increased cross-sectional area of the soft palate and an increased airway volume in men compared with women. Using signal-averaged anatomic data from male and female subjects, we developed representative male and female finite element airway models. This model demonstrated the male airway to be substantially more collapsible than the female airway, solely on the basis of anatomic differences. This study suggests that the male predisposition to pharyngeal collapse is anatomically based, primarily as the result of an increased length of vulnerable airway as well as increased soft palate size.

Obstructive sleep apnea is a common disorder with important sequelae. 1-7 Aging substantially increases the risk of obstructive apnea, 8-11 although the mechanisms underlying this predisposition remain unclear. 8,12-15 Most current evidence suggests that obstructive apnea results from an interaction of the anatomy of the upper airway with the control of pharyngeal dilator muscles. 4 Afflicted patients have compromised pharyngeal anatomy with reduced airway lumen. 16-19,20 Through reflex mechanisms that drive activation of dilator muscles, pharyngeal patency is well maintained during wakefulness. 21-23 However, these protective reflexes are diminished during sleep, thereby leading to collapse of the pharyngeal airway in anatomically predisposed people. 24 Thus, aging could predispose to apnea via changes in pharyngeal anatomy and biomechanics or via deterioration in the function of pharyngeal dilator muscles. 25-31 By combining magnetic resonance imaging techniques with pharyngeal physiological assessments, we sought to determine the structural and functional basis for the increased propensity for airway collapse among older persons. We included normal and near-normal controls to avoid the confounding influences of repetitive pharyngeal collapse as might occur with sleep apnea. METHODS Subjects Eighteen men and 20 women across a range of ages were enrolled (Table). The subjects were recruited using e-mail announcements and posters and through the Harvard Cooperative on Aging. Although some of our subjects had participated in prior studies, none of the agingrelated findings of the present study have been previously reported. The women under 50 were premenopausal based on regular menstrual cycles, whereas women over age 50 were postmenopausal for at least 2 years. All were free from comorbid conditions, including snoring and were taking no medications, based on a thorough history and physical examination by a pulmonary specialist. All provided informed consent for the protocol, which was approved by the Brigham and Women's Hospital Human Subjects' Committee. Equipment and Procedures Overnight Polysomnography-Patients were monitored for a minimum of 7 hours of sleep by electroencephalography, electromyography, electrooculography, nasal pressure, nasal and oral airflow by thermister, chest and abdominal wall motion using piezo electrodes, electrocardiography, anterior tibialis electromyography, and arterial oxygen saturation using Requests for reprints should be addressed to