Noe Zamel

Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease: A Randomized Trial

Context Physicians use multiple medications to treat chronic obstructive pulmonary disease (COPD). Contribution In this multicenter trial, 449 adults with moderate or severe COPD were randomly assigned to receive tiotropium and placebo, tiotropium and salmeterol, or tiotropium and fluticasonesalmeterol for 1 year. About 63%, 65%, and 60% of patients, respectively, had exacerbations. The third group, but not the second group, had better lung function and fewer hospitalizations than the first group. Caution Many patients discontinued assigned medications. Implications Adding fluticasonesalmeterol to tiotropium may improve lung function and decrease hospitalizations, but it does not affect reduce exacerbations in patients with moderate or severe COPD. The Editors Most patients with moderate or severe chronic obstructive pulmonary disease (COPD) experience chronic progressive dyspnea that is not alleviated by short-acting bronchodilators. It is therefore not surprising that many patients are treated with multiple inhaled medications to optimize their lung function and minimize symptoms (1). Published guidelines on COPD state that the goals of pharmacologic therapy should be to control symptoms, improve health status, and reduce the frequency of COPD exacerbations (2, 3), and many published guidelines advocate combining different classes of long-acting bronchodilators or inhaled steroids to achieve these goals (2, 3). In the past several years, several studies have shown that treatment of COPD with the long-acting anticholinergic tiotropium (47); the long-acting 2-agonist salmeterol (810); or products that combine inhaled steroids and long-acting 2-agonists, such as fluticasonesalmeterol or budesonideformoterol (1114), improve dyspnea and quality of life and decrease exacerbation rates compared with placebo. However, no studies have assessed whether therapy with a combination of these products provides greater clinical benefit than does therapy with these agents used alone. 2-Agonists and anticholinergics work by different mechanisms to cause bronchodilation (15), and inhaled corticosteroids may have an anti-inflammatory effect in COPD (16). Thus, it makes theoretical and intuitive sense that combining these therapies might be more beneficial than therapy with 1 agent alone. However, safety concerns, such as side effects associated with long-term use of long-acting 2-agonists and inhaled corticosteroids, and economic issues related to the additional costs of these medications may argue against routine use of inhaled medication polypharmacy without evidence of efficacy. We therefore conducted a randomized, double-blind, placebo-controlled clinical trial to determine whether combining tiotropium with salmeterol or fluticasonesalmeterol produces greater improvements in clinical outcomes for adults with moderate or severe COPD compared with tiotropium therapy alone. Methods Design We designed a parallel-group, 3-group, randomized, double-blind, placebo-controlled trial in patients with moderate or severe COPD that was conducted from October 2003 to January 2006. The study protocol has been published elsewhere (17). The research ethics boards of all participating centers approved the study, and all trial participants provided written informed consent. Setting and Participants We enrolled patients with diagnosed moderate or severe COPD from 27 Canadian medical centers. Twenty centers were academic hospitalbased pulmonary clinics, 5 were community-based pulmonary clinics, and 2 were community-based primary care clinics. Eligible patients had to have had at least 1 exacerbation of COPD that required treatment with systemic steroids or antibiotics within the 12 months before randomization. Additional inclusion criteria were age older than 35 years; a history of 10 pack-years or more of cigarette smoking; and documented chronic airflow obstruction, with an FEV1FVC ratio less than 0.70 and a postbronchodilator FEV1 less than 65% of the predicted value. We excluded patients with a history of physician-diagnosed asthma before 40 years of age; those with a history of physician-diagnosed chronic congestive heart failure with known persistent severe left ventricular dysfunction; those receiving oral prednisone; those with a known hypersensitivity or intolerance to tiotropium, salmeterol, or fluticasonesalmeterol; those with a history of severe glaucoma or severe urinary tract obstruction, previous lung transplantation or lung volume reduction surgery, or diffuse bilateral bronchiectasis; and those who were pregnant or were breastfeeding. Persons with a recent COPD exacerbation requiring oral or intravenous antibiotics or steroids were required to wait until treatment with these agents had been discontinued for 28 days before entering the study. Randomization and Interventions We randomly assigned patients to 1 of 3 treatment groups for 52 weeks: tiotropium (Spiriva [Boehringer Ingelheim Pharma, Ingelheim, Germany]), 18 g once daily, plus placebo inhaler, 2 puffs twice daily; tiotropium, 18 g once daily, plus salmeterol (Serevent [GlaxoSmithKline, Research Triangle Park, North Carolina]), 25 g/puff, 2 puffs twice daily; or tiotropium, 18 g once daily, plus fluticasonesalmeterol (Advair [GlaxoSmithKline]), 250/25 g/puff, 2 puffs twice daily. Randomization was done through central allocation of a randomization schedule that was prepared from a computer-generated random listing of the 3 treatment allocations, blocked in variable blocks of 9 or 12 and stratified by site. Neither research staff nor patients were aware of the treatment assignment before or after randomization. All study patients were provided with inhaled albuterol and were instructed to use it when necessary to relieve symptoms. Any treatment with inhaled corticosteroids, long-acting 2-agonists, and anticholinergics that the patient may have been using before entry was discontinued on entry into the study. Therapy with other respiratory medications, such as oxygen, antileukotrienes, and methylxanthines, was continued in all patient groups. Tiotropium was administered by using a Handihaler device (Boehringer Ingelheim). Study drugs were administered through a pressurized metered-dose inhaler using a spacer device (Aerochamber Plus, Trudell Medical, London, Ontario, Canada), and patients were taught the correct inhalation technique to ensure adequate drug delivery. The metered-dose inhalers containing placebo, salmeterol, and fluticasonesalmeterol were identical in taste and appearance, and they were enclosed in identical tamper-proof blinding devices. The medication canisters within the blinding devices were stripped of any identifying labeling. Adherence to therapy was assessed by weighing the returned inhaler canisters. Measurements and Outcomes The primary outcome was the proportion of patients in each treatment group who experienced a COPD exacerbation within 52 weeks of randomization. Respiratory exacerbations were defined, according to the 2000 Aspen Lung Conference Consensus definition, as a sustained worsening of the patients respiratory condition, from the stable state and beyond normal day-to-day variations, necessitating a change in regular medication in a patient with underlying COPD (18). An acute change in regular COPD medications was defined as physician-directed, short-term use of oral or intravenous steroids, oral or intravenous antibiotics, or both therapies. Secondary outcomes were the mean number of COPD exacerbations per patient-year; the total number of exacerbations that resulted in urgent visits to a health care provider or emergency department; the number of hospitalizations for COPD; the total number of hospitalizations for all causes; and changes in health-related quality of life, dyspnea, and lung function. Health-related quality of life was assessed by using the St. Georges Respiratory Questionnaire (19), dyspnea was assessed by using the Transitional Dyspnea Index (20) and the dyspnea domain of the Chronic Respiratory Disease Questionnaire (21), and lung function was assessed by measuring the FEV1 according to established criteria of the American Thoracic Society. Follow-up Procedures Patients were monitored for exacerbations by monthly telephone calls. Exacerbations and all secondary outcomes were also assessed through patient visits at baseline and at 4, 20, 36, and 52 weeks after randomization. For every suspected exacerbation, we contacted both the patient and the patients treating physician to ensure that the medical encounter had been prompted by acute respiratory symptoms and a full report, including physician, emergency department, and hospital records that described the circumstances of each suspected exacerbation, was prepared. The assembled data from the visit for the suspected exacerbation were presented to a blinded adjudication committee for review, and the committee confirmed whether the encounter met the study definition of COPD exacerbation. For the purposes of the trial, we considered that a patient had experienced a new COPD exacerbation if he or she had not been receiving oral steroids and antibiotics for at least 14 days after the previous exacerbation. Patients were followed for the full 52-week duration of the trial, and primary and secondary outcomes were recorded throughout the 1-year period regardless of whether patients had experienced an exacerbation or discontinued treatment with study medications. We did not break the study blinding for patients who prematurely discontinued treatment with study medications. Adverse events were captured by the research coordinators through monthly patient telephone interviews and at scheduled patient visits by using checklists of potential side effects. Physicians rated events as expected or unexpected, and they were asked to rate event severity and attribute causality of adverse events to the study drugs. Statistical Analysis We designed the study to detect an 18% absolute d

Effect of low concentrations of ozone on inhaled allergen responses in asthmatic subjects

The relation between inhalation of ambient concentrations of ozone and airway reactivity to inhaled allergens may be important in asthma, since both agents can produce inflammatory changes in the airways. Seven asthmatic patients (mean age 40 [SD 13] years), with seasonal symptoms of asthma and positive skin tests for ragweed or grass, took part in a study to investigate whether exposure to low concentrations of ozone potentiates the airway allergic response. The patients were studied during 4 separate weeks in the winter. In each week there were 3 study days: on days 1 and 3 methacholine challenges were carried out; and on day 2 the subject received one of four combined challenges in a single-blind design--air breathing followed by inhalation of allergen diluent (placebo); ozone followed by inhalation of allergen diluent; air followed by allergen; or ozone followed by allergen. The ozone concentration was 0.12 ppm during 1 h of tidal breathing at rest, and allergens were inhaled until the forced expiratory volume in 1 s (FEV1) had fallen by 15% (PC15). There were no significant differences in baseline FEV1 after exposure to ozone but PC15 was significantly reduced when allergen was preceded by ozone inhalation: the mean PC15 after air was 0.013 (SD 0.017) mg/ml compared with 0.0056 (0.0062) mg/ml after ozone (p = 0.042). Thus, low ozone concentrations, similar to those commonly occurring in urban areas, can increase the bronchial responsiveness to allergen in atopic asthmatic subjects. This effect does not seem to be the result of changes in baseline airway function.

Pharyngeal Size in Snorers, Nonsnorers, and Patients with Obstructive Sleep Apnea

We measured pharyngeal cross-sectional area and its change with alterations in lung volume in 10 subjects who snored and had obstructive sleep apnea, 6 subjects who snored and did not have obstructive sleep apnea, and 9 subjects who did not snore. Pharyngeal area was measured with use of an acoustic-reflection technique. We found that snorers with and without sleep apnea had a significantly smaller mean (+/- SE) pharyngeal cross-sectional area (4.1 +/- 0.2 and 3.7 +/- 0.9 cm2, respectively) at functional residual capacity than nonsnorers (5.4 +/- 0.5 cm2, P less than 0.025). When lung volume decreased from functional residual capacity to residual volume, both nonsnorers and snorers with sleep apnea had a decrease in pharyngeal area (from 5.4 +/- 0.5 to 4.5 +/- 0.4 cm2 and 4.1 +/- 0.2 to 3.4 +/- 0.2 cm2, respectively), whereas snorers without sleep apnea had no such decrease, suggesting that their pharynxes were less collapsible at low lung volumes. We conclude that snorers with and without sleep apnea have smaller pharyngeal cross-sectional areas than nonsnorers and that snorers with sleep apnea have a further decrease as lung volume falls.

Exhaled nitric oxide in pulmonary diseases: a comprehensive review

The upregulation of nitric oxide (NO) by inflammatory cytokines and mediators in central and peripheral airway sites can be monitored easily in exhaled air. It is now possible to estimate the predominant site of increased fraction of exhaled NO (FeNO) and its potential pathologic and physiologic role in various pulmonary diseases. In asthma, increased FeNO reflects eosinophilic-mediated inflammatory pathways moderately well in central and/or peripheral airway sites and implies increased inhaled and systemic corticosteroid responsiveness. Recently, five randomized controlled algorithm asthma trials reported only equivocal benefits of adding measurements of FeNO to usual clinical guideline management including spirometry; however, significant design issues may exist. Overall, FeNO measurement at a single expiratory flow rate of 50 mL/s may be an important adjunct for diagnosis and management in selected cases of asthma. This may supplement standard clinical asthma care guidelines, including spirometry, providing a noninvasive window into predominantly large-airway-presumed eosinophilic inflammation. In COPD, large/central airway maximal NO flux and peripheral/small airway/alveolar NO concentration may be normal and the role of FeNO monitoring is less clear and therefore less established than in asthma. Furthermore, concurrent smoking reduces FeNO. Monitoring FeNO in pulmonary hypertension and cystic fibrosis has opened up a window to the role NO may play in their pathogenesis and possible clinical benefits in the management of these diseases.

Airflow Limitation in Morbidly Obese, Nonsmoking Men

STUDY OBJECTIVE To determine the effect of obesity on pulmonary function. DESIGN Case-control study, using nonobese, age- and height-matched [corrected] nonsmokers. SETTING Metabolic and obesity clinics of two major teaching hospitals. PATIENTS One hundred and three obese, lifelong nonsmokers without cardiopulmonary disease. CONTROLS One hundred and ninety healthy, nonobese nonsmokers recruited from among hospital personnel. MEASUREMENTS AND MAIN RESULTS Complete pulmonary function measurements in all patients and controls. These measurements included maximum expiratory flow-volume curve, lung volumes and airway resistance using body plethysmograph, single-breath diffusing capacity for carbon monoxide, and total lung capacity using the helium dilution technique. Obese persons were found to have lower functional residual capacity, expiratory reserve volume, and total lung capacity by helium dilution than nonobese controls. In addition, residual volume and diffusing capacity were higher in the obese group. Finally, we found that obese men, but not women, had reduced maximum expiratory flow rates at 50% and 75% of exhaled vital capacity. CONCLUSION Obesity may contribute independently of smoking habits to chronic airflow limitation in men.

Acoustic rhinometry in the evaluation of nasal obstruction.

Acoustic rhinometry (AR) is a recently developed objective technique for assessment of geometry of the nasal cavity. The technique is based on the analysis of sound waves reflected from the nasal cavities. It measures cross‐sectional areas and nasal volume (NV). To obtain dependable assessments of nasal resistance by rhinomanometry or cross‐sectional area measurements by AR, it is essential that the structural relations of the compliant vestibular region remain undisturbed by the measuring apparatus. The use of nozzles in making these measurements carries a great risk of direct distortion of the nasal valve. We used a nasal adapter that does not invade the nasal cavity and a chin support that stabilizes the head. In 51 healthy nasal cavities, the average minimum cross‐sectional area (MCA) was 0.62 cm2 at 2.35 cm from the nostril and 0.67 cm2 at 2 cm from the nostril, respectively, before and after topical decongestion of the nasal mucosa. The MCA and NV findings in this group were significantly higher than MCA and NV (P<0.001) in people with structural or mucosal abnormalities before mucosal decongestion. After mucosal decongestion, the MCA and NV were significantly higher in healthy nasal cavities than in nasal cavities with structural abnormalities (P<0.001) but were not higher than nasal cavities with mucosal abnormalities (MCA, P = 0.05; NV, P = 0.06). A nozzle was applied in 20 healthy nasal cavities after mucosal decongestion, and a significantly higher MCA was found compared to measurements made with the nasal adapter (P = 0.02). We conclude that the nasal adapter, which does not invade the nasal cavities, avoids the distortion of the nasal valve and gives more accurate results.

Exhaled nitric oxide and bronchial reactivity during and after inhaled beclomethasone in mild asthma.

The measurement of exhaled nitric oxide (ENO) is recognized as a marker of airway inflammation. ENO was measured in 10 nonsteroid-treated asthmatics at recruitment, during 3 weeks of inhaled beclomethasone (1000 microg/day) and for 3 weeks after withdrawal. Baseline ENO was increased in asthma compared with nonasthmatics (85.0+/-54.5 vs. 24.5+/-14.8 ppb, p < 0.0001). After inhaled steroid, there was no significant change in forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC), but methacholine PC20 rose significantly (p = 0.0345). ENO (mean+/-SD; % baseline) fell after 1 week on steroid to 60.6+/-31.1 and rose to 95.3+/-46.1 at 1 week after withdrawal. ENO did not correlate with PC20 or FEV1. The changes in ENO and PC20 were inversely correlated (r2 = 0.325). ENO may be an index of airway inflammation and therapeutic response in bronchial asthma.

A significant proportion of exhaled nitric oxide arises in large airways in normal subjects

Nitric oxide (NO) of endogenous origin is present in exhaled breath. An increase in exhaled NO concentration (ENO) has been described in bronchial asthma and ENO falls after inhaled steroid therapy. The sources of ENO may include pulmonary blood, the gas exchange region, conducting airways and the nasal cavity. In four healthy volunteers, a catheter was placed in a main bronchus after topical anesthesia in order to sample airway NO (CNO). Exhaled nitric oxide of bronchopulmonary and oropharyngeal origin (ENO(b/o)) was measured while excluding nasal NO and was controlled for expiratory flow. During the same exhalation, ENO(b/o) was compared to CNO at multiple sites in the airway as the catheter was progressively withdrawn. Mean CNO concentration in a position corresponding to a main bronchus was 51.4 +/- 10.8% of ENO(b/o). As the catheter was withdrawn, mean CNO concentration progressively increased both in absolute values and as a proportion of ENO(b/o), until in the oropharynx, it was 96.1 +/- 5.2% ENO(b/o). We conclude that a significant proportion of ENO(b/o) arises in the large airways and trachea in normal subjects and contains a minor oropharyngeal component.

Acoustic rhinometric assessment of the nasal valve.

The aims of this study are to assess nasal valve cross-sectional areas in healthy noses and in patients with nasal obstruction after rhinoplasty and to evaluate the effect of an external nasal dilator on both healthy and obstructive nasal valves. Subjects consisted of (i) volunteers with no nasal symptoms, nasal cavities unremarkable to rhinoscopy and normal nasal resistance and (ii) patients referred to our clinic complaining of postrhinoplasty nasal obstruction. All subjects were tested before and after topical decongestion of the nasal mucosa and with an external nasal dilator. In 79 untreated healthy nasal cavities the nasal valve area showed two constrictions: the proximal constriction averaged 0.78 cm2 cross-section and was situated 1.18 cm from the nostril, the distal constriction averaged 0.70 cm2 cross-section at 2.86 cm from the nostril. Mucosal decongestion increased cross-sectional area of the distal constriction significantly (p < 0.0001) but not the proximal. External dilation increased cross-sectional area of both constrictions significantly (p < 0.0001). In 26 post-rhinoplasty obstructed nasal cavities, only a single constriction was detected, averaging 0.34 cm2 cross-section at 2.55 cm from the nostril and 0.4 cm2 at 2.46 cm from the nostril, before and after mucosal decongestion respectively. External dilation increased the minimum cross-sectional area to 0.64 cm2 in these nasal cavities (p < 0.0001). We conclude that the nasal valve area in patients with postrhinoplasty nasal obstruction is significantly smaller than in healthy nasal cavities as shown by acoustic rhinometry. Acoustic rhinometry objectively determines the structural and mucovascular components of the nasal valve area and external dilation is an effective therapeutical approach in the management of nasal valve obstruction.

Exhaled nitric oxide in chronic obstructive pulmonary disease: relationship to pulmonary function

The following study was undertaken in order to determine how exhaled nitric oxide (eNO) levels in former smokers with chronic obstructive pulmonary disease (COPD) compared to eNO levels in patients with asthma and in healthy nonsmoking volunteers. The study also aimed to determine any relationship between eNO levels in COPD and: 1) conventional measures of lung function; and 2) inhaled corticosteroid (ICS) use. In former smokers with COPD, nonsmokers with asthma and volunteers, eNO levels, spirometry, lung volumes, carbon monoxide diffusion capacity of the lung (DL,CO) and resting oxygen saturation (Sa,O2) were measured. Median eNO was significantly higher among patients with COPD than among healthy volunteers (p = 0.003) but lower than among patients with asthma (p < 0.01). There was no significant difference in eNO levels between COPD patients using ICS and those not using ICS. By contrast, eNO was lower among asthma patients who used ICS (median 32 parts per billion (ppb); 25-75% range 16-54) than among asthma patients who did not (51 ppb; 32-87) (p = 0.034). Among patients with COPD, eNO was inversely correlated with forced expiratory volume in one second, DL,CO and Sa,O2, and was positively correlated with the residual lung volume/total lung capacity ratio. Among patients with asthma, no significant correlations were found. Exhaled nitric oxide is increased in patients with chronic obstructive pulmonary disease, an increase that is influenced by structural abnormalities of tobacco-induced lung damage.