Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee Effect of salmeterol/fluticasone propionate on airway inflammation in COPD: a randomised controlled trial A 4-year trial of tiotropium in chronic obstructive pulmonary disease. Fast onset of effect of budesonide/formoterol versus salmeterol/fluticasone and salbutamol in patients with chronic obstructive pulmonary disease and reversible airway obstruction. Efficacy and Tolerability of Budesonide/Formoterol in One Hydrofluoroalkane Pressurized Metered-Dose Inhaler in Patients with Chronic Obstructive Pulmonary Disease Comparison of tiotropium plus fluticasone propionate/salmeterol with tiotropium in COPD: a randomized controlled study. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. Diagnosis and Management of Stable Chronic Obstructive Pulmonary Disease: A Clinical Practice Guideline from the American College of Physicians Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results The TORCH (TOwards a Revolution in COPD Health) survival study protocol Premature discontinuation of patients: a potential bias in COPD clinical trials Prednisolone response in patients with chronic obstructive pulmonary disease: results from the ISOLDE study Effect of fluticasone propionate/salmeterol on lung hyperinflation and exercise endurance in COPD. Inhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary disease. A Short-Term Comparison of Fluticasone Propionate/Salmeterol with Ipratropium Bromide/Albuterol for the Treatment of COPD Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD. The Canadian Optimal Therapy of COPD Trial: design, organization and patient recruitment. Adherence to inhaled therapy, mortality and hospital admission in COPD Inhaled corticosteroids in COPD: quantifying risks and benefits Comparison of the effects of salmeterol/fluticasone propionate with fluticasone propionate on airway physiology in adults with mild persistent asthma Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial Maintenance therapy with budesonide and formoterol in chronicobstructive pulmonary disease Lower inhaled steroid requirement with a fluticasone/salmeterol combination in family practice patients with asthma or COPD. Can inhaled fluticasone alone or in combination with salmeterol reduce systemic inflammation in chronic obstructive pulmonary disease? – study protocol for a randomized controlled trial [NCT00120978] Is treatment with ICS and LABA cost-effective for COPD? Multinational economic analysis of the TORCH study Cardiovascular events in patients with COPD: TORCH Study results Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: a randomised controlled trial Budesonide added to formoterol contributes to improved exercise tolerance in patients with COPD. Salmeterol/fluticasone propionate in a Single Inhaler Device versus theophylline+fluticasone propionate in patients with COPD. Early onset of effect of salmeterol and fluticasone propionate in chronic obstructive pulmonary disease Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Cost effectiveness of budesonide/formoterol in a single inhaler for COPD compared with each monocomponent used alone Investigating New Standards for Prophylaxis in Reduction of Exacerbations—The INSPIRE Study Methodology Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial Tiotropium in Combination with Placebo, Salmeterol, or FluticasoneSalmeterol for Treatment of Chronic Obstructive Pulmonary Disease Prevalence and progression of osteoporosis in patients with COPD: results from the TOwards a Revolution in COPD Health study. Efficacy and safety of budesonide/formoterol via a dry powder inhaler in Chinese patients with chronic obstructive pulmonary disease Bronchodilator effect of an inhaled combination therapy with salmeterol + fluticasone and formoterol + budesonide in patients with COPD. Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial. Use of dry powder inhalers in COPD. The effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease. The effect of bronchodilators and oxygen alone and in combination on self-paced exercise performance in stable COPD. Additive effects of salmeterol and fluticasone or theophylline in COPD. Antiinflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease. Gender does not influence the response to the combination of salmeterol and fluticasone propionate in COPD. Onset of action of formoterol/budesonide in single inhaler vs. formoterol in patients with COPD. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. Quality of life changes in COPD patients treated with salmeterol. The Effect of Inhaled Corticosteroids on the Development of Emphysema in Smokers Assessed by Annual Computed Tomography Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. Eosinophil and neutrophil activity in asthma in a one-year trial with inhaled budesonide. The impact of smoking. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial Cost Effectiveness of Budesonide/Formoterol Added to Tiotropium Bromide versus Placebo Added to Tiotropium Bromide in Patients with Chronic Obstructive Pulmonary Disease Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonary disease.
Background : TORCH ( Towards a Revolution in COPD Health ) is an international multicentre , r and omised , placebo-controlled clinical trial of inhaled fluticasone propionate/salmeterol combination treatment and its monotherapy components for maintenance treatment of moderately to severely impaired patients with chronic obstructive pulmonary disease ( COPD ) . The primary outcome is all-cause mortality . Cause-specific mortality and deaths related to COPD are additional outcome measures , but systematic methods for ascertainment of these outcomes have not previously been described . Methods : A Clinical Endpoint Committee ( CEC ) was tasked with categorising the cause of death and the relationship of deaths to COPD in a systematic , unbiased and independent manner . The key elements of the operation of the committee were the use of predefined principles of operation and definitions of cause of death and COPD -relatedness ; the independent review of cases by all members with development of a consensus opinion ; and a substantial infrastructure to collect medical information . Results : 911 deaths were review ed and consensus was reached in all . Cause-specific mortality was : cardiovascular 27 % , respiratory 35 % , cancer 21 % , other 10 % and unknown 8 % . 40 % of deaths were definitely or probably related to COPD . Adjudications were identical in 83 % of blindly re-adjudicated cases ( κ = 0.80 ) . COPD -relatedness was reproduced 84 % of the time ( κ = 0.73 ) . The CEC adjudication was equivalent to the primary cause of death recorded by the site investigator in 52 % of cases . Conclusion : A CEC can provide st and ardised , reliable and informative adjudication of COPD mortality that provides information which frequently differs from data collected from assessment by site investigators Background : Airway inflammation in chronic obstructive pulmonary disease ( COPD ) is characterised by infiltration of CD8 + T cells and CD68 + macrophages and an increased number of neutrophils , whereas few studies have described the presence of eosinophils . Although the anti-inflammatory effects of corticosteroids in stable COPD are unclear , recent studies suggest that combination therapy could be beneficial . A study was therefore undertaken to evaluate combined salmeterol/fluticasone propionate ( SFC ) and fluticasone propionate ( FP ) alone on inflammatory cells in the airways of patients with COPD . Methods : Patients were treated in a r and omised , double blind , parallel group , placebo-controlled trial with either a combination of 50 µg salmeterol and 500 µg FP twice daily  ( SFC , n = 19 , 19 men , mean age 62 years ) , 500 µg FP twice daily ( n = 20 , 15 men , mean age 64 years ) or placebo  ( n = 21 , 17 men , mean age 66 years ) for 3 months . At the start and end of treatment bronchoscopy with bronchial biopsies was performed and the numbers of CD8 + T lymphocytes , CD68 + macrophages , neutrophils and eosinophils were measured . Results : CD8 + cells were significantly reduced by SFC compared with placebo ( difference −98.05 cells/mm2 ; 95 % CI −143.14 to −52.9 ; p<0.001 ) . Such a marked effect was not seen with FP alone ( −44.67 cells/mm2 ; 95 % CI −90.92 to 1.57 ; p = 0.06 ) . CD68 + macrophages were also reduced by SFC compared with placebo ( difference −31.68 cells/mm2 ; 95 % CI −61.07 to −2.29 ; p = 0.03 ) but not by FP . SFC did not significantly change neutrophils and eosinophils compared with placebo . Conclusions : SFC has airway anti-inflammatory effects not seen with inhaled corticosteroids alone BACKGROUND Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease ( COPD ) led us to examine the long-term effects of tiotropium therapy . METHODS In this r and omized , double-blind trial , we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs . The patients were at least 40 years of age , with a forced expiratory volume in 1 second ( FEV(1 ) ) of 70 % or less after bronchodilation and a ratio of FEV(1 ) to forced vital capacity ( FVC ) of 70 % or less . Co primary end points were the rate of decline in the mean FEV(1 ) before and after bronchodilation beginning on day 30 . Secondary end points included measures of FVC , changes in response on St. George 's Respiratory Question naire ( SGRQ ) , exacerbations of COPD , and mortality . RESULTS Of a total of 5993 patients ( mean age , 65+/-8 years ) with a mean FEV(1 ) of 1.32+/-0.44 liters after bronchodilation ( 48 % of predicted value ) , we r and omly assigned 2987 to the tiotropium group and 3006 to the placebo group . Mean absolute improvements in FEV(1 ) in the tiotropium group were maintained throughout the trial ( ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation ) , as compared with the placebo group ( P<0.001 ) . After day 30 , the differences between the two groups in the rate of decline in the mean FEV(1 ) before and after bronchodilation were not significant . The mean absolute total score on the SGRQ was improved ( lower ) in the tiotropium group , as compared with the placebo group , at each time point throughout the 4-year period ( ranging from 2.3 to 3.3 units , P<0.001 ) . At 4 years and 30 days , tiotropium was associated with a reduction in the risks of exacerbations , related hospitalizations , and respiratory failure . CONCLUSIONS In patients with COPD , therapy with tiotropium was associated with improvements in lung function , quality of life , and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1 ) . ( Clinical Trials.gov number , NCT00144339 . BACKGROUND AND OBJECTIVES Data on the onset of action of COPD medications are lacking . This study compared the onset of bronchodilation following different inhaled therapies in patients with moderate-to-severe COPD and reversible airway obstruction . METHODS In this double-blind , double-dummy , crossover study , 90 patients ( aged > or=40 years ; FEV(1 ) 30 - 70 % predicted ) were r and omized to a single dose ( two inhalations ) of budesonide/formoterol 160/4.5 microg , salmeterol/fluticasone 25/250 microg , salbutamol 100 microg or placebo ( via pressurized metered-dose inhalers ) on four visits . The primary end-point was change in FEV(1 ) 5 min after drug inhalation ; secondary end-points included inspiratory capacity ( IC ) and perception of onset of effect . RESULTS Budesonide/formoterol significantly improved FEV(1 ) at 5 min compared with placebo ( P < 0.0001 ) and salmeterol/fluticasone ( P = 0.0001 ) . Significant differences were first observed at 3 min . Onset of effect was similar with budesonide/formoterol and salbutamol . Improvements in FEV(1 ) following active treatments were superior to placebo after 180 min ( all P < 0.0001 ) ; both combinations were better than salbutamol at maintaining FEV(1 ) improvements ( P < or= 0.0001 ) at 180 min . Active treatments improved IC at 15 and 185 min compared with placebo ( P < 0.0001 ) . Maximal IC was greater with budesonide/formoterol than salmeterol/fluticasone ( P = 0.0184 ) at 65 min . Patients reported a positive response to the perceptions of the onset of effect question shortly after receiving active treatments ( median time to onset 5 min for active treatments vs 20 min for placebo ) , with no significant difference between active treatments . CONCLUSION Budesonide/formoterol has an onset of bronchodilatory effect in patients with COPD and reversible airway obstruction that is faster than salmeterol/fluticasone and similar to salbutamol Background : Combination therapy with a long-acting bronchodilator and an inhaled corticosteroid ( ICS ) is recommended in patients with chronic obstructive pulmonary disease ( COPD ) who have frequent exacerbations . The efficacy and tolerability of the combination of budesonide/formoterol have been demonstrated in patients with COPD when administered via the dry powder inhaler ( DPI ) in a 1-year study and when administered via the hydrofluoroalkane ( HFA ) pressurized metered-dose inhaler ( pMDI ) in a 6-month study . Objective : This study assessed the long-term efficacy and tolerability of budesonide/formoterol HFA pMDI in patients with moderate to very severe COPD . Methods : This was a 12-month , r and omized , double-blind , double-dummy , parallel-group , active- and placebo-controlled , multicentre study ( NCT00206167 ) of 1964 patients aged ≥40 years with moderate to very severe COPD conducted from 2005 to 2007 at 237 sites in the US , Europe and Mexico . After 2 weeks of treatment based on previous therapy ( ICSs , short-acting bronchodilators allowed ) , patients received one of the following treatments twice daily : budesonide/formoterol pMDI 160/4.5 μg × two inhalations ( 320/9 μg ) ; budesonide/formoterol pMDI 80/4.5 μg × two inhalations ( 160/9 μg ) ; formoterol DPI 4.5 μg × two inhalations ( 9 μg ) ; or placebo . Main outcome measures : The co- primary efficacy variables were pre-dose forced expiratory volume in 1 second ( FEV1 ) and 1-hour post-dose FEV1 . Results : Budesonide/formoterol 320/9 μg demonstrated greater improvements in pre-dose FEV1  versus formoterol ( p = 0.008 ) , and both budesonide/formoterol doses demonstrated greater improvements in 1-hour post-dose FEV1  versus placebo ( p < 0.001 ) . The rate of COPD exacerbations was lower in both budesonide/formoterol groups compared with formoterol and placebo ( p ≤ 0.004 ) . Both budesonide/formoterol doses were more effective  than placebo ( p ≤ 0.006 ) for controlling dyspnoea and improving health status ( St George ’s Respiratory Question naire ) . All treatments were generally well tolerated . The incidence of pneumonia was not different for active ( 3.4–4.0 % ) and placebo ( 5.0 % ) groups . Conclusions : Budesonide/formoterol pMDI ( 320/9 μg and 160/9 μg ) improved pulmonary function and reduced symptoms and exacerbations over 1 year in patients with moderate to very severe COPD .  Only budesonide/formoterol pMDI 320/9 μg demonstrated greater efficacy for both co- primary variables compared with formoterol DPI 9 μg . Both budesonide/formoterol pMDI dosages were well tolerated relative to formoterol and placebo BACKGROUND The combination of tiotropium and fluticasone propionate/salmeterol ( FSC ) is commonly used to treat chronic obstructive pulmonary disease ( COPD ) , but no study had evaluated the effectiveness of tiotropium plus FSC with 250 μg of fluticasone propionate . Our aim was to assess whether tiotropium ( 18 μg once daily ) plus FSC ( 250/50 μg twice daily ) provides better clinical outcomes compared to tiotropium monotherapy . METHODS In this 24-week , r and omized , open label , multicenter two-arm parallel study , 479 patients received tiotropium plus FSC ( n = 237 ) or tiotropium alone ( n = 242 ) . RESULTS After 24 weeks of treatment , the triple-inhaled treatment group had a significant improvement in pre-bronchodilator FEV(1 ) ( L ) compared to the tiotropium-only group ( 0.090 L vs. 0.038 L ; P = 0.005 ) . Regarding health-related quality of life , the mean change in total score on the St. George 's Respiratory Question naire for COPD patients ( SGRQ-C ) was -6.6 points in the tiotropium plus FSC group , but -1.5 points in the tiotropium-only group ( P = 0.001 ) . In the subgroup of GOLD stage II patients with COPD , treatment with tiotropium plus FSC also improved FEV(1 ) compared to tiotropium alone ( 0.088 L vs. 0.030 L ; P = 0.011 ) and improved the total SGRQ-C score  than tiotropium alone ( -4.5 points vs. -1.0 points , respectively ) . This triple-inhaled treatment approach did not induce more adverse events , such as pneumonia . CONCLUSION Over the course of 24 weeks , FSC ( 250/50 μg twice daily ) added to tiotropium provided greater improvement in lung function and quality of life in patients with COPD ( FEV(1 ) ≤ 65 % ) than tiotropium alone RATIONALE Chronic obstructive pulmonary disease ( COPD ) is characterized by an accelerated decline in lung function . No drug has been shown conclusively to reduce this decline . OBJECTIVES In a post hoc analysis of the Toward a Revolution in COPD Health ( TORCH ) study , we investigated the effects of combined salmeterol 50 microg plus fluticasone propionate 500 microg , either component alone or placebo , on the rate of post-bronchodilator FEV(1 ) decline in patients with moderate or severe COPD . METHODS A r and omized , double-blind , placebo-controlled study was conducted from September 2000 to November 2005 in 42 countries . Of 6,112 patients from the efficacy population , 5,343 were included in this analysis . MEASUREMENTS AND MAIN RESULTS Spirometry was measured every 24 weeks for 3 years . There were 26,539 on-treatment observations . The adjusted rate of decline in FEV(1 ) was 55 ml/year for placebo , 42 ml/year for salmeterol , 42 ml/year for fluticasone propionate , and 39 ml/year for salmeterol plus fluticasone propionate . Salmeterol plus fluticasone propionate reduced the rate of FEV(1 ) decline by 16 ml/year compared with placebo ( 95 % confidence interval [ CI ] , 7 - 25 ; P < 0.001 ) . The difference was smaller for fluticasone propionate and salmeterol compared with placebo ( 13 ml/year ; 95 % CI , 5 - 22 ; P = 0.003 ) . Rates of decline were similar among the active treatment arms . FEV(1 ) declined faster in current smokers and patients with a lower body mass index , and varied between world regions . Patients who exacerbated more frequently had a faster FEV(1 ) decline . CONCLUSIONS Pharmacotherapy with salmeterol plus fluticasone propionate , or the components , reduces the rate of decline of FEV(1 ) in patients with moderate-to-severe COPD , thus slowing disease progression . Clinical trial ( GSK Study Code SCO30003 ) registered with www . clinical trials.gov ( NCT00268216 ) Chronic obstructive pulmonary disease ( COPD ) is a slowly progressive lung disease involving the airways and /or pulmonary parenchyma , result ing in a gradual loss of lung function . The symptoms of COPD range from chronic cough , sputum production , and wheezing to more severe symptoms , such as dyspnea , poor exercise tolerance , and signs or symptoms of right-sided heart failure . In the United States , COPD affects more than 5 % of the adult population and is the 4th leading cause of death and the 12th leading cause of morbidity ( 1 , 2 ) . The purpose of this guideline is to present the available evidence on the diagnosis and management of COPD . The target audience for this guideline is all physicians , and the target patient population is all adults with COPD . These recommendations are based on the systematic evidence review in this issue by Wilt and colleagues ( 3 ) and the Agency for Healthcare Research and Quality sponsored Minnesota Evidence -based Practice Center evidence report ( 4 ) . Methods The literature search included studies from MEDLINE and the Cochrane data base from 1966 to May 2005 ( 4 ) . In addition , search es for oxygen , inhaled therapies , and disease management were up date d through March 2007 . The exclusion criteria were children or individuals with asthma , restrictive lung disease , or 1-antitrypsin deficiency . The methods of Schulz and colleagues ( 5 ) were used to assess the quality of r and omized , controlled trials . Results from the individual studies were aggregated to produce pooled estimates . Heterogeneity was assessed by using the chi-square and I2 tests ( 6 ) , and the DerSimonianLaird r and om-effects model was used ( 7 ) . Details about the methods used for the systematic evidence review may be found in detail in the background paper by Wilt and colleagues in this issue ( 3 ) . This guideline grade s the evidence and recommendations by using the American College of Physicians ' clinical practice guidelines grading system adopted from the classification developed by the Grading of Recommendations , Assessment , Development , and Evaluation ( GRADE ) workgroup ( Table 1 ) . Table 1 . American College of Physicians ' Clinical Practice Guidelines Grading System The objective of this guideline is to analyze the evidence for the following questions : 1 . What is the value of clinical examination for prediction of airflow obstruction ( AO ) ? 2 . What is the incremental value of spirometry for case finding and diagnosis of adults who are COPD treatment c and i date s ? 3 . What management strategies are effective for the treatment for COPD ( inhaled therapies , pulmonary rehabilitation programs , and supplemental long-term oxygen therapy ) ? Clinical Examination for Prediction of Airflow Obstruction The National Health and Nutrition Examination Survey III and a systematic review of 19 studies examining the accuracy of clinical examination to predict AO were used to estimate the prevalence of COPD and AO and clinical diagnostic accuracy ( 8 , 9 ) . Cigarette smoking is the most common cause of COPD . A 70pack-year history of smoking was the best predictor of AO , with a positive likelihood ratio of 8.0 but a sensitivity of only 40 % . The literature showed that findings from physical examination also had high specificity ( > 90 % ) but poor sensitivity . In addition , sputum production or wheezing was also associated with an increased likelihood of AO . Evidence to assess the utility of combining items that were included in a clinical examination to predict AO showed that combinations of findings were more helpful for diagnosing the presence of AO ( 1015 ) . The best combination to exclude COPD included never having smoked , no reported wheezing , and no wheezing on examination . A patient with any combination of 2 findings ( 70pack-year history of smoking , history of COPD , or decreased breath sounds ) can be considered likely to have AO ( defined as FEV1 less than 60 % predicted or FEV1FVC ratio less than 0.60 ) ( positive likelihood ratio , 34 ) ( 915 ) . Incremental Value of Spirometry Spirometry may be useful to identify patients who may benefit from initiating therapy ( Table 2 ) . The evidence supports inhaled treatment in patients who have symptoms and FEV1 less than 60 % predicted . The literature also showed that respiratory symptom status is not a reliable indicator of the presence of AO . However , as spirometric values worsened , individuals reported more respiratory symptoms , such as cough , sputum , wheezing , or dyspnea . But 33 % of individuals with normal spirometric values reported respiratory symptoms . In addition , 21 % of individuals who had severe to very severe AO by spirometry reported no symptoms . Nearly 80 % of persons reporting any respiratory symptom had normal airflow , and only 3 % to 4 % had severe to very severe AO ( 8) . Table 2 . Spirometric Classifications of Chronic Obstructive Pulmonary Disease Evidence is insufficient to support widespread use of spirometry for testing adults with no respiratory symptoms , including those with current and past exposure to COPD risk factors . Spirometry may be beneficial in symptomatic adults who have an FEV1 greater than 60 % predicted for determining when to initiate therapy . The evidence does not support periodic spirometry after initiation of therapy to monitor ongoing disease status or to modify therapy . Furthermore , no high- quality evidence supports the use of obtaining and providing spirometry results to improve smoking cessation , identify and treat asymptomatic individuals to prevent future respiratory symptoms , or reduce spirometric decline in lung function . Inhaled Therapies Exacerbations The literature showed that monotherapy with long-acting inhaled -agonists , a long-acting inhaled anticholinergic , or inhaled corticosteroids was superior to placebo or short-acting anticholinergics in reducing exacerbations .  Tiotropium ( relative risk , 0.84 [ 95 % CI , 0.78 to 0.90 ] ) , long-acting -agonists ( relative risk , 0.87 [ CI , 0.82 to 0.93 ] ) , and corticosteroids ( relative risk , 0.85 [ CI , 0.75 to 0.96 ] ) reduce the relative risk for at least 1 exacerbation compared with placebo . However , ipratropium , a short-acting anticholinergic , was not superior to placebo ( relative risk , 0.95 [ CI , 0.78 to 1.15 ] ) . In comparison studies , long-acting -agonists were as effective as  ipratropium  ( relative risk , 0.89 [ CI , 0.72 to 1.10 ] ) ,  corticosteroids  ( relative risk , 1.06 [ CI , 0.84 to 1.34 ] ) , or a  long-acting anticholinergic ( tiotropium ) ( relative risk , 1.11 [ CI , 0.93 to 1.33 ] ) . Also , long-acting -agonists were slightly superior to dual D2 dopamine receptor2-agonist ( sibenadet ) ( relative risk , 0.80 [ CI , 0.63 to 1.02 ] ) , and tiotropium was more effective than  ipratropium  ( relative risk , 0.77 [ CI , 0.62 to 0.95 ] ) . Compared with tiotropium alone , the combination of tiotropium with a long-acting -agonist and inhaled corticosteroid has been shown to improve respiratory symptoms related to quality of life and lung function ( 16 ) . Patients treated with tiotropium plus a long-acting -agonist and inhaled corticosteroid had an increase of greater than 4 points on the St. George Respiratory Question naire , which is considered to be clinical ly significant ( 16 ) . Evidence comparing the combination of inhaled corticosteroids and long-acting -agonists with either monotherapy or placebo was evaluated in 5 multigroup studies that lasted from 6 to 23 months in patients with a mean baseline FEV1 less than 50 % predicted ( 1721 ) . Combination therapy with long-acting -agonists and inhaled corticosteroids showed an absolute risk decrease in the percentage of individuals with at least 1 exacerbation compared with placebo . The combination of long-acting -agonists and corticosteroid therapy did not reduce the percentage of individuals with at least 1 exacerbation compared with inhaled corticosteroid monotherapy ( 17 , 18 , 20 , 21 ) . However , adding an inhaled corticosteroid to a long-acting -agonist may reduce exacerbations compared with long-acting -agonist monotherapy ( 3 ) . The combination of a short-acting -agonist ( albuterol ) and ipratropium reduced exacerbations compared with albuterol alone ( 2224 ) . Hospitalizations and Death Use of tiotropium ( absolute risk difference , 2 % [ CI , 4 % to 1 % ) ( 2528 ) and ipratropium ( absolute risk difference , 4 % [ CI , 10 % to 1 % ] ) reduced hospitalizations for patients with COPD ( 29 ) . However , the Lung Health Study I and II trials showed no significant difference in hospitalizations per 100 person-years of exposure between ipratropium and placebo or between inhaled corticosteroids and placebo ( 30 , 31 ) . The TORCH ( Towards a Revolution in COPD Health ) study ( 32 ) showed that use of a combination of a long-acting -agonist and an inhaled corticosteroid reduces deaths compared with use of an inhaled corticosteroid alone ( relative risk , 0.79 [ CI , 0.67 to 0.94 ] ) . Results from a meta- analysis by Salpeter and colleagues ( 33 ) showed an increase in respiratory deaths with long-acting -agonists and a decrease with anticholinergics . However , a recently released TORCH study found no difference in deaths due to pulmonary causes between placebo and salmeterol ( 34 ) . In addition , serious adverse effects occurred in 10 % of the persons receiving inhaled corticosteroids  as monotherapy or combination therapy compared with 6 % of persons receiving placebo or long-acting -agonists ( 34 ) . Adverse Effects Evidence for withdrawals from treatment and nonadherence showed that individuals using long-acting -agonists , tiotropium , or inhaled corticosteroids were less likely to withdraw from treatment for any reason compared with those receiving placebo ( 17 , 18 , 21 , 26 , 27 , 29 , 35 , 36 ) . In trials of combination therapy with corticosteroids and long-acting -agonists , withdrawals were lower for combination therapy than for placebo but were similar to either type of monotherapy ( 17 , 18 , 21 , 26 , 27 , 29 , 35 , 36 ) . Adverse events during follow-up also were minor and were similar to those with placebo . The main adverse reactions included oropharyngeal c and idiasis and a moderate to severe degree of easy Inhaled corticosteroids ( ICS ) are important in reducing exacerbation frequency associated with chronic obstructive pulmonary disease ( COPD ) . However , little is known about the risk of associated infections . In a post hoc analysis of the TOwards a Revolution in COPD Health ( TORCH ) study , we analysed and identified potential risk factors for adverse event reports of pneumonia in this r and omised , double-blind trial comparing twice-daily inhaled salmeterol ( SAL ) 50 μg , fluticasone propionate ( FP ) 500 μg , and the combination ( SFC ) with placebo in 6,184 patients with moderate-to-severe COPD over 3 yrs . Despite a higher withdrawal rate in the placebo arm , after adjusting for time on treatment , a greater rate of pneumonia was reported in the FP and SFC treatment arms ( 84 and 88 per 1,000 treatment-yrs , respectively ) compared with SAL and placebo ( 52 and 52 per 1,000 treatment-yrs , respectively ) . Risk factors for pneumonia were age ≥55 yrs , forced expiratory volume in 1 s < 50 % predicted , COPD exacerbations in the year prior to the study , worse Medical Research Council dyspnoea scores and body mass index < 25 kg·m−2 . No increase in pneumonia deaths with SFC was observed ; this could not be concluded for FP . Despite the benefits of ICS-containing regimens in COPD management , healthcare providers should remain vigilant regarding the possible development of pneumonia as a complication in COPD patients receiving such therapies Only long-term home oxygen therapy has been shown in r and omised controlled trials to increase survival in chronic obstructive pulmonary disease ( COPD ) . There have been no trials assessing the effect of inhaled corticosteroids and long-acting bronchodilators , alone or in combination , on mortality in patients with COPD , despite their known benefit in reducing symptoms and exacerbations . The “ TOwards a Revolution in COPD Health ” ( TORCH ) survival study is aim ing to determine the impact of salmeterol/fluticasone propionate ( SFC ) combination and the individual components on the survival of COPD patients . TORCH is a multicentre , r and omised , double-blind , parallel-group , placebo-controlled study . Approximately 6,200 patients with moderate-to-severe COPD were r and omly assigned to b.i.d . treatment with either SFC ( 50/500 µg ) , fluticasone propionate ( 500 µg ) , salmeterol ( 50 µg ) or placebo for 3 yrs . The primary end-point is all-cause mortality ; secondary end-points are COPD morbidity relating to rate of exacerbations and health status , using the St George 's Respiratory Question naire . Other end-points include other mortality and exacerbation end-points , requirement for long-term oxygen therapy , and clinic lung function . Safety end-points include adverse events , with additional information on bone fractures . The first patient was recruited in September 2000 and results should be available in 2006 . This paper describes the “ TOwards a Revolution in COPD Health ” study and explains the rationale behind it Premature discontinuation from clinical trials may bias results against effective therapies . In the present study mortality rates were retrospectively review ed in a 6-month , r and omised , placebo-controlled trial in which tiotropium 18 μg daily was shown to decrease chronic obstructive pulmonary disease exacerbations . Patients participated for 6 months even if trial medication was prematurely discontinued . Exposure-adjusted incidence rates ( IRs ) were calculated for r and omisation – end trial , r and omisation – end trial drug ( 0–ED ) and end trial drug – end trial ( ED – ET ) . Of 1,829 patients ( forced expiratory volume in one second 1.04 L ( 36 % predicted ) , mean age 68 yrs , 99 % male ) , 16  % tiotropium  and 27 % placebo patients prematurely stopped trial medication . The number of fatal events for the entire cohort was : 62 all cause , including 16 cardiac and 16 lower respiratory . IRs for fatal events per 100 patient-yrs were higher in the discontinued period : 1.9 ( 0–ED ) versus 23.0 ( ED – ET ) in the tiotropium group and 1.8 versus 19.0 in the placebo group . Respective IRs for fatal cardiac events were 0.7 versus 2.8 ( tiotropium ) and 0.5 versus 6.2 ( placebo ) ; for fatal lower respiratory events were 0.7 versus 2.8 ( tiotropium ) and 0.8 versus 5.4 (  placebo ) . Rate ratios ( tiotropium/placebo ) for fatal events were lower in the discontinued period : 1.4 versus 0.5 for cardiac and 0.9 versus 0.5 for lower respiratory . Higher incidence rates of fatal events occurred following premature discontinuation of study medication . Incomplete information from rate ratios occurs as a result of failure to consider outcomes of patients who discontinue early from clinical trials Background : A trial of corticosteroids has been recommended for all patients with chronic obstructive pulmonary disease ( COPD ) , with the subsequent “ response ” determining the treatment selected . This approach assumes that patients can be reliably divided into responder and non-responder groups . We have assessed whether such a separation is statistically valid , which factors influence the change in forced expiratory volume in 1 second ( FEV1 ) after prednisolone , and whether the prednisolone response predicts 3 year changes in FEV1 , health status , or number of exacerbations during placebo or fluticasone propionate treatment . Methods : Oral prednisolone 0.6 mg/kg was given for 14 days to 524 patients with COPD before r and omised treatment for 3 years with fluticasone propionate or placebo . Factors relating to change in FEV1 after prednisolone were investigated using multiple regression . The response to prednisolone was entered into separate mixed effects models of decline in FEV1 and health status during the 3 years of the study . Results : The post-bronchodilator FEV1 increased by a mean 60 ml ( CI 46 to 74 ) after prednisolone with a wide unimodal distribution . Current smoking was the factor most strongly associated with the change in FEV1 after prednisolone , with an increase of 35 ml in current smokers and 74 ml in confirmed ex-smokers ( p<0.001 ) . There was no relationship between the change in FEV1 after prednisolone  and the response to inhaled bronchodilators , baseline FEV1 , atopic status , age , or sex . The response to prednisolone  , however expressed , was unrelated to the subsequent change in FEV1 over the following 3 years on either placebo or fluticasone propionate . Regression to the mean effects explained much of the apparent prednisolone response . The significant effect of treatment on decline in health status was not predicted by the prednisolone response . Conclusion : Patients with COPD can not be separated into discrete groups of corticosteroid responders and non-responders . Current smoking reduces the FEV1 response to prednisolone . Prednisolone testing is an unreliable predictor of the benefit from inhaled fluticasone propionate in individual patients STUDY OBJECTIVE To examine the effect of fluticasone propionate , 250 microg/salmeterol , 50 microg combination ( FSC 250/50 ) twice daily on lung hyperinflation and associated measures of exercise performance in patients with COPD . DESIGN This was a r and omized , double-blind , parallel-group study . PATIENTS Eligible patients were > or = 40 years old with a diagnosis of COPD , prealbuterol FEV(1 ) < 70 % of predicted , FEV1/FVC ratio > or = 0.70 , and functional residual capacity ( FRC ) > or = 120 % of predicted normal . INTERVENTIONS Patients were r and omized to FSC 250/50 ; salmeterol , 50 microg ; or placebo twice daily for 8 weeks . Predose and postdose spirometry , plethysmography , and constant-load cycle cardiopulmonary exercise test evaluations were compared . The primary comparison was FSC 250/50 with placebo . The salmeterol group was included for exploratory comparisons with FSC 250/50 . RESULTS A total of 185 patients ( mean baseline FEV1 of 41 % predicted ) were enrolled . At rest , FSC 250/50 significantly reduced postdose FRC and increased inspiratory capacity ( IC ) compared with placebo ( differences of - 0.35 + /- 0.12 L and 0.33 + /- 0.06 L [ mean + /- SE ] , respectively , at week 8 ; p > or = 0.003 ) and increased exercise endurance time ( difference , 132 + /- 45 s ; p = 0.004 ) . At a st and ardized time during exercise ( isotime ) , FSC 250/50 increased postdose IC by 0.20 + /- 0.05 L over placebo with associated improvements in tidal volume and minute ventilation ( p < 0.05 vs placebo at week 8) . Improvement in exercise time was significantly correlated with the increase in IC ( r = 0.45 , p < 0.001 ) but not FEV1 ( r = 0.23 , p = 0.08 ) . Predose comparisons of FSC 250/50 with salmeterol and placebo favored FSC 250/50 . CONCLUSION We conclude that FSC 250/50 decreases lung hyperinflation at rest and during exercise with an associated increase in exercise endurance time when compared with placebo We compared the effectiveness of inhaled formoterol with that of ipratropium in the treatment of chronic obstructive pulmonary disease ( COPD ) . After a 2-wk run-in period , 780 patients with COPD were r and omized to receive for 12 wk formoterol dry powder 12 or 24 microg twice daily , ipratropium bromide 40 microg four times daily , or placebo in a multicenter , double-blind , parallel-group study . The primary efficacy variable was the area under the curve for forced expiratory volume in 1 s ( FEV(1 ) ) measured over 12 h after 12 wk of treatment . Secondary variables included diary symptoms and quality of life . Both doses of formoterol and ipratropium significantly increased the area under the curve for FEV(1 ) in comparison with placebo ( all p < 0.001 ) . Both doses of formoterol were also significantly superior to ipratropium ( all p < 0.025 ) . Compared with placebo , both doses of formoterol significantly improved symptoms ( all p < or = 0.007 ) and quality of life ( p < 0.01 for total scores ) whereas ipratropium did not show significant effects ( all p > or = 0.3 ) . All study treatments exhibited a similar safety profile . We conclude that formoterol is more effective than ipratropium bromide in the treatment of COPD , as the efficacy of ipratropium on airflow obstruction does not translate into a clinical benefit that patients can perceive Abstract Background : This is the first comparison of two combination therapies , fluticasone propionate/salmeterol and ipratropium bromide/albuterol ( salbutamol ) , for the treatment of patients with COPD . Methods : A r and omized , double-blind , double-dummy , parallel group , multicenter evaluation of fluticasone propionate/salmeterol 250/50 µg twice daily via DISKUS ® and ipratropium bromide/albuterol 36/206 µg four times daily via metered-dose inhaler over 8 weeks was conducted at 41 research sites in the US .  Morning pre-dose FEV1 , 6-hour serial spirometry , PEF , dyspnea , night-time awakenings , supplemental albuterol use , and patient diary evaluations of symptoms were evaluated . Results : A total of 365 patients with symptomatic COPD were enrolled . The treatment groups were similar in mean age ( 63.3 and 63.9 years ) , screening pulmonary function ( 44.1 % and 43.2 % of predicted FEV1 ) , race ( 96 % and 95 % White ) , and sex distribution ( 59 % and 60 % male ) . Both fluticasone propionate/salmeterol and ipratropium bromide/albuterol  improved lung function , symptoms , and supplemental albuterol use compared with baseline . Fluticasone propionate/salmeterol was more effective than ipratropium bromide/albuterol for improvement in morning pre-dose FEV1 , morning PEF , 6-hour FEV1 area under the curve ( AUC6 ) , Transition Dyspnea Index ® ( TDI ) focal score , daytime symptom score , night-time awakenings , sleep symptoms , and albuterol-free nights ( p ≤ 0.013 ) . Compared with day 1 , at week 8 the FEV1 AUC6 significantly increased with fluticasone propionate/salmeterol and significantly decreased with ipratropium bromide/albuterol ( p ≤ 0.003 ) . The incidence of adverse events was similar between treatment groups , except for a higher incidence of oral c and idiasis with fluticasone propionate/salmeterol . Conclusions : Short-term treatment with the combined inhaled corticosteroid and long-acting β2-adrenoceptor agonist fluticasone propionate/salmeterol result ed in greater control of lung function and symptoms than combined ipratropium bromide/albuterol bronchodilator therapy , in patients with COPD STUDY OBJECTIVE To compare the efficacy , tolerability , and safety of therapy with formoterol and oral slow-release theophylline ( THEO ) in patients with COPD . DESIGN A r and omized , parallel-group study , with double-blind arms for formoterol and placebo ( PL ) and an open arm for oral slow-release THEO administered in individual doses on the basis of plasma concentrations . SETTING Eighty-one centers worldwide . PATIENTS Eight hundred fifty-four patients with symptomatic COPD . INTERVENTION Comparison of twice-daily inhaled formoterol dry powder ( 12 or 24 microg ) , PL , and THEO ( individualized doses ) over 12 months . MEASUREMENTS AND RESULTS Compared to PL , doses of formoterol and THEO both significantly improved the area under the curve for FEV(1 ) measured over a period of 12 h following the morning dose of study medication at 3 and 12 months ( p < 0.001 for all comparisons ) . Therapy with formoterol , 12 microg , was significantly more effective than that with THEO ( p < or = 0.026 ) . Formoterol significantly reduced the percentage of " bad days " ( i.e. , days with at least two individual symptom scores > or = 2 and /or a reduction in peak expiratory flow from a baseline of > 20 % ; p < or = 0.035 vs. PL and THEO ) , and the use of salbutamol rescue medication ( p < or = 0.003 vs PL ) over the whole treatment period , while the effect of THEO was similar to that of PL . Therapy with formoterol and THEO was more effective than PL at improving quality of life for > 12 months ( p < or = 0.030 ) . Treatment-related adverse events and discontinuations were more frequent among patients receiving THEO than among those receiving formoterol . CONCLUSIONS Long-term treatment with inhaled formoterol dry powder is more effective and better tolerated than treatment with therapeutically appropriate doses of oral slow-release THEO in symptomatic patients with COPD BACKGROUND There are no published studies that have assessed whether adding long-acting beta 2-agonist bronchodilators and /or inhaled steroids to chronic therapy with tiotropium would provide additional clinical benefit to patients with moderate to severe chronic obstructive pulmonary disease ( COPD ) . METHODS The Canadian Optimal Therapy of COPD Trial is a r and omized , prospect i ve , double-blind , placebo-controlled , multicentre trial funded by the Canadian Institutes of Health Research that has been design ed to determine which combination of inhaled medications will most effectively prevent exacerbations and optimize disease-specific quality of life in patients with COPD . The trial is the first to evolve from the Canadian Thoracic Society Clinical Trials Group . The study will r and omize 432 patients with moderate to severe COPD to one of three parallel treatment arms for 52 weeks : tiotropium and fluticasone/salmeterol ; tiotropium and salmeterol ; or tiotropium and placebo inhaler . The participants will be allowed to use salbutamol as required throughout the trial period . OUTCOMES The primary outcome measure is the proportion of patients in the three treatment groups who experienced a respiratory exacerbation within 52 weeks of r and omization . Other outcomes that will be assessed over the 52-week trial period will include : changes in disease-specific quality of life and changes in dyspnea , health care use and changes in lung function . A pharmacoeconomic analysis will also be performed to evaluate the cost of these therapies . RESULTS The study commenced recruitment in October 2003 . It is currently operating at 22 centres across Canada and has r and omized 137 patients during the first four months of recruitment . Recruitment is scheduled to continue until April 2005 or until 432 patients have been r and omized . CONCLUSION The present r and omized , placebo-controlled trial offers a unique opportunity to answer the question , what is the best combination of inhaled medications to use for COPD patients ? It is hoped that optimal use of inhaled medications will improve patient health and quality of life , reduce patient respiratory exacerbations , and ultimately , reduce health care re source use Background : Little is known about adherence to inhaled medication in chronic obstructive pulmonary disease ( COPD ) and the impact on mortality and morbidity . Methods : Data on drug adherence from a r and omised double-blind trial comparing inhaled salmeterol 50 μg + fluticasone propionate 500 μg twice daily with placebo and each drug individually in 6112 patients with moderate to severe COPD over 3 years in the TORCH study were used  . All-cause mortality and exacerbations leading to hospital admission were primary and secondary end points . The study of adherence was not specified a priori as an ancillary study . Results : Of the 4880 patients ( 79.8 % ) with good adherence defined as > 80 % use of study medication  , 11.3 % died compared with 26.4 % of the 1232 patients ( 20.2 % ) with poor adherence .  The annual rates of hospital admission for exacerbations were 0.15 and 0.27 , respectively . The association between adherence and mortality remained unchanged and statistically significant after adjusting for other factors related to prognosis ( hazard ratio 0.40 ( 95 % CI 0.35 to 0.46 ) , p<0.001 ) . The association was even stronger when analysing on-treatment deaths only . Similarly , the association between adherence and hospital admission remained unchanged and significant in a multivariate analysis ( rate ratio 0.58 ( 95 % CI 0.44 to 0.73 , p<0.001 ) . The association between increased adherence and improved mortality and reduction in hospital admission was independent of study treatment . The effect of treatment was more pronounced in patients with good adherence than in those with poor adherence . Conclusion : Adherence to inhaled medication is significantly associated with reduced risk of death and admission to hospital due to exacerbations in COPD . Further research is needed to underst and these strong associations It is by no means straightforward to analyse the change in the rate of  chronic obstructive pulmonary disease ( COPD ) exacerbations in clinical trials . Exacerbation rates do not follow a normal distribution , nor do they occur at r and om . High exacerbation rates in a few patients can make average rates difficult to calculate and interpret . So , surely , transforming exacerbation rates into numbers needed to treat ( NNT ) should help . Not necessarily so — this is the message from Professor Suissa 's paper.1 He points out that the simplistic transformation from annual exacerbation rates to NNT in some published papers is misleading . He then goes on to present an alternative way of calculating NNT from survival curves showing time to first exacerbation , and a model to estimate such curves even if they are not presented . I have used the exponential model suggested by Suissa , with the data from two of the arms of the Towards a Revolution in Chronic obstructive pulmonary disease Health ( TORCH ) trial2 to show how this works in practice . I chose the arms in TORCH , that compared combination fluticasone/salmeterol therapy with salmeterol alone , as this seems to me to be a fair way to estimate the impact of additional inhaled corticosteroids . Figure 1 shows pairs of modelled survival curves for pneumonia ( in the upper part ) , and for COPD exacerbation ( in the lower part ) . Background This study compared the effect of inhaled fluticasone propionate ( FP ) with the combination of salmeterol/fluticasone propionate ( SFC ) on lung function parameters in patients with mild asthma . Methods Adult patients with mild persistent asthma ( ≥ 80 % predicted FEV1 ) receiving 200–500 μg of BDP or equivalent were r and omised to receive either FP 100 μg or SFC 50/100 μg twice daily from a Diskus ® inhaler for four weeks . The primary outcome was the change from baseline in airway resistance ( sRaw ) at 12 hrs post dose measured by whole body plethysmography . Impulse oscillometry and spirometry were also performed . Results A comparison of the geometric mean sRaw at 12 hrs post dose in the SFC group to the FP group gave a ratio of 0.76 ( 0.66 – 0.89 , p < 0.001 ) at week 2 and 0.81 ( 0.71 – 0.94 , p = 0.006 ) at week 4 . Similarly , significant results in favour of SFC for oscillometry measurements of resistance and reactance were observed . FEV1 was also significantly superior at week 2 in the SFC group ( mean difference 0.16L , 95 % CI ; 0.03 – 0.28 , p = 0.015 ) , but not at week 4 ( mean difference 0.17L , 95 % CI -0.01 – 0.34 , p = 0.060 ) . ConclusionS FC is superior to  FP in reducing airway resistance in mild asthmatics with near normal FEV1 values . This study provides evidence that changes in pulmonary function in patients with mild asthma are detected more sensitively by plethysmography compared to spirometryTrial registration numberNCT00370591 The efficacy and safety of budesonide/formoterol in a single inhaler compared with placebo , budesonide and formoterol were evaluated in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . In a 12-month , r and omised , double-blind , placebo-controlled , parallel-group study in 812 adults ( mean age 64 yrs , mean forced expiratory volume in one second ( FEV1 ) 36 % predicted normal ) , patients received two inhalations twice daily of either budesonide/formoterol ( Symbicort ® ) 160/4.5 µg ( delivered dose ) , budesonide 200 µg ( metered dose ) , formoterol 4.5 µg or placebo . Severe exacerbations and FEV1 ( primary variables ) , peak expiratory flow ( PEF ) , COPD symptoms , health-related quality of life ( HRQL ) , mild exacerbations , use of reliever β2‐agonist and safety variables were recorded .  Budesonide/formoterol reduced the mean number of severe exacerbations per patient per year by 24 % versus placebo and 23 % versus formoterol . FEV1 increased by 15 % versus placebo and 9 % versus budesonide . Morning PEF improved significantly on day 1 versus placebo and budesonide ; after 1 week , morning PEF was improved versus placebo , budesonide and formoterol . Improvements in morning and evening PEF versus comparators were maintained over 12 months . Budesonide/formoterol decreased all symptom scores and use of reliever β2‐agonists significantly versus placebo and budesonide , and improved HRQL versus placebo . All treatments were well tolerated . These results suggest a role for budesonide/formoterol in the long-term management of moderate-to-severe chronic obstructive pulmonary disease BACKGROUND Inhaled long-acting beta2 agonists improve lung function and health status in symptomatic chronic obstructive pulmonary disease ( COPD ) , whereas inhaled corticosteroids reduce the frequency of acute episodes of symptom exacerbation and delay deterioration in health status . We postulated that a combination of these treatments would be better than each component used alone . METHODS 1465 patients with COPD were recruited from outpatient departments in 25 countries . They were treated in a r and omised , double-blind , parallel-group , placebo-controlled study with either 50 microg salmeterol twice daily ( n=372 ) , 500 microg fluticasone twice daily ( n=374 ) , 50 microg salmeterol and 500 microg fluticasone twice daily ( n=358 ) , or placebo ( n=361 ) for 12 months . The primary outcome was the pretreatment forced expiratory volume in 1s ( FEV1 ) after 12 months treatment ' and after patients had abstained from all bronchodilators for at least 6h and from study medication for at least 12h . Secondary outcomes were other lung function measurements , symptoms and rescue treatment use , the number of exacerbations , patient withdrawals , and disease-specific health status . We assessed adverse events , serum cortisol concentrations , skin bruising , and electrocardiograms . Analysis was as predefined in the study protocol . FINDINGS All active treatments improved lung function , symptoms , and health status and reduced use of rescue medication and frequency of exacerbations . Combination therapy improved pretreatment FEV1 significantly more than did placebo ( treatment difference 133 mL , 95 % CI 105 - 161 , p<0.0001 ) , salmeterol ( 73 mL , 46 - 101 , p<0.0001 ) , or fluticasone alone ( 95 mL , 67 - 122 , p<0.0001 ) . Combination treatment produced a clinical ly significant improvement in health status and the greatest reduction in daily symptoms . All treatments were well tolerated with no difference in the frequency of adverse events , bruising , or clinical ly significant falls in serum cortisol concentration . INTERPRETATION Because inhaled long-acting beta2 agonists and corticosteroid combination treatment produces better control of symptoms and lung function , with no greater risk of side-effects than that with use of either component alone , this combination treatment should be considered for patients with COPD Lung function in chronic obstructive pulmonary disease ( COPD ) can be improved acutely by oral corticosteroids and bronchodilators . Whether clinical improvement can be maintained by subsequent inhaled therapy is unknown . COPD patients ( n=1,022 , mean prebronchodilator forced expiratory volume in one second ( FEV1 ) 36 % predicted ) initially received formoterol ( 9 µg b.i.d . ) and oral prednisolone ( 30 mg o.d . ) for 2 weeks . After this time , patients were r and omised to b.i.d . inhaled budesonide/formoterol 320/9 µg , budesonide 400 µg , formoterol 9 µg or placebo for 12 months . Postmedication FEV1 improved by 0.21 L and health-related quality of life using the St George 's Respiratory Question naire ( SGRQ ) by 4.5 units after run-in . Fewer patients receiving budesonide/formoterol withdrew from the study than those receiving budesonide , formoterol or placebo . Budesonide/formoterol patients had a prolonged time to first exacerbation ( 254 versus 96 days ) and maintained higher FEV1 ( 99 % versus 87 % of baseline ) , both primary variables versus placebo . They had fewer exacerbations ( 1.38 versus 1.80 exacerbations per patient per year ) , had higher prebronchodilator peak expiratory flow , and showed clinical ly relevant improvements in SGRQ versus placebo ( −7.5 units ) . Budesonide/formoterol was more effective than either monocomponent in both primary variables . Budesonide/formoterol in a single inhaler ( Symbicort ® ) maintains the benefit of treatment optimisation , stabilising lung function and delaying exacerbations more effectively than either component drug alone or placebo BACKGROUND Previous studies on inhaled steroid and long-acting beta2-agonist combination products may not be representative for the asthma and chronic obstructive pulmonary disease ( COPD ) patients in family practice . OBJECTIVES To compare in a group of doctor-diagnosed patients with asthma or COPD , the effects of a lower dose of fluticasone in a combination product with salmeterol with conventional treatment ( i.e. a higher dose of fluticasone ) , both supplemented with as-needed use of a short-acting bronchodilator . METHODS The study was a 12-week multicentre , r and omized controlled , double-blind trial . In all , 41 family practice s recruited 137 patients diagnosed with asthma and 40 patients diagnosed with COPD . Primary outcome was the forced expiratory volume in 1 second ( FEV1 ) as percentage of predicted . Morning peak expiratory flow ( PEF ) , symptom-free days , health status [ Asthma Quality of Life Question naire ( AQLQ ) and St. George 's Respiratory Question naire ( SGRQ ) ] , exacerbations , use of short-acting bronchodilators and adverse events were secondary outcomes . RESULTS FEV1 % predicted increased 2.6 % ( SD 8.3 ) in fluticasone/salmeterol- and 0.01 % ( SD 6.6 ) in fluticasone-treated patients ( overall : P=0.036 , asthma : P=0.025 and COPD : P=0.700 ) . PEF increased in favour of fluticasone/salmeterol in asthma patients only ( P=0.016 ) . Fluticasone/salmeterol-treated asthma patients had 1.1 more symptom-free days per week ( P=0.044 ) ; no such effect was observed for COPD ( P=0.769 ) . There were no differences in total AQLQ and SGRQ scores , exacerbations , use of reliever puffs or adverse effects . CONCLUSIONS In family practice patients diagnosed with asthma , several treatment goals were better achieved with a lower dose of fluticasone and salmeterol in a combination product than with a higher dose of fluticasone . We found no differences between the two approaches for patients with COPD Background Systemic inflammation is associated with various complications in chronic obstructive pulmonary disease including weight loss , cachexia , osteoporosis , cancer and cardiovascular diseases . Inhaled corticosteroids attenuate airway inflammation , reduce exacerbations , and improve mortality in chronic obstructive pulmonary disease . Whether inhaled corticosteroids by themselves or in combination with a long-acting β2-adrenoceptor agonist repress systemic inflammation in chronic obstructive pulmonary disease is unknown . The Advair Biomarkers in COPD ( ABC ) study will determine whether the effects of inhaled corticosteroids alone or in combination with a long-acting β2-adrenoceptor agonist reduce systemic inflammation and improve health status in patients with chronic obstructive pulmonary disease . Methods / Design After a 4-week run-in phase during which patients with stable chronic obstructive pulmonary disease will receive inhaled fluticasone ( 500 micrograms twice daily ) , followed by a 4-week withdrawal phase during which all inhaled corticosteroids and long acting β2-adrenoceptor agonists will be discontinued , patients will be r and omized to receive fluticasone ( 500 micrograms twice daily ) , fluticasone/salmeterol combination ( 500/50 micrograms twice daily ) , or placebo for four weeks . The study will recruit 250 patients across 11 centers in western Canada . Patients must be 40 years of age or older with at least 10 pack-year smoking history and have chronic obstructive pulmonary disease defined as forced expiratory volume in one second to vital capacity ratio of 0.70 or less and forced expiratory volume in one second that is 80 % of predicted or less . Patients will be excluded if they have any known chronic systemic infections , inflammatory conditions , history of previous solid organ transplantation , myocardial infa rct ion , or cerebrovascular accident within the past 3 months prior to study enrolment . The primary end-point is serum C-reactive protein level . Secondary end-points include circulating inflammatory cytokines such as interleukin-6 and interleukin-8 as well as health-related quality of life and lung function . Discussion If inhaled corticosteroids by themselves or in combination with a long-acting β2-adrenoceptor agonist could repress systemic inflammation , they might greatly improve clinical prognosis by reducing various complications in chronic obstructive pulmonary disease The TOwards a Revolution in COPD Health ( TORCH ) study was a 3-yr multicentre trial of 6,112 patients r and omised to salmeterol ( Salm ) , fluticasone propionate ( FP ) , a Salm/FP combination ( SFC ) or placebo ( P ) .  Here the cost-effectiveness of treatments evaluated in the TORCH study is assessed . For four regions , 3-yr all-cause hospitalisation , medication and outpatient care costs were calculated . The sample was restricted to the 21 countries ( n = 4,237 ) in which European quality of life five-dimension ( EQ-5D ) data were collected in order to estimate the number of quality -adjusted life years ( QALYs ) . Regression models were fitted to survival , study medication cost , other medication cost and EQ-5D data in order to estimate total cost , number of QALYs and cost per QALY , adjusted for missing data and region . SFC had a trial-wide estimate of cost per QALY of 43,600 US dollars ( USD ) compared with P ( 95 % confidence interval 21,400–123,500 USD ) . Estimates for Salm versus P ( 197,000 USD ) and FP versus P ( 78,000 USD ) were less favourable . The US estimates were greater than those from other regions ; for SFC versus P , the cost per QALY was 77,100 ( 46,200–241,700 ) USD compared to 24,200 ( 15,200–56,100 ) USD in Western Europe . Compared with P , SFC has a lower incremental cost-effectiveness ratio than either FP or Salm used alone , and is , therefore , preferred to these monotherapies on the grounds of cost-effectiveness Background Previous studies have suggested that long-term use of β agonists to treat chronic obstructive pulmonary disease ( COPD ) may increase the risk of cardiovascular adverse events . In this post hoc analysis , data from the TOwards a Revolution in COPD Health ( TORCH ) study were used to investigate whether use of the long-acting β2 agonist salmeterol over 3 years increased the risk of cardiovascular adverse events in patients with moderate to severe COPD . Methods TORCH was a r and omised , double-blind , placebo controlled study conducted at 444 centres in 42 countries . Patients ( n=6184 ; safety population ) received twice daily combined salmeterol 50 μg plus fluticasone propionate 500 μg ( SFC ) , either component alone , or placebo . Adverse events were recorded every 12 weeks for 3 years . Results The probability of having a cardiovascular adverse event by 3 years was 24.2 % for placebo , 22.7 % for salmeterol , 24.3 % for fluticasone propionate and 20.8 % for SFC . Although a history of myocardial infa rct ion doubled the probability of cardiovascular adverse events , the event rates remained similar across treatment groups . Conclusion Post hoc analysis of the 3-year TORCH data set showed that salmeterol alone or in combination ( SFC ) did not increase the risk of cardiovascular events in patients with moderate to severe COPD Background : Guidelines recommend inhaled corticosteroids ( ICS ) as maintenance treatment for patients with chronic obstructive pulmonary disease ( COPD ) with a post-bronchodilator forced expiratory volume in 1 second ( FEV1 ) < 50 % predicted and frequent exacerbations , although they have only a small preventive effect on the accelerated decline in lung function . Combined treatment with ICS and long acting β2 agonists ( LABA ) may provide benefit to the stability of COPD , but it is unknown if withdrawal of ICS will result in disease deterioration . Methods : The effects of 1 year withdrawal of the ICS fluticasone propionate ( FP ) after a 3 month run-in treatment period with FP combined with the LABA salmeterol ( S ) ( 500 μg FP + 50 μg S twice daily ; SFC ) were investigated in patients with COPD in a r and omised , double blind study . 497 patients were enrolled from 39 centres throughout the Netherl and s ; 373 were r and omised and 293 completed the study . Results : The drop out rate after r and omisation was similar in the two groups . Withdrawal of FP result ed in a sustained decrease in FEV1 : mean ( SE ) change from baseline −4.4 (0.9)% ( S ) v −0.1 (0.9)% ( SFC ) ; adjusted difference 4.1 ( 95 % CI 1.6 to 6.6 ) percentage points ( p<0.001 ) . Corresponding figures for the FEV1/FVC ratio were −3.7 (0.8)% ( S ) v 0.0 (0.8)% ( SFC ) ( p = 0.002 ) . The annual moderate to severe exacerbation rate was 1.6 and 1.3 in the S and SFC groups , respectively ( adjusted rate ratio 1.2 ; 95 % CI 0.9 to 1.5 ; p = 0.15 ) . The mean annual incidence rate of mild exacerbations was 1.3 ( S ) v 0.6 ( SFC ) , p = 0.020 . An immediate and sustained increase in dyspnoea score ( scale 0–4 ; mean difference between groups 0.17 ( 0.04 ) , p<0.001 ) and in the percentage of disturbed nights ( 6 ( 2 ) percentage points , p<0.001 ) occurred after withdrawal of fluticasone . Conclusions : Withdrawal of FP  in COPD patients using SFC result ed in acute and persistent deterioration in lung function and dyspnoea and in an increase in mild exacerbations and percentage of disturbed nights . This study clearly indicates a key role for ICS in the management of COPD as their discontinuation leads to disease deterioration , even under treatment with a LABA BACKGROUND Breathlessness and exercise intolerance frequently impact the daily life of patients with COPD . METHODS This double-blind , multicentre , three-period crossover study r and omised 111 patients with COPD ( mean age 64 years , mean FEV(1 ) 38 % of predicted normal ) to budesonide/formoterol 320/9 microg , formoterol 9 microg or placebo , twice daily for 1 week , following a 1-week run-in period with 1-week wash-out between treatments . Terbutaline ( 0.5 mg/dose ) was used as needed . The primary efficacy variable was exercise endurance time ( EET ) at 75 % peak work capacity with cycle ergometry assessed 1 h post-morning dose . RESULTS Budesonide/formoterol  prolonged EET 1 h post-morning dose versus formoterol by 69 s ( P < 0.005 ) and placebo by 105 s ( P < 0.0001 ) and improved inspiratory capacity ( IC ) at isotime during exercise versus formoterol by 8 % ( P = 0.011 ) and placebo by 16 % ( P < 0.0001 ) . Borg score at isotime was reduced by 0.48 ( P = 0.12 ) and 0.78 ( P = 0.014 ) compared with formoterol and placebo , respectively . At the repeated cycle test 6 h after morning dose , the effect on EET still favoured budesonide/formoterol over formoterol and placebo , while the isotime IC and Borg score were similar but better than placebo for the active study drugs . Budesonide/formoterol and formoterol improved health status ( St George 's Respiratory Question naire total score : mean difference versus placebo -2.4 and -2.2 , respectively ) . All treatments were well tolerated . CONCLUSIONS Budesonide/formoterol result ed in a significant improvement in endurance time 1 h after the last morning dose in a 1-week treatment period versus formoterol and placebo . This study demonstrates , for the first time , the benefit of inhaled corticosteroids in addition to long-acting beta(2)-agonists on exercise tolerance in COPD patients . www . clinical trials.gov registration number : NCT00489853 STUDY OBJECTIVES The aim of this study was to compare the relative efficacy in terms of improvement in symptoms and lung function of salmeterol/fluticasone propionate ( SLM/FP ) combination administered through the Diskus inhaler versus theophylline ( THEO ) added to FP Diskus in patients with stable chronic obstructive pulmonary disease ( COPD ) . METHODS AND MEASUREMENTS Eighty patients were r and omized to receive 4 months of treatment in one of two treatment groups : ( 1 ) fixed combination of SLM 50 microg and FP 500 microg Diskus , 1 inhalation twice daily ; or ( 2 ) FP Diskus 500 microg , 1 inhalation twice daily , plus oral titrated THEO twice daily . Patients attended the clinic before and after 4 , 8 , 12 and 16 weeks of treatment for evaluations of pulmonary function , and dyspnea , which was assessed using an analogic visual scale . Also the supplemental salbutamol use was measured . RESULTS . Sixty-six patients completed the 4-month treatment period : 37 patients receiving SLM/FP  and 29 patients receiving THEO+FP . Patients were withdrawn for various reasons , the most common of which were poor compliance with the protocol , exacerbation and GI events . A gradual increase in FEV(1 ) was observed with each treatment . Maximum significant increases in FEV(1 ) over baseline values that were observed after 4 months of treatment were as follows : SLM/FP 0.172 l ( 95 % CI : 0.084 - 0.260 ) and THEO+FP 0.155 l ( 95 % CI : 0.054 - 0.256 ) . SLM/FP experienced significantly ( p<0.05 ) greater improvements in dyspnea , and required significantly fewer supplemental salbutamol treatments than the THEO+FP group . CONCLUSIONS Our results suggest that SLM/FP combination may provide substantial benefits in both physiologic and clinical outcomes in symptomatic patients with COPD . It also causes a more effective control than THEO+FP Background : Combined treatment with inhaled corticosteroids and long acting β2 agonists is approved for the treatment of chronic obstructive pulmonary disease ( COPD ) , but little is known about the onset of effect of the combination . Methods : Data were used from 1465 patients with COPD entered into a large 1 year double blind trial with daily measurements of peak expiratory flow ( PEF ) and symptom scores . Results : PEF was significantly higher after 1 day in patients treated with salmeterol 50 μg twice daily or the salmeterol/fluticasone propionate combination 50/500 μg twice daily than placebo . In patients treated with fluticasone propionate 500 μg twice daily alone , PEF differed from placebo after 2 days . The differences after 2 weeks compared with placebo were 16 l/min ( 95 % confidence interval ( CI ) 11 to 21 ) , 11 l/min ( 95 % CI 6 to 16 ) , and 27 l/min ( 95 % CI 22 to 33 ) for salmeterol , fluticasone propionate , and the salmeterol/fluticasone propionate combination , respectively . For all treatments the effect on PEF after 2 weeks was comparable to that seen at the end of the study . The difference between the salmeterol/fluticasone propionate combination and placebo after 2 weeks as a percentage of baseline was similar for PEF and clinic forced expiratory volume in 1 second ( FEV1 ) . Differences in breathlessness scores were statistically significant after 1 day for the group treated with salmeterol alone and after 2 days for the combination group . The 2 week change in FEV1 was only partly indicative of a long term response in individual patients . Conclusions : The effects of salmeterol and fluticasone propionate , alone or in combination , on PEF and breathlessness are seen within days and most of the obtainable effect on these parameters is reached within 2 weeks BACKGROUND Inhaled corticosteroids ( ICSs ) and long-acting beta(2)-agonists ( LABAs ) are used to treat moderate to severe chronic obstructive pulmonary disease ( COPD ) . OBJECTIVE To determine whether long-term ICS therapy , with and without LABAs , reduces inflammation and improves pulmonary function in COPD . DESIGN R and omized , placebo-controlled trial . ( Clinical Trials.gov registration number : NCT00158847 ) SETTING 2 university medical centers in The Netherl and s. PATIENTS 114 steroid-naive current or former smokers with moderate to severe COPD . MEASUREMENTS Cell counts in bronchial biopsies and sputum ( primary outcome ) ; methacholine responsiveness at baseline , 6 , and 30 months ; and clinical outcomes every 3 months . INTERVENTION R and om assignment by minimization method to receive fluticasone propionate , 500 microg twice daily , for 6 months ( n = 31 ) or 30 months ( n = 26 ) ; fluticasone , 500 microg twice daily , and salmeterol , 50 microg twice daily , for 30 months ( single inhaler ; n = 28 ) ; or placebo twice daily ( n = 29 ) . RESULTS 101 patients were greater than 70 % adherent to therapy . Fluticasone therapy decreased counts of mucosal CD3(+ ) cells ( -55 % [ 95 % CI , -74 % to -22 % ] ; P = 0.004 ) , CD4(+ ) cells ( -78 % [ CI , -88 % to 60 % ] ; P < 0.001 ) , CD8(+ ) cells ( -57 % [ CI , -77 % to -18 % ] ; P = 0.010 ) , and mast cells ( -38 % [ CI , -60 % to -2 % ] ; P = 0.039 ) and reduced hyperresponsiveness ( P = 0.036 ) versus placebo at 6 months , with effects maintained after 30 months . Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium , with accompanying reductions in sputum neutrophil , macrophage , and lymphocyte counts and improvements in FEV(1 ) decline , dyspnea , and quality of life . Reductions in inflammatory cells correlated with clinical improvements . Discontinuing fluticasone therapy at 6 months increased counts of CD3(+ ) cells ( 120 % [ CI , 24 % to 289 % ] ; P = 0.007 ) , mast cells ( 218 % [ CI , 99 % to 407 % ] ; P < 0.001 ) , and plasma cells ( 118 % [ CI , 9 % to 336 % ] ; P = 0.028 ) and worsened clinical outcome . Adding salmeterol improved FEV(1 ) level . LIMITATIONS The study was not design ed to evaluate clinical outcomes . Measurement of primary outcome was not available for 24 % of patients at 30 months . CONCLUSION ICS therapy  decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD . Adding LABAs does not enhance these effects . This r and omized controlled trial examined the benefits of combining an inhaled corticosteroid , fluticasone propionate ( F ) , with an inhaled long-acting beta(2)-agonist , salmeterol ( S ) , to treat the inflammatory and bronchoconstrictive components of chronic obstructive pulmonary disease ( COPD ) . A total of 691 patients with COPD received the combination of F and S ( FSC ) , S ( 50 mcg ) , F ( 500 mcg ) , or placebo twice daily via the Diskus device for 24 weeks . A significantly greater increase in predose FEV(1 ) at the endpoint was observed after FSC ( 156 ml ) compared with S ( 107 ml , p = 0.012 ) and placebo ( -4 ml , p < 0.0001 ) . A significantly greater increase in 2-hour postdose FEV(1 ) at the endpoint was observed after treatment with FSC ( 261 ml ) compared with F ( 138 ml , p < 0.001 ) and placebo ( 28 ml , p < 0.001 ) . There were greater improvements in the Transition Dyspnea Index with FSC ( 2.1 ) compared with F ( 1.3 , p = 0.033 ) , S ( 0.9 , p < 0.001 ) , and placebo ( 0.4 , p < 0.0001 ) . The incidence of adverse effects ( except for an increase in oral c and idiasis with FSC and F ) was similar among the treatment groups . We conclude that FSC improved lung function and reduced the severity of dyspnea compared with individual components and placebo Abstract Objective : To compare the healthcare costs and effects of budesonide/formoterol in a single inhaler with those of budesonide and formoterol monotherapies , and placebo , in a multinational study in patients with chronic obstructive pulmonary disease ( COPD ) , National Heart , Lung and Blood Institute (NHLBI)/WHO Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) stages III or IV . Previous analysis of the clinical data from the study had shown that budesonide/formoterol was associated with better lung function and improved health-related QOL compared with the monocomponents or placebo and lower frequency of exacerbations compared with formoterol and placebo . Method : Patients ( n = 1022 ) were r and omised to twice-daily treatment with two inhalations of budesonide/formoterol ( 160μg/4.5μg ) in a single inhaler , budesonide 200μg , formoterol 4.5μg or placebo for 12 months . Data on medication and healthcare use were combined with Swedish unit cost data to estimate the total annual healthcare cost per patient from the Swedish healthcare payer perspective . Costs were valued in Swedish kronor ( SEK ) [ 2001 values ] and converted to euros ( SEK1 = € 0.11 , 25th April 2003 ) . Results : This evaluation estimated the total annual healthcare costs per patient to be numerically lower for budesonide/formoterol ( € 2518 ) than for budesonide ( € 3194 ) , formoterol ( € 3653 ) or placebo ( € 3213 ) . Cost-effectiveness acceptability curves suggest that budesonide/formoterol may be cost effective compared with formoterol , even if the decision maker is not willing to pay anything for the additional clinical effects , and that budesonide/formoterol  is cost effective  compared with placebo if a decision maker is willing to pay about € 2 per day , per avoided exacerbation . Conclusion : This economic analysis suggests that the clinical benefits of using budesonide/formoterol in a single inhaler are achieved at a numerically lower total healthcare cost  than either monocomponent or placebo . Budesonide/formoterol in patients with severe COPD ( GOLD stages III or IV ) may be cost effective , from the healthcare provider perspective , compared with either monocomponent Bronchodilators , including long-acting β2-adrenoceptor agonists and anticholinergic bronchodilators , are effective in the treatment of chronic obstructive pulmonary disease . Evidence suggests that the addition of a long-acting β2-agonist to an inhaled corticosteroid is associated with a reduced rate of exacerbations compared with either treatment alone or placebo . However , it is not known whether a long-acting β2-agonist/inhaled corticosteroid combination is more effective than an anticholinergic bronchodilator alone in reducing exacerbations . The Investigating New St and ards for Prophylaxis In Reduction of Exacerbations ( INSPIRE ) trial will study salmeterol ( a long-acting β2-agonist ) in combination with fluticasone propionate ( an inhaled corticosteroid ) compared with tiotropium bromide ( an anticholinergic bronchodilator ) in patients with moderate-to-severe chronic obstructive pulmonary disease . The INSPIRE study is a multicentre , r and omised , double-blind , double dummy , parallel group study conducted over 104 weeks . This is the first study to use two parallel definitions of an exacerbation ; an event-based exacerbation is defined as one that requires use of healthcare re sources , including additional treatment and hospitalization , whereas a symptom-based exacerbation is defined as one that satisfies the 1987 Anthonisen criteria . It is also the first study to compare the long-term effects of salmeterol/fluticasone propionate with tiotropium bromide on the rate of event-based exacerbations . Endpoints include rate of exacerbations ( primary endpoint ) , time to first exacerbation , and duration of exacerbations . Health outcomes will be assessed via the St George 's Respiratory Question naire . If the innovative methodology of utilizing 2 definitions of exacerbation proves successful , it will set the benchmark for future studies in chronic obstructive pulmonary disease RATIONALE Exacerbations of chronic obstructive pulmonary disease ( COPD ) greatly contribute to declining health status and the progression of the disease , thereby incurring significant direct and indirect health care costs . The prevention of exacerbations , therefore , is an important treatment goal . OBJECTIVES To assess the impact of combination therapy with salmeterol/fluticasone propionate compared with salmeterol alone on moderate and severe exacerbations in patients with severe COPD and a history of repeated exacerbations . METHODS R and omized , double-blind , parallel-group study . After a 4-wk run-in period , 994 clinical ly stable patients were r and omized to one of two treatment groups : 507 patients received the salmeterol/fluticasone combination 50/500 micro g twice daily and 487 received salmeterol 50 micro g twice daily for 44 wk . MAIN RESULTS The total number of exacerbations was 334 in the combination therapy and 464 in the salmeterol group ( p < 0.0001 ) . The annualized rate of moderate and severe exacerbations per patient was 0.92 in the combination therapy and 1.4 in the salmeterol group , corresponding to a 35 % decrease . In addition , the mean time to first exacerbation in the combination therapy group was significantly longer compared with that of the salmeterol group ( 128 vs. 93 d , p < 0.0001 ) . Other endpoints , including health-related quality of life , peak expiratory flow , and use of rescue medication , were significantly improved in the combination therapy group . Both treatments were well tolerated . CONCLUSIONS This study demonstrates that combination therapy with salmeterol/fluticasone compared with salmeterol monotherapy significantly reduces the frequency of moderate/severe exacerbations in patients with severe COPD BACKGROUND Little is known about the long-term efficacy of inhaled corticosteroids in chronic obstructive pulmonary disease ( COPD ) . We investigated the efficacy of inhaled budesonide on decline in lung function and respiratory symptoms in a 3-year placebo-controlled study of patients with COPD . METHODS We used a parallel-group , r and omised , double-blind , placebo-controlled design in a singlecentre study , nested in a continuing epidemiological survey ( the Copenhagen City Heart Study ) . Inclusion criteria were as follows : no asthma ; a ratio of forced expiratory volume in 1 s ( FEV1 ) and vital capacity of 0.7 or less ; FEV1 which showed no response ( < 15 % change ) to 1 mg inhaled terbutaline or prednisolone 37.5 mg orally once daily for 10 days . 290 patients were r and omly assigned  budesonide , 800 microg plus 400 microg daily for 6 months followed by 400 microg twice daily for 30 months , or placebo for 36 months . The mean age of the participants was 59 years and the mean FEV1 2.37 L or 86 % of predicted . The main outcome measure was rate of FEV1 decline . Analyses were by intention to treat . FINDINGS The crude rates of FEV1 decline were slightly smaller than expected ( placebo group 41.8 mL per year , budesonide group 45.1 mL per year ) . The estimated rates of decline from the regression model did not differ significantly ( 49.1 mL vs 46.0 mL per year ; difference 3.1 mL per year [ 95 % CI -12.8 to 19.0 ] ; p=0.7 ) . Before the study , the minimum relevant difference was defined as 20 mL per year ; this difference was outside the 95 % CI . No effect of inhaled budesonide was seen on respiratory symptoms . 316 exacerbations occurred during the study period , 155 in the budesonide group and 161 in the placebo group . Treatment was well tolerated . INTERPRETATION Inhaled budesonide was of no clinical benefit in COPD patients recruited from the general population by screening . We question the role of long-term inhaled corticosteroids in the treatment of mild to moderate COPD 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 r and omly 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 . Implication s 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 r and omized , 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 design ed a parallel-group , 3-group , r and omized , 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 r and omization . 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 . R and omization and Interventions We r and omly 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 . R and omization was done through central allocation of a r and omization schedule that was prepared from a computer-generated r and om 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 r and omization . 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 H and ihaler 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 r and omization . Respiratory exacerbations were defined , according to the 2000 Aspen Lung Conference Consensus definition , as a sustained worsening of the patient 's 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 result ed 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. George 's Respiratory Question naire ( 19 ) , dyspnea was assessed by using the Transitional Dyspnea Index ( 20 ) and the dyspnea domain of the Chronic Respiratory Disease Question naire ( 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 r and omization . For every suspected exacerbation , we contacted both the patient and the patient 's 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 purpose s 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 design ed the study to detect an 18 % absolute BACKGROUND Osteoporosis is common in patients with COPD , but its prevalence and progression are not well characterized . Concerns have been raised over the possible deleterious effect of long-term therapy with inhaled corticosteroids ( ICSs ) on bone density in this population . Here , we investigated the long-term effects of therapy with fluticasone propionate ( FP ) alone , salmeterol ( SAL ) alone , and a SAL/FP combination ( SFC ) on bone mineral density ( BMD ) and bone fractures in patients with moderate-to-severe COPD in the TOwards a Revolution in COPD Health ( TORCH ) study . METHODS A r and omized , double-blind , parallel-group , placebo-controlled study conducted at 88 US centers involving 658 patients ( a subset of 6,184 international subjects in TORCH ) . Therapy with placebo , SAL ( 50 microg ) , FP ( 500 microg ) , or SFC ( SAL 50 microg/FP 500 microg ) twice daily was administered for 3 years . Baseline and yearly measurements of BMD at the hip and lumbar spine were performed . The incidence of traumatic and nontraumatic bone fractures was recorded . RESULTS At baseline , 18 % of men and 30 % of women had osteoporosis , and 42 % of men and 41 % of women had osteopenia based on BMD assessment s. Forty-three percent of subjects completed all testing . The changes in BMD at the hip and lumbar spine over 3 years were small . No significant differences were observed between treatment arms ( adjusted mean percent change from baseline at hip was -3.1 % for placebo , -1.7 % for SAL , -2.9 % for FP , and -3.2 % for SFC therapy , respectively ; while , the corresponding changes for the lumbar spine were 0 , 1.5 % , -0.3 % , and -0.3 % for placebo , respectively , SAL , FP , and SFC therapy ) . The incidence of fractures was low and was similar for all treatments ( 5.1 % to 6.3 % ) . CONCLUSIONS Osteoporosis is highly prevalent in patients with COPD , irrespective of gender . In the TORCH study , no significant effect on BMD was detected for ICS therapy compared with placebo . TRIAL REGISTRATION Clinical Trials.gov Identifier : NTC00268216 Abstract Objective : To evaluate the efficacy and safety of budesonide (BUD)/formoterol ( FORM ) compared with BUD , both administered by way of a dry powder inhaler ( Turbuhaler * ) . * Turbuhaler is a registered trade name of AstraZeneca , Södertälje , Sweden . Methods : This was a 6-month , multicenter , r and omized , parallel-group , double-blind , double-dummy design study ( NCT 00421122 ) . Patients were r and omized to either BUD/FORM 160/4.5 μg , two inhalations twice daily , or BUD 200 μg , two inhalations twice daily .  Improvement of lung function , daily symptoms , reliever use and health-related quality -of-life ( St George ’s Respiratory Question naire [ SGRQ ] score ) were compared between the two treatment groups . Results : A total of 308 patients with moderate to very severe COPD from 12 centers in China were r and omized to BUD/FORM ( n = 156 ) or BUD ( n = 152 ) . The primary endpoint , 1-hour post-dose forced expiratory volume in 1 second ( FEV1 ) , in the BUD/FORM group improved by 0.18 L ( from 0.83 L at baseline to 1.01 L ) and this was significantly better ( p < 0.001 ) than the small increase ( 0.03 L ) observed in the BUD group after 24 weeks ’ treatment . Increases in pre-dose and 15-min post-dose FEV1 together with 1-hour post-dose forced vital capacity were also significantly larger with BUD/FORM than BUD ( p < 0.001 for all ) . Compared with BUD alone , BUD/FORM improved COPD total symptom scores ( −1.04 ± 0.16 vs. −0.55 ± 0.17 ; p = 0.03 ) , reduced reliever use ( −0.85 ± 0.16 puffs/day vs. −0.31 ± 0.16 puffs/day ; p = 0.012 ) and improved health-related quality -of-life ( mean change of total SGRQ score −4.5 points ( p = 0.0182 ) . Overall , both treatments were well tolerated . Conclusions : In Chinese patients with moderate to very severe COPD , fixed combination treatment with BUD/FORM result ed in clinical ly meaningful improvements in lung function , health-related quality -of-life , COPD symptoms and a reduction in  reliever use , compared with BUD alone and both treatments were well tolerated . Treatment of BUD/FORM for milder patients with COPD and head to head comparison of Chinese and Caucasians in future studies will be helpful to exp and upon the findings of the current clinical trial In the present trial , we compared the broncholytic efficacy of the combination therapy with 50 microg salmeterol + 250 microg fluticasone and 12 microg formoterol + 400 microg budesonide , both in a single inhaler device , in 16 patients with moderate-to-severe COPD . The study was performed using a single-blind crossover r and omized study . Lung function , pulse oximetry ( SpO2 ) and heart rate were monitored before and 15 , 30 , 60 , 120 , 180 , 240 , 300 , 360 , 480 , 600 , and 720 min after bronchodilator inhalation . Both combinations were effective in reducing airflow obstruction . FEV1 AUC(0 - 12 h ) was 2.83 l ( 95 % CI : 2.13 - 3.54 ) after salmeterol/fluticasone and 2.57 l ( 95 % CI : 1.97 - 3.2 ) after formoterol/budesonide . Formoterol/budesonide elicited the mean maximum improvement in FEV1 above baseline after 120 min ( 0.29 l ; 95 % CI : 0.21 - 0.37 ) and salmeterol/fluticasone after 300 min ( 0.32 l ; 95 % CI : 0.23 - 0.41 ) . At 720 min , the increase in FEV1 over baseline values was 0.10 l ( 95 % CI : 0.07 - 0.12 ) after salmeterol/fluticasone and 0.10 l ( 95 % CI : 0.07 - 0.13 ) after formoterol/budesonide . The mean peak increase in heart rate occurred 300 min after formoterol/budesonide ( 1.5 b/min ; 95 % CI--2.3 to 5.3 ) and 360 min after salmeterol/fluticasone ( 2.6 b/min ; 95 % CI--1.9 to 7.0 ) . SpO2 did not change . All differences between salmeterol/fluticasone and formoterol/budesonide were not significant ( P > 0.05 ) except those in FEV1 at 120 and 360 min . The results indicate that an inhaled combination therapy with a long-acting beta2-agonist and an inhaled corticosteroid appears to be effective in improving airway limitation after acute administration in patients suffering from COPD BACKGROUND The combination of an inhaled corticosteroid ( ICS ) and a long-acting bronchodilator is recommended in the treatment of patients with chronic obstructive pulmonary disease ( COPD ) who have frequent exacerbations .  Budesonide/formoterol dry powder inhaler ( DPI ) has demonstrated efficacy and tolerability in patients with COPD . OBJECTIVE To evaluate the efficacy and tolerability of budesonide/formoterol administered via one hydrofluoroalkane pressurized metered-dose inhaler ( pMDI ) in patients with COPD . METHODS This was a 6-month , r and omized , double-blind , double-dummy , placebo-controlled , parallel-group , multicentre study ( NCT00206154 ) of 1704 patients aged > or = 40 years with moderate to very severe COPD conducted in 194 centres in the US , Czech Republic , the Netherl and s , Pol and and South Africa . After 2 weeks of treatment based on previous therapy ( ICSs and short-acting bronchodilators allowed during the run-in period ) , patients received one of the following treatments administered twice daily : budesonide/formoterol pMDI 160/4.5 microg x two inhalations ( 320/9 microg ) ; budesonide/formoterol pMDI 80/4.5 microg x two inhalations ( 160/9 microg ) ; budesonide pMDI 160 microg x two inhalations ( 320 microg ) plus formoterol DPI 4.5 microg x two inhalations ( 9 microg ) ; budesonide pMDI 160 microg x two inhalations ( 320 microg ) ; formoterol DPI 4.5 microg x two inhalations ( 9 microg ) ; or placebo . MAIN OUTCOME MEASURES The co- primary efficacy variables were pre-dose forced expiratory volume in 1 second ( FEV(1 ) ) and 1-hour post-dose FEV(1 ) . RESULTS Budesonide/formoterol 320/9 microg demonstrated significantly greater improvements in pre-dose FEV(1 ) versus formoterol ( p = 0.026 ; pre-specified primary comparator ) and 1-hour post-dose FEV(1 ) versus budesonide ( p < 0.001 ; pre-specified primary comparator ) ; budesonide/formoterol 160/9 microg demonstrated significantly greater improvements versus budesonide ( p < 0.001 ) for 1-hour post-dose FEV(1 ) but not versus formoterol for pre-dose FEV(1 ) . Dyspnoea ( measured using the Breathlessness Diary ) and health-related quality -of-life ( HR-QOL ) scores ( based on the St George 's Respiratory Question naire total score ) were significantly improved with both dosage strengths of budesonide/formoterol compared with budesonide , formoterol and placebo ( p < or = 0.044 for all ) . Although not powered a priori for comparisons , the number of exacerbations per patient-treatment year requiring treatment with oral corticosteroids and /or hospitalization was numerically ( 20 - 25 % ) lower with the budesonide-containing treatments ( 0.710 - 0.884 ) versus formoterol ( 1.098 ) and placebo ( 1.110 ) . This result was driven by the exacerbations requiring treatment with oral corticosteroids ( 79 - 120 events ) . The number of exacerbations result ing in hospitalization was very low across treatment groups ( 11 - 22 ) ; the number per patient-treatment year was significantly different for budesonide/formoterol 320/9 microg ( 0.158 ) versus other treatment groups ( 0.081 - 0.108 ) except budesonide/formoterol 160/9 microg ( 0.139 ) , and for budesonide/formoterol 160/9 microg versus formoterol ( 0.081 ) [ p < or = 0.05 ] . All treatments were generally well tolerated . The incidence of individual non-fatal serious adverse events was similar across all treatment groups , except COPD , which was highest in the budesonide/formoterol 320/9 microg group ( 6.1 % ) and lowest in the budesonide ( 3.6 % ) and formoterol ( 3.9 % ) groups , with a range of 4.3 - 4.6 % in the budesonide/formoterol 160/9 microg , budesonide plus formoterol and placebo groups . Budesonide/formoterol had a safety profile comparable with that of the monocomponents and placebo . There was no increase in the incidence of pneumonia in the active treatment groups relative to placebo . CONCLUSIONS Budesonide/formoterol pMDI 320/9 microg demonstrated significantly greater efficacy for pulmonary function on both co- primary endpoints versus the pre-specified comparators ( formoterol DPI 9 microg for pre-dose FEV(1 ) and budesonide pMDI 320 microg for 1-hour post-dose FEV(1 ) ) . Budesonide/formoterol pMDI 160/9 microg demonstrated significantly greater efficacy for 1-hour post-dose FEV(1 ) versus budesonide pMDI 320 microg . Dyspnoea scores and HR-QOL were significantly improved with both budesonide/formoterol pMDI dosage strengths versus both monocomponents and placebo . Both budesonide/formoterol pMDI dosage strengths were well tolerated relative to the monocomponents and placebo INTRODUCTION This was a study of 30 chronic obstructive pulmonary disease ( COPD ) patients to assess the ease of use and preference of four dry powder inhalers -- accuhaler , aerolizer , h and ihaler , turbohaler -- the accuhaler and turbohaler are multidose devices , whereas the aerolizer and h and ihaler are single dose devices . METHOD None of the subjects had previous experience of dry powder inhalers . The correct technique for each inhaler was divided into 12 steps including one critical step that if not performed would result in no drug delivery . Subjects were shown the correct technique for each inhaler in a r and om order and were assessed immediately and 1 h later . Each subject was asked to rank the four devices for preference and ease of use , as well as to assess how comfortable it felt to inhale through the device using a visual analogue scale . RESULTS The numbers of perfect scores were not significantly different between devices , but the number of fatal errors that would result in no drug delivery was significantly more common in single dose devices ( p < 0.01 ) . There were significant differences in the rankings of each device ( Friedman test , p < 0.005 ) with the turbohaler being ranked first most often and the h and ihaler last . The turbohaler scored highest for comfort of inhalation and the accuhaler lowest , but differences were small . CONCLUSIONS In COPD patients starting on dry powder inhalers , multidose devices appear to be preferred , have fewer problems and are easier to use effectively RATIONALE Small studies have suggested that inhaled corticosteroids can suppress systemic inflammation in chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES To determine the effect of inhaled corticosteroids with or without long-acting beta(2)-adrenergic agonist on systemic biomarkers of inflammation . METHODS We conducted a double-blind r and omized placebo-controlled trial across 11 centers ( n = 289 patients with FEV(1 ) of 47.8 + /- 16.2 % of predicted ) to compare the effects of inhaled fluticasone alone or in combination with salmeterol against placebo on circulating biomarkers of systemic inflammation over 4 weeks . The primary endpoint was C-reactive protein ( CRP ) level . Secondary molecules of interest were IL-6 and surfactant protein D ( SP-D ) . MEASUREMENTS AND MAIN RESULTS Neither fluticasone nor the combination of fluticasone/salmeterol had a significant effect on CRP or IL-6 levels . There was , however , a significant reduction in SP-D levels with fluticasone and fluticasone/salmeterol compared with placebo ( P = 0.002 ) . Health status also improved significantly in both the fluticasone and fluticasone/salmeterol groups compared with placebo , driven mostly by improvements in the symptom scores . Changes in the circulating SP-D levels were related to changes in health status scores . FEV(1 ) improved significantly only in the fluticasone/salmeterol group compared with placebo . CONCLUSIONS ICS in conjunction with long-acting beta(2)-adrenergic agonist do not reduce CRP or IL-6 levels in serum of patients with COPD over 4 weeks . They do , however , significantly reduce serum SP-D levels . These data suggest that these drugs reduce lung-specific but not generalized biomarkers of systemic inflammation in COPD Both oxygen therapy and bronchodilators reduce exertional breathlessness and improve exercise tolerance in patients with stable chronic obstructive pulmonary disease ( COPD ) . However their relative effectiveness and the value of their combined use on exercise performance has not been assessed . The effects of 5 mg of salbutamol plus 500 microg ipratropium bromide nebulisation followed by a 6-min walking test while breathing O(2 ) were studied in a r and omised , single-blind , placebo controlled , crossover trial in 28 patients with severe or very severe COPD , breathless on exertion and with oxygen saturation < or = 89 % at rest or on exercise . Bronchodilator reversibility was minimal . The 6-min walking distance increased from 356 (128)m to 377 (117)m after the bronchodilator ( P<0.05 ) , to 406 (109)m after supplementary oxygen but without bronchodilators ( P 0.011 versus bronchodilators/air and 0.001 versus placebo/air ) , and to 430 (109)m after the combination of oxygen and the bronchodilators ( P<0.0001 versus placebo/air and bronchodilators/air ; P=0.014 versus placebo/oxygen ) . End-exercise dyspnea only fell significantly when oxygen and bronchodilator were combined . In severe or very severe COPD patients with relatively fixed airway obstruction bronchodilators enhance exercise performance obtained with oxygen . Clinical ly relevant improvement is possible when therapies with a different mechanism of action are combined BACKGROUND ss(2)-Agonists and corticosteroids or theophylline can interact to produce beneficial effects on airway function in asthma , but this has not been established in COPD . METHODS Eighty patients with well-controlled COPD were r and omized to receive 3 months of treatment in one of four treatment groups : ( 1 ) salmeterol , 50 microg bid ; ( 2 ) salmeterol , 50 microg , plus fluticasone propionate , 250 microg bid ; ( 3 ) salmeterol , 50 microg , plus fluticasone propionate , 500 microg bid ; and ( 4 ) salmeterol , 50 microg , plus titrated theophylline bid . At each visit , a dose-response curve to inhaled salbutamol was constructed using a total cumulative dose of 800 microg . RESULTS A gradual increase in FEV(1 ) was observed with each of the four treatments . Maximum significant increases in FEV(1 ) over baseline values that were observed after 3 months of treatment were as follows : salmeterol , 50 microg bid , 0.163 L ( 95 % confidence interval [ CI ] , 0.080 to 0.245 L ) ; salmeterol , 50 microg , plus fluticasone propionate , 250 microg bid , 0.188 L ( 95 % CI , 0.089 to 0 . 287 L ) ; salmeterol , 50 microg , plus fluticasone propionate , 500 microg bid , 0.239 L ( 95 % CI , 0.183 to 0.296 L ) ; and salmeterol , 50 microg , plus titrated theophylline bid , 0.157 L ( 95 % CI , 0.027 to 0 . 288 L ) . Salbutamol always caused a significant dose-dependent increase in FEV(1 ) ( p < 0.001 ) , although the 800-microg dose never induced further significant benefit when compared with the 400-microg dose . The mean differences between the highest salbutamol FEV(1 ) after salmeterol , 50 microg , plus fluticasone propionate , 500 microg bid , and that after salmeterol , 50 microg , plus titrated theophylline bid or salmeterol , 50 microg bid , were statistically significant ( p < 0.05 ) . CONCLUSION These data show that both long-acting ss(2)-agonists and inhaled corticosteroids have a role in COPD . The data also show that fluticasone propionate and salmeterol given together are more effective than salmeterol alone . Moreover , it suggests that the addition of fluticasone propionate to salmeterol allows a greater improvement in lung function after salbutamol , although regular salmeterol is able to improve lung function in COPD patients without development of a true subsensitivity to its bronchodilator effect . In any case , patients must be treated for at least 3 months before a real improvement in lung function is achieved RATIONALE No currently available treatment is reported to reduce the exaggerated airway wall inflammation of chronic obstructive pulmonary disease . OBJECTIVES We tested the hypothesis that inhaled combined long-acting beta2-agonist ( salmeterol ) and corticosteroid ( fluticasone propionate ) will reduce inflammation . METHODS Bronchial biopsies and induced sputum were taken from 140 current and former smokers ( mean age , 64 yr ) with moderate to severe disease , r and omized in a 13-wk double-blind study to placebo  ( n = 73 ) or  salmeterol/fluticasone propionate 50/500 microg ( n = 67 ) twice daily . Biopsies were repeated at 12 wk and sputa at 8 and 13 wk . After adjustment for multiplicity , comparisons between active and placebo were made for median change from baseline in the numbers of biopsy CD8 + and CD68 + cells/mm2 and sputum neutrophils . MEASUREMENTS AND MAIN RESULTS Combination therapy was associated with a reduction in biopsy CD8 + cells of -118 cells/mm2 ( 95 % confidence interval [ CI ] , -209 to -42 ; p = 0.02 ) , a reduction of 36 % over placebo ( p = 0.001 ) . CD68 + cells were unaffected by combination treatment . Sputum differential ( but not total ) neutrophils reduced progressively and , at Week 13 , significantly with combination treatment ( median treatment difference , 8.5 % ; 95 % CI , 1.75%-15.25 % ; p = 0.04 ) . The combination also significantly reduced biopsy CD45 + and CD4 + cells and cells expressing genes for tumor necrosis factor-alpha and IFN-gamma and sputum total eosinophils ( all p < or = 0.03 ) . These antiinflammatory effects were accompanied by a 173-ml ( 95 % CI , 104 - 242 ; p < 0.001 ) improvement in prebronchodilator FEV1 . CONCLUSIONS The combination of salmeterol and fluticasone propionate has a broad spectrum of antiinflammatory effects in both current and former smokers with chronic obstructive pulmonary disease , which may contribute to clinical efficacy The prevalence of chronic obstructive pulmonary disease ( COPD ) in women is increasing worldwide . Women may have greater susceptibility to COPD progression than men , and differences in efficacy and safety of respiratory medications by gender are largely unexplored . We aim ed to determine whether the response to treatment in women with COPD differed from men in a large , 1-year double-blind trial ( ' TRISTAN ' ) . In a sensitivity analysis , we compared 539 male and 180 female COPD patients , who were r and omized to the saLmeterol/fluticasone combination 50/500mcg bid or placebo for 12 months .  Combination therapy  improved pre-treatment FEV1 significantly more than placebo in women by 152 ml ( 95 % confidence interval 95 - 208 ) and in men by 127 ml ( 94 - 159 ) . Similarly , a reduction in COPD exacerbation rates of 31 % in women ( 9 - 48 % ) and of 23 % in men ( 8 - 35 % ) was observed . Combination therapy  reduced COPD exacerbations requiring treatment with oral corticosteroids by 36 % in women and by 41 % in men . Finally , combination treatment produced a better improvement in health status than placebo with a decrease in the SGRQ scores in women by -2.3 ( -4.6 - 0.1 ) and in men by -2.1 ( -3.5 to -0.8 ) . No gender interaction was found for any outcome . Treatments were well tolerated with no difference in the frequency of adverse events in women and men . In this trial , therapy with the salmeterol/fluticasone combination produced significant improvements compared to placebo on all main endpoints and the magnitude of these improvements was similar for both men and women Formoterol is a beta(2)-agonist bronchodilator that combines a fast onset of action with a long duration of broncholytic effect . An increasing documentation is showing that the combination of a long acting beta(2)-adrenoceptor agonist bronchodilator and an inhaled corticosteroid targets the airways obstruction in patients with COPD . In this study , we have explored whether the acute addition of an inhaled corticosteroid influences the fast bronchodilator response to formoterol . A total of 20 patients with stable COPD were r and omized . Single doses of formoterol/budesonide 2 x (4.5/160)microg or formoterol 2 x 4.5 microg were given via Turbuhaler . Serial measurements of FEV(1 ) were performed over 60 min . Formoterol/budesonide elicited a significantly larger mean FEV(1)-AUC(0 - 15 min ) than formoterol alone . Also the change in FEV(1 ) 15 min after inhalation of formoterol/budesonide combination ( 0.197 l ; 95 % CI : to 0.142 - 0.252 ) was greater than that induced by formoterol alone ( 0.147 l ; 95 % CI : to 0.092 - 0.201 ) . The mean increases in FEV(1 ) were always higher after budesonide/formoterol than formoterol alone , although both treatments induced a significant improvement over baseline at each explored time point . Even the FEV(1)-AUC(0 - 60 min ) after formoterol/budesonide was significantly larger than that after formoterol . Both treatments induced a significant reduction in VAS score but did not modify heart rate in a statistically significant manner . This study indicates that the addition of budesonide influences the fast onset of action of formoterol , but does not induce systemic effects , in patients with stable COPD BACKGROUND Long-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease ( COPD ) , but their effect on survival is unknown . METHODS We conducted a r and omized , double-blind trial comparing salmeterol at a dose of 50 microg plus fluticasone propionate at a dose of 500 microg twice daily ( combination regimen ) , administered with a single inhaler , with placebo , salmeterol alone , or fluticasone propionate alone for a period of 3 years . The primary outcome was death from any cause for the comparison between the combination regimen and placebo ; the frequency of exacerbations , health status , and spirometric values were also assessed . RESULTS Of 6112 patients in the efficacy population , 875 died within 3 years after the start of the study treatment .  All-cause mortality rates were 12.6 % in the combination-therapy group , 15.2 % in the placebo group , 13.5 % in the salmeterol group , and 16.0 % in the fluticasone group . The hazard ratio for death in the combination-therapy group , as compared with the placebo group , was 0.825 ( 95 % confidence interval [ CI ] , 0.681 to 1.002 ; P=0.052 , adjusted for the interim analyses ) , corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5 % . The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo . As compared with placebo , the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values ( P<0.001 for all comparisons with placebo ) . There was no difference in the incidence of ocular or bone side effects . The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate ( 19.6 % in the combination-therapy group and 18.3 % in the fluticasone group ) than in the placebo group ( 12.3 % , P<0.001 for comparisons between these treatments and placebo ) . CONCLUSIONS The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance . There were significant benefits in all other outcomes among these patients . ( Clinical Trials.gov number , NCT00268216 [ Clinical Trials.gov ] . ) Changes in health-related quality of life ( HRQoL ) were evaluated in patients with chronic obstructive pulmonary disease ( COPD ) following treatment with placebo , salmeterol 50 microg twice a day or 100 microg twice a day by metered-dose inhaler . Patients completed the disease-specific St. George 's Respiratory Question naire ( SGRQ ) and the Medical Outcomes Study Short Form 36 ( SF-36 ) at baseline and after 16 wk of treatment . Data from 283 patients ( 95 patients in the placebo group and 94 in each salmeterol group ) were available for HRQoL analysis . Apart from a small difference in ages , all treatment groups were well matched at baseline in terms of forced expiratory volume in one second ( FEV1 ) and HRQoL scores . Compared with placebo , salmeterol 50 microg twice a day was associated with significant improvements in SGRQ " Total " and " Impacts " scores which exceeded the threshold for a clinical ly significant change . This was not seen with salmeterol 100 microg twice a day . Changes in SGRQ and SF-36 scores correlated . They also showed a weak but significant relationship with FEV1 . This study has shown that a modest change in lung function may be associated with clinical ly significant gain in health and well-being in COPD patients The objective was to evaluate the effect of inhaled corticosteroids on disease progression in smokers with moderate to severe chronic obstructive pulmonary disease ( COPD ) , as assessed by annual computed tomography ( CT ) using lung density ( LD ) measurements . Two hundred and fifty-four current smokers with COPD were r and omised to treatment with either an inhaled corticosteroids ( ICS ) , budesonide 400 μ g bid , or placebo . COPD was defined as FEV1 ≤ 70 % pred , FEV1/FVC ≤ 60 % and no reversibility to β2-agonists and oral corticosteroids . The patients were followed for 2–4 years with biannual spirometry and annual CT and comprehensive lung function tests ( LFT ) . CT images were analysed using Pulmo-CMS software . LD was derived from a pixel-density histogram of the whole lung as the 15thpercentile density ( PD15 ) and the relative area of emphysema at a threshold of −910 Hounsfield units ( RA-910 ) , and both were volume-adjusted to predicted total lung capacity . At baseline , mean age was 64 years and 64 years ; mean number of pack-years was 56 and 56 ;  mean FEV1 was 1.53 L ( 51 % pred ) and 1.53 L ( 53 % pred ) ; mean PD15 was 103 g/L and 104 g/L ; and mean RA-910 was 14 % and 13 % , respectively , for the budesonide and placebo groups . The annual fall in PD15 was −1.12 g/L in the budesonide group and −1.81 g/L in the placebo group ( p = 0.09 ) ; the annual increase in RA–910 was 0.4 % in the budesonide group and 1.1 % in the placebo group ( p = 0.02 ) . There was no difference in annual decline in FEV1 between ICS ( −54 mL ) and placebo ( −56 mL ) ( p = 0.89 ) . Long-term budesonide inhalation shows a non-significant trend towards reducing the progression of emphysema as determined by the CT-derived 15th percentile lung density from annual CT scans in current smokers with moderate to severe COPD BACKGROUND Chronic obstructive pulmonary disease ( COPD ) results from a progressive decline in lung function , which is thought to be the consequence of airway inflammation . We hypothesized that antiinflammatory therapy with inhaled corticosteroids would slow this decline . METHODS We enrolled 1116 persons with COPD whose forced expiratory volume in one second ( FEV1 ) was 30 to 90 percent of the predicted value in a 10-center , placebo-controlled , r and omized trial of inhaled triamcinolone acetonide administered at a dose of 600 microg twice daily . The primary outcome measure was the rate of decline in FEV1 after the administration of a bronchodilator . The secondary outcome measures included respiratory symptoms , use of health care services , and airway reactivity . In a sub study of 412 participants , we measured bone density in the lumbar spine and femur at base line and one and three years after the beginning of treatment . RESULTS The mean duration of follow-up was 40 months . The rate of decline in the FEV1 after bronchodilator use was similar in the 559 participants in the triamcinolone group and the 557 participants in the placebo group ( 44.2+/-2.9 vs. 47.0+/-3.0 ml per year , P= 0.50 ) . Members of the triamcinolone group had fewer respiratory symptoms during the course of the study ( 21.1 per 100 person-years vs. 28.2 per 100 person-years , P=0.005 ) and had fewer visits to a physician because of a respiratory illness ( 1.2 per 100 person-years vs. 2.1 per 100 person-years , P=0.03 ) . Those taking triamcinolone also had lower airway reactivity in response to methacholine challenge at 9 months and 33 months ( P=0.02 for both comparisons ) . After three years , the bone density of the lumbar spine and the femur was significantly lower in the triamcinolone group ( P < or = 0.007 ) . CONCLUSIONS Inhaled triamcinolone does not slow the rate of decline in lung function in people with COPD , but it improves airway reactivity and respiratory symptoms and decreases the use of health care services for respiratory problems . These benefits should be weighed against the potential long-term adverse effects of triamcinolone on bone mineral density The object of this investigation was to study the long-term effects of antiasthma treatment on blood markers of inflammation and lung function in adult asthmatic subjects . For this purpose 85 allergic and nonallergic asthmatic subjects were r and omized into three groups , which were given high-dose ( 1,600 micrograms/d ) inhaled budesonide , low-dose ( 400 micrograms/d ) inhaled budesonide , and oral theophylline ( 600 mg/d ) , respectively , and were followed for 11 mo with testing of lung function and blood sampling for the assay in serum of eosinophil cationic protein ( ECP ) , eosinophil protein x/eosinophil derived neurotoxin ( EPX/EDN ) as eosinophil markers , and myeloperoxidase ( MPO ) and lactoferrin ( LF ) as neutrophil markers . Lung functions ( FEV1 % predicted , and histamine PC20 ) and the eosinophil markers ECP and EPX/EDN were improved and reduced , respectively , by budesonide in a dose-dependent and temporally parallel fashion . Theophylline did not alter lung functions but reduced ECP and EPX/EDN after prolonged treatment . The treatment efficacy of budesonide was attributed solely to an effect on nonsmoking asthmatic subjects , since neither lung functions nor eosinophil markers changed in smokers even with high-dose budesonide . MPO but not LF was reduced after several months of treatment in all three groups , but only in nonsmokers . We conclude that ECP and EPX/EDN may be used to monitor antiinflammatory treatment in asthmatic patients , and that smoking asthmatic subjects are resistant to inhaled corticosteroids Abstract Objectives : To determine the effect of long term inhaled corticosteroids on lung function , exacerbations , and health status in patients with moderate to severe chronic obstructive pulmonary disease . Design : Double blind , placebo controlled study . Setting : Eighteen UK hospitals . Participants : 751 men and women aged between 40 and 75 years with mean forced expiratory volume in one second ( FEV1 ) 50 % of predicted normal . Interventions : Inhaled fluticasone propionate 500 μg twice daily from a metered dose inhaler or identical placebo . Main outcome measures : Efficacy measures : rate of decline in FEV1 after the bronchodilator and in health status , frequency of exacerbations , respiratory withdrawals . Safety measures : morning serum cortisol concentration , incidence of adverse events . Results : There was no significant difference in the annual rate of decline in FEV1 ( P=0.16 ) . Mean FEV1 after bronchodilator remained significantly higher throughout the study with fluticasone propionate compared with placebo ( P<0.001 ) . Median exacerbation rate was reduced by 25 % from 1.32 a year on placebo to 0.99 a year on with fluticasone propionate ( P=0.026 ) . Health status deteriorated by 3.2 units a year on placebo and 2.0 units a year on fluticasone propionate ( P=0.0043 ) . Withdrawals because of respiratory disease not related to malignancy were higher in the placebo group ( 25 % v 19 % , P=0.034 ) . Conclusions : Fluticasone propionate 500 μg twice daily did not affect the rate of decline in FEV1 but did produce a small increase in FEV1 . Patients on fluticasone propionate  had fewer exacerbations and a slower decline in health status . These improvements in clinical outcomes support the use of this treatment in patients with moderate to severe chronic obstructive pulmonary disease Abstract Background : Chronic obstructive pulmonary disease ( COPD ) is a progressive inflammatory lung disease associated with increasing morbidity and mortality and an economic burden that stretches beyond the patient to healthcare systems . Avoiding exacerbations and subsequent hospitalizations is an important clinical aim and can avoid significant costs associated with the disease . International guidelines recommend the addition of an inhaled corticosteroid ( ICS ) to a long-acting β2-adrenoceptor agonist ( LABA ) for patients with severe to very severe COPD and a history of exacerbations . Objective : To evaluate retrospectively over a 3-month period , the cost effectiveness of budesonide/formoterol added to tiotropium bromide ( tiotropium ) compared with placebo added to tiotropium in COPD patients eligible for ICS/LABA combination therapy , based on the CLIMB study ( NCT00496470 ) . Methods : A cost-effectiveness analysis of data from the 12-week , r and omized , double-blind CLIMB study of COPD patients ( n = 659 ; eligible for ICS/ LABA ; aged ≥40 years )  comparing budesonide/formoterol ( Symbicort ® Turbuhaler ® 320/9 μg twice daily ) added to tiotropium ( 18 μg daily ) or placebo added to tiotropium was conducted . A severe exacerbation was defined as a requirement for systemic glucocorticosteroids and /or ED visit and /or hospitalization . The effectiveness variable used for this analysis was the number of severe exacerbations avoided . Direct costs ( medications , hospitalizations , ED and GP visits ) were calculated by applying year 2009 unit costs from Australia ( $ A ) , Canada ( $ Can ) and Sweden ( Swedish krona [ SEK ] ) to the study ’s pooled re source use . One-way sensitivity analyses for each country ’s mean incremental cost-effectiveness ratio and sensitivity to overall exacerbations were conducted . Bootstrapping was performed to estimate the variation around re source use , exacerbations and each country ’s mean incremental cost-effectiveness ratio . Results : The mean number of severe exacerbations per patient 3-month period was 0.11 in the budesonide/formoterol added to tiotropium arm and 0.29 in the placebo added to tiotropium arm – a 62 % reduction in the rate of severe exacerbations . Treatment with budesonide/formoterol added to tiotropium costs less in Australia and Canada ( -$A90 [ -€58 ] and -$Can4.51 [ -€3 ] ) and only slightlymore in Sweden ( SEK444 [ € 43 ] ) , i.e. the savings associated with fewer exacerbations more than offset the additional budesonide/formoterol drug cost in Australia and Canada , and partially offset it in Sweden . In the Australian and Canadian perspectives , budesonide/formoterol added to tiotropium was a dominant treatment ( fewer exacerbations at a lower cost ) comparedwithplacebo added to tiotropium . In Sweden , the estimated incremental cost per avoided exacerbation was SEK2502 ( € 244.40 ) . Conclusion : Budesonide/formoterol added to tiotropium was the dominant strategy compared with placebo added to tiotropium based on a 12-week study in COPD patients eligible for ICS/LABA combination therapy in Australia and Canada , and appears to be a cost-effective strategy in Sweden RATIONALE Budesonide/formoterol and tiotropium are commonly used maintenance treatments for patients with chronic obstructive pulmonary disease . Combining these medications may provide additional benefits . OBJECTIVES To assess the efficacy and tolerability of budesonide/formoterol added to tiotropium in patients eligible for inhaled corticosteroid/long-acting beta(2)-agonist combination therapy . METHODS In this 12-week , r and omized , double-blind , parallel-group , multicenter study , after a 2-week run-in , 660 subjects ( 75 % male ; mean age , 62 yr ; FEV(1 ) , 1.1 L ; 38 % predicted normal ) , 40 years of age or older , received tiotropium ( 18 microg once daily )  plus either budesonide/formoterol ( 320/9 microg ) ( n = 329 ) or placebo ( n = 331 ) twice daily . MEASUREMENTS AND MAIN RESULTS Clinic predose ( primary outcome ) and postdose FEV(1 ) , predose and postdose forced vital capacity and inspiratory capacity , and health status were measured . Other outcomes included daily measurements taken at home ( pre- and postdose morning FEV(1 ) and peak expiratory flow , morning symptoms and activities , and morning reliever use ) , severe exacerbations , and tolerability . Over the treatment period , budesonide/formoterol plus tiotropium significantly increased predose FEV(1 ) by 6 % ( 65 ml ) and postdose by 11 % ( 123 and 131 ml at 5 and 60 min postdose , respectively ) versus tiotropium alone ( both P < 0.001 ) . Other outcomes all significantly improved with budesonide/formoterol plus tiotropium versus tiotropium alone . The number of severe exacerbations decreased by 62 % ( rate ratio , 0.38 ; 95 % confidence interval , 0.25 - 0.57 ; P < 0.001 ) . Both treatments were well tolerated . CONCLUSIONS In patients with chronic obstructive pulmonary disease , budesonide/formoterol added to tiotropium versus tiotropium alone provides rapid and sustained improvements in lung function , health status , morning symptoms and activities , and reduces severe exacerbations . Clinical trial registered with www . clinical trials.gov ( NCT00496470 )
BACKGROUND Both long-acting beta2-agonists ( LABA ) and inhaled corticosteroids ( ICS ) have been recommended in guidelines for the treatment of chronic obstructive pulmonary disease ( COPD ) .
Their coadministration in a combination inhaler may facilitate adherence to medication regimens and improve efficacy .
OBJECTIVES To determine the efficacy and safety of combined ICS and LABA for stable COPD in comparison with placebo .