Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Prediction of Long-Term Benefits of Inhaled Steroids by Phenotypic Markers in Moderate-to-Severe COPD: A Randomized Controlled Trial Identification of responders to inhaled corticosteroids in a chronic obstructive pulmonary disease population using cluster analysis Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial. Chronic obstructive pulmonary disease and the risk of cardiovascular diseases Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial Blood eosinophils and treatment response with triple and dual combination therapy in chronic obstructive pulmonary disease: analysis of the IMPACT trial. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD.
BACKGROUND Whether the combination of a once-daily inhaled corticosteroid with a once-daily longacting β(2 ) agonist is more protective than a once-daily longacting β(2 ) agonist alone against exacerbations of chronic obstructive pulmonary disease ( COPD ) is unknown . We hypothesised that fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol alone . METHODS We did two replicate double-blind parallel-group 1 year trials . Both studies began on Sept 25 , 2009 . Study 1 ended on Oct 31 , 2011 , and study 2 on Oct 17 , 2011 . Eligible patients were aged 40 years or older , had a history of COPD , a smoking history of 10 or more pack-years , a ratio of forced expiratory volume in 1 s ( FEV(1 ) ) to forced vital capacity of 0·70 or less after bronchodilators ( and an FEV(1 ) of 70 % or less of predicted ) , and a documented history of one or more moderate or severe disease exacerbations in the year before screening . Patients were r and omly assigned ( 1:1:1:1 ) on the basis of the Registration and Medication Ordering System to 25 μg vilanterol alone or 25 μg vilanterol combined with either 50 μg , 100 μg , or 200 μg fluticasone furoate once daily . Our primary endpoint was the yearly rate of moderate and severe exacerbations . The trials were analysed separately and a pooled analysis was also done . These trials are registered with Clinical Trials.gov ( NCT01009463 and NCT01017952 ) . FINDINGS 1622 patients in study 1 and 1633 patients in study 2 were r and omly assigned . In study 1 , no significant difference in exacerbation rate was noted between the 200/25 μg fluticasone furoate/vilanterol group and the vilanterol only group ( mean 0·90 events vs 1·05 events per year ; ratio 0·9 [ 95 % CI 0·7 - 1·0 ] ) . Because of the statistical hierarchy used , we could not infer significance for the 50 μg and 100 μg groups . In study 2 , significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group ( p=0·0398 for the 50 μg group , 0·0244 for the 100 μg group , and 0·0004 for the 200 μg group ) . In the pooled analysis , significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group ( 0·0141 for the 50 μg group , < 0·0001 for the 100 μg group , and 0·0003 for the 200 μg group ) . Nasopharyngitis was the most frequently reported adverse event in both studies . Pneumonia and fractures were reported more frequently with fluticasone furoate and vilanterol than with vilanterol alone . Eight deaths from pneumonia were noted in the fluticasone furoate/vilanterol groups compared with none in the vilanterol only group . INTERPRETATION Addition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD  in patients with a history of exacerbation , but was also associated with an increased pneumonia risk . FUNDING GlaxoSmithKline Background The decline in lung function can be reduced by long-term inhaled corticosteroid ( ICS ) treatment in subsets of patients with chronic obstructive pulmonary disease ( COPD ) . We aim ed to identify which clinical , physiological and non-invasive inflammatory characteristics predict the benefits of ICS on lung function decline in COPD . Methods Analysis was performed in 50 steroid-naive compliant patients with moderate to severe COPD ( postbronchodilator forced expiratory volume in one second ( FEV1 ) , 30–80 % of predicted , compatible with GOLD stages II-III ) , age 45–75 years , > 10 packyears smoking and without asthma . Patients were treated with fluticasone propionate ( 500 μg bid ) or placebo for 2.5 years . Postbronchodilator FEV1 , dyspnea and health status were measured every 3 months ; lung volumes , airway hyperresponsiveness ( PC20 ) , and induced sputum at 0 , 6 and 30 months . A linear mixed effect model was used for analysis of this hypothesis generating study . Results Significant predictors of attenuated FEV1-decline by fluticasone treatment compared to placebo were : fewer packyears smoking , preserved diffusion capacity , limited hyperinflation and lower inflammatory cell counts in induced sputum ( p<0.04 ) . Conclusions Long-term benefits of ICS  on lung function decline in patients with moderate-to-severe COPD are most pronounced in patients with fewer packyears , and less severe emphysema and inflammation . These data generate novel hypotheses on phenotype-driven therapy in COPD . Trial Registration Clinical Trials.gov Objectives To identify clusters of patients who may benefit from treatment with an inhaled corticosteroid (ICS)/long-acting β2 agonist ( LABA ) versus LABA  alone , in terms of exacerbation reduction , and to vali date previously identified clusters of patients with chronic obstructive pulmonary disease ( COPD ) ( based on diuretic use and reversibility ) . Design Post hoc supervised cluster analysis using a modified recursive partitioning algorithm of two 1-year r and omised , controlled trials of fluticasone furoate (FF)/vilanterol ( VI ) versus VI alone , with the primary end points of the annual rate of moderate-to-severe exacerbations . Setting Global . Participants 3255 patients with COPD ( intent-to-treat population s ) with a history of exacerbations in the past year . Interventions FF/VI 50/25 µg , 100/25 µg or 200/25 µg , or VI 25 µg ; all one time per day . Outcome measures Mean annual COPD exacerbation rate to identify clusters of patients who benefit from adding an ICS ( FF ) to VI bronchodilator therapy . Results Three clusters were identified , including two groups that benefit from FF/VI versus VI : patients with blood eosinophils > 2.4 % ( RR=0.68 , 95 % CI 0.58 to 0.79 ) , or blood eosinophils ≤2.4 % and smoking history ≤46 pack-years , experienced a reduced rate of exacerbations with FF/VI versus VI ( RR=0.78 , 95 % CI 0.63 to 0.96 ) , whereas those with blood eosinophils ≤2.4 % and smoking history > 46 pack-years were identified as non-responders ( RR=1.22 , 95 % CI 0.94 to 1.58 ) . Clusters of patients previously identified in the fluticasone propionate/salmeterol ( SAL ) versus SAL trials of similar design were not vali date d ; all clusters of patients tended to benefit from FF/VI versus VI alone irrespective of diuretic use and reversibility . Conclusions In patients with COPD with a history of exacerbations , those with greater blood eosinophils or a lower smoking history may benefit more from ICS/LABA versus LABA alone as measured by a reduced rate of exacerbations . In terms of eosinophils , this finding is consistent with findings from other studies ; however , the validity of the 2.4 % cut-off and the impact of smoking history require further investigation . Trial registration numbers NCT01009463 ; NCT01017952 ; Post- results 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 . Previous large epidemiological studies reporting on the association between chronic obstructive pulmonary disease ( COPD ) and cardiovascular diseases mainly focussed on prevalent diseases rather than on the incidence of newly diagnosed cardiovascular outcomes . We used the UK-based General Practice Research Data base ( GPRD ) to assess the prevalence and incidence of cardiovascular diseases in COPD patients aged 40–79 between 1995 and 2005 , and we r and omly matched COPD -free comparison patients to COPD patients .  In nested-case control analyses , we compared the risks of developing an incident diagnosis of cardiac arrhythmias , venous thromboembolism , myocardial infa rct ion , or stroke between patients with and without COPD , stratifying the analyses by COPD -severity , using COPD -treatment as proxy for disease severity . We identified 35,772 patients with COPD and the same number of COPD -free patients . Most cardiovascular diseases were more prevalent among COPD patients than among the comparison group of COPD -free patients . The relative risk estimates of developing an incident diagnosis of cardiac arrhythmia ( OR 1.19 , 95 % CI 0.98–1.43 ) , deep vein thrombosis ( OR 1.35 , 95 % CI 0.97–1.89 ) , pulmonary embolism ( OR 2.51 , 95 % CI 1.62–3.87 ) , myocardial infa rct ion ( OR 1.40 , 95 % CI 1.13–1.73 ) , or stroke ( OR 1.13 , 95 % CI 0.92–1.38 ) , tended to be increased for patients with COPD as compared to COPD -free controls . The findings of this large observational study provide further evidence that patients with COPD are at increased risk for most cardiovascular diseases BACKGROUND The peripheral blood eosinophil count might help identify those patients with chronic obstructive pulmonary disease ( COPD ) who will experience fewer exacerbations when taking inhaled corticosteroids ( ICS ) . Previous post-hoc analyses have proposed eosinophil cutoffs that are both arbitrary and limited in evaluating complex interactions of treatment response . We modelled eosinophil count as a continuous variable to determine the characteristics that determine both exacerbation risk and clinical response to ICS in patients with COPD . METHODS We analysed data from three AstraZeneca r and omised controlled trials of budesonide-formoterol in patients with COPD with a history of exacerbations and available blood eosinophil counts . Patients with any history of asthma were excluded . Negative binomial regression analysis was done using splines for modelling of continuous variables to study the primary outcome of annual exacerbation rate adjusted for exposure time and study design . The trials are registered with Clinical Trials.gov , NCT00206167 , NCT00206154 , and NCT00419744 . FINDINGS 4528 patients were studied . A non-linear increase in exacerbations occurred with increasing eosinophil count in patients who received formoterol alone . At eosinophil counts of 0·10 × 109 cells per L or more , a significant treatment effect was recorded for exacerbation reduction  with budesonide-formoterol compared with formoterol alone ( rate ratio 0·75 , 95 % CI 0·57 - 0·99 ; pinteraction=0·015 ) . Interactions were observed between eosinophil count and the treatment effects  of budesonide-formoterol over formoterol on St George 's Respiratory Question naire ( pinteraction=0·0043 ) and pre-bronchodilator FEV1 ( linear effect p<0·0001 , pinteraction=0·067 ) . Only eosinophil count and smoking history were independent predictors of response to budesonide-formoterol in reducing exacerbations ( eosinophil count , pinteraction=0·013 ; smoking history , pinteraction=0·015 ) . INTERPRETATION In patients with COPD  treated with formoterol  , blood eosinophil count predicts exacerbation risk and the clinical response to ICS . FUNDING AstraZeneca 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 BACKGROUND Previous studies have highlighted a relationship between reduction in rate of exacerbations with therapies containing inhaled corticosteroids ( ICS ) and baseline blood eosinophil count in patients with chronic obstructive pulmonary disease ( COPD ) . The IMPACT trial showed that once-daily single-inhaler triple therapy significantly reduced exacerbations versus dual therapies .  Blood eosinophil counts and smoking status could be important modifiers of treatment response to ICS . We aim ed to model these relationships and their interactions , including outcomes other than exacerbations . METHODS IMPACT was a phase 3 , r and omised , double-blind , parallel-group , 52-week global study comparing once-daily single-inhaler triple therapy ( fluticasone furoate-umeclidinium-vilanterol ) with dual inhaled therapy ( fluticasone furoate-vilanterol or umeclidinium-vilanterol ) .  Eligible patients had moderate-to-very-severe COPD and at least one moderate or severe exacerbation in the previous year . We used fractional polynomials to model continuous blood eosinophil counts . We used negative binomial regression for numbers of moderate and severe exacerbations , severe exacerbations , and pneumonia . We modelled differences at week 52 in trough FEV1 , St George 's Respiratory Question naire ( SGRQ ) total score , and Transition Dyspnoea Index using repeated measurements mixed effect models . IMPACT was registered with Clinical Trials.gov , number NCT02164513 . FINDINGS The magnitude of benefit of regimens containing ICS ( fluticasone furoate-umeclidinium-vilanterol n=4151 and fluticasone furoate-vilanterol n=4134 ) in reducing rates of moderate and severe exacerbations increased in proportion with blood eosinophil count , compared with a non-ICS dual long-acting bronchodilator ( umeclidinium-vilanterol n=2070 ) . The moderate and severe exacerbation rate ratio for triple therapy versus umeclidinium-vilanterol was 0·88 ( 95 % CI 0·74 to 1·04 ) at blood eosinophil count less than 90 cells per μL and 0·56 ( 0·47 to 0·66 ) at counts of 310 cells per μL or more ; the corresponding rate ratio for fluticasone furoate-vilanterol versus umeclidinium-vilanterol was 1·09 ( 0·91 to 1·29 ) and 0·56 ( 0·47 to 0·66 ) , respectively . Similar results were observed for FEV1 , Transition Dyspnoea Index , and SGRQ total score ; however , the relationship with FEV1 was less marked . At blood eosinophil counts less than 90 cells per μL and at counts of 310 cells per μL or more , the triple therapy versus umeclidinium-vilanterol treatment difference was 40 mL ( 95 % CI 10 to 70 ) and 60 mL ( 20 to 100 ) for trough FEV1 , -0·01 ( -0·68 to 0·66 ) and 0·30 ( -0·37 to 0·97 ) for Transition Dyspnoea Index score , and -0·01 ( -1·81 to 1·78 ) and -2·78 ( -4·64 to -0·92 ) for SGRQ total score , respectively . Smoking status modified the relationship between observed efficacy and blood eosinophil count for moderate or severe exacerbations , Transition Dyspnoea Index , and FEV1 , with  former smokers being more corticosteroid responsive at any eosinophil count than current smokers . INTERPRETATION This analysis of the IMPACT trial shows that assessment of blood eosinophil count and smoking status has the potential to optimise ICS use in clinical practice in patients with COPD and a history of exacerbations . FUNDING GlaxoSmithKline BACKGROUND Most guidelines recommend either a long-acting beta-agonist ( LABA ) plus an inhaled glucocorticoid or a long-acting muscarinic antagonist ( LAMA ) as the first-choice treatment for patients with chronic obstructive pulmonary disease ( COPD ) who have a high risk of exacerbations . The role of treatment with a LABA-LAMA regimen in these patients is unclear . METHODS We conducted a 52-week , r and omized , double-blind , double-dummy , noninferiority trial . Patients who had COPD with a history of at least one exacerbation during the previous year were r and omly assigned to receive , by inhalation , either the LABA indacaterol ( 110 μg ) plus the LAMA glycopyrronium ( 50 μg ) once daily or the LABA salmeterol ( 50 μg ) plus the inhaled glucocorticoid fluticasone ( 500 μg ) twice daily . The primary outcome was the annual rate of all COPD exacerbations . RESULTS A total of 1680 patients were assigned to the indacaterol-glycopyrronium group , and 1682 to the salmeterol-fluticasone group .  Indacaterol-glycopyrronium showed not only noninferiority but also superiority to salmeterol-fluticasone in reducing the annual rate of all COPD exacerbations ; the rate was 11 % lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group ( 3.59 vs. 4.03 ; rate ratio , 0.89 ; 95 % confidence interval [ CI ] , 0.83 to 0.96 ; P=0.003 ) . The indacaterol-glycopyrronium group had a longer time to the first exacerbation than did the salmeterol-fluticasone group ( 71 days [ 95 % CI , 60 to 82 ] vs. 51 days [ 95 % CI , 46 to 57 ] ; hazard ratio , 0.84 [ 95 % CI , 0.78 to 0.91 ] , representing a 16 % lower risk ; P<0.001 ) . The annual rate of moderate or severe exacerbations was lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group ( 0.98 vs. 1.19 ; rate ratio , 0.83 ; 95 % CI , 0.75 to 0.91 ; P<0.001 ) , and the time to the first moderate or severe exacerbation was longer in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group ( hazard ratio , 0.78 ; 95 % CI , 0.70 to 0.86 ; P<0.001 ) , as was the time to the first severe exacerbation ( hazard ratio , 0.81 ; 95 % CI , 0.66 to 1.00 ; P=0.046 ) . The effect of indacaterol-glycopyrronium versus salmeterol-fluticasone on the rate of COPD exacerbations was independent of the baseline blood eosinophil count . The incidence of adverse events and deaths was similar in the two groups . The incidence of pneumonia was 3.2 % in the indacaterol-glycopyrronium group and 4.8 % in the salmeterol-fluticasone group ( P=0.02 ) . CONCLUSIONS Indacaterol-glycopyrronium was more effective than salmeterol-fluticasone in preventing COPD exacerbations in patients with a history of exacerbation during the previous year . ( Funded by Novartis ; FLAME Clinical Trials.gov number , NCT01782326 . )
OBJECTIVES Inhaled corticosteroids ( ICS ) reduce exacerbation rates and the decline in lung function in people with chronic obstructive pulmonary disease ( COPD ) .
There is evidence that smoking causes ' steroid resistance ' and thus reduces the effect of ICS .
This systematic review aim ed to investigate the effect of smoking on efficacy of ICS in COPD in terms of lung function and exacerbation rates .