Blood eosinophils as a marker of response to inhaled corticosteroids in COPD Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial. Once‐Daily Single‐Inhaler Triple versus Dual Therapy in Patients with COPD The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Fluticasone propionate/formoterol for COPD management: a randomized controlled trial Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial How representative are clinical study patients with asthma or COPD for a larger "real life" population of patients with obstructive lung disease? Long‐Term Triple Therapy De‐escalation to Indacaterol/Glycopyrronium in Patients with Chronic Obstructive Pulmonary Disease (SUNSET): A Randomized, Double‐Blind, Triple‐Dummy Clinical Trial Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials. Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials. Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial. Blood eosinophilia, use of inhaled corticosteroids, and risk of COPD exacerbations and mortality Comparative Effectiveness and Safety of LABA-LAMA vs LABA-ICS Treatment of COPD in Real-World Clinical Practice. Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial Blood Eosinophils and Response to Maintenance Chronic Obstructive Pulmonary Disease Treatment. Data from the FLAME Trial
Identification of a biomarker that predicts response to inhaled corticosteroids ( ICS ) would help evaluate the risk/benefit profile of ICS in chronic obstructive pulmonary disease ( COPD ) and guide treatment . The ISOLDE study r and omised 751 patients ( mean post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) 1.4 L : 50 % predicted normal ) to fluticasone propionate 500 μg twice daily or placebo for 3 years , finding no difference in FEV1 rate of decline between treatments ( p=0.16 ) and a significant reduction in median exacerbation rate with fluticasone propionate versus placebo ( p=0.026 ) . We re-analysed ISOLDE results by baseline blood eosinophil count to investigate whether eosinophil level predicts ICS benefit . Patients with eosinophils < 2 % ( n=456 ) had a similar rate of post-bronchodilator FEV1 decline  with fluticasone propionate as placebo ( –2.9 mL·year−1 ; p=0.688 ) . With eosinophils ≥2 % ( n=214 ) , the rate of decline decreased by 33.9 mL·year−1 with fluticasone propionate versus placebo ( p=0.003 ) . Exacerbation rate reduction on ICS  for fluticasone propionate versus placebo was higher in the eosinophil < 2 % group compared with the ≥2 % group ; time-to-first moderate/severe exacerbation was not different between treatments in either group . A baseline blood eosinophil count of ≥2 % identifies a group of COPD patients with slower rates of decline in FEV1 when treated with ICS : prospect i ve testing of this hypothesis is now warranted . Blood eosinophil level identifies COPD patients showing a slower rate of lung function decline when treated with ICS BACKGROUND Evidence is scarce on the relative risk-benefit of inhaled triple therapy , consisting of inhaled corticosteroid , long-acting muscarinic antagonist , and long-acting β2-agonist , versus dual bronchodilation for chronic obstructive pulmonary disease ( COPD ) . We aim ed to compare a single-inhaler triple combination of beclometasone dipropionate , formoterol fumarate , and glycopyrronium ( BDP/FF/G ) versus a single-inhaler dual bronchodilator combination of indacaterol plus glycopyrronium ( IND/GLY ) in terms of the rate of moderate-to-severe COPD exacerbations over 52 weeks of treatment . METHODS This r and omised , parallel-group , double-blind , double-dummy study was done at 187 sites across 17 countries . Eligible patients had symptomatic COPD , severe or very severe airflow limitation , at least one moderate or severe exacerbation in the previous year , and were receiving inhaled maintenance medication . After a 2 week run-in period with one inhalation per day of IND/GLY ( 85 μg/43 μg ) , patients were r and omly assigned ( 1:1 ) , via an interactive response technology system , to receive 52 weeks of treatment with two inhalations of extrafine BDP/FF/G ( 87 μg/5 μg/9 μg ) twice per day or one inhalation of IND/GLY ( 85 μg/43 μg ) per day . R and omisation was stratified by country and severity of airflow limitation . The primary endpoint was the rate of moderate-to-severe COPD exacerbations across 52 weeks of treatment in all r and omised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment . Safety was assessed in all patients who received at least one dose of study drug . This study is registered with Clinical Trials.gov , number NCT02579850 . FINDINGS Between May , 29 2015 , and July 10 , 2017 , 1532 patients received BDP/FF/G ( n=764 ) or IND/GLY ( n=768 ) . Moderate-to-severe exacerbation rates were 0·50 per patient per year ( 95 % CI 0·45 - 0·57 ) for BDP/FF/G and 0·59 per patient per year ( 0·53 - 0·67 ) for IND/GLY , giving a rate ratio of 0·848 ( 0·723 - 0·995 , p=0·043 ) in favour of BDP/FF/G. Adverse events were reported by 490 ( 64 % ) of 764 patients receiving BDP/FF/G and 516 ( 67 % ) of 768 patients receiving IND/GLY . Pneumonia occurred in 28 ( 4 % ) patients receiving BDP/FF/G versus 27 ( 4 % ) patients receiving IND/GLY . One treatment-related serious adverse event occurred in each group : dysuria in a patient receiving BDP/FF/G and atrial fibrillation in a patient receiving IND/GLY . INTERPRETATION In patients with symptomatic COPD , severe or very severe airflow limitation , and an exacerbation history despite maintenance therapy , extrafine BDP/FF/G significantly reduced the rate of moderate-to-severe exacerbations compared with IND/GLY , without increasing the risk of pneumonia . FUNDING Chiesi Farmaceutici BACKGROUND Findings from previous studies showed that mepolizumab significantly reduces the rate of exacerbations in patients with severe eosinophilic asthma . To assess the relationship between baseline blood eosinophil counts and efficacy of mepolizumab we did a secondary analysis of data from two studies , stratifying patients by different baseline blood eosinophil thresholds . METHODS We did a post-hoc analysis of data , which was completed on Sept 25 , 2015 , from two r and omised , double-blind , placebo-controlled studies of at least 32 weeks duration ( NCT01000506 [ DREAM ] and NCT01691521 [ MENSA ] ) done between 2009 and 2014 . In these studies , mepolizumab ( DREAM 75 mg , 250 mg , or 750 mg intravenously ; MENSA : 75 mg intravenously or 100 mg subcutaneously ) versus placebo was given at 4-week intervals in addition to st and ard care ( high-dose inhaled corticosteroids plus ≥1 additional controller with or without daily oral corticosteroids ) to patients aged 12 years or older with a clinical diagnosis of asthma , a history of at least two exacerbations in the previous year that required systemic corticosteroid treatment , and evidence of eosinophilic airway inflammation . The primary endpoint in both studies was the annual rate of clinical ly significant exacerbations ( defined as worsening of asthma that required the use of systemic corticosteroids , or admission to hospital , or an emergency-room visit , or a combination of these occurrences ) . In our analysis , the primary outcome was the annualised rate of exacerbations in patients stratified by baseline eosinophil counts ( ≥150 cells per μL , ≥300 cells per μL , ≥400 cells per μL , and ≥500 cells per μL ) and baseline blood eosinophil ranges ( < 150 cells per μL , ≥150 cells per μL to < 300 cells per μL , ≥300 cells per μL to < 500 cells per μL , and ≥500 cells per μL ) . We based our analysis on the intention-to-treat population s of the two original studies , and all mepolizumab doses were combined for analysis . FINDINGS Of 1192 patients , 846 received mepolizumab and 346 received placebo  . The overall rate of mean exacerbations per person per year was reduced from 1·91 with placebo to 1·01 with mepolizumab ( 47 % reduction ; rate ratio [ RR ] 0·53 , 95 % CI 0·44 - 0·62 ; p<0·0001 ) . The exacerbation rate reduction  with mepolizumab versus placebo increased progressively from 52 % ; 0·48 , 0·39 - 0·58 ) in patients with a baseline blood eosinophil count of at least 150 cells per μL to 70 % ; 0·30 , 0·23 - 0·40 ] ) in patients with a baseline count of at least 500 cells per μL. At a baseline count less than 150 cells per μL , predicted efficacy of mepolizumab was reduced . INTERPRETATION Our analysis has shown a close relationship between baseline blood eosinophil count and clinical efficacy of mepolizumab in patients with severe eosinophilic asthma and a history of exacerbations . We noted clinical ly relevant reductions in exacerbation frequency in patients with a count of 150 cells per μL or more at baseline . The use of this baseline biomarker will help to select patients who are likely to achieve important asthma outcomes with mepolizumab . FUNDING GlaxoSmithKline BACKGROUND Blood eosinophil counts might predict response to inhaled corticosteroids ( ICS ) in patients with chronic obstructive pulmonary disease ( COPD ) and a history of exacerbations . We used data from the WISDOM trial to assess whether patients with COPD with higher blood eosinophil counts would be more likely to have exacerbations if ICS treatment was withdrawn . METHODS WISDOM was a 12-month , r and omised , parallel-group trial in which patients received 18 μg tiotropium , 100 μg salmeterol , and 1000 μg fluticasone propionate daily for 6 weeks and were then r and omly assigned ( 1:1 ) electronically to receive either continued or reduced ICS over 12 weeks . We did a post-hoc analysis after complete ICS withdrawal ( months 3 - 12 ) to compare rate of exacerbations and time to exacerbation outcomes on the basis of blood eosinophil subgroups of increasing cutoff levels . The WISDOM trial is registered at Clinical Trials.gov , number NCT00975195 . FINDINGS In the 2296 patients receiving treatment after ICS withdrawal  , moderate or severe exacerbation rate  was higher in the ICS-withdrawal group versus the ICS-continuation group in patients with eosinophil counts ( out of total white blood cell count ) of 2 % or greater ( rate ratio 1·22 [ 95 % CI 1·02 - 1·48 ] ) , 4 % or greater ( 1·63 [ 1·19 - 2·24 ] ) , and 5 % or greater ( 1·82 [ 1·20 - 2·76 ] ) . The increase in exacerbation rate became more pronounced as the eosinophil cutoff level rose , with significant treatment-by-subgroup interaction reached for 4 % and 5 % only . Similar results were seen with eosinophil cutoffs of 300 cells per μL and 400 cells per μL , and mutually exclusive subgroups . INTERPRETATION Blood eosinophil counts at screening were related to the exacerbation rate after complete ICS withdrawal in patients with severe to very severe COPD and a history of exacerbations . Our data suggest that counts of 4 % or greater or 300 cells per μL or more might identify a deleterious effect of ICS withdrawal , an effect not seen in most patients with eosinophil counts below these thresholds . FUNDING Boehringer Ingelheim BACKGROUND The benefits of triple therapy for chronic obstructive pulmonary disease ( COPD ) with an inhaled glucocorticoid , a long‐acting muscarinic antagonist ( LAMA ) , and a long‐acting β2‐agonist ( LABA ) , as compared with dual therapy ( either inhaled glucocorticoid – LABA or LAMA – LABA ) , are uncertain . METHODS In this r and omized trial involving 10,355 patients with COPD , we compared 52 weeks of a once‐daily combination of fluticasone furoate ( an inhaled glucocorticoid ) at a dose of 100 μg , umeclidinium ( a LAMA ) at a dose of 62.5 μg , and vilanterol ( a LABA ) at a dose of 25 μg ( triple therapy ) with fluticasone furoate – vilanterol ( at doses of 100 μg and 25 μg , respectively ) and umeclidinium – vilanterol ( at doses of 62.5 μg and 25 μg , respectively ) . Each regimen was administered in a single Ellipta inhaler . The primary outcome was the annual rate of moderate or severe COPD exacerbations during treatment . RESULTS The rate of moderate or severe exacerbations in the triple‐therapy group was 0.91 per year , as compared with 1.07 per year in the fluticasone furoate – vilanterol group ( rate ratio with triple therapy , 0.85 ; 95 % confidence interval [ CI ] , 0.80 to 0.90 ; 15 % difference ; P<0.001 ) and 1.21 per year in the umeclidinium – vilanterol group ( rate ratio with triple therapy , 0.75 ; 95 % CI , 0.70 to 0.81 ; 25 % difference ; P<0.001 ) . The annual rate of severe exacerbations result ing in hospitalization in the triple‐therapy group was 0.13 , as compared with 0.19 in the umeclidinium – vilanterol group ( rate ratio , 0.66 ; 95 % CI , 0.56 to 0.78 ; 34 % difference ; P<0.001 ) . There was a higher incidence of pneumonia in the inhaled‐glucocorticoid groups than in the umeclidinium – vilanterol group , and the risk of clinician‐diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium – vilanterol , as assessed in a time‐to‐first‐event analysis ( hazard ratio , 1.53 ; 95 % CI , 1.22 to 1.92 ; P<0.001 ) . CONCLUSIONS Triple therapy with fluticasone furoate , umeclidinium , and vilanterol result ed in a lower rate of moderate or severe COPD exacerbations than fluticasone furoate – vilanterol or umeclidinium – vilanterol in this population . Triple therapy also result ed in a lower rate of hospitalization due to COPD than umeclidinium – vilanterol . ( Funded by GlaxoSmithKline ; IMPACT Clinical Trials.gov number , NCT02164513 . Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Purpose To evaluate fluticasone propionate/formoterol ( FP/FORM ) in COPD . Patients and methods COPD patients with forced expiratory volume in 1 s ( FEV1 ) ≤50 % predicted and ≥1 moderate/severe COPD exacerbation in the last 12 months were r and omized to FP/FORM 500/20 or 250/10 µg bid , or formoterol ( FORM ) 12 µg bid for 52 weeks . The primary outcome was the annualized rate of moderate/severe COPD exacerbations . Results In total , 1,765 patients were r and omized . There were fewer discontinuations with FP/FORM 500/20 µg ( 20.6 % ) and 250/10 µg ( 24.0 % ) compared with FORM ( 26.1 % ) . None of the two FP/FORM doses reduced the moderate/severe exacerbation rate versus FORM ( rate ratios [ RR ] : 0.93 ; P≤0.402 ) . There was a trend toward a lower moderate/severe exacerbation rate with FP/FORM 500/20 µg versus FORM in patients with ≥2 exacerbations in the preceding year ( RR : 0.79 ; P=0.084 ) . Pre- and post-dose FEV1 and forced vital capacity were greater with FP/FORM 500/20 µg versus FORM ( P≤0.039 ) . There was a trend toward a lower EXAcerbations of Chronic pulmonary disease Tool ( EXACT ) exacerbation rate with FP/FORM 500/20 µg versus FORM ( RR : 0.87 ; P=0.077 ) . There were more St George ’s Respiratory Question naire for COPD ( SGRQ-C ) responders with FP/FORM 500/20 µg than FORM ( odds ratios [ OR ] at weeks 6 , 23 and 52 ≥1.28 ; P≤0.054 ) . EXACT-respiratory symptoms total and breathlessness scores were lower with both FP/FORM 500/20 µg and 250/10 µg versus FORM ( P≤0.066 ) . Acute β2-agonist-induced effects and 24-hour Holter findings were similar for all treatments . Mean 24-hour urinary cortisol was similarly reduced with both FP/FORM doses . Radiologically confirmed pneumonia was seen in 2.4 % , 3.2 % and 1.5 % of FP/FORM 500/20 µg , FP/FORM 250/10 µg and FORM-treated patients , respectively . Adverse events were otherwise similar across treatment groups . Conclusion FP/FORM did not reduce exacerbation rates versus FORM . Numerical benefits were observed with FP/FORM 500/20 µg versus FORM for secondary variables , including lung function , EXACT exacerbations , SGRQ-C and EXACT-respiratory symptoms total and breathlessness scores . Few efficacy differences were evident between FP/FORM 250/10 µg and FORM . Pneumonia was more frequent in FP/FORM-treated patients , although the absolute difference was low . Adverse events were otherwise similar between treatments Evidence suggests that eosinophilic airway inflammation is important in the pathogenesis of severe chronic obstructive pulmonary disease ( COPD ) exacerbations . The present authors tested the hypothesis that a management strategy that aims to reduce sputum eosinophil counts is associated with a reduction in exacerbations of COPD . A total of 82 patients with COPD were r and omised into two groups . One group was treated according to traditional guidelines ( British Thoracic Society ( BTS ) group ) and the other ( sputum group ) was treated with the additional aim of minimising eosinophilic airway inflammation , assessed using the induced sputum eosinophil count . The primary outcome was exacerbations , which were categorised as mild , moderate or severe . The frequency of severe exacerbations per patient per year was 0.5 and 0.2 in the BTS and sputum groups , respectively ( mean reduction 62 % ) . The majority of this benefit was confined to patients with eosinophilic airway inflammation .  There was no difference in the frequency of mild and moderate exacerbations . The average daily dose of inhaled or oral corticosteroids during the trial did not differ between the groups . Out of 42 patients in the sputum group , 17 required regular oral corticosteroids to minimise eosinophilic airway inflammation . A management strategy that aims to minimise eosinophilic airway inflammation , as well as symptoms , is associated with a reduction in severe exacerbations of chronic obstructive pulmonary disease Evidence -based medicine is a corner stone in treatment decision making and large r and omised , clinical trials are usually design ed in order to provide highly significant results . This study was conducted in order to find out to what extend a " real life " patient population with obstructive lung disease could fit into criteria commonly used in clinical research trials . As a secondary aim of the study , we wanted to compare the OLD population recruited from GP 's and specialist outpatient clinics , respectively . Eight-hundred and seventy prospect i ve OLD patients were included . Criteria 's for selecting asthma patients to a clinical trial were , absence of co-morbidity , FEV 50 - 85 % of predicted , present or historical reversibility 12 % last year , non-smoke or if ex-smoke a smoke burden less then 10 pack years . Only 5.4 % of the study asthma patients met with these criteria . Additional criteria as being symptomatic and regular use of inhaled corticosteroids reduced the numbers of eligible asthma patients to 3.3 % representing 1.3 % of the entire population . The same procedure was applied for the COPD patients , requesting a FEV1 < 70 % of predicted normal , significant smoke history ( > 15 pack years ) and absence of atopy . This selected 17 % of the COPD population , representing 7 % of the entire population . We conclude that " evidence based " treatment decisions for OLD are based on studies which include a very small and highly selected fraction of this patient population . It is question able whether such data can extrapolated to a larger , " real life " population of patients with obstructive lung disease . Moreover , we found surprisingly minor differences between the Specialist and GP population & NA ; Rationale : There are no studies on withdrawal of inhaled corticosteroids in patients on long‐term triple therapy in the absence of frequent exacerbations . Objectives : To evaluate the efficacy and safety of direct de‐escalation from long‐term triple therapy to indacaterol/glycopyrronium in nonfrequently exacerbating patients with chronic obstructive pulmonary disease ( COPD ) . Methods : This 26‐week , r and omized , double‐blind , triple‐dummy study assessed the direct change from long‐term triple therapy to indacaterol/glycopyrronium ( 110/50 & mgr;g once daily ) or continuation of triple therapy ( tiotropium [ 18 & mgr;g ] once daily plus combination of salmeterol/fluticasone propionate [ 50/500 & mgr;g ] twice daily ) in nonfrequently exacerbating patients with moderate‐to‐severe COPD . Primary endpoint was noninferiority on change from baseline in trough FEV1 . Moderate or severe exacerbations were predefined secondary endpoints . Measurements and Main Results : A total of 527 patients were r and omized to  indacaterol/glycopyrronium and 526 to triple therapy . Inhaled corticosteroids withdrawal led to a reduction in trough FEV1 of −26 ml ( 95 % confidence interval , −53 to 1 ml ) with confidence limits exceeding the noninferiority margin of −50 ml . The annualized rate of moderate or severe COPD exacerbations did not differ between treatments ( rate ratio , 1.08 ; 95 % confidence interval , 0.83 to 1.40 ) . Patients with ≥300 blood eosinophils/&mgr;l at baseline presented greater lung function loss and higher exacerbation risk . Adverse events were similar in the two groups . Conclusions : In patients with COPD without frequent exacerbations on long‐term triple therapy  , the direct de‐escalation to indacaterol/glycopyrronium led to a small decrease in lung function , with no difference in exacerbations . The higher exacerbation risk in patients with ≥300 blood eosinophils/&mgr;l suggests that these patients are likely to benefit from triple therapy . Clinical trial registered with www . clinical trials.gov ( NCT 02603393 ) BACKGROUND The short-term benefits of inhaled corticosteroids for patients with chronic obstructive pulmonary disease ( COPD ) are greater in patients with evidence of eosinophilic airway inflammation . We investigated whether blood eosinophil count is a useful biomarker of the long-term effect of the inhaled corticosteroid fluticasone furoate on exacerbation frequency . METHODS We did a post-hoc analysis of data from two replicate , r and omised , double-blind trials of 12 months ' duration ( Sept 25 , 2009 to Oct 21 , 2011 and Oct 17 , 2011 ) in which once a day vilanterol 25 μg was compared with 25 μg vilanterol plus 50 μg , 100 μg , or 200 μg fluticasone furoate in patients with moderate-to-severe COPD and a history of one or more exacerbation in the previous year . We compared exacerbation rates according to two baseline eosinophil cell count strata ( < 2 % and ≥2 % ) , and according to four baseline percentage groupings . We also assessed lung function and incidence of pneumonia per strata in treatment groups . FINDINGS We included 3177 patients in the analyses , with 2083 patients ( 66 % ) having an eosinophil count of 2 % or higher at study entry . Across all doses of inhaled corticosteroids , fluticasone furoate and vilanterol  reduced exacerbations by 29 % compared with vilanterol alone ( mean 0·91 vs 1·28 exacerbations per patient per year ; p<0·0001 ) in patients with eosinophil counts of 2 % or higher , and by 10 % ( 0·79 vs 0·89 ; p=0·2827 ) in patients with eosinophil counts lower than 2 % . Reductions in exacerbations  with fluticasone furoate and vilanterol , compared with vilanterol alone , were 24 % in patients with baseline eosinophil counts of ≥2-<4 % , 32 % for those with counts of 4-<6 % , and 42 % for those with eosinophil counts of ≥6 % . In patients treated with vilanterol alone , exacerbation rates increased progressively with increasing eosinophil count percentage category . Improvement in trough forced expiratory volume in 1 s ( FEV1 ) and the increased risk of pneumonia  with fluticasone furoate and vilanterol compared with vilanterol alone were not associated with eosinophil count . INTERPRETATION Blood eosinophil count is a promising biomarker of response to inhaled corticosteroids in patients with COPD . Blood eosinophil count could potentially be used to stratify patients for different exacerbation rate reduction strategies . FUNDING GlaxoSmithKline ( study ID 201595 ) 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 BACKGROUND Inhaled corticosteroids have been used in patients with chronic obstructive pulmonary disease ( COPD ) , but the potential benefits of their use in triple therapy are not well known . We aim ed to compare the efficacy of a triple therapy with corresponding dual therapies in symptomatic patients with moderate to very severe COPD , without a requirement for a history of exacerbations . METHODS In this double-blind , parallel-group , multicentre phase 3 r and omised controlled trial , we recruited patients from hospitals and care centres in Canada , China , Japan , and the USA . Eligible patients were 40 - 80 years of age , were current or former smokers ( with a smoking history of ≥10 pack-years ) , had an established clinical history of COPD , and were symptomatic for COPD , despite receiving two or more inhaled maintenance therapies for at least 6 weeks before screening . We r and omly assigned patients ( 2:2:1:1 ) using an interactive web response system to receive budesonide/glycopyrrolate/formoterol fumarate metered-dose inhaler 320/18/9·6 μg ( BGF MDI ) , glycopyrrolate/ formoterol fumarate metered-dose inhaler 18/9·6 μg ( GFF MDI ) , budesonide/formoterol fumarate metered-dose inhaler 320/9·6 μg ( BFF MDI ) , or open-label budesonide/formoterol fumarate dry-powder inhaler 400/12 μg ( BUD/ FORM DPI ) . Primary endpoints for the Europe/Canada statistical analysis approach were FEV1 area under the curve from 0 - 4 h ( AUC0 - 4 ) for BGF MDI versus BFF MDI and BGF MDI versus BUD/FORM DPI over 24 weeks ; and change from baseline in morning pre-dose trough FEV1 for BGF MDI versus GFF MDI and non-inferiority of BFF MDI versus BUD/FORM DPI ( margin of -50 mL from lower bound of 95 % CI ) over 24 weeks . Comparisons with BUD/FORM DPI were made for the Europe/Canada statistical analysis approach only . This study is registered with Clinical Trials.gov , number NCT02497001 . FINDINGS Between Aug 20 , 2015 , and Jan 5 , 2018 , 3047 patients were screened from 215 sites , and 1902 were r and omly assigned to receive BGF MDI ( n=640 ) , GFF MDI ( n=627 ) , BFF MDI ( n=316 ) , or BUD/FORM DPI ( n=319 ) . Over 24 weeks , BGF MDI  significantly improved FEV1 AUC0 - 4 versus BFF MDI ( least squares mean difference 104 mL , 95 % CI 77 to 131 ; p<0·0001 ) and BUD/FORM DPI ( 91 mL , 64 to 117 ; p<0·0001  ) . BGF MDI also significantly improved pre-dose trough FEV1 versus GFF MDI ( 22 mL , 4 to 39 ; p=0·0139 ) and was non-inferior to BUD/FORM DPI ( -10 mL , -36 to 16 ; p=0·4390 ) . At week 24 , patients in the BGF MDI group had a significantly improved FEV1 AUC0 - 4 compared with patients receiving BFF MDI ( 116 mL , 95 % CI 80 to 152 ; p<0·0001 ) ; there was a non-significant improvement in the change from baseline in morning pre-dose trough FEV1 at week 24 versus GFF MDI ( 13 mL , -9 to 36 mL ; p=0·2375 ) . The most common treatment-emergent adverse events were nasopharyngitis ( n=49 [ 8 % ] in the BGF MDI group ; n=41 [ 7 % ] in the GFF MDI group ; n=26 [ 8 % ] in the BFF MDI group ; and n=30 [ 9 % ] in the BUD/FORM DPI group ) and upper respiratory tract infection ( n=65 [ 10 % ] ; n=38 [ 6 % ] ; n=18 [ 6 % ] ; and n=22 [ 7 % ] ) . Pneumonia incidence was low ( < 2 % ) and similar across treatments . There were two treatment-related deaths , both in the GFF MDI group . INTERPRETATION BGF MDI was efficacious , well tolerated , and could be a more appropriate treatment than the corresponding dual therapies for symptomatic patients with moderate to very severe COPD , irrespective of exacerbation history . FUNDING Pearl-a member of the AstraZeneca Group Abstract Purpose It remains unclear whether eosinophilia is useful for in guiding inhaled corticosteroid ( ICS ) therapy in chronic obstructive pulmonary disease ( COPD ) patients . The goal of this study is to evaluate the risk of acute exacerbations , COPD ‐related hospitalisations/accident and emergency visits , and all‐cause mortality with various levels of eosinophil counts among COPD patients using ICS . Methods A cohort study was conducted using the UK Clinical Practice Research Data link . Patients were aged 40 + and had COPD ( n = 32 693 ) . Current users of ICS were stratified by relative and absolute eosinophil counts to determine the risk of outcomes with blood eosiniphilia using Cox regression analysis . Results Among COPD patients , current use of ICS was not associated with a reduced risk of acute COPD exacerbations , COPD ‐related hospitalisations/accident and emergency visits , and all‐cause mortality . Stratification of ICS use by absolute or relative eosinophil counts did not result in significant differences in risk of COPD exacerbations or hospitalisations/accident and emergency visits . However , all‐cause mortality was reduced by 12 % to 24 % among patients with eosinophilia . Conclusions COPD ‐related acute exacerbations or hospitalisations/accident and emergency visits were not reduced with eosinophilia among users of ICS with COPD .  However , all‐cause mortality was reduced by 12 % to 24 % . These findings are potentially important and require further evaluation in prospect i ve studies BACKGROUND Long-acting β2-agonists ( LABAs ) and long-acting muscarinic antagonists ( LAMAs ) are recommended as initial maintenance treatments for COPD , with their combination ( LABA-LAMA ) advocated as the disease progresses . R and omized trials comparing the effectiveness of this combination with the alternative combination of LABA with inhaled corticosteroid ( LABA-ICS ) have reported conflicting data , while there are no real-world comparative effectiveness and safety studies of these regimens in clinical practice setting s. METHODS We identified a cohort of patients with COPD during 2002 - 2015 , age 55 years or older , from the United Kingdom 's Clinical Practice Research Data link . Patients initiating LABA-LAMA on the same day ( no ICS ) were matched on time-conditional high-dimensional propensity scores with patients initiating LABA-ICS on the same day ( no LAMA ) , and monitored for 1 year for the occurrence of a moderate or severe COPD exacerbation and severe pneumonia . RESULTS The cohort included 1,977 initiators of  LABA-LAMA matched with 1,977 initiators of LABA-ICS . The hazard ratio ( HR ) of moderate or severe COPD exacerbation associated with LABA-LAMA initiation , relative to LABA-ICS initiation , was 1.04 ( 95 % CI , 0.90 - 1.20 ) , while for a severe exacerbation it was 0.94 ( 95 % CI , 0.65 - 1.36 ) . The incidence of severe pneumonia requiring hospitalization was lower with LABA-LAMA initiation ( HR , 0.66 ; 95 % CI , 0.41 - 1.05 ) , particularly in the on-treatment analysis ( HR , 0.66 ; 95 % CI , 0.50 - 0.87 ) . CONCLUSIONS In a real-world clinical practice setting of COPD treatment , combined LABA-LAMA inhalers appear to be as effective as combined LABA-ICS inhalers in preventing COPD exacerbations . However , a LABA-LAMA combination may be preferred because it is associated with fewer severe pneumonias BACKGROUND Limited data are available for the efficacy of triple therapy with two long-acting bronchodilators and an inhaled corticosteroid in chronic obstructive pulmonary disease ( COPD ) . We compared treatment with extrafine beclometasone dipropionate , formoterol fumarate , and glycopyrronium bromide ( BDP/FF/GB ; fixed triple ) with tiotropium , and BDP/FF plus tiotropium ( open triple ) . METHODS For this double-blind , parallel-group , r and omised , controlled trial , eligible patients had COPD , post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) of less than 50 % , at least one moderate-to-severe COPD exacerbation in the previous 12 months , and a COPD Assessment Test total score of at least 10 . After a 2-week run-in period receiving one inhalation per day via single-dose dry-powder inhaler of open-label 18 μg tiotropium , patients were r and omised ( 2:2:1 ) using a interactive response technology system to 52 weeks treatment with tiotropium , fixed triple , or open triple . R and omisation was stratified by country and severity of airflow limitation . The primary endpoint was moderate-to-severe COPD exacerbation rate . The key secondary endpoint was change from baseline in pre-dose FEV1 at week 52 . The trial is registered with Clinical Trials.gov , number NCT01911364 . FINDINGS Between Jan 21 , 2014 , and March 18 , 2016 , 2691 patients received fixed triple ( n=1078 )  , tiotropium ( n=1075 ) , or open triple ( n=538 ) . Moderate-to-severe exacerbation rates were 0·46 ( 95 % CI 0·41 - 0·51 ) for fixed triple , 0·57 ( 0·52 - 0·63 ) for tiotropium , and 0·45 ( 0·39 - 0·52 ) for open triple ; fixed triple  was superior to tiotropium ( rate ratio 0·80 [ 95 % CI 0·69 - 0·92 ] ; p=0·0025 ) . For week 52 pre-dose FEV1 , fixed triple was superior to tiotropium ( mean difference 0·061 L [ 0·037 to 0·086 ] ; p<0·0001 ) and non-inferior to open triple ( -0·003L [ -0·033 to 0·027 ] ; p=0·85 ) . Adverse events were reported by 594 ( 55 % ) patients with fixed triple , 622 ( 58 % ) with tiotropium , and 309 ( 58 % ) with open triple . INTERPRETATION In our TRINITY study , treatment with extrafine fixed triple therapy  had clinical benefits compared with tiotropium  in patients with symptomatic COPD , FEV1 of less than 50 % , and a history of exacerbations . FUNDING Chiesi Farmaceutici Rationale : Post hoc analyses suggest that blood eosinophils have potential as a predictive biomarker of inhaled corticosteroid efficacy in the management of chronic obstructive pulmonary disease ( COPD ) . Objectives : We prospect ively investigated the value of blood eosinophils as a predictor of responsiveness to an inhaled corticosteroid/long‐acting & bgr;2‐agonist combination versus a long‐acting & bgr;2‐agonist/long‐acting muscarinic antagonist combination for exacerbation prevention . Methods : We conducted prespecified analyses of data from the FLAME ( Effect of Indacaterol Glycopyronium vs Fluticasone Salmeterol on COPD Exacerbations ) study , which compared once‐daily long‐acting & bgr;2‐agonist/long‐acting muscarinic antagonist indacaterol/glycopyrronium 110/50 & mgr;g with twice‐daily long‐acting & bgr;2‐agonist/inhaled corticosteroid salmeterol/fluticasone combination 50/500 & mgr;g in patients with one or more exacerbations in the preceding year . Subsequent post hoc analyses were conducted to address further cutoffs and endpoints . Measurements and Main Results : We compared treatment efficacy according to blood eosinophil percentage ( < 2 % and ≥2 % , <3 % and ≥3 % , and < 5 % and ≥5 % ) and absolute blood eosinophil count ( < 150 cells/&mgr;l , 150 to < 300 cells/&mgr;l , and ≥300 cells/&mgr;l ) . Indacaterol/glycopyrronium was significantly superior to salmeterol/fluticasone for the prevention of exacerbations ( all severities , or moderate or severe ) in the < 2 % , ≥2 % , < 3 % , < 5 % , and < 150 cells/&mgr;l subgroups , and at no cutoff was salmeterol/fluticasone superior to indacaterol/glycopyrronium . Furthermore , the rate of moderate or severe exacerbations did not increase with increasing blood eosinophils . The incidence of pneumonia was higher in patients receiving salmeterol/fluticasone than indacaterol/glycopyrronium in both the < 2 % and ≥2 % subgroups . Conclusions : Our prospect i ve analyses indicate that indacaterol/glycopyrronium provides superior or similar benefits over salmeterol/fluticasone regardless of blood eosinophil levels in patients with COPD . Clinical trial registered with www . clinical trials.gov ( NCT01782326 )
Background Blood eosinophil count has been proposed as a predictor of response to inhaled corticosteroid ( ICS ) in the prevention of acute exacerbations of COPD .
An optimal threshold of blood eosinophil count for prescribing ICS has not been agreed .
Doubt has been cast on the role by observational studies .
The role of inhaled corticosteroids in this relationship , independent of long-acting bronchodilators , has not been examined .