human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    
agent
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    