Roflumilast treatment in symptomatic chronic obstructive ...
Effect of fluticasone furoate and vilanterol on exacerbations of COPD in patients with moderate airflow obstructionFernando Martinez,1,2 J?rgen Vestbo,3 Julie A. Anderson,4 Robert D Brook,2 Bartolome R Celli,5 Nicholas J. Cowans6, Courtney Crim,7 Mark Dransfield8, Sally Kilbride,4 Julie Yates,7 David E Newby9, Dennis Niewoehner10*, Peter MA Calverley11* on behalf of the SUMMIT InvestigatorsDivision of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, New York, USAUniversity of Michigan Health System, Ann Arbor, Michigan, USADivision of Infection, Immunity and Respiratory Medicine, Manchester Academic Health Sciences Centre, The University of Manchester and South Manchester University Hospital NHS Foundation Trust, Manchester, UKResearch & Development, GlaxoSmithKline, Stockley Park, Middlesex, UKPulmonary and Critical Care Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA Veramed Ltd., Twickenham, UKResearch & Development, GlaxoSmithKline, Research Triangle Park, North Carolina, USAUniversity of Alabama Birmingham, Birmingham, ALA.Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UKUniversity of Minnesota, Minneapolis, MN.University of Liverpool, Department of Medicine, Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK* Co-senior authors.Address correspondence to: Fernando J. Martinez, M.D., M.S.Joan and Sanford I. Weill Department of MedicineWeill Cornell Medical CollegeNew York-Presbyterian Hospital/Weill Cornell Medical Center525 East 68th St, Room M-522 Box 130New York, NY?10065; Telephone: 212.746.6420; Email: fjm2003@med.cornell.eduRunning head: Fluticasone furoate and vilanterol for exacerbations of COPDWord count (main text,): AbstractBackground: Inhaled corticosteroids have been shown to decrease exacerbations in COPD patients with moderate to severe COPD. Their effect in patients with milder airflow obstruction remains unclear. Objective: This was an analysis of exacerbations in the Study to Understand Mortality and MorbidITy (SUMMIT) study. Design: In a double-blind randomized controlled trial, once daily inhaled placebo, fluticasone furoate (FF, 100 μg), vilanterol (VI, 25 μg) or the combination (FF/VI) was administered. The primary outcome was all-cause mortality. Exacerbations of COPD were an additional pre-defined endpoint.Setting: 1,368 centers in 43 countries.Participants: 16,485 patients with moderate COPD and heightened cardiovascular risk.Results: Compared with placebo, FF/VI reduced the rate of moderate/severe exacerbations by 29% (95% CI 22, 35; p<0.001) and the rate of hospitalized exacerbations by 27 % (95% CI 13, 39; p<0.001). These relative effects were similar regardless of whether subjects had a history of exacerbation in the year prior to the study or an FEV1 less than or ≥ 60% predicted. The number needed to treat was not influenced by baseline FEV1 but was influenced by the prior history of exacerbations. FF/VI also reduced the rate of exacerbations treated with corticosteroids alone or with corticosteroids and antibiotics but not those treated with antibiotics alone.Conclusions: Patients with moderate chronic airflow obstruction experienced a reduction in exacerbations with FF/VI, compared with placebo, irrespective of a prior history of exacerbations or baseline FEV1. Word count (max 250): 232Manuscript body word count (max 3500): 2842Key words: COPD; cardiovascular disease; fluticasone furoate; vilanterol; combination therapy, exacerbationsIntroductionChronic obstructive pulmonary disease (COPD) is a chronic syndrome that is associated with acute worsening of symptomsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZXN0Ym88L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (1). These events, exacerbations of COPD (eCOPD), have been associated with impaired health status as well as increased morbidity and mortality ADDIN EN.CITE <EndNote><Cite><Author>Pavord</Author><Year>2016</Year><RecNum>466</RecNum><DisplayText>(2)</DisplayText><record><rec-number>466</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1471187272">466</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pavord, I. D.</author><author>Jones, P. W.</author><author>Burgel, P. R.</author><author>Rabe, K. F.</author></authors></contributors><auth-address>Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Division of Clinical Science, St George's, University of London, London, UK.
Department of Respiratory Medicine, Cochin Hospital, University Paris Descartes, Sorbonne Paris Cite, Paris, France.
Department of Medicine, Christian Albrecht University, Kiel, Germany; LungenClinic, Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany.</auth-address><titles><title>Exacerbations of COPD</title><secondary-title>Int J Chron Obstruct Pulmon Dis</secondary-title></titles><periodical><full-title>Int J Chron Obstruct Pulmon Dis</full-title><abbr-1>International journal of chronic obstructive pulmonary disease</abbr-1></periodical><pages>21-30</pages><volume>11 Spec Iss</volume><keywords><keyword>Copd</keyword><keyword>biomarker</keyword><keyword>bronchodilator</keyword><keyword>exacerbation</keyword><keyword>phenotype</keyword></keywords><dates><year>2016</year></dates><isbn>1178-2005 (Electronic)
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ADDIN EN.CITE.DATA (1-3). In an effort to move towards more personalized therapy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb29kcnVmZjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb29kcnVmZjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+
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ADDIN EN.CITE.DATA (4) several investigative groups have examined the factors associated with an increased patient level risk of suffering an eCOPD; the most frequently cited is a history of previous events with two in the previous year considered the most stable and predictive PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdXJzdDwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (6). This present report describes the effects of fluticasone furoate (FF), vilanterol (VI) and their combination (FF/VI) on eCOPD, an additional pre-defined endpoint, in a COPD population with milder COPD and without a prespecified requirement of previous eCOPD where we anticipated that this therapy might be beneficial.MethodsDetails of the study design and the analysis approach were published previously ADDIN EN.CITE <EndNote><Cite><Author>Vestbo</Author><Year>2013</Year><RecNum>1977</RecNum><DisplayText>(7)</DisplayText><record><rec-number>1977</rec-number><foreign-keys><key app="EN" db-id="zxspwaaa3resrpe92v35t9scp0seaaxfdxx2">1977</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vestbo, J.</author><author>Anderson, J.</author><author>Brook, R. D.</author><author>Calverley, P. M.</author><author>Celli, B. R.</author><author>Crim, C.</author><author>Haumann, B.</author><author>Martinez, F. J.</author><author>Yates, J.</author><author>Newby, D. E.</author></authors></contributors><auth-address>Dept of Respiratory Medicine J, Odense University Hospital and University of Southern Denmark, Odense, Denmark. jvestbo@dadlnet.dk</auth-address><titles><title>The Study to Understand Mortality and Morbidity in COPD (SUMMIT) study protocol</title><secondary-title>Eur Respir J</secondary-title><alt-title>The European respiratory journal</alt-title></titles><periodical><full-title>Eur Respir J</full-title></periodical><alt-periodical><full-title>The European respiratory journal</full-title></alt-periodical><pages>1017-22</pages><volume>41</volume><number>5</number><dates><year>2013</year><pub-dates><date>May</date></pub-dates></dates><isbn>1399-3003 (Electronic)
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ADDIN EN.CITE.DATA (6). Exclusion criteria included respiratory disorders other than COPD, lung reduction surgery, receiving long-term oxygen or oral corticosteroid therapy, severe heart failure (New York Heart Association Class IV or ejection fraction <30%) and life expectancy <3 years ADDIN EN.CITE <EndNote><Cite><Author>Vestbo</Author><Year>2013</Year><RecNum>1977</RecNum><DisplayText>(7)</DisplayText><record><rec-number>1977</rec-number><foreign-keys><key app="EN" db-id="zxspwaaa3resrpe92v35t9scp0seaaxfdxx2">1977</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vestbo, J.</author><author>Anderson, J.</author><author>Brook, R. D.</author><author>Calverley, P. M.</author><author>Celli, B. R.</author><author>Crim, C.</author><author>Haumann, B.</author><author>Martinez, F. J.</author><author>Yates, J.</author><author>Newby, D. E.</author></authors></contributors><auth-address>Dept of Respiratory Medicine J, Odense University Hospital and University of Southern Denmark, Odense, Denmark. jvestbo@dadlnet.dk</auth-address><titles><title>The Study to Understand Mortality and Morbidity in COPD (SUMMIT) study protocol</title><secondary-title>Eur Respir J</secondary-title><alt-title>The European respiratory journal</alt-title></titles><periodical><full-title>Eur Respir J</full-title></periodical><alt-periodical><full-title>The European respiratory journal</full-title></alt-periodical><pages>1017-22</pages><volume>41</volume><number>5</number><dates><year>2013</year><pub-dates><date>May</date></pub-dates></dates><isbn>1399-3003 (Electronic)
0903-1936 (Linking)</isbn><accession-num>23018908</accession-num><urls><related-urls><url>;(7). Participants were allocated equally to one of four treatments (placebo, fluticasone furoate (FF, 100 μg; GlaxoSmithKline), vilanterol (VI, 25 ?g; GlaxoSmithKline) or the combination of fluticasone furoate and vilanterol (100/25 μg; FF/VI, Relvar?/Breo?, GlaxoSmithKline)) administered once daily as a dry powder with the use of an inhaler (Ellipta?, GlaxoSmithKline). Exacerbations were assessed every 3 months and at the end of study treatment.Outcome MeasurementsECOPD were a pre-defined outcome. COPD exacerbations were defined by use of treatment for increased respiratory symptoms in the judgment of the investigator. Treatment was based on events reported by the subject. Moderate exacerbations were defined as a symptomatic deterioration treated with antibiotic agents (AB) and/or systemic corticosteroids (SCS), whereas severe exacerbations of COPD were those leading to hospital admission. We had information on treatment with AB and SCS separately for moderate exacerbations, allowing analyses by exacerbation treatment. Statistical AnalysisThe analyses of time to first and rate of exacerbations to compare between treatment arms in the ITT population (moderate/severe, hospitalized and treated with SCS with or without ABI) were pre-specified while analyses of subgroups and analyses of exacerbations treated with other combinations (i.e. treated with SCS alone, ABI alone and or both SCS and ABI) were post-hoc. Event based number needed to treat (NNT) were calculated ADDIN EN.CITE <EndNote><Cite><Author>Halpin</Author><Year>2005</Year><RecNum>1003</RecNum><DisplayText>(9)</DisplayText><record><rec-number>1003</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1472313925">1003</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Halpin, D. M.</author></authors></contributors><auth-address>Department of Respiratory Medicine, Royal Devon and Exeter Hospital, Exeter, UK. david.halpin@rdehc-tr.swest.nhs.uk</auth-address><titles><title>Evaluating the effectiveness of combination therapy to prevent COPD exacerbations: the value of NNT analysis</title><secondary-title>Int J Clin Pract</secondary-title></titles><periodical><full-title>Int J Clin Pract</full-title><abbr-1>International journal of clinical practice</abbr-1></periodical><pages>1187-94</pages><volume>59</volume><number>10</number><keywords><keyword>Administration, Inhalation</keyword><keyword>Adrenergic beta-Agonists/*therapeutic use</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Bronchodilator Agents/*therapeutic use</keyword><keyword>Budesonide/therapeutic use</keyword><keyword>Data Interpretation, Statistical</keyword><keyword>Drug Combinations</keyword><keyword>Ethanolamines/therapeutic use</keyword><keyword>Female</keyword><keyword>Formoterol Fumarate</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Pulmonary Disease, Chronic Obstructive/*prevention & control</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2005</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1368-5031 (Print)
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ADDIN EN.CITE.DATA (12) we separated exacerbations into those which occurred in winter or summer.? Role of the funding sourceFunding for SUMMIT was provided by GlaxoSmithKline. Scientific oversight of the trial was provided by a scientific steering committee composed of six academic researchers and three employees from GlaxoSmithKline, who were collectively responsible for the study design and conduct, for approval of the statistical analysis plan, and for the review and interpretation of the data. Statistical analyses were performed by a contract research organization (Veramed Ltd, Twickenham, UK; funded by GSK) on behalf of, and with oversight from, employees of the sponsor.ResultsStudy PopulationA total of 16,485 patients were included in the intent-to-treat efficacy (ITT) population. The patients were 65 years of age (SD 8 years); had a post-bronchodilator FEV1 % predicted at screening of 60% (SD 6%); were predominately male (75%) and had a smoking history of 41 pack-years (SD 24 pack-years). Further information is available elsewhere PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZXN0Ym88L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (6). Approximately one third (6464, 39%) of patients reported having at least one exacerbation in the year prior to study entry. Of these, 2444 (15%) patients had 2 or more exacerbations in the year prior to study entry and 2205 (13%) experienced at least one eCOPD requiring hospitalization in the previous year.Overall effect on eCOPDThe rates of moderate/severe eCOPD are presented in Table 1. Treatment with FF/VI reduced the rate of eCOPD by 29% (95%confidence interval (CI) 22-35; p<0.001) compared with placebo (Table 1). Treatment with FF/VI reduced the rate of eCOPD by 19% (95% CI 12, 26; p<0.001) compared with FF, reflecting the contribution of VI to the combination, and reduced the rate of eCOPD by 21% (95% CI 14, 28; p<0.001) compared with VI, reflecting the contribution of FF to the combination. The risk of a first moderate/severe eCOPD was reduced with FF/VI compared with placebo by 21% (95% CI 14-27; p<0.001) (Figure 1). All other comparisons for time to first analyses are presented in Table e1.Treatment with FF/VI reduced the rate of hospitalized eCOPD by 27% (95% CI 13-39; p<0.001) compared with placebo (Table 1). Treatment with FF/VI numerically reduced the rate of hospitalized eCOPD by 11% (95% CI -6, 25; p=0.204) compared with FF, assessing the contribution of VI to the combination, and the rate of eCOPD by 9% (95% CI -8, 24; p=0.282) compared with VI, assessing the contribution of FF to the combination. The risk of a first hospitalized eCOPD was reduced with FF/VI compared with placebo by 22% (95% CI 8, 33; p=0.002) (Figure 1). All comparisons for time to first analyses are presented in Table e1. There appeared to be a higher probability of exacerbating in the winter than in the summer, although the treatment effect was very similar for the winter exacerbations as for the summer exacerbations.??Effect on eCOPD as a function of subgroups The rate ratios for the comparison of FF/VI with placebo for moderate/severe eCOPD for subgroups of interest are presented in Fig 2A. The reductions in rate of moderate/severe eCOPD were similar for all the subgroups (including baseline %predicted FEV1 cut at 60% and whether or not patients had a prior history of eCOPD or a prior history of hospitalized eCOPD). The CIs for some subgroups are wide, reflecting the small number of subjects in that group. The event based NNTs for subgroups by previous exacerbation history are enumerated in Table e2a. There was little difference in the NNT for preventing one on-treatment moderate/severe eCOPD (10 for FEV1 < 60% and 12 for FEV1 > 60% predicted) (data not shown).The rate ratios for the comparison of FF/VI with placebo for hospitalized eCOPD for subgroups of interest are presented in Fig 2B. The reductions in rate of hospitalized eCOPD were similar for most of the subgroups (including baseline %predicted FEV1 cut at 60% and whether or not patients had a prior history of eCOPD or a prior history of hospitalized eCOPD). The exception to this is for some of the race subgroups, where there were very small numbers of patients and events. The event based NNTs for the comparison of FF/VI with placebo by previous exacerbation history are enumerated in Table e2a. The rate ratios for the comparisons of FF/VI vs VI for moderate/severe eCOPD and for hospitalized eCOPD for subgroups of interest are presented in the supplement (Fig e1a, e1b, e2a and e2b). The event based NNTs for the comparison of FF/VI vs VI by previous exacerbation history are enumerated in Table e2b.Effect on eCOPDs treated with antibiotics and systemic corticosteroidsTreatment with FF/VI reduced the rate of eCOPD treated with both AB and SCS by 38%. Substantial effects were also seen for those eCOPD treated with SCS alone (61%), as well as those requiring SCS with or without AB (45%). Treatment with FF/VI did not affect eCOPD treated with AB alone (Table 2). For the eCOPD treated with SCS with or without antibiotics, FF and VI individually also reduced the rate of eCOPD compared with placebo, although to a lesser extent that FF/VI. Neither FF nor VI reduced the rate of eCOPD treated with AB alone compared with placebo (12% increase and 6% increase respectively) (table 2). DiscussionSUMMIT is the largest survival study to date of an inhaled corticosteroid and long-acting beta-agonist in patients with COPD and heightened cardiovascular riskPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZXN0Ym88L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (13-15) but the large sample size and nature of our study allowed us to identify a positive effect of treatment. Treatment with FF/VI decreased the rate of moderate to severe eCOPD and prolonged the time to the first moderate/severe eCOPD to the same relative extent independent of the baseline FEV1% predicted. The positive effect of FF/VI on exacerbation numbers was entirely due to a reduction in the rate of eCOPD requiring systemic steroids alone or eCOPD requiring systemic antibiotics and steroids. There was little effect of the combination on eCOPD requiring antibiotic therapy alone. Additional analyses suggest that this effect is more consistently driven by the ICS. Previous studies have suggested that ICS containing regimens decrease the likelihood of systemic steroid treated exacerbationsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TemFmcmFuc2tpPC9BdXRob3I+PFllYXI+MjAwMzwvWWVh
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ADDIN EN.CITE.DATA (15). Our data support the results of previous controlled trials performed in patients with generally more severe airflow obstruction PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYW5uaW5pPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48
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ADDIN EN.CITE.DATA (6). Nevertheless, the possible adverse impact on antibiotic treated eCOPD with ICS monotherapy suggests that the recommendation to avoid ICS monotherapy in COPDPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZXN0Ym88L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (1) is likely wise.Previous studies have identified different phenotypes of acute exacerbation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWZhZGhlbDwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+
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AG==
ADDIN EN.CITE.DATA (22). Particular attention has been given to the relationship between increased sputum or systemic number of eosinophils and inhaled corticosteroids responsePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXZvcmQ8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXZvcmQ8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (28). However, neither sputum nor systemic eosinophil determinations were included in SUMMIT and we cannot address this interesting question. On the other hand, some authors have suggested that sub-groups may be identified by the presenting symptom complexPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbnRob25pc2VuPC9BdXRob3I+PFllYXI+MTk4NzwvWWVh
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ADDIN EN.CITE.DATA (29, 30) and that therapeutic approaches may serve as a surrogate of the event trigger ADDIN EN.CITE <EndNote><Cite><Author>MacDonald</Author><Year>2011</Year><RecNum>975</RecNum><DisplayText>(31)</DisplayText><record><rec-number>975</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1471963331">975</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>MacDonald, M.</author><author>Beasley, R. W.</author><author>Irving, L.</author><author>Bardin, P. G.</author></authors></contributors><auth-address>Respiratory and Sleep Medicine, Monash Medical Centre, Melbourne, Australia.</auth-address><titles><title>A hypothesis to phenotype COPD exacerbations by aetiology</title><secondary-title>Respirology</secondary-title></titles><periodical><full-title>Respirology</full-title></periodical><pages>264-8</pages><volume>16</volume><number>2</number><keywords><keyword>Depression/complications</keyword><keyword>Humans</keyword><keyword>Pneumonia/complications</keyword><keyword>Pulmonary Disease, Chronic Obstructive/*classification/etiology/therapy</keyword><keyword>Pulmonary Embolism/complications</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1440-1843 (Electronic)
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ADDIN EN.CITE.DATA (32, 33). Although we did not provide explicit guidance to practitioners on how to manage individual exacerbation events, our data suggest their choice of therapy for the individual event therapy was influenced by therapy with an ICS. There is a need for more studies examining characteristics of recurrent exacerbations within individual patients and a better characterization of why clinicians choose the treatment they do to manage these events.Although SUMMIT was not powered or designed to primarily address the issue of exacerbations in patients with moderate obstruction, the results provide potential insights into how ICS based regimens could be considered in patients with COPD. The SUMMIT patient population’s milder airflow limitation and lack of enrichment for eCOPD meant that the overall rates of moderate/severe eCOPD and eCOPD requiring hospitalization were low but variable. Although NNTs must be calculated and interpreted with caution ADDIN EN.CITE <EndNote><Cite><Author>Suissa</Author><Year>2013</Year><RecNum>1863</RecNum><DisplayText>(34)</DisplayText><record><rec-number>1863</rec-number><foreign-keys><key app="EN" db-id="zxspwaaa3resrpe92v35t9scp0seaaxfdxx2">1863</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Suissa, S.</author></authors></contributors><auth-address>Centre for Clinical Epidemiology, Lady Davis Institute-Jewish General Hospital, Montreal,Quebec, Canada.</auth-address><titles><title>Number needed to treat in COPD: exacerbations versus pneumonias</title><secondary-title>Thorax</secondary-title><alt-title>Thorax</alt-title></titles><periodical><full-title>Thorax</full-title></periodical><alt-periodical><full-title>Thorax</full-title></alt-periodical><pages>540-3</pages><volume>68</volume><number>6</number><keywords><keyword>Anti-Inflammatory Agents/*therapeutic use</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Pneumonia/*drug therapy/*epidemiology</keyword><keyword>Pulmonary Disease, Chronic Obstructive/*drug therapy/*epidemiology</keyword><keyword>World Health</keyword></keywords><dates><year>2013</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1468-3296 (Electronic)
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ADDIN EN.CITE.DATA (1) baseline FEV1 does not appear to influence therapeutic responsiveness to the combination of an ICS/LABA. A previous history of exacerbations does modify the likelihood of therapeutic response to this therapeutic combination vs placebo although there was little difference in those with a history of 1 vs > 2 moderate/severe events in the previous year. This was numerically different for a history of previous hospitalized eCOPD. Additional analyses are needed to better define the optimal patient population with moderate airflow obstruction who may benefit from early therapy with a combination of an ICS/LABA. This would advance the evolving concepts of personalized therapeutic approachesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb29kcnVmZjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+
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ADDIN EN.CITE.DATA (4).Our results are limited by the negative primary endpoint of the overall SUMMIT study. As such, our results should be considered as nominal and should be interpreted with caution. We studied patients with overt or at heightened risk of cardiovascular disease but we have no reason to believe that such patients would behave differently from other COPD patients of similar severity without this burdensome co-morbidity. Indeed our data on exacerbations contrast with the negative findings of these therapies on overall and cardiac mortality suggesting that we were able to manage the respiratory problems of the patients more effectively without influencing mortality driven mainly by cardiac factors. This is in keeping with the idea that the cardiac and respiratory co-morbidity of our patients co-exist without directly interacting, at least in patients with this degree of COPD. We did identify significant numbers of people who exacerbated and were hospitalized as a result of this even among milder patients than those included in earlier clinical trials. As the general management approach moves towards a more personalized approachPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb29kcnVmZjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+
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ADDIN EN.CITE.DATA (4) these data offer new insight into the potential role of combination inhaled therapy in appropriately identified individuals. Members of the Steering CommitteeJ?rgen Vestbo (co-chair, UK), Robert Brook (USA), Peter Calverley (UK), Bartolome Celli (USA), Fernando Martinez (USA), David Newby (UK), Courtney Crim, (co-chair, GlaxoSmithKline, USA), Julie Anderson (GlaxoSmithKline, UK), Julie Yates (GlaxoSmithKline, USA).Members of the Independent Data Monitoring Committee Peter Lange (chair, Denmark), Richard Kay (UK), Mark Dransfield (USA), Sanjay Rajagopalan (USA).Members of the Clinical Endpoint CommitteeRobert Wise (chair, USA), Dennis Niewoehner (USA), Camilo Gomez (USA), Sheldon Madger (Canada), Martin Denvir (UK), Pierre Amarenco (France).Declaration of interestsDr. Vestbo reports personal fees from GlaxoSmithKline during the conduct of the study as well as personal fees from GlaxoSmithKline, Chiesi Pharmaceuticals, Boehringer-Ingelheim, Novartis, and AstraZeneca outside the submitted work. Ms. Anderson is an employee of GlaxoSmithKline and therefore reports personal fees from GlaxoSmithKline during the conduct of the study as well as outside the submitted work. Dr. Brook reports personal fees from GSK during the conduct of the study. Dr Calverley reports personal fees from GlaxoSmithKline during the conduct of the study as well as personal fees from Boehringer-Ingelheim, GSK, AstraZeneca and Takeda outside the submitted work. Dr Celli reports personal fees from GlaxoSmithKline during the conduct of the study as well as personal fees from Boehringer-Ingelheim, AstraZeneca, Almirall, Rox Medical, and Novartis outside the submitted work. Dr Crim is an employee of GlaxoSmithKline and therefore reports personal fees from GlaxoSmithKline during the conduct of the study as well as outside the submitted work. Dr. Martinez reports non-financial support from GlaxoSmithKline during the conduct of the study as well as personal fees from Forest, Janssens, Nycomed/Takeda, Actelion, Amgen, Astra Zeneca, Carden Jennings, CSA Medical, Ikaria, Genentech, Merck, Pearl, Pfizer, Roche, American College of Chest Physicians, CME Incite, Center for Healthcare Education, Inova Health System, MedScape, Miller Medical, National Association for Continuing Education, Paradigm, Peer Voice, Projects in Knowledge, St. John's Hospital, St. Mary's Hospital, University of Illinois Chicago, University of Virginia, UpToDate, Wayne State University, Boehringer Ingelheim, Bayer, Merion, Informa, GlaxoSmithKline, Western Society of Allergy and Clinical Immunology, Theravance, Novartis, Haymarket, Annenberg, Academic CME, Integritas, Unity, and Sunovion outside the submitted work. Ms. Yates is an employee of GlaxoSmithKline and therefore reports personal fees from GlaxoSmithKline during the conduct of the study as well as outside the submitted work. Dr. Newby reports personal fees from GSK during the conduct of the study. Mr. Cowans is an employee of Veramed Limited, a contract research?organisation?that receives funding from GlaxoSmithKline. Dr. Niewoehner reports personal fees from GlaxoSmithKline during the conduct of the study as well as personal fees from Boehringer-Ingelheim, AstraZeneca, and Forest Research outside the submitted work.Table 1: The effect of fluticasone furoate, vilanterol or their combination on the rate of moderate/severe eCOPD or eCOPD requiring hospitalization.Placebo(N=4111)Fluticasone furoate(N=4135)Vilanterol(N=4118)Fluticasone furoate/vilanterol(N=4121)Moderate/severe eCOPDModelled rate (exacerbations per year)0.350.310.310.25Active vs. Placebo %Reduction in rate of eCOPD (95% CI) p-value12% (4%, 19%)0.00410% (2%, 18%)0.01729% (22%, 35%)<0.001Combination vs. Component %Reduction in rate of eCOPD (95% CI) p-value19% (12%, 26%)<0.00121% (14%, 28%)<0.001eCOPD Requiring HospitalizationModelled rate (exacerbations per year)0.070.060.060.05Active vs. Placebo %Reduction in rate of eCOPD (95% CI) p-value18% (3%, 31%)0.02320% (5%, 32%)0.01327% (13%, 39%)<0.001Combination vs. Component %Reduction in rate of eCOPD (95% CI) p-value11% (-6%, 25%)0.2049% (-8%, 24%)0.282Table 2. The effect of fluticasone furoate, vilanterol, or their combination on the rate of eCOPD treated with systemic corticosteroids alone, antibiotics alone, or systemic corticosteroids plus antibiotics.Placebo(N=4111)Fluticasone furoate(N=4135)Vilanterol(N=4118)Fluticasone furoate/vilanterol(N=4121)eCOPD Treated with Systemic Corticosteroids with or without AntibioticsModelled rate (exacerbations per year)0.230.170.190.13Active vs. Placebo %Reduction in rate of eCOPD (95% CI) p-value25% (15%, 33%)<0.00118% (8%, 27%)<0.00145% (38%, 42%)<0.001Combination vs. Component %Reduction in rate of eCOPD (95% CI) p-value27% (18%, 36%)<0.00133% (24%, 41%)<0.001eCOPD Treated with Systemic Corticosteroids AloneModelled rate (exacerbations per year)0.070.040.060.03Active vs. Placebo %Reduction in rate of eCOPD (95% CI) p-value45% (32%, 56%)<0.00117% (-1%, 32%)0.06461% (51%, 69%)<0.001Combination vs. Component %Reduction in rate of eCOPD (95% CI) p-value28% (9%, 43%)0.00552% (40%, 62%)<0.001eCOPD Treated with Antibiotics AloneModelled rate (exacerbations per year)0.120.130.120.12Active vs. Placebo %Reduction in rate of eCOPD (95% CI) p-value-12% (-26%, -0%)0.049-6% (-19%, 6%)0.333-2% (-15%, 9%)0.748Combination vs. Component %Reduction in rate of eCOPD (95% CI) p-value9% (-2%, 19%)0.0954% (-8%, 14%)0.512eCOPD Treated with Both Systemic Corticosteroids and AntibioticsModelled rate (exacerbations per year)0.160.130.130.10Active vs. Placebo %Reduction in rate of eCOPD (95% CI) p-value15% (3%, 25%)0.01418% (7%, 28%)0.00238% (29%, 45%)<0.001Combination vs. Component %Reduction in rate of eCOPD (95% CI) p-value27% (17%, 36%)<0.00124% (13%, 34%)<0.001FIGURE LEGENDSFigure 1: Time to the first moderate/severe eCOPD or eCOPD requiring hospitalization for the combination of fluticasone furoate and vilanterol compared with placebo.Figure 2: The effect of the combination of fluticasone furoate and vilanterol compared with placebo on the rate of moderate/severe eCOPD (Panel A) or eCOPD requiring hospitalization (Panel B) by subgroups. Figure 1: Figure 2A.Figure 2B.References ADDIN EN.REFLIST 1.Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez-Roisin R. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: Gold executive summary. Am J Respir Crit Care Med 2013;187:347-365.2.Pavord ID, Jones PW, Burgel PR, Rabe KF. Exacerbations of copd. International journal of chronic obstructive pulmonary disease 2016;11 Spec Iss:21-30.3.Criner GJ, Bourbeau J, Diekemper RL, Ouellette DR, Goodridge D, Hernandez P, Curren K, Balter MS, Bhutani M, Camp PG, Celli BR, Dechman G, Dransfield MT, Fiel SB, Foreman MG, Hanania NA, Ireland BK, Marchetti N, Marciniuk DD, Mularski RA, Ornelas J, Road JD, Stickland MK. Executive summary: Prevention of acute exacerbation of copd: American college of chest physicians and canadian thoracic society guideline. 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Respir Res 2009;10:59.17.Szafranski W, Cukier A, Ramirez A, Menga G, Sansores R, Nahabedian S, Peterson S, Olsson H. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. The European respiratory journal 2003;21:74-81.18.Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. The European respiratory journal 2003;22:912-919.19.Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775-789.20.Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari Z, Stockley RA, Investigators I. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med 2008;177:19-26.21.Pragman AA, Kim HB, Reilly CS, Wendt C, Isaacson RE. The lung microbiome in moderate and severe chronic obstructive pulmonary disease. PLoS One 2012;7:e47305.22.Wang Z, Bafadhel M, Haldar K, Spivak A, Mayhew D, Miller BE, Tal-Singer R, Johnston SL, Ramsheh MY, Barer MR, Brightling CE, Brown JR. Lung microbiome dynamics in copd exacerbations. The European respiratory journal 2016;47:1082-1092.23.Freeman CM, Crudginton SW, Stolberg VR, McCubbrey AL, Todt JC, Brown JP, McCloskey L, Curtis JL. Glucocorticoid-augmented efferocytosis impairs host defense by alveolar macrophages of human smokers by reducing specific micrornas. Am J Respir Crit Care Med 2015;191:A5383.24.Calverley PM, Stockley RA, Seemungal TA, Hagan G, Willits LR, Riley JH, Wedzicha JA, Investigating New Standards for Prophylaxis in Reduction of Exacerbations I. Reported pneumonia in patients with copd: Findings from the inspire study. Chest 2011;139:505-512.25.Crim C, Dransfield MT, Bourbeau J, Jones PW, Hanania NA, Mahler DA, Vestbo J, Wachtel A, Martinez FJ, Barnhart F, Lettis S, Calverley PM. Pneumonia risk with inhaled fluticasone furoate and vilanterol compared with vilanterol alone in patients with copd. Ann Am Thorac Soc 2015;12:27-34.26.Iannella H, Luna C, Waterer G. Inhaled corticosteroids and the increased risk of pneumonia: What's new? A 2015 updated review. Ther Adv Respir Dis 2016;10:235-255.27.Bafadhel M, McKenna S, Terry S, Mistry V, Reid C, Haldar P, McCormick M, Haldar K, Kebadze T, Duvoix A, Lindblad K, Patel H, Rugman P, Dodson P, Jenkins M, Saunders M, Newbold P, Green RH, Venge P, Lomas DA, Barer MR, Johnston SL, Pavord ID, Brightling CE. Acute exacerbations of chronic obstructive pulmonary disease: Identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med 2011;184:662-671.28.Pavord ID, Lettis S, Locantore N, Pascoe S, Jones PW, Wedzicha JA, Barnes NC. Blood eosinophils and inhaled corticosteroid/long-acting beta-2 agonist efficacy in copd. Thorax 2016;71:118-125.29.Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987;106:196-204.30.Huerta A, Donaldson GC, Singh R, Mackay AJ, Allinson JP, Brill SE, Kowlessar B, Torres A, Wedzicha JA. Upper respiratory symptoms worsen over time and relate to clinical phenotype in chronic obstructive pulmonary disease. Ann Am Thorac Soc 2015;12:997-1004.31.MacDonald M, Beasley RW, Irving L, Bardin PG. A hypothesis to phenotype copd exacerbations by aetiology. Respirology 2011;16:264-268.32.MacDonald M, Korman T, King P, Hamza K, Bardin P. Exacerbation phenotyping in chronic obstructive pulmonary disease. Respirology 2013;18:1280-1281.33.Lopez-Campos JL, Agusti A. Heterogeneity of chronic obstructive pulmonary disease exacerbations: A two-axes classification proposal. Lancet Respir Med 2015;3:729-734.34.Suissa S. Number needed to treat in copd: Exacerbations versus pneumonias. Thorax 2013;68:540-543.35.Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, Thach C, Fogel R, Patalano F, Vogelmeier CF, Investigators F. Indacaterol-glycopyrronium versus salmeterol-fluticasone for copd. N Engl J Med 2016;374:2222-2234.Effect of Fluticasone furoate and vilanterol on exacerbations of COPD in patients with moderate airflow obstructionFernando Martinez,1,2 J?rgen Vestbo,3 Julie A. Anderson,4 Robert D Brook,2 Bartolome R Celli,5 Nicholas J. Cowans6, Courtney Crim,7 Mark Dransfield8, Sally Kilbride,4 Julie Yates,7 David E Newby9, Dennis Niewhoener10*, Peter MA Calverley11* on behalf of the SUMMIT InvestigatorsOn-Line supplementTable e1: Impact of fluticasone furoate, vilanterol or their combination on the time to first moderate/severe eCOPD or eCOPD requiring hospitalization.Placebo(N=4111)Fluticasone furoate(N=4135)Vilanterol(N=4118)Fluticasone furoate/vilanterol(N=4121)Moderate/severe eCOPDHad eCOPD, n (%)1221 (30%)1232 (30%)1176 (29%)1075 (26%)Active vs. Placebo Hazard Ratio %Reduction in risk of first eCOPD (95% CI) p-value0.973% (-5%, 10%)0.4700.919% (1%, 16%)0.0230.7921% (14%, 27%)<0.001Combination vs. Component Hazard Ratio %Reduction in risk of first eCOPD (95% CI) p-value0.8218% (11%, 25%)<0.0010.8713% (5%, 20%)0.001eCOPD Requiring HospitalizationHad eCOPD, n (%)356 (9%)321 (8%)316 (8%)300 (7%)Active vs. Placebo Hazard Ratio %Reduction in risk of first eCOPD (95% CI) p-value0.8812% (-2%, 25%)0.0860.8515% (2%, 27%)0.0310.7822% (8%, 33%)0.002Combination vs. Component Hazard ratio %Reduction in risk of first eCOPD (95% CI) p-value0.9010% (-5%, 23%)0.1730.937% (-9%, 21%)0.353Table e2a: Percent reduction in exacerbation rates for FF/VI vs Placebo by previous exacerbation history Number of PatientsCOPD Exacerbation Rate per yearExacerbation EndpointSubgroup by history of moderate/severe exacerbationsPlaceboFF/VI Placebo FF/VI% reduction (95% CI) FF/VI vs placebo Event Based NNT* FF/VI vs placebo Moderate/severeITT411141210.350.2529 (22, 35) 100 exacerbations244725280.290.2129 (20, 37)121 exacerbation10449980.390.2731 (18, 42)8≥2 exacerbations6205950.560.4226 (9, 39 )7HospitalisedITT411141210.070.0527 (13, 39) 530 exacerbations244725280.050.0430 (10, 46) 631 exacerbation10449980.070.0616 ( -18, 40)84≥2 exacerbations6205950.170.1232 (4, 51)18Treated with SCS with or without ABITT411141210.230.1345 (38, 52) 100 exacerbations244725280.190.1049 (40, 57)101 exacerbation10449980.250.1539 (23, 52)10≥2 exacerbations6205950.410.2442 (23, 56)6*NNT = Number Needed to Treat (event based), i.e. the number of patients needed to be treated for 1 year to prevent 1 additional eCOPD, calculated as 1/(rate per year on placebo – rate per year on FF/VI). Table e2b: Percent reduction in exacerbation rates for FF/VI vs VI by previous exacerbation history Number of PatientsCOPD Exacerbation Rate per yearExacerbation EndpointSubgroup by history of moderate/severe exacerbationsVIFF/VI VIFF/VI% reduction (95% CI) FF/VI vs VI Event Based NNT* FF/VI vs VI Moderate/severeITT411841210.310.2521 (14, 28) 150 exacerbations250025280.260.2119 (8, 28) 201 exacerbation9889980.360.2726 (12, 38)10≥2 exacerbations6305950.510.4218 (0, 33)11HospitalisedITT411841210.060.059 (-8, 24) 1930 exacerbations250025280.040.041 (-29, 24) 30791 exacerbation9889980.080.0620 (-12, 43)65≥2 exacerbations6305950.130.1210 (-27, 36)76Treated with SCS with or without ABITT411841210.190.1333 (24, 41) 160 exacerbations250025280.150.1032 (19, 43) 211 exacerbation9889980.230.1536 (18, 50)12≥2 exacerbations6305950.340.2430 (8, 46)10*NNT = Number Needed to Treat (event based), i.e. the number of patients needed to be treated for 1 year to prevent 1 additional eCOPD, calculated as 1/(rate per year on VI – rate per year on FF/VI). Figure e1. The effect of the combination of fluticasone furoate and vilanterol vs. vilanterol alone (Panel A) and fluticasone furoate alone (Panel B) on the rate of moderate/severe eCOPD by subgroups.B. Figure e2. The effect of the combination of fluticasone furoate and vilanterol vs. vilanterol alone (Panel A) and fluticasone furoate alone (Panel B) on the rate of eCOPD requiring hospitalization by subgroups.A.B. ................
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