ORIGINAL RESEARCH Pneumonia Risk with Inhaled Fluticasone Furoate and Vilanterol Compared with Vilanterol Alone in Patients with COPD Courtney Crim1, Mark T. Dransfield2, Jean Bourbeau3, Paul W. Jones4, Nicola A. Hanania5, Donald A. Mahler6, Jørgen Vestbo7,8,9, Andrew Wachtel10, Fernando J. Martinez11, Frank Barnhart1, Sally Lettis12, and Peter M. A. Calverley13 1
GSK, Research Triangle Park, North Carolina; 2Lung Health Center, University of Alabama at Birmingham, Birmingham, Alabama; 3McGill University, Montreal, Quebec, Canada; 4St. George’s, University of London, London, United Kingdom; 5Baylor College of Medicine, Houston, Texas; 6Geisel School of Medicine at Dartmouth, Hanover, New Hampshire; 7Gentofte Hospital, Hellerup, Denmark; 8Odense University Hospital/University of Southern Denmark, Odense, Denmark; 9Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom; 10Southern California Institute for Respiratory Diseases, Los Angeles, California; 11University of Michigan, Ann Arbor, Michigan; 12GSK, Stockley Park, London, United Kingdom; and 13University of Liverpool, Liverpool, United Kingdom
Abstract Rationale: Radiographically confirmed pneumonia risk with inhaled corticosteroid use in chronic obstructive pulmonary disease (COPD) has not been assessed to date. Objectives: To determine the incidence of pneumonia, risk factors, and clinical attributes with inhaled fluticasone furoate (FF) in patients with COPD with an exacerbation history. Methods: Two replicate, 1-year, double-blind clinical trials enrolled subjects with COPD with moderate to very severe airflow limitation and at least one exacerbation within the prior year. Subjects were randomized 1:1:1:1 to receive inhaled once-daily vilanterol (VI) 25 mg or VI 25 mg combined with 50, 100, or 200 mg FF. Subjects were required to have a chest radiograph at screening and within 48 hours of any suspected pneumonia or exacerbation. Measurements and Main Results: Among 3,255 randomized subjects, 205 pneumonia events occurred in 181 subjects. Chest
imaging was available for 195 (95%) of these events. Chest radiographs were also obtained for 1,793 (70%) of the 2,545 moderate and severe exacerbations. For VI alone and the combination with 50, 100, or 200 mg FF, reported pneumonia incidence was 3, 6, 6, and 7%, respectively. However, for events with compatible parenchymal infiltrates, the respective incidences were 2, 4, 4, and 5%. Factors associated with at least a twofold increase in the risk of pneumonia with FF/VI treatment were being a current smoker, having prior pneumonia, body mass index ,25 kg/m2, and severe airflow limitation. Conclusions: Radiographically confirmed pneumonia risk is increased with inhaled FF/VI, although at less than investigatordefined rates. Modifiable pneumonia risk factors should be considered when attempting to optimize COPD management. Clinical trial registered with www.clinicaltrials.gov (NCT01009463 [HZC102871]; NCT01017952 [HZC102970]). Keywords: chronic obstructive pulmonary disease; corticosteroids; pneumonia
(Received in original form September 4, 2014; accepted in final form November 11, 2014 ) Supported by GSK. Author Contributions: C.C., J.B., J.V., F.J.M., F.B., S.L., P.M.A.C.: study conception and design; C.C., M.T.D., J.B., P.W.J., N.A.H., J.V., A.W., F.J.M., F.B., S.L., P.M.A.C.: analysis and interpretation; C.C., M.T.D., J.B., P.W.J., N.A.H., D.A.M., J.V., A.W., F.J.M., F.B., S.L., P.M.A.C.: drafting the manuscript for important intellectual content. Correspondence and requests for reprints should be sent to Courtney Crim, M.D., Respiratory Therapeutic Area Unit, GSK, Five Moore Drive, 5.3317.3A, Research Triangle Park, NC 27709-3398. E-mail: [email protected] This article has an online supplement, which is available from the issue’s table of contents at www.atsjournals.org Ann Am Thorac Soc Vol 12, No 1, pp 27–34, Jan 2015 Copyright © 2015 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201409-413OC Internet address: www.atsjournals.org
Pneumonia causes significant morbidity and mortality, and chronic obstructive pulmonary disease (COPD) is a known risk factor (1). Risk factors for pneumonia in
patients with COPD include age .65 years, prior COPD exacerbation requiring hospitalization, dyspnea, low FEV1, and low body mass index (BMI) (2, 3). Moreover,
Crim, Dransfield, Bourbeau, et al.: Pneumonia Risk with Inhaled Steroids in COPD
COPD exacerbations associated with pneumonia have greater morbidity (worse hypoxemia, intensive care unit admissions, need for mechanical ventilation, longer 27
ORIGINAL RESEARCH hospital stays) and mortality than nonpneumonic exacerbations (4), and data from the Copenhagen City Heart study also identified age and low FEV1 as risk factors for serious and fatal pneumonia (5). Inhaled corticosteroids (ICSs) reduce the risk of COPD exacerbations but increase the probability of having a clinically defined pneumonia, although this association has not been universally reported (6, 7). A nested case–control analysis of managed care databases in the United States found no increased pneumonia risk among patients with COPD using ICSs or combination of an ICS with a long-acting b2-agonist (LABA) (8). However, we and other investigators have reported that use of ICS in patients with COPD is associated with increased risk for pneumonia and pneumonia requiring hospitalization (3, 9–11). In the TOwards a Revolution in COPD Health (TORCH) trial, the largest of the prospective studies thus far that included an ICS-containing regimen, only 72% of subjects hospitalized with presumptive pneumonia underwent chest radiography (3). Although parenchymal pathology was present in 81% of these chest radiographs, other nonpneumonic disorders were present, including lung neoplasia and congestive heart failure. A recent Cochrane review reported an increase in serious (i.e., hospitalized) pneumonia events in patients with COPD for the inhaled corticosteroids fluticasone and budesonide compared with placebo (12). However, both retrospective and prospective studies of patients with COPD have reported that, compared with non-ICS users, ICS users had no increase in morbidity or mortality (13, 14). Recently, we reported the results from two replicate studies of a new once-daily ICS/LABA combination product, fluticasone furoate and vilanterol trifenatate (FF/VI), confirming its efficacy in reducing COPD exacerbations compared with VI alone (15). In that study, we reported a doubling in the incidence of pneumonia with FF/VI compared with VI. Unlike TORCH, these studies required chest imaging in all cases of clinical pneumonia, as well as in all moderate and severe exacerbations. The objectives of the current study were to determine the incidence of radiographically confirmed pneumonia and risk factors from the previously reported trials with FF/VI in patients with COPD with an exacerbation history (15). We hypothesized that the incidence of radiographically confirmed 28
pneumonia would be lower than that previously reported.
Methods Study Design and Subjects
We performed a predefined analysis within the replicate FF/VI COPD exacerbation studies described previously (15). In brief, identical, replicate, multicenter, doubleblind, parallel-group trials compared three strengths of FF/VI (50, 100, or 200 mg of FF combined with 25 mg of VI) (corresponding to emitted FF doses of 44, 92, and 184 mg, respectively, and an emitted VI dose of 22 mg) with VI 25 mg administered once daily in the morning via the ELLIPTA dry powder inhaler (GSK, UK; ELLIPTA is a trademark of the GSK group of companies). Participants were >40 years old, had a history of COPD as defined by the American Thoracic Society and the European Respiratory Society (16), a smoking history of >10 pack-years, a post-bronchodilator FEV1/FVC ratio of 65 yr), sex, cardiovascular history/risk factors (File E6), BMI (,25, >25 kg/m2), post-bronchodilator % predicted FEV1 (,30%, 30% to ,60%, >60%), history of pneumonia within year prior to screening, geographic region, and the relationship of each factor to treatment. Each model included the subgroup factor and the interaction of the subgroup factor and treatment. Hazard ratios were obtained for each level of the subgroup factor for FF/VI compared with VI, irrespective of whether the interaction was statistically significant. A similar post hoc analysis was performed with BMI categories
of
GSK, Research Triangle Park, North Carolina; 2Lung Health Center, University of Alabama at Birmingham, Birmingham, Alabama; 3McGill University, Montreal, Quebec, Canada; 4St. George’s, University of London, London, United Kingdom; 5Baylor College of Medicine, Houston, Texas; 6Geisel School of Medicine at Dartmouth, Hanover, New Hampshire; 7Gentofte Hospital, Hellerup, Denmark; 8Odense University Hospital/University of Southern Denmark, Odense, Denmark; 9Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom; 10Southern California Institute for Respiratory Diseases, Los Angeles, California; 11University of Michigan, Ann Arbor, Michigan; 12GSK, Stockley Park, London, United Kingdom; and 13University of Liverpool, Liverpool, United Kingdom
Abstract Rationale: Radiographically confirmed pneumonia risk with inhaled corticosteroid use in chronic obstructive pulmonary disease (COPD) has not been assessed to date. Objectives: To determine the incidence of pneumonia, risk factors, and clinical attributes with inhaled fluticasone furoate (FF) in patients with COPD with an exacerbation history. Methods: Two replicate, 1-year, double-blind clinical trials enrolled subjects with COPD with moderate to very severe airflow limitation and at least one exacerbation within the prior year. Subjects were randomized 1:1:1:1 to receive inhaled once-daily vilanterol (VI) 25 mg or VI 25 mg combined with 50, 100, or 200 mg FF. Subjects were required to have a chest radiograph at screening and within 48 hours of any suspected pneumonia or exacerbation. Measurements and Main Results: Among 3,255 randomized subjects, 205 pneumonia events occurred in 181 subjects. Chest
imaging was available for 195 (95%) of these events. Chest radiographs were also obtained for 1,793 (70%) of the 2,545 moderate and severe exacerbations. For VI alone and the combination with 50, 100, or 200 mg FF, reported pneumonia incidence was 3, 6, 6, and 7%, respectively. However, for events with compatible parenchymal infiltrates, the respective incidences were 2, 4, 4, and 5%. Factors associated with at least a twofold increase in the risk of pneumonia with FF/VI treatment were being a current smoker, having prior pneumonia, body mass index ,25 kg/m2, and severe airflow limitation. Conclusions: Radiographically confirmed pneumonia risk is increased with inhaled FF/VI, although at less than investigatordefined rates. Modifiable pneumonia risk factors should be considered when attempting to optimize COPD management. Clinical trial registered with www.clinicaltrials.gov (NCT01009463 [HZC102871]; NCT01017952 [HZC102970]). Keywords: chronic obstructive pulmonary disease; corticosteroids; pneumonia
(Received in original form September 4, 2014; accepted in final form November 11, 2014 ) Supported by GSK. Author Contributions: C.C., J.B., J.V., F.J.M., F.B., S.L., P.M.A.C.: study conception and design; C.C., M.T.D., J.B., P.W.J., N.A.H., J.V., A.W., F.J.M., F.B., S.L., P.M.A.C.: analysis and interpretation; C.C., M.T.D., J.B., P.W.J., N.A.H., D.A.M., J.V., A.W., F.J.M., F.B., S.L., P.M.A.C.: drafting the manuscript for important intellectual content. Correspondence and requests for reprints should be sent to Courtney Crim, M.D., Respiratory Therapeutic Area Unit, GSK, Five Moore Drive, 5.3317.3A, Research Triangle Park, NC 27709-3398. E-mail: [email protected] This article has an online supplement, which is available from the issue’s table of contents at www.atsjournals.org Ann Am Thorac Soc Vol 12, No 1, pp 27–34, Jan 2015 Copyright © 2015 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201409-413OC Internet address: www.atsjournals.org
Pneumonia causes significant morbidity and mortality, and chronic obstructive pulmonary disease (COPD) is a known risk factor (1). Risk factors for pneumonia in
patients with COPD include age .65 years, prior COPD exacerbation requiring hospitalization, dyspnea, low FEV1, and low body mass index (BMI) (2, 3). Moreover,
Crim, Dransfield, Bourbeau, et al.: Pneumonia Risk with Inhaled Steroids in COPD
COPD exacerbations associated with pneumonia have greater morbidity (worse hypoxemia, intensive care unit admissions, need for mechanical ventilation, longer 27
ORIGINAL RESEARCH hospital stays) and mortality than nonpneumonic exacerbations (4), and data from the Copenhagen City Heart study also identified age and low FEV1 as risk factors for serious and fatal pneumonia (5). Inhaled corticosteroids (ICSs) reduce the risk of COPD exacerbations but increase the probability of having a clinically defined pneumonia, although this association has not been universally reported (6, 7). A nested case–control analysis of managed care databases in the United States found no increased pneumonia risk among patients with COPD using ICSs or combination of an ICS with a long-acting b2-agonist (LABA) (8). However, we and other investigators have reported that use of ICS in patients with COPD is associated with increased risk for pneumonia and pneumonia requiring hospitalization (3, 9–11). In the TOwards a Revolution in COPD Health (TORCH) trial, the largest of the prospective studies thus far that included an ICS-containing regimen, only 72% of subjects hospitalized with presumptive pneumonia underwent chest radiography (3). Although parenchymal pathology was present in 81% of these chest radiographs, other nonpneumonic disorders were present, including lung neoplasia and congestive heart failure. A recent Cochrane review reported an increase in serious (i.e., hospitalized) pneumonia events in patients with COPD for the inhaled corticosteroids fluticasone and budesonide compared with placebo (12). However, both retrospective and prospective studies of patients with COPD have reported that, compared with non-ICS users, ICS users had no increase in morbidity or mortality (13, 14). Recently, we reported the results from two replicate studies of a new once-daily ICS/LABA combination product, fluticasone furoate and vilanterol trifenatate (FF/VI), confirming its efficacy in reducing COPD exacerbations compared with VI alone (15). In that study, we reported a doubling in the incidence of pneumonia with FF/VI compared with VI. Unlike TORCH, these studies required chest imaging in all cases of clinical pneumonia, as well as in all moderate and severe exacerbations. The objectives of the current study were to determine the incidence of radiographically confirmed pneumonia and risk factors from the previously reported trials with FF/VI in patients with COPD with an exacerbation history (15). We hypothesized that the incidence of radiographically confirmed 28
pneumonia would be lower than that previously reported.
Methods Study Design and Subjects
We performed a predefined analysis within the replicate FF/VI COPD exacerbation studies described previously (15). In brief, identical, replicate, multicenter, doubleblind, parallel-group trials compared three strengths of FF/VI (50, 100, or 200 mg of FF combined with 25 mg of VI) (corresponding to emitted FF doses of 44, 92, and 184 mg, respectively, and an emitted VI dose of 22 mg) with VI 25 mg administered once daily in the morning via the ELLIPTA dry powder inhaler (GSK, UK; ELLIPTA is a trademark of the GSK group of companies). Participants were >40 years old, had a history of COPD as defined by the American Thoracic Society and the European Respiratory Society (16), a smoking history of >10 pack-years, a post-bronchodilator FEV1/FVC ratio of 65 yr), sex, cardiovascular history/risk factors (File E6), BMI (,25, >25 kg/m2), post-bronchodilator % predicted FEV1 (,30%, 30% to ,60%, >60%), history of pneumonia within year prior to screening, geographic region, and the relationship of each factor to treatment. Each model included the subgroup factor and the interaction of the subgroup factor and treatment. Hazard ratios were obtained for each level of the subgroup factor for FF/VI compared with VI, irrespective of whether the interaction was statistically significant. A similar post hoc analysis was performed with BMI categories
of
