Fluticasone propionate/salmeterol 250/50 μg versus salmeterol 50 μg after chronic obstructive pulmonary disease exacerbation

Jill A Ohar, Glenn D Crater, Amanda Emmett, Thomas J Ferro, Andrea N Morris, Ibrahim Raphiou, Peruvemba S Sriram, Mark T Dransfield, Jill A Ohar, Glenn D Crater, Amanda Emmett, Thomas J Ferro, Andrea N Morris, Ibrahim Raphiou, Peruvemba S Sriram, Mark T Dransfield

Abstract

Background: Inhaled long-acting beta2 agonists used alone and in combination with an inhaled corticosteroid reduce the risk of exacerbations in patients with stable COPD. However, the relative efficacy of these agents in preventing recurrent exacerbations in those recovering from an initial episode is not known. This study compared the rate of COPD exacerbations over the 26 weeks after an initial exacerbation in patients receiving the combination of fluticasone propionate and salmeterol (FP/SAL) or SAL alone.

Methods: Patients (n = 639) aged ≥40 years were randomized to either twice-daily inhaled FP/SAL 250/50 μg or SAL 50 μg. Primary, and secondary, endpoints were rates of recurrent severe, and moderate/severe, exacerbations of COPD. Lung function, health outcomes and levels of biomarkers of systemic inflammation were also assessed.

Results: There was no statistically significant treatment difference in rates of recurrent severe exacerbations (treatment ratio 0.92 [95% CI: 0.58, 1.45]) and moderate/severe exacerbations (0.82 [0.64, 1.06]) between FP/SAL and SAL in the intent-to-treat population. Pre-dose morning FEV1 change from baseline was greater (0.10 L [0.04, 0.16]) with FP/SAL than SAL. No treatment difference was seen for other endpoints including patient-reported health outcomes and biomarker levels for the full cohort.

Conclusions: No significant treatment difference between FP/SAL and SAL was seen in COPD exacerbation recurrence for the complete cohort. Treatment benefit with FP/SAL over SAL (treatment ratio 0.68 [0.47, 0.97]) was seen in patients having FEV1 ≥ 30% and prior exposure to ICS. No unexpected safety issues were identified with either treatment. Patients with the most severe COPD may be more refractory to treatment.

Trial registration: ClinicalTrials.gov (identifier NCT01110200). This study was funded by GlaxoSmithKline (study number ADC113874).

Figures

Figure 1
Figure 1
Chronological schematic of experimental design. Note: 1. Duration of index hospitalization is ≤10 days. Time from hospital discharge, ER, or physician’s office visit (due to the recent exacerbation) to Randomization (Visit 2) is ≤14 days. Visit 1 (Screening) and Visit 2 can occur during the hospitalization, ER visit, physician’s office visit, and up to 14 days afterward. 2. Duration of subjects’ participation in study is 29 weeks (completing subjects), approximately (unless subject is prematurely withdrawn from the study). ER: Emergency Room; F/U: Follow-up; TC: Telephone call; V: Visit; Wks: Weeks.
Figure 2
Figure 2
Patient disposition and reasons for study withdrawal. FP = fluticasone propionate; SAL = salmeterol.
Figure 3
Figure 3
Kaplan-Meier estimates for A) time to first COPD exacerbation requiring oral corticosteroids, antibiotics and/or hospitalization, and B) time to withdrawal from study, over 26 weeks of treatment following the 3-week stabilization period, ITT population. COPD = chronic obstructive pulmonary disease; FP = fluticasone propionate; ITT = intent-to-treat; SAL = salmeterol.
Figure 4
Figure 4
Overall numbers of exacerbations by 4-week period, over 26 weeks of treatment following the 3-week stabilization period, ITT population. *Weeks from end of 21-day stabilization period. FP = fluticasone propionate; ITT = intent-to-treat; SAL: salmeterol.
Figure 5
Figure 5
Summary of pre-dose morning FEV1during the 3-week stabilization period, over Weeks 0–26, and at endpoint, ITT population. FEV1 = forced expiratory volume in one second; FP = fluticasone propionate; ITT = intent-to-treat; SAL = salmeterol.

References

    1. Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet. 2007;370:786–796. doi: 10.1016/S0140-6736(07)61382-8.
    1. Jenkins CR, Celli B, Anderson JA, Ferguson GT, Jones PW, Vestbo J, Yates JC, Calverley PM. Seasonality and determinants of moderate and severe COPD exacerbations in the TORCH study. Eur Respir J. 2012;39:38–45. doi: 10.1183/09031936.00194610.
    1. Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H, Tal-Singer R, Miller B, Lomas DA, Agusti A, Macnee W, Calverley P, Rennard S, Wouters EF, Wedzicha JA, Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363:1128–1138. doi: 10.1056/NEJMoa0909883.
    1. Vestbo J, Edwards LD, Scanlon PD, Yates JC, Agusti A, Bakke P, Calverley PM, Celli B, Coxson HO, Crim C, Lomas DA, MacNee W, Miller BE, Silverman EK, Tal-Singer R, Wouters E, Rennard SI, ECLIPSE Investigators Changes in forced expiratory volume in 1 second over time in COPD. New Engl J Med. 2011;365:1184–1192. doi: 10.1056/NEJMoa1105482.
    1. Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57:847–852. doi: 10.1136/thorax.57.10.847.
    1. Nishimura K, Sato S, Tsukino M, Hajiro T, Ikeda A, Koyama H, Oga T. Effect of exacerbations on health status in subjects with chronic obstructive pulmonary disease. Health Qual Life Outcomes. 2009;7:69. doi: 10.1186/1477-7525-7-69.
    1. Spencer S, Calverley PMA, Burge PS, Jones PW. Impact of preventing exacerbations on deterioration of health status in COPD. Eur Respir J. 2004;23:698–702. doi: 10.1183/09031936.04.00121404.
    1. Anzueto A. Impact of exacerbations on COPD. Eur Respir Rev. 2010;19:113–118. doi: 10.1183/09059180.00002610.
    1. Hurst JR, Donaldson GC, Quint JK, Goldring JJP, Baghai-Ravary R, Wedzicha JA. Temporal clustering of exacerbations in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;179:368–374. doi: 10.1164/rccm.200807-1067OC.
    1. Suissa S, Dell’Aniello S, Ernst P. Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality. Thorax. 2012;67:957–963. doi: 10.1136/thoraxjnl-2011-201518.
    1. Halpin DMG, Decramer M, Celli B, Kesten S, Leimer I, Tashkin DP. Risk of nonlower respiratory serious adverse events following COPD exacerbations in the 4-year UPLIFT® trial. Lung. 2011;189:261–268. doi: 10.1007/s00408-011-9301-8.
    1. Seemungal T, Harper-Owen R, Bhowmik A, Moric I, Sanderson G, Message S, Maccallum P, Meade TW, Jeffries DJ, Johnston SL, Wedzicha JA. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164:1618–1623. doi: 10.1164/ajrccm.164.9.2105011.
    1. Executive Summary: Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease. 2013.
    1. Soriano JB, Kiri VA, Pride NB, Vestbo J. Inhaled corticosteroids with/without long-acting beta2 agonists reduce the risk of rehospitalization and death in COPD patients. Am J Respir Med. 2003;2:67–74. doi: 10.1007/BF03256640.
    1. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J, TORCH investigators Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. New Engl J Med. 2007;356:775–789. doi: 10.1056/NEJMoa063070.
    1. Ferguson GT, Anzueto A, Fei R, Emmett A, Knobil K, Kalberg C. Effect of fluticasone propionate/salmeterol (250/50 microg) on COPD exacerbations. Respir Med. 2008;102:1099–1108. doi: 10.1016/j.rmed.2008.04.019.
    1. Anzueto A, Ferguson GT, Feldman G, Chinsky K, Seibert A, Emmett A, Knobil K, O'Dell D, Kalberg C, Crater G. Effect of fluticasone propionate/salmeterol (250/50) on COPD exacerbations and impact on patient outcomes. COPD. 2009;6(5):320–329. doi: 10.1080/15412550903140881.
    1. Leidy NK, Wilcox TK, Jones PW, Roberts L, Powers JH, Sethi S, EXACT-PRO Study Group Standardizing measurement of chronic obstructive pulmonary disease exacerbations: reliability and validity of a patient-reported diary. Am J Respir Crit Care Med. 2011;183:323–329. doi: 10.1164/rccm.201005-0762OC.
    1. Lomas DA, Silverman EK, Edwards LD, Locantore NW, Miller BE, Horstman DH, Tal-Singer R, Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study investigators Serum surfactant protein D is steroid sensitive and associated with exacerbations of COPD. Eur Respir J. 2009;34:95–102. doi: 10.1183/09031936.00156508.
    1. Dickens JA, Miller BE, Edwards LD, Silverman EK, Lomas DA, Tal-Singer R. COPD association and repeatability of blood biomarkers in the ECLIPSE cohort. Respir Res. 2011;12:146. doi: 10.1186/1465-9921-12-146.
    1. American Thoracic Society Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1995;152:S78–S121. doi: 10.1164/ajrccm/152.5_Pt_2.S78.
    1. Schünemann JH, Puhan M, Goldstein R, Jaeschke R, Guyatt GH. Measurement properties and interpretability of the Chronic Respiratory Questionnaire (CRQ) COPD. 2005;2:81–89. doi: 10.1081/COPD-200050651.
    1. ADVAIR DISKUS®: Full Prescribing Information. 2008.
    1. Escarrabill J. Discharge planning and home care for end-stage COPD patients. Eur Respir J. 2009;34:507–512. doi: 10.1183/09031936.00146308.
    1. Hernandez C, Jansa M, Vidal M, Nuñez M, Bertran MJ, Garcia-Aymerich J, Roca J. The burden of chronic disorders on hospital admissions prompts the need for new modalities of care: a cross-sectional analysis in a tertiary hospital. QJM. 2009;102:193–202. doi: 10.1093/qjmed/hcn172.
    1. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161:1608–1613. doi: 10.1164/ajrccm.161.5.9908022.
    1. Rodrigo GJ, Castro-Rodriguez JA, Plaza V. Safety and efficacy of combined long-acting β-agonists and inhaled corticosteroids vs long-acting β-agonists monotherapy for stable COPD. Chest. 2009;136:1029–1038. doi: 10.1378/chest.09-0821.
    1. Readmissions Reduction Program. 2013.
    1. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients in the Medicare fee-for-service program. New Engl J Med. 2009;360:1418–1428. doi: 10.1056/NEJMsa0803563.
    1. Hanania NA1, Darken P, Horstman D, Reisner C, Lee B, Davis S, Shah T. The efficacy and safety of fluticasone propionate (250 μg)/salmeterol (50 μg) combined in the Diskus inhaler for the treatment of COPD. Chest. 2003;124:834–843. doi: 10.1378/chest.124.3.834.
    1. Sethi S. Personalised medicine in exacerbations of COPD: the beginnings. Eur Respir J. 2012;40:1318–1319. doi: 10.1183/09031936.00136412.
    1. Bafadhel M, McKenna S, Terry S, Mistry V, Pancholi M, Venge P, Lomas DA, Barer MR, Johnston SL, Pavord ID, Brightling CE. Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial. Am J Respir Crit Care Med. 2012;186:48–55. doi: 10.1164/rccm.201108-1553OC.
    1. Wouters EF, Postma DS, Fokkens B, Hop WC, Prins J, Kuipers AF, Pasma HR, Hensing CA, Creutzberg EC, COSMIC (COPD and Seretide: a Multi-Center Intervention and Characterization) Study Group Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: a randomised controlled trial. Thorax. 2005;60:480–487. doi: 10.1136/thx.2004.034280.
    1. van der Valk P, Monninkhof E, van der Palen J, Zielhuis G, Van Herwaarden C. Effect of discontinuation of inhaled corticosteroids in patients with Chronic Obstructive Pulmonary Disease: the COPE study. Am J Respir Crit Care Med. 2002;166:1858–1868. doi: 10.1164/rccm.200206-512OC.
    1. Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, Balter M, O'Donnell D, McIvor A, Sharma S, Bishop G, Anthony J, Cowie R, Field S, Hirsch A, Hernandez P, Rivington R, Road J, Hoffstein V, Hodder R, Marciniuk D, McCormack D, Fox G, Cox G, Prins HB, Ford G, Bleskie D, Doucette S, Mayers I, Chapman K, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007;146:545–555. doi: 10.7326/0003-4819-146-8-200704170-00152.
    1. Short PM, Williamson PA, Elder DHJ, Lipworth SIW, Schembri S, Lipworth BJ. The impact of tiotropium on mortality and exacerbations when added to inhaled corticosteroids and long-acting β-agonist therapy in COPD. Chest. 2012;141:81–86. doi: 10.1378/chest.11-0038.
    1. Wedzicha JA1, Calverley PM, Seemungal TA, Hagan G, Ansari Z, Stockley RA, INSPIRE Investigators The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med. 2007;177:19–26. doi: 10.1164/rccm.200707-973OC.
    1. Koutsokera A, Stolz D, Loukides S, Kostikas K. Systemic biomarkers in exacerbations of COPD: the evolving clinical challenge. Chest. 2012;141:396–405. doi: 10.1378/chest.11-0495.
    1. Groenewegen KH, Postma DS, Hop WCJ, Wielders PLML, Schlösser NJJ, Wouters EFM. Increased systemic inflammation is a risk factor for COPD exacerbations. Chest. 2008;133:350–357. doi: 10.1378/chest.07-1342.
    1. Perera WR, Hurst JR, Wilkinson TM, Sapsford RJ, Müllerova H, Donaldson GC, Wedzicha JA. Inflammatory changes, recovery and recurrence at COPD exacerbation. Eur Respir J. 2007;29:527–534. doi: 10.1183/09031936.00092506.
    1. Fingleton J, Weatherall M, Beasley R. Towards individualised treatment in COPD. Thorax. 2011;66:363–364. doi: 10.1136/thx.2010.155564.

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