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N Engl J Med. 2016 Jun 9;374(23):2222-34. doi: 10.1056/NEJMoa1516385. Epub 2016 May 15.

Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD.

Collaborators (463)

Ambrosino N, Budani H, Carminio C, Casal E, De Salvo M, Delgado Vizcarra G, Fazio C, Gene R, Hasner C, Luna C, Maillo M, Mariño G, Massola F, Mattarucco W, Molina A, Otaola M, Rey LB, Rodriguez A, Rojas RA, Taborda J, Tolcachier A, Victorio C, Wehbe L, Willigs Rolon M, Yanez A, Voves R, Wuertz J, Wuertz P, Ablinger O, Forstner B, Wallner G, Olschewski H, Koeberl G, Studnicka M, Kaehler C, Vincken W, Driesen P, Demedts I, Janssens W, Martinot JB, Aumann J, Derom E, Ninane V, Corhay JL, Bogerd SP, Vanderheyde K, Fremault A, Schlesser M, Janssens E, Jordens P, Verhaeghe W, Verbuyst R, Ilieva-Fartunova V, Shikov R, Hodzhev V, Kostov K, Ivanov Y, Peneva M, Youroukova V, Georgiev O, Subashki M, Milcheva V, Chapman KR, Del Carpio J, Fera T, Field S, Killorn P, Landry D, Larivee P, Pek B, Tellier G, Mazza G, Sherkin M, Frechette A, Soler T, Pavie J, Miranda G, Zheng J, Huang W, Wen Z, Wang H, Cai B, Sun S, Wen F, Xiong W, Wang C, Huang Y, Wang L, Xiao Z, Wen G, Liu J, Wan H, Chen P, Yan X, Huang J, Cao J, Li Z, Huang M, Vallejo JS, Cardona G, Isaza D, Bolivar F, Tudoric N, Vuksan-Cusa T, Samarzija M, Tauchman A, Hadrava M, Holub S, Zitkova M, Ali M, Kopecka D, Presperinova J, Povysilova L, Cmakalova M, Mares J, Kocianova J, Skacel Z, Kasak V, Musil J, Blahova M, Jirmanova I, Kolek V, Backer V, Ulrik CS, Nielsen C, Ottesen A, Seersholm N, Bodtger U, Grzywacz Z, Meyer CN, Nielsen S, Jogi R, Meren M, Samaruutel P, Venho K, Elo J, Patovirta RL, Nieminen E, Raatikainen L, Saarelainen P, Herer B, Deslee G, Devouassoux G, Jasnot JY, Berger P, Proust A, Bourdin A, Boye A, Ballenberger S, Beck E, Benedix A, Birkholz SC, Bollmann L, Budweiser S, Deckelmann R, Deimling A, Eberhardt F, Eckhardt G, Eller J, Esselmann A, Feldmeyer F, Feussner W, Foerster K, Franz KH, Fritzsche A, Gebhardt R, Gernhold M, Gessner C, Haase PU, Heindl S, Hoheisel G, Hueting R, Jaeger B, Jandl M, Junggeburth J, Kaessner F, Keller C, Kirschner J, Kleinecke-Pohl U, Kroker A, Lammert-Huenger G, Ludwig-Sengpiel A, Mikloweit P, Mueller H, Noga O, Reinhardt J, Rueckert P, Schaper L, Schlegel V, Schmoller T, Schuermann W, Toepfer V, Wiemer S, Winkler J, Botzen U, Djacenko S, Entzian P, Herzig J, Hofbauer P, Kornmann O, Marten I, Overlack A, Preiss G, Schlenska C, Sohrab S, Steffen H, Westerhausen U, Zeisler KH, Zemke K, Zingler W, Zuechner D, Kaiser A, Tyler K, Ginko T, Marosis K, Gaga A, Siafakas N, Kakoura M, Koulouris N, Vasilakopoulos T, Papiris S, Zarogoulidis K, Antoniadis A, Kallergis K, Gourgoulianis K, Contreras E, Espana E, Gonzalez E, Guerra J, Martinez G, Hui DS, Losonczy G, Vasas S, Varga J, Mark Z, Schlezak J, Balint B, Somfay A, Jonsson M, D'Souza G, Arbat A, Sundarakumar S, Vijaykumar NB, Dhar R, Shah N, Kashyap AK, Srikanth K, Tripathi S, Gupta N, Samiuddin M, Swarnakar R, Paggiaro PL, Idotta G, Mazza F, Cerveri I, Colombo F, Barbaro MP, Riario Sforza GG, Pomari C, Zucchi L, Gigliotti F, Clini E, Aiolfi S, Gasparini S, Ceriana P, Spanevello A, Carone M, Barisione G, Miyao N, Kiyosue A, Nakatani Y, Harada T, Hayakawa H, Kato M, Ogushi F, Nakamura H, Yoshida M, Hataji O, Matsui H, Matsumoto M, Taniguchi H, Takeda A, Kishimoto N, Nishio M, Kinoshita M, Kato R, Hara N, Tamada T, Hashimoto S, Suzuki M, Hiramatsu T, Shuto H, In KH, Lee S, Kim S, Kim J, Kim D, Park M, Kim J, Yoo C, Lee Y, Babjoniseva A, Mitrofanova L, Smiltena I, Matukiene V, Nausediene V, Miliauskas S, Susinskiene D, Vebriene J, Vaicius D, Volosevic T, Kiziela A, Sileikiene V, Sansores R, Ramirez E, Diaz J, Caleco M, Llamas FS, Bantje T, Gans SJ, Goosens M, Sinninghe-Damste HE, de Hosson SM, Wielders PL, van der Valk P, Michels AJ, Gronert J, Norheim PD, Sparby JA, Risberg K, Karlsson T, Roedolen T, Tomala T, Diaz D, Maliwat A, Hernandez JF, Antczak A, Mroz R, Siergiejko Z, Waszkuc-Golonko J, Olechnowicz D, Napora P, Batura-Gabryel H, Barbara C, Cardoso J, Moita J, Rodrigues B, Pires N, Guimaraes JM, Andre N, Ribeiro V, Mihaicuta S, Petrui ID, Tudorache V, Bulugean L, Adina M, Rajnoveanu R, Olar D, Matei D, Toma C, Gica C, Ambert L, Mihaescu T, Alexandrescu D, Popovici C, Glontescu ID, Boisteanu D, Vigdorovits M, Jimborean G, Mihaltan F, Abrosimov V, Platonov D, Astafieva N, Nosov V, Martynenko T, Gantseva K, Shilkina N, Gaydar E, Ignatova G, Khamitov R, Stankovic I, Cekerevac I, Ilic A, Vukcevic M, Hrebenar S, Lescisinova H, Golubov A, Oravcova H, Zacik M, Zambova RT, Arpasova K, Orolin M, Jurco P, Kretik V, Kavkova D, Mihalecova Y, Sarkanova K, Kovacikova L, Kubikova Y, Rozborilova E, Smith C, Abdullah I, Bruning A, Visser S, Abdullah I, van Zyl-Smit R, Richter D, Ras G, Joubert J, Irusen, de Saracho JO, Echave-Sustaeta J, Pascual LR, Casan P, Ramos D, Roldan J, Gonzalez JE, Lista JD, Morera J, Sanchez I, Caballero LM, Rodriguez E, Galdiz J, Naval E, Fernandez E, Santa Cruz A, Ruiz AB, Costa JS, Ferrer A, Roig V, Velasco JL, Bjermer L, Jul-Nielsen H, Tengmark BO, Blom KB, Perng DW, Yu CJ, Cheng SL, Hsu WH, Tsai YH, Hsiue TR, Lin MC, Boonsawat W, Pothirat C, Keeratichananont W, Nayci S, Saryal S, Gunen H, Sayiner A, Ortakoylu G, Yorgancioglu A, Ozkurt S, Harrison R, Jones N, Bourne S, Saralaya D, Kerrane J, DeSoyza A, Fuller L, Litchfield J, Bourke S, Collier D, Gunstone A.

Author information

1
From the National Heart and Lung Institute, Imperial College London, London (J.A.W.), and the Centre for Respiratory Medicine and Allergy, University of Manchester and University Hospital South Manchester NHS Foundation Trust, Manchester (J.V.) - all in the United Kingdom; Novartis Pharmaceuticals, East Hanover, NJ (D.B., R.T.A., C.T., R.F.); Asthma and Airway Centre, University Health Network and University of Toronto, Toronto (K.R.C.); Service de Pneumologie Assistance Publique-Hôpitaux de Paris, University Paris Descartes (EA2511), Paris (N.R.); Novartis Pharma AG, Basel, Switzerland (F.P.); and the Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Marburg, Germany (C.F.V.).

Abstract

BACKGROUND:

Most guidelines recommend either a long-acting beta-agonist (LABA) plus an inhaled glucocorticoid or a long-acting muscarinic antagonist (LAMA) as the first-choice treatment for patients with chronic obstructive pulmonary disease (COPD) who have a high risk of exacerbations. The role of treatment with a LABA-LAMA regimen in these patients is unclear.

METHODS:

We conducted a 52-week, randomized, double-blind, double-dummy, noninferiority trial. Patients who had COPD with a history of at least one exacerbation during the previous year were randomly assigned to receive, by inhalation, either the LABA indacaterol (110 μg) plus the LAMA glycopyrronium (50 μg) once daily or the LABA salmeterol (50 μg) plus the inhaled glucocorticoid fluticasone (500 μg) twice daily. The primary outcome was the annual rate of all COPD exacerbations.

RESULTS:

A total of 1680 patients were assigned to the indacaterol-glycopyrronium group, and 1682 to the salmeterol-fluticasone group. Indacaterol-glycopyrronium showed not only noninferiority but also superiority to salmeterol-fluticasone in reducing the annual rate of all COPD exacerbations; the rate was 11% lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (3.59 vs. 4.03; rate ratio, 0.89; 95% confidence interval [CI], 0.83 to 0.96; P=0.003). The indacaterol-glycopyrronium group had a longer time to the first exacerbation than did the salmeterol-fluticasone group (71 days [95% CI, 60 to 82] vs. 51 days [95% CI, 46 to 57]; hazard ratio, 0.84 [95% CI, 0.78 to 0.91], representing a 16% lower risk; P<0.001). The annual rate of moderate or severe exacerbations was lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (0.98 vs. 1.19; rate ratio, 0.83; 95% CI, 0.75 to 0.91; P<0.001), and the time to the first moderate or severe exacerbation was longer in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (hazard ratio, 0.78; 95% CI, 0.70 to 0.86; P<0.001), as was the time to the first severe exacerbation (hazard ratio, 0.81; 95% CI, 0.66 to 1.00; P=0.046). The effect of indacaterol-glycopyrronium versus salmeterol-fluticasone on the rate of COPD exacerbations was independent of the baseline blood eosinophil count. The incidence of adverse events and deaths was similar in the two groups. The incidence of pneumonia was 3.2% in the indacaterol-glycopyrronium group and 4.8% in the salmeterol-fluticasone group (P=0.02).

CONCLUSIONS:

Indacaterol-glycopyrronium was more effective than salmeterol-fluticasone in preventing COPD exacerbations in patients with a history of exacerbation during the previous year. (Funded by Novartis; FLAME ClinicalTrials.gov number, NCT01782326.).

PMID:
27181606
DOI:
10.1056/NEJMoa1516385
[Indexed for MEDLINE]
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