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N Engl J Med. 2016 May 12;374(19):1822-30. doi: 10.1056/NEJMoa1511049. Epub 2016 Mar 6.

Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone.

Collaborators (885)

Altieri HH, Antuni JD, Bergna MA, Cuadrado JA, De Gennaro MS, Fazio Lizandrelo CL, Gattolin G, Gosn AM, Larrateguy LD, Marcipar AM, Maspero JF, Medina IV, Perez Chada RD, Silva D, Victorio CF, Bardin PG, Carroll PA, Clements BS, Dore ND, Robinson PD, Fitzgerald DA, Robinson PJ, Russo MA, Sajkov D, Thomas PS, Upham JW, Forstner B, Kaik G, Koeberl GH, Studnicka M, Wallner G, Balthazar Y, Bauler A, Dupont LJ, Martinot JB, Ninane V, Peché R, Pilette C, Dimitrova R, Dimova D, Kissyova Ibrishimova G, Loboshka Becheva M, Machkovska M, Madjarov S, Mandazhieva Pepelanova M, Naidenova I, Noleva K, Takovska N, Terziev C, Aggarwal NK, Chapman KR, Csanadi MA, Dhillon R, Henein S, Kelly AJ, Lam AS, Liem JJ, Lougheed MD, Lowe DW, Rizvi Q, van den Berg L, Zidel B, Barros Monge MJ, Calvo Gil MA, Castillo Hofer CR, Diaz Amor PV, Lezana Soya V, Quilodran Silva CN, Bolivar Grimaldos F, Solarte-Rodriguez I, Butkovic-Tomljanovic R, Hegedus-Jungvirth M, Ivkovic-Jurekovic I, Simunov-Karuza G, Buresova M, Bursova J, Fratrik J, Guttlerova E, Hartman P, Jirmanova I, Kalina P, Kolman P, Kucera M, Povysilova L, Pravda P, Svabkova A, Zakova L, Backer V, Maltbaek N, Johnsen CR, Aries SP, Babyesiza A, Barth D, Benedix A, Berg P, Bergtholdt B, Bettig U, Bindig HW, Botzen U, Brehler R, Breyer GO, Bruckhaus-Walter M, Dapper T, Eckhard JG, Engelhard R, Feldmeyer F, Fissan H, Franz KH, Frick BS, Funck J, Gessner CM, Ginko T, Grigat CE, Grimm-Sachs V, Groth G, Hampf J, Hanf G, Havasi-Jost G, Heinz GU, Helm K, Hoeltz S, Hofmann S, Jander R, Jandl M, Jasch-Hoppe B, Jung T, Junggeburth JJ, Kardos P, Knueppel W, Koch T, Kolorz C, Korduan M, Korth-Wiemann B, Krezdorn HG, Kroker A, Kruell M, Kuehne P, Lenk U, Liefring E, Merke J, Micke L, Mitlehner W, Mueller H, Naudts IF, Neumann G, Oldenburg W, Overlack A, Panzer F, Reinholz N, Remppis R, Riegel P, Rueckert P, Schaetzl RJ, Schauer U, Hamelmann E, Schenkenberger I, Schlegel V, Scholz G, Schroers M, Schwittay A, Sebert M, Tyler K, Soemantri PA, Stock P, Stuchlik G, Unland M, von Mallinckrodt C, Wachter J, Weber U, Weberling F, Wehgartner-Winkler S, Weimer J, Wiemer S, Winkelmann EJ, Zeisler KH, Ziegner A, Zimny HH, Andrasofszky Z, Bartha A, Farkas M, Gömöri K, Kis S, Major K, Mészáros I, Mezei M, Rakvacs M, Szalai Z, Szántó J, Szentesi M, Szolnoki E, Valyon E, Zibotics H, Anwar J, Arimah C, Djajalaksana S, Rai IB, Setijadi AR, Setyanto DB, Susanti F, Syafiuddin T, Syamsi LN, Wijanarko P, Yunus F, Bonavia M, Braga M, Chetta AA, Cerveri I, Luisetti M, Crimi N, Cutrera R, De Rosa M, Esposito S, Foresi A, Gammeri E, Iemoli E, Legnani DL, Michetti G, Pastorello EA, Pesci A, Pistolesi M, Riva E, Romano A, Scichilone N, Terracciano L, Tripodi S, Choi I, Kim C, Kim JS, Kim WJ, Koh YY, Kwon SS, Lee SH, Lee S, Lee SK, Park CS, Cirule I, Eglite R, Petrova I, Poga M, Smiltena I, Chomiciene A, Davoliene I, Griskeviciene V, Naudziunas A, Naudziunas S, Rudzeviciene O, Sitkauskiene B, Urbonas G, Vaicius D, Valavicius A, Valiulis A, Vebriene J, bin Abdul Aziz FA, Daud M, Ismail AI, Tengku Saifudin TI, Md Kassim RM, Mohd Fadzli FB, Wan Mohamad WH, Aguilar Dominguez PE, Aguilar-Orozco RA, Garza-Salinas S, Ramirez-Diaz SP, Sánchez Llamas F, Soto-Ramos M, Velarde-Mora HJ, Aguirre Sosa I, Cisneros AM, Estrella Viladegut RA, Matsuno Fuchigami A, Adiaz-Baui TT, Bernan AP, Onia AF, Sandagon MJ, S-Naval S, Yu CY, Bartuzi Z, Bielous-Wilk A, Błażowski Ł, Bożek A, Brzostek J, Chorostowska-Wynimko J, Ciekalska K, Ziora D, Cieslicki J, Emeryk A, Folcik K, Gałuszka-Bilińska A, Gawlik R, Giejlo M, Harat R, Hofman T, Jahnz-Różyk K, Jedrzejczak M, Kachel T, Kamiński D, Kelm Warchol A, Konieczny Z, Kwasniewski A, Leszczyński W, Mincewicz G, Niezgoda K, Olszewska-Ziąber A, Onasz-Manitius M, Pawlukiewicz M, Piotrowicz P, Piotrowski W, Pisarczyk-Bogacka E, Piskorz P, Prokop-Staszecka A, Roslan A, Słomka A, Smalera E, Stelmach I, Swierczynska-Krepa M, Szmidt M, Tarnowska-Matusiak M, Tłuczykont B, Tyminska K, Waszkuc-Golonko J, Wojciechowska I, Alexandrescu DS, Neamtu ML, Todea D, Alekseeva E, Aleksandrova E, Asherova I, Barbarash OL, Bugrova O, Bukreeva EB, Chermenskiy A, Chizhova O, Demko I, Evdokimova A, Giorgadze ML, Grigoryev S, Irkhina I, Khurkhurova NV, Kondyurina EG, Kostin VI, Kudelya L, Laleko SL, Lenskaya L, Levashov S, Logvinenko N, Martynov A, Mizernitski Y, Nemtsov B, Novozhenov VG, Pavlishchuk S, Popova VV, Reshetko OV, Sherenkov A, Shirinsky VS, Shpagina L, Soloviev KI, Tkachev A, Trofimov VI, Vertkin AL, Vorobeva E, Idrisova E, Yakushin S, Zadionchenko V, Zhiglinskaya O, Zykov K, Dopudja Pantic V, Nadaskic R, Nestorovic B, Skodric Trifunovic V, Stojanovic A, Vukcevic M, Vujic T, Mitic Milikic M, Banovcin P, Horvathova H, Karako P Sr, Plutinsky J, Pribulova E, Szarazova M, Zlatos A, Adams L, Badat A, Bassa A, Breedt J, Bruning A, Ellis GC, Emanuel S, Fouche LF, Fulat MA, Gani M, Ismail MS, Jurgens JC, Nell H, Nieuwoudt G, Noor F, Bolliger CT, Puterman AS, Siddique N, Trokis JS, Vahed YA, Van Der Berg BJ, Van der Linden M, Van Zyl L, Visser SS, Antépara Ercoreca I, Arnedillo Muñoz A, Barbe Illa F, Barreiro López B, Blanco Aparicio M, Boada Valmaseda A, Bosque García M, Bustamante Ruiz A, Carretero Anibarro P, Del Campo Matias F, Echave-Sustaet JM, Espinosa de los Monteros Garde MJ, Garcia Hernandez GM, López Viña A, Lores Obradors L, Luengo Planas MT, Monsó Molas E, Navarro Dourdil A, Nieto García AJ, Perpina Tordera M, Picado Valles C, Rodriguez Alvarez Mdel M, Saura Vinuesa A, Serra Batlles J, Soler Sempere MJ, Toran Montserrat P, Valdés Cuadrado LG, Villasante Fernandez-Montes C, Cheng SL, Chern JH, Chiu MH, Chung CL, Lai RS, Lin CK, Liu YC, Wang CC, Wei YF, Amer L, Berenfus VI, Besh L, Duka KD, Fushtey IM, Garmash N, Dudnyk O, Godlevska O, Vlasenko MA, Hospodarskyy I, Iashyna L, Kaladze M, Khvelos SI, Kostromina VP, Krakhmalova O, Kryuchko T, Kulynych OV, Krasko MP, Levchenko O, Litvinova T, Panina SS, Pasiyeshvili LM, Prystupa LN, Romaniuk LI, Sirenko I, Synenko VI, Vynnychenko LB, Yatsyshyn RI, Zaitsev I, Zhebel V, Zubarenko O, Arthur CP, Brown V, Burhan H, Chaudhuri R, Collier D, Barnes NC, Davies EJ, Ellery A, Kwok S, Lenney W, Nordstrom M, Pandya HC, Parker IW, Rajakulasingam K, Seddon P, Sharma R, Thomas EC, Wakeling JA, Abalos-Galito M, Abboy C, Abreu E, Ackerman IF, Acosta IA, Adaoag AA, Ahmed M, Ali MI, Allen DR, Allen GG Jr, Diogo JJ, Allison DC, Alwine LK, Apaliski SJ, Arastu RS, Arora CM, Auerbach D, Azzam SJ, Badar FL 3rd, Baker JW, Barasch JP, Barber MA, Bardinas-Rodriguez R, Barreiro TJ, Baumbach RR, Baur CE, Baxter BS, Beach JL, Beasley RL, Beavins JE, Beliveau WJ, Benbow MJ, Bennett NL, Bennett RL, Bernal H, Bernstein DI, Blaiss MS, Blumenthal KW, Boas SR, Borders JL, Boscia JA, Boulware WN, Bowling BT, Brabec BA, Bramlet DG, Figueroa DP, Brautigam DF, Brownell JM, Bruce TR, Call RS, Campbell CA, Canaan YA, Cannon DF, Carpio JM, Cathcart WS, Cevallos JP, Chauhan AV, Chuang RB, Chevalier D, Christensen J, Christensen TA, Christina MO, Chrzanowski RR, Civitarese FA, Clark JP, Clifford DP, Lapidus RJ, Coggi JA, Lenz JJ, Cohen KR, Collins BG, Collins H, Comellas A, Condit J, Cordasco EM Jr, Corder CN, Covar RA, Coverston KD, Croce SA, Cruz H, Curtis CT, Daftary PK, Dalan D, Dalawari SP, Daly WC, Davis KC, Dawes KW, DeCotiis BA, Deluca RF, DeSantis DM, De Valle OL, Diaz JL, Diaz JD, Dice JP, Elizalde A, Hosler MR, Dixon C, Dobkin LA, Dobrusin RS, Dransfield MT, Ebbeling WL, Edwards JD, Elacion JM, Elkayam D, Ellison WT, Elsen JR, Engel LR, Ensz DJ, Ericksen CL, Ervin JE, Fang C, Abrahamian F, Farrah VB, Field JD, Fishman HJ, Florea R, Nayyar S, Focil A, Focauld F, Franco MA Jr, Frandsen BR, Ganti K, Garcia FL, Lee WM, Garscadden AG, Gatti EA, Gellady AM, George AR, Gibbon GW, Gleason GP, Goldberg P, Goldstein MF, Gonzalez GE, Gower RG, Grande JA, Gregory D, Grubb SD, Guthrie RP, Haas TA, Haft KS, Hajal R, Hammond GD, Hansel NN, Hansen VR, Harris AF, Hartman AN, Harvey RR, Hazan-Steinberg S, Headley DM, Heigerick GC, Heller BN, Hendrix EL, Herrod JN, Hewitt MJ, Hines RL, Hirdt AP, Hirschfield JA, Hoffman KS, Hogan AD, Howland WC, Hsu CC, Hsu FJ, Hubbard WM, Hudson JD, Huffman C, Hussain M, Ioachimescu OC, Ismail YM, Jaffrani NA, Jiang N, Jones SW, Jordan RS, Joshi KE, Kaashmiri MW, Kalafer M, Kamdar BA, Kanuga JG, Kao NL, Karetzky M, Katsetos JC, Kay JS, Kimmel MA, Kimura SH, Kingsley JK, Mahmood SM, Subich DC, Kirstein JL, Kleerup EC, Klein RM, Koh DW, Kohli N, Koura FA, Kovacs SP, Kratzer J, Kreit CI, Kreutter FM, Kubicki TM, Labuda JM, Latorre AJ, Lara MM, Lechin AE, Lee JJ, Lee MD, Lentnek AL, Lesh KW, Levins PF, Anspach RB, Levinsky DM, Lillestol MJ, Lim H, Livezey MD, Lloyd-Turney CW, Lockey RF, Long RA, Lynch MJ, MacGillivray BK, Mahadevan KP, Makam SK, Maloney MJ, Mapel D, Margolis BD, Margulies J, Martin EF, Martin EE, Mascolo M, Mataria H, Sunbuli M, Mathur RN, Mattar PN, Maynard KM, Maynard N, McCormick B, McElya M, McEvoy CE, McKenzie WC, Medwedeff LE, Mehta KD, Melamed IR, Meli JV, Merrick BH, Meyers PJ, Miller BT, Minton SM, Miranda FG, Mohar DE, Montenegro CH, Morris FA, Morrison BS, Moss MH, Munoz F, Naini GR, Nakamura CT, Naseeruddin S, Nassim C, Navazo LJ, Nissim JE, Norman D, Oberoi MS, O'Connor TM, Offenberger J, Orr RR, Osea EA, Paine WJ, Rasmussen NL, Palatnik M, Pangtay D, Panuto JA, Patel M, Perera MS, Perez A, Peters PH Jr, Pimentel SM Jr, Pluto TM, Pollock MT, Posner LS, Pritchard JC, Pudi KK, Puig CM, Qaqundah PY, Radbill MK, Rahman ST, Raikhel M, Raissy HH, Ramstad DS, Ranasinghe ES, Rangel OS, Rapo SE, Raschal SP, Reddy DG, Rehman SM, Reyes SR, Rhodes RB, Riffer E, Rihal PS, Riley ED 4th, Rodriguez DH, Rogers CM, Rohlf JL, Romeu H, Roney CW, Ronsick SO, Rosen JB, Rowe MS, Ruoff GE, Ryan EH, Saff RH, Saini N, Anand S, Balakrishnan K, Samuels BS, Samuelson RJ, Saniuk RJ, Sargeant WO, Saunders MK, Saway W, Scarupa MD, White MV, Schear MJ, Schwarz CM, Scott RB, Segall N, Seibert AF, Seidmeyer V, Seidner MR, Seifer FD, Serje J, Shah MS, Shah SB, Shapero PA, Shearer SD, Sheikh SQ, Shepherd TS, Sher ER, Sher LD, Short BH, Silas PE, Alvey JC, Silverfield JC, Simon SJ, Sitar S, Skoner DP, Smallow SA, Smart BA, Smith CA, Smith KE, Smith SK, Snyders GC, Soong W, Soufer J, Spangenthal S, Stahlman JE, Steele LG, Stegemoller RK, Stocks J, Storms WW, Suen J, Surowitz RZ, Swauger JR, Taber LA, Tan AE, Pratt SE, Tanus T, Tarpay MM, Tarshis GA, Tenney JW, Tilghman KG, Trevino ME, Troyan BE, Twiddy SK, Updegrove JD, Urval KR, Uusinarkaus KT, Vaela R, Van Cleeff M, Varano S, Vo QD, Wainz RJ, Wald JA, Wall SJ, Wasserman RL, Weinstein DL, Welker JA, Wellmon B 2nd, Wells T, Wenocur HS, Williams DL, Williams SL, Win PH, Wingo TD, Wisman PP Jr, Wyszomierski DA, Yamada HM, Yarows S, Yunger TM Jr, Ziering RW.

Abstract

BACKGROUND:

The safe and appropriate use of long-acting beta-agonists (LABAs) for the treatment of asthma has been widely debated. In two large clinical trials, investigators found a potential risk of serious asthma-related events associated with LABAs. This study was designed to evaluate the risk of administering the LABA salmeterol in combination with an inhaled glucocorticoid, fluticasone propionate.

METHODS:

In this multicenter, randomized, double-blind trial, adolescent and adult patients (age, ≥12 years) with persistent asthma were assigned to receive either fluticasone with salmeterol or fluticasone alone for 26 weeks. All the patients had a history of a severe asthma exacerbation in the year before randomization but not during the previous month. Patients were excluded from the trial if they had a history of life-threatening or unstable asthma. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization). Noninferiority of fluticasone-salmeterol to fluticasone alone was defined as an upper boundary of the 95% confidence interval for the risk of the primary safety end point of less than 2.0. The efficacy end point was the first severe asthma exacerbation.

RESULTS:

Of 11,679 patients who were enrolled, 67 had 74 serious asthma-related events, with 36 events in 34 patients in the fluticasone-salmeterol group and 38 events in 33 patients in the fluticasone-only group. The hazard ratio for a serious asthma-related event in the fluticasone-salmeterol group was 1.03 (95% confidence interval [CI], 0.64 to 1.66), and noninferiority was achieved (P=0.003). There were no asthma-related deaths; 2 patients in the fluticasone-only group underwent asthma-related intubation. The risk of a severe asthma exacerbation was 21% lower in the fluticasone-salmeterol group than in the fluticasone-only group (hazard ratio, 0.79; 95% CI, 0.70 to 0.89), with at least one severe asthma exacerbation occurring in 480 of 5834 patients (8%) in the fluticasone-salmeterol group, as compared with 597 of 5845 patients (10%) in the fluticasone-only group (P<0.001).

CONCLUSIONS:

Patients who received salmeterol in a fixed-dose combination with fluticasone did not have a significantly higher risk of serious asthma-related events than did those who received fluticasone alone. Patients receiving fluticasone-salmeterol had fewer severe asthma exacerbations than did those in the fluticasone-only group. (AUSTRI ClinicalTrials.gov number, NCT01475721.).

PMID:
26949137
[PubMed - indexed for MEDLINE]
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