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.

Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone / Stempel, Da; Raphiou, Ih; Kral, Km; Yeakey, Am; Emmett, Ah; Prazma, Cm; Buaron, Ks; Pascoe, Sj; Austri, Investigators; 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; 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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; 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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; 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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.. - In: THE NEW ENGLAND JOURNAL OF MEDICINE. - ISSN 0028-4793. - 374:19(2016), pp. 1822-1830. [10.1056/NEJMoa1511049]

Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone

Chetta AA;Esposito S;
2016-01-01

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.
2016
Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone / Stempel, Da; Raphiou, Ih; Kral, Km; Yeakey, Am; Emmett, Ah; Prazma, Cm; Buaron, Ks; Pascoe, Sj; Austri, Investigators; 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; 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[10.1056/NEJMoa1511049]
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