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; Investigators, Austri; 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; Cy, Yu; 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; Qd, Vo; 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.

doi:10.1056/NEJMoa1511049

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; 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.. - In: THE NEW ENGLAND JOURNAL OF MEDICINE. - ISSN 0028-4793. - 374:19(2016), pp. 1822-1830. [10.1056/NEJMoa1511049]