@article{8716283,
  abstract     = {{IMPORTANCE Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm.

OBJECTIVE To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes.

DATA SOURCES Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts.

STUDY SELECTION Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria.

DATA EXTRACTION AND SYNTHESIS In this prospectivemeta-analysis, risk of biaswas assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I-2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality.

MAIN OUTCOMES AND MEASURES The primary outcome measurewas all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days.

RESULTS A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P =.003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P <.001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P =.52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16).

CONCLUSIONS AND RELEVANCE In this prospectivemeta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.}},
  author       = {{The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, [missing] and Domingo, Pere and Mur, Isabel and Mateo, Gracia María and Gutierrez, Maria del Mar and Pomar, Virginia and de Benito, Natividad and Corbacho, Noemí and Herrera, Silvia and Millan, Lucia and Muñoz, Jessica and Malouf, Jorge and Molas, Maria Ema and Asensi, Victor and Horcajada, Juan Pablo and Estrada, Vicente and Gutierrez, Felix and Torres, Ferran and Perez-Molina, Jose A and Fortun, Jesús and Villar, Luisa M and Hohenthal, Ulla and Marttila, Harri and Vuorinen, Tytti and Nordberg, Marika and Valtonen, Mika and Frigault, Matthew J and Mansour, Michael K and Patel, Naomi J and Fernandes, Ana and Harvey, Liam and Foulkes, Andrea S and Healy, Brian C and Shah, Ruta and Bensaci, Ana Maria and Woolley, Ann E. and Nikiforow, Sarah and Lin, Nina and Sagar, Manish and Shrager, Harry and Huckins, David S. and Axelrod, Matthew and Pincus, Michael D and Fleisher, Jorge and Lampa, Jon and Nowak, Piotr and Vesterbacka, Jan C. and Rasmuson, Johan and Skorup, Paul and Janols, Helena and Niward, Katarina F and Chatzidionysiou, Katerina and Asgeirsson, Hilmir and Parke, Åsa and Blennow, Ola and Svensson, Anna-Karin and Aleman, Soo and Sönnerborg, Anders and Henter, Jan-Inge and Horne, Anna Carin and Al-Beidh, Farah and Angus, Derek and Annane, Djillali and Arabi, Yaseen and Beane, Abigail and Berry, Scott and Bhimani, Zahra and Bonten, Marc and Bradbury, Charlotte and Brunkhorst, Frank and Buxton, Meredith and Cheng, Allen and Cove, Matt and De Jong, Menno and Derde, Lennie and Estcourt, Lise and Goossens, Herman and Gordon, Anthony and Green, Cameron and Haniffa, Rashan and Ichihara, Nao and Lamontagne, Francois and Lawler, Patrick and Litton, Ed and Marshall, John and McArthur, Colin and McAuley, Daniel and McGuinness, Shay and McVerry, Bryan and Montgommery, Stephanie and Mouncey, Paul and Murthy, Srinivas and Nichol, Alistair and Parke, Rachael and Parker, Jane and Reyes, Felipe and Rowan, Kathryn and Saito, Hiroki and Santos, Marlene and Seymour, Chris and Shankar-Hari, Manu and Turgeon, Alexis and Turner, Anne and van Bentum-Puijk, Wilma and van de Veerdonk, Frank and Webb, Steve and Zarychanski, Ryan and Baillie, J Kenneth and Beasley, Richard and Cooper, Nichola and Fowler, Robert and Galea, James and Hills, Thomas and King, Andrew and Morpeth, Susan and Netea, Mihai and Ogungbenro, Kayode and Pettila, Ville and Tong, Steve and Uyeki, Tim and Youngstein, Taryn and Higgins, Alisa and Lorenzi, Elizabeth and Berry, Lindsay and Salama, Carlos and Rosas, Ivan O. and Ruiz-Antorán, Belén and Muñez Rubio, Elena and Ramos Martínez, Antonio and Campos Esteban, José and Avendaño Solá, Cristina and Pizov, Reuven and Sanz Sanz, Jesus and Abad-Santos, Francisco and Bautista-Hernández, Azucena and García-Fraile, Lucio and Barrios, Ana and Gutiérrez Liarte, Ángela and Alonso Pérez, Tamara and Rodríguez-García, Sebastian C and Mejía-Abril, Gina and Prieto, Jose Carlos and Leon, Rafael and VEIGA, VIVIANE C. and SCHEINBERG, PHILLIP and FARIAS, DANIELLE L.C. and PRATS, JOÃO G. and CAVALCANTI, ALEXANDRE B. and MACHADO, FLAVIA R. and ROSA, REGIS G. and BERWANGER, OTÁVIO and AZEVEDO, LUCIANO C.P. and LOPES, RENATO D. and DOURADO, LETICIA K. and CASTRO, CLAUDIO G. and ZAMPIERI, FERNANDO G. and AVEZUM, ALVARO and LISBOA, THIAGO C. and ROJAS, SALOMÓN S.O. and COELHO, JULIANA C. and LEITE, RODRIGO T. and CARVALHO, JULIO CESAR and ANDRADE, LUIS E.C. and SANDES, ALEX R. and PINTÃO, MARIA CAROLINA T. and SANTOS, SUELI V. and ALMEIDA, THIAGO M.L. and COSTA, ANDRÉ N. and GEBARA, OTAVIO  C.E. and FREITAS, FLAVIO G.R. and PACHECO, EDUARDO S. and MACHADO, DAVID J.B. and MARTIN, JOSIANE and CONCEIÇÃO, FABIO G. and SIQUEIRA, SUELLEN R.R. and DAMIANI, LUCAS P. and ISHIHARA, LUCIANA M. and SCHNEIDER, DANIEL and DE SOUZA, DENISE and Hermine, Olivier and Mariette, Xavier and Tharaux, Pierre Louis and Resche Rigon, Matthieu and Porcher, Raphael and Ravaud, Philippe and Azoulay, Elie and Cadranel, Jacques and Emmerich, Joseph and Fartoukh, Muriel and Guidet, Bertrand and Humbert, Marc and Lacombe, Karine and Mahevas, Matthieu and Pene, Frédéric and Pourchet-Martinez, Valérie and Schlemmer, Frédéric and Tibi, Annick and Yazdanpanah, Yazdan and Dougados, Maxime and Bureau, Serge and Horby, Peter W and Landray, Martin J and Baillie, Kenneth J and Buch, Maya H and Chappell, Lucy C and Day, Jeremy N and Faust, Saul N and Haynes, Richard and Jaki, Thomas and Jeffery, Katie and Juszczak, Edmund and Lim, Wei Shen and Mafham, Marion and Montgomery, Alan and Mumford, Andrew and Thwaites, Guy and Kamarulzaman, Adeeba and Syed Omar, Sharifah Faridah and Ponnampalavanar, Sasheela and Raja Azwa, Raja Iskandar Syah and Wong, Pui Li and Kukreja, Anjanna and Ong, Hang Cheng and Sulaiman, Helmi and Basri, Sazali and Ng, Rong Xiang and Megat Johari, Bushra and Rajasuriar, Reena and Chong, Meng Li and Neelamegam, Malinee and Syed Mansor, Syed Mukhtar and Zulhaimi, Nurul Syuhada and Lee, Cheng Siang and Altice, Frederick and Price, Christina and Malinis, Maricar and Hasan, Mohd Shahnaz and Wong, Chee Kuan and Chidambaram, Suresh and Misnan, Nor Arisah and Mohd Thabit, Alif Adlan and Sim, Benedict and Bidin, Farah Nadiah and Mohd Abd Rahim, Mohd Abd Hafiz and Saravanamuttu, Sujana and Tuang, Wei Xuan and Mohamed Gani, Yasmin and Thangavelu, Suvintheran and Tay, Kim Heng and Ibrahim, Nur Munirah and Halid, Luqman Alhakim and Tan, Kok Tong and Mukri, Mohd Noor Azreet and Arip, Masita and Koh, Hui Moon and Syed Badaruddin, Syarifah Nurul Ain and Raja Sureja, Letchumi and Chun, Geok Ying and TORRE-CISNEROS, JULIAN and MERCHANTE, NICOLAS and LEON, RAFAEL and CARCEL, SHEILA and GARRIDO, JOSE CARLOS and Galun, Eitan and Soriano, Alex and Martínez, José Antonio and Castán, Clara and Paredes, Roger and Dalmau, David and Carbonell, Cristina and Espinosa, Gerard and Castro, Pedro and Muñóz, José and Almuedo, Alex and Prieto, Sergio and Pacheco, Iván and Ratain, Mark and Pisano, Jennifer and Strek, Mary and Adegunsoye, Ayodeji and Karrison, Theodore and Declercq, Jozefien and Van Damme, Karel and De Leeuw, Elisabeth and Bosteels, Cedric and Maes, Bastiaan and Shankar-Hari, Manu and Vale, Claire L. and Godolphin, Peter J. and Fisher, David and Higgins, Julian P. T. and Spiga, Francesca and Savovic, Jelena and Tierney, Jayne and Baron, Gabriel and Benbenishty, Julie S. and Berry, Lindsay R. and Broman, Niklas and Cavalcanti, Alexandre Biasi and Colman, Roos and De Buyser, Stefanie and Derde, Lennie P. G. and Domingo, Pere and Omar, Sharifah Faridah and Fernandez-Cruz, Ana and Feuth, Thijs and Garcia, Felipe and Garcia-Vicuna, Rosario and Gonzalez-Alvaro, Isidoro and Gordon, Anthony C. and Haynes, Richard and Hermine, Olivier and Horby, Peter W. and Horick, Nora K. and Kumar, Kuldeep and Lambrecht, Bart and Landray, Martin J. and Leal, Lorna and Lederer, David J. and Lorenzi, Elizabeth and Mariette, Xavier and Merchante, Nicolas and Misnan, Nor Arisah and Mohan, Shalini V. and Nivens, Michael C. and Oksi, Jarmo and Perez-Molina, Jose A. and Pizov, Reuven and Porcher, Raphael and Postma, Simone and Rajasuriar, Reena and Ramanan, Athimalaipet V. and Ravaud, Philippe and Reid, Pankti D. and Rutgers, Abraham and Sancho-Lopez, Aranzazu and Seto, Todd B. and Sivapalasingam, Sumathi and Soin, Arvinder Singh and Staplin, Natalie and Stone, John H. and Strohbehn, Garth W. and Sunden-Cullberg, Jonas and Torre-Cisneros, Julian and Tsai, Larry W. and van Hoogstraten, Hubert and van Meerten, Tom and Veiga, Viviane Cordeiro and Westerweel, Peter E. and Murthy, Srinivas and Diaz, Janet V. and Marshall, John C. and Sterne, Jonathan A. C.}},
  issn         = {{0098-7484}},
  journal      = {{JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION}},
  keywords     = {{General Medicine,METAANALYSIS}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{499--518}},
  title        = {{Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19 : a meta-analysis}},
  url          = {{http://doi.org/10.1001/jama.2021.11330}},
  volume       = {{326}},
  year         = {{2021}},
}

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