Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19
The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Pere Domingo, Isabel Mur, Gràcia Mateo, María del Mar Gutiérrez, Virginia Pomar, Natividad Benito, Noemí Corbacho, Silvia Herrera, L F Pascual Millán, Jessica Muñoz, Jorge Malouf, Maria Ema Molas, Víctor Asensi, Juan Pablo Horcajada, Vicente Estrada, Félix Gutiérrez, Ferràn Torres, José A. Pérez‐Molina, Jesús Fortün, Luisa María Villar, Ulla Hohenthal, Harri Marttila, Tytti Vuorinen, Marika Nordberg, Mika Valtonen, Matthew J. Frigault, Michael K. Mansour, Naomi J. Patel, Ana D. Fernandes, Liam Harvey, Andrea S. Foulkes, Brian C. Healy, Ruta Shah, Ana Maria Bensaci, Ann E. Woolley, Sarah Nikiforow, Nina Lin, Manish Sagar, Harry Shrager, David S. Huckins, Matthew Axelrod, Michael Pincus, Jorge Fleisher, Jon Lampa, Piotr Nowak, Jan Vesterbacka, Johan Rasmuson, Paul Skorup, Helena Janols, Katarina Niward, Katerina Chatzidionysiou, Hilmir Ásgeirsson, Åsa Parke, Ola Blennow, Anna‐Karin Svensson, Soo Aleman, Anders Sönnerborg, Jan‐Inge Henter, AnnaCarin Horne, Farah Al-Beidh, Derek C. Angus, Djillali Annane, Yaseen M. Arabi, Abi Beane, Scott Berry, Zahra Bhimani, Marc J. M. Bonten, Charlotte Bradbury, Frank Brunkhorst, Meredith Buxton, Allen Cheng, Matt Cove, Menno D. de Jong, Lennie Derde, Lise J Estcourt, Herman Goossens, Anthony Gordon, Cameron Green, Rashan Haniffa, Nao Ichihara, François Lamontagne, Patrick R. Lawler, Edward Litton, John Marshall, Colin McArthur, Daniel F. McAuley, Shay McGuinness, Bryan J. McVerry, Stephanie Montgommery, Paul Mouncey, Srinivas Murthy, Alistair Nichol, Rachael Parke, Rachael Parke, Felipe Reyes, Kathryn Rowan, Hiroki Saito, Marlene Santos, Chris Seymour
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 prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 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 measure was 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 prospective meta-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. Trial Registration: PROSPERO Identifier: CRD42021230155.