Interleukin-6 receptor antagonists in critically ill patients with Covid-19.
Open accessAbstract
BACKGROUND: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTS: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. CONCLUSIONS: In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Concurrent administration of IL-6 antagonists and corticosteroids, which both have anti-inflammatory effects, may provide greater improvement than either type of drug given individually.
“Concurrent administration of IL-6 antagonists 5 and corticosteroids, 26 which both have anti-inflammatory effects, may provide greater improvement than either type of drug given individually.8,9”
From Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis (2021) · cites this paper as [8]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z., Xiang, J., Wang, Y., Song, B., Gu, X., et al. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30566-3 · Cited by 27,263 · see citing works
Dexamethasone in Hospitalized Patients with Covid-19
The RECOVERY Collaborative Group (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2021436 · Cited by 11,477 · see citing works
Fajgenbaum, D. C., & June, C. H. (2020) · New England Journal of Medicine · doi:10.1056/nejmra2026131 · Cited by 3,196 · see citing works
Effective treatment of severe COVID-19 patients with tocilizumab
Xu, X., Han, M., Li, T., Sun, W., Wang, D., Fu, B., Zhou, Y., Zheng, X., Yang, Y., Li, X., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2005615117 · Cited by 2,636 · see citing works
The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne, J. A. C., Murthy, S., Diaz, J. V., Slutsky, A. S., Villar, J., Angus, D. C., Annane, D., Azevedo, L. C. P., Berwanger, O., et al. (2020) · JAMA · doi:10.1001/jama.2020.17023 · Cited by 2,257 · see citing works
A minimal common outcome measure set for COVID-19 clinical research
Marshall, J. C., Murthy, S., Diaz, J. V., Adhikari, N. K., Angus, D., Arabi, Y. M., Baillie, J. K., Bauer, M. W., Berry, S., Blackwood, B., et al. (2020) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(20)30483-7 · Cited by 1,605 · see citing works
Efficacy of Tocilizumab in Patients Hospitalized with Covid-19
Stone, J. H., Frigault, M. J., Serling-Boyd, N. J., Fernandes, A. D., Harvey, L., Foulkes, A. S., Horick, N. K., Healy, B. C., Shah, R., Bensaci, A. M., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2028836 · Cited by 1,362 · see citing works
Genetic mechanisms of critical illness in COVID-19
The GenOMICC Investigators, Pairo‐Castineira, E., The ISARIC4C Investigators, Initiative, T. C.-1. H. G., 23andMe Investigators, BRACOVID Investigators, Gen-COVID Investigators, Clohisey, S., Klarić, L., Bretherick, A. D., et al. (2020) · Nature · doi:10.1038/s41586-020-03065-y · Cited by 1,335 · see citing works
Self-citationPathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients
Zhou, Y., Fu, B., Zheng, X., Wang, D., Zhao, C., Qi, Y., Sun, R., Tian, Z., Xu, X., & Wei, H. (2020) · National Science Review · doi:10.1093/nsr/nwaa041 · Cited by 1,295 · see citing works
Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia
Salama, C., Han, J., Yau, L., Reiss, W. G., Krämer, B., Neidhart, J. D., Criner, G. J., Kaplan‐Lewis, E., Baden, R. P., Pandit, L. M., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2030340 · Cited by 1,285 · see citing works
Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia
Rosas, I. O., Bräu, N., Waters, M., Go, R. C., Hunter, B. D., Bhagani, S. R., Skiest, D. J., Aziz, M. S., Cooper, N., Douglas, I. S., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2028700 · Cited by 1,124 · see citing works
Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19
Angus, D. C., Derde, L. P. G., Al-Beidh, F., Annane, D., Arabi, Y. M., Beane, A., van Bentum-Puijk, W., Berry, L. R., Bhimani, Z., Bonten, M. J. M., et al. (2020) · JAMA · doi:10.1001/jama.2020.17022 · Cited by 845 · see citing works
Hermine, O., Mariette, X., Tharaux, P.-L., Resche-Rigon, M., Porcher, R., Ravaud, P., CORIMUNO-19 Collaborative Group, Bureau, S., Dougados, M., Tibi, A., et al. (2021) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2020.6820 · Cited by 734 · see citing works
Salvarani, C., Dolci, G., Massari, M., Merlo, D. F., Cavuto, S., Savoldi, L., Bruzzi, P., Boni, F., Braglia, L., Turrà, C., et al. (2020) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2020.6615 · Cited by 684 · see citing works
Use of historical control data for assessing treatment effects in clinical trials
Viele, K., Berry, S. M., Neuenschwander, B. E., Amzal, B., Chen, F., Enas, N. H., Hobbs, B. P., Ibrahim, J. G., Kinnersley, N., Lindborg, S. R., et al. (2013) · Pharmaceutical Statistics · doi:10.1002/pst.1589 · Cited by 519 · see citing works
Tocilizumab for Treatment of Mechanically Ventilated Patients With COVID-19
Somers, E. C., Eschenauer, G. A., Troost, J. P., Golob, J. L., Gandhi, T. N., Wang, L., Zhou, N., Petty, L. A., Baang, J. H., Dillman, N. O., et al. (2020) · Clinical Infectious Diseases · doi:10.1093/cid/ciaa954 · Cited by 495 · see citing works
Angus, D. C., Berry, S. M., Lewis, R. J., Al-Beidh, F., Arabi, Y. M., van Bentum-Puijk, W., Bhimani, Z., Bonten, M. J. M., Broglio, K. R., Brunkhorst, F. M., et al. (2020) · Annals of the American Thoracic Society · doi:10.1513/annalsats.202003-192sd · Cited by 456 · see citing works
Veiga, V. C., Prats, J. A. G. G., Farias, D. L. C., Rosa, R. G., Dourado, L. K., Zampieri, F. G., Machado, F. R., Lopes, R. D., Berwanger, O., Azevedo, L. C. P., et al. (2021) · BMJ · doi:10.1136/bmj.n84 · Cited by 388 · see citing works
Sinha, P., Calfee, C. S., Cherian, S., Brealey, D. A., Cutler, S., King, C., Killick, C., Richards, O., Cheema, Y., Bailey, C., et al. (2020) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(20)30366-0 · Cited by 253 · see citing works
Laterre, P.-F., Berry, S. M., Blemings, A., Carlsen, J. E., François, B., Graves, T., Jacobsen, K., Lewis, R. J., Opal, S. M., Perner, A., et al. (2019) · JAMA · doi:10.1001/jama.2019.14607 · Cited by 147 · see citing works
Elevated interleukin‐6 is associated with severity of COVID‐19: A meta‐analysis
Zhu, J.-Y., Pang, J.-L., Ji, P., Zhong, Z., Li, H.-Y., Li, B., & Zhang, J.-F. (2020) · Journal of Medical Virology · doi:10.1002/jmv.26085 · Cited by 117 · see citing works
Sarilumab use in severe SARS-CoV-2 pneumonia
Gremese, E., Cingolani, A., Bosello, S. L., Alivernini, S., Tolusso, B., Perniola, S., Landi, F., Pompili, M., Murri, R., Santoliquido, A., et al. (2020) · EClinicalMedicine · doi:10.1016/j.eclinm.2020.100553 · Cited by 75 · see citing works
Flagged first, then by citations
Research works printed but not linked: 4
- [1]World Health Organization Coronavirus disease (COVID-19) pandemic 2021 https://www.who.int/emergencies/diseases/novel-coronavirus-2019 37184163
- [16]Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19 2020 6 16 Press release, https://www.recoverytrial.net/news/low-cost-dexamethasone-reduces-death-by-up-to-one-third-in-hospitalised-patients-with-severe-respiratory-complications-of-covid-19
- [23]Sanofi provides update on Kevzara (sarilumab) phase 3 trial in severe and critically ill COVID-19 patients outside the U.S 2020 9 1 Press release https://www.sanofi.com/en/media-room/press-releases/2020/2020-09-01-07-00-00
- [24]Sanofi and Regeneron provide update on Kevzara (sarilumab) phase 3 U.S. trial in COVID-19 patients 2020 7 2 Press release https://www.sanofi.com/en/media-room/press-releases/2020/2020-07-02-22-30-00
Cited by
Sorted by citations
A living WHO guideline on drugs for covid-19 (2020-2023)
Agarwal, A., Hunt, B. J., Stegemann, M., Rochwerg, B., Lamontagne, F., Siemieniuk, R. A., Agoritsas, T., Askie, L., Lytvyn, L., Leo, Y.-S., et al. (2020) · BMJ · doi:10.1136/bmj.m3379 · Cited by 1,041 · see citing works
Drug treatments for covid-19: living systematic review and network meta-analysis
Siemieniuk, R. A., Bartoszko, J. J., Zeraatkar, D., Kum, E., Qasim, A., Díaz Martinez, J. P., Izcovich, A., Rochwerg, B., Lamontagne, F., Han, M. A., et al. (2020) · BMJ · doi:10.1136/bmj.m2980 · Cited by 846 · see citing works
Neutralizing monoclonal antibodies for treatment of COVID-19
Taylor, P. C., Adams, A. C., Hufford, M. M., de la Torre, I., Winthrop, K., & Gottlieb, R. L. (2021) · Nature Reviews Immunology · doi:10.1038/s41577-021-00542-x · Cited by 732 · see citing works
The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Domingo, P., Mur, I., Mateo, G. M., Gutierrez, M. D. M., Pomar, V., de Benito, N., Corbacho, N., Herrera, S., Millan, L., et al. (2021) · JAMA · doi:10.1001/jama.2021.11330 · Cited by 678 · see citing works
Self-citationTargeting IL-6 trans-signalling: past, present and future prospects
Rose-John, S., Jenkins, B. J., Garbers, C., Moll, J. M., & Scheller, J. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-023-00856-y · Cited by 524 · see citing works
COVID-19-associated fungal infections
Hoenigl, M., Seidel, D., Sprute, R., Cunha, C., Oliverio, M., Goldman, G. H., Ibrahim, A. S., & Carvalho, A. (2022) · Nature Microbiology · doi:10.1038/s41564-022-01172-2 · Cited by 482 · see citing works
A blood atlas of COVID-19 defines hallmarks of disease severity and specificity
Ahern, D. J., Ai, Z., Ainsworth, M., Allan, C., Allcock, A., Angus, B., Ansari, M. A., Arancibia-Cárcamo, C. V., Aschenbrenner, D., Attar, M., et al. (2022) · Cell · doi:10.1016/j.cell.2022.01.012 · Cited by 328 · see citing works
Epigenetic memory of coronavirus infection in innate immune cells and their progenitors
Cheong, J.-G., Ravishankar, A., Sharma, S., Parkhurst, C. N., Grassmann, S. A., Wingert, C. K., Laurent, P., Ma, S., Paddock, L., Miranda, I. C., et al. (2023) · Cell · doi:10.1016/j.cell.2023.07.019 · Cited by 309 · see citing works
Sparks, J. A., Wallace, Z. S., Seet, A. M., Gianfrancesco, M. A., Izadi, Z., Hyrich, K. L., Strangfeld, A., Gossec, L., Carmona, L., Mateus, E. F., et al. (2021) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2021-220418 · Cited by 238 · see citing works
COVID-19 and pulmonary fibrosis: a potential role for lung epithelial cells and fibroblasts
John, A. E., Joseph, C., Jenkins, G., & Tatler, A. L. (2021) · Immunological Reviews · doi:10.1111/imr.12977 · Cited by 219 · see citing works
Writing Committee for the REMAP-CAP Investigators, Abdelhady, H., Abdelrazik, M., Abdi, Z., Abdo, D., Abdulle, A., Abel, L., Abouzeenni, S., Abrahamson, G., Abusamra, Y., et al. (2021) · JAMA · doi:10.1001/jama.2021.18178 · Cited by 212 · see citing works
Mariette, X., Hermine, O., Tharaux, P.-L., Resche-Rigon, M., Steg, P. G., Porcher, R., & Ravaud, P. (2021) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2021.2209 · Cited by 140 · see citing works
IL-6 Revisited: From Rheumatoid Arthritis to CAR T Cell Therapy and COVID-19
Kishimoto, T., & Kang, S. (2022) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101220-023458 · Cited by 140 · see citing works
Articular cartilage repair biomaterials: strategies and applications
Wang, M., Wu, Y., Li, G., Lin, Q., Zhang, W., Liu, H., & Su, J. (2024) · Materials Today Bio · doi:10.1016/j.mtbio.2024.100948 · Cited by 145 · see citing works
Cell deaths: Involvement in the pathogenesis and intervention therapy of COVID-19
Li, X., Zhang, Z., Wang, Z., Gutiérrez-Castrellón, P., & Shi, H. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01043-6 · Cited by 67 · see citing works
COVID-19 as a Risk Factor for Alzheimer’s Disease
Golzari-Sorkheh, M., Weaver, D. F., & Reed, M. A. (2023) · Journal of Alzheimer's Disease · doi:10.3233/jad-220800 · Cited by 39 · see citing works
Hayward, G., Yu, L.-M., Little, P., Gbinigie, O., Shanyinde, M., Harris, V., Dorward, J., Saville, B. R., Berry, N., Evans, P. H., et al. (2024) · Journal of Infection · doi:10.1016/j.jinf.2024.106130 · Cited by 31 · see citing works
Proactive vs Reactive Machine Learning in Health Care: Lessons From the COVID-19 Pandemic
Luo, Y., Wunderink, R. G., & Lloyd-Jones, D. (2022) · JAMA · doi:10.1001/jama.2021.24935 · Cited by 24 · see citing works
Predisposition of COVID-19 patients to secondary infections: set in stone or subject to change?
Sopirala, M. M. (2021) · Current Opinion in Infectious Diseases · doi:10.1097/qco.0000000000000736 · Cited by 8 · see citing works
Acute management of sepsis beyond 24 hours
Premachandra, A., & Heming, N. (2024) · Seminars in Respiratory and Critical Care Medicine · doi:10.1055/s-0044-1787991 · Cited by 2 · see citing works
- Authors
- The REMAP-CAP Investigators
- Affiliations
- University College Dublin (IE)
- Corresponding author
- The REMAP-CAP Investigators
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2021-04-22
- Volume
- 384
- Issue
- 16
- Pages
- 1491-1502
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC7953461
- OpenAlex
- W3130126061
- Cited by
- 1,962
- References
- 22
- Citations by year
- 2026: 87 · 2025: 120 · 2024: 220 · 2023: 320 · 2022: 589 · 2021: 615 · 2020: 7 · 2013: 1
- FWCI
- 138.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Sussex Research Online (University of Sussex) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
- HAL (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- ePrints Soton (University of Southampton) (submittedVersion)
- Figshare (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Research Portal (Queen's University Belfast) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion, other-oa)
- The Sydney eScholarship Repository (The University of Sydney) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Apollo
- Funders
- Wellcome Trust Innovations Project (215522)
- National Institute for Health Research, Research Professorship (RP-2015-06-18)
- National Institute for Health Research, Clinician ScientistNational Institute for Health Research, Research Professorship (CS-2016-16-011)
- European Union, FP7 (#602525)
- European Union Horizon 2020 (#101003589)
- Australian National Health and Medical Research Council (#APP1101719)
- Health Research Council of New Zealand (#16/631)
- Canadian Institute of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program (#158584)
- National Institute for Health Research
- Health Research Board of Ireland (CTN 2014-012)
- UPMC Learning While Doing Program
- Breast Cancer Research Foundation
- French Ministry of Health (PHRC-20-0147)
- Minderoo Foundation
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Respiratory Support and Mechanisms
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Keywords
- IL-6 receptor inhibitor, tocilizumab, sarilumab, COVID-19 pandemic, critically ill patients, organ support, intensive care unit, cytokine storm
- MeSH terms
- COVID-19, COVID-19 Drug Treatment, Adult, Aged, Female, Humans, Intensive Care Units, Male, Middle Aged, Respiration, Artificial, Odds Ratio, Critical Illness, Hospital Mortality, Receptors, Interleukin-6, Antibodies, Monoclonal, Humanized
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
