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Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19.
JAMA Intern Med. 2021 01 01; 181(1):41-51.JIM

Abstract

Importance

Therapies that improve survival in critically ill patients with coronavirus disease 2019 (COVID-19) are needed. Tocilizumab, a monoclonal antibody against the interleukin 6 receptor, may counteract the inflammatory cytokine release syndrome in patients with severe COVID-19 illness.

Objective

To test whether tocilizumab decreases mortality in this population.

Design, Setting, and Participants

The data for this study were derived from a multicenter cohort study of 4485 adults with COVID-19 admitted to participating intensive care units (ICUs) at 68 hospitals across the US from March 4 to May 10, 2020. Critically ill adults with COVID-19 were categorized according to whether they received or did not receive tocilizumab in the first 2 days of admission to the ICU. Data were collected retrospectively until June 12, 2020. A Cox regression model with inverse probability weighting was used to adjust for confounding.

Exposures

Treatment with tocilizumab in the first 2 days of ICU admission.

Main Outcomes and Measures

Time to death, compared via hazard ratios (HRs), and 30-day mortality, compared via risk differences.

Results

Among the 3924 patients included in the analysis (2464 male [62.8%]; median age, 62 [interquartile range {IQR}, 52-71] years), 433 (11.0%) received tocilizumab in the first 2 days of ICU admission. Patients treated with tocilizumab were younger (median age, 58 [IQR, 48-65] vs 63 [IQR, 52-72] years) and had a higher prevalence of hypoxemia on ICU admission (205 of 433 [47.3%] vs 1322 of 3491 [37.9%] with mechanical ventilation and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of <200 mm Hg) than patients not treated with tocilizumab. After applying inverse probability weighting, baseline and severity-of-illness characteristics were well balanced between groups. A total of 1544 patients (39.3%) died, including 125 (28.9%) treated with tocilizumab and 1419 (40.6%) not treated with tocilizumab. In the primary analysis, during a median follow-up of 27 (IQR, 14-37) days, patients treated with tocilizumab had a lower risk of death compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56-0.92). The estimated 30-day mortality was 27.5% (95% CI, 21.2%-33.8%) in the tocilizumab-treated patients and 37.1% (95% CI, 35.5%-38.7%) in the non-tocilizumab-treated patients (risk difference, 9.6%; 95% CI, 3.1%-16.0%).

Conclusions and Relevance

Among critically ill patients with COVID-19 in this cohort study, the risk of in-hospital mortality in this study was lower in patients treated with tocilizumab in the first 2 days of ICU admission compared with patients whose treatment did not include early use of tocilizumab. However, the findings may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed.

Authors+Show Affiliations

Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts.Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, Massachusetts.Division of Cardiology, Department of Medicine, University of Michigan, Ann Arbor.Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Emergency Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.Department of Medicine, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York.Department of Internal Medicine, Hackensack Meridian School of Medicine at Seton Hall, Nutley, New Jersey. Department of Internal Medicine, Hackensack Meridian Health, Hackensack University Medical Center, Hackensack, New Jersey.Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia.Divison of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine Center, New York, New York.Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.Department of Medicine, Rush University Medical Center, Chicago, Illinois.Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus Aurora, Aurora.Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois.Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee.Department of Medicine, Division of Infectious Diseases, New Jersey Medical School, Rutgers University, Newark.Division of Critical Care, Cooper University Health Care, Camden, New Jersey.Division of Nephrology, Kings County Hospital Center, New York City Health and Hospital Corporation, Brooklyn, New York.Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center, Boston, Massachusetts.Division of Nephrology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.Department of Nephrology, Ochsner Health System, New Orleans, Louisiana. Ochsner Clinical School, University of Queensland, Brisbane, Australia.Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.Division of Nephrology, Johns Hopkins School of Medicine, Baltimore, Maryland.Division of Nephrology, Department of Medicine, NYU (New York University) Langone Medical Center, New York, New York.Division of Nephrology, Cook County Health, Chicago, Illinois.Department of Medicine, Indiana University School of Medicine/Indiana University Health, Indianapolis.ProMedica Research, ProMedica Toledo Hospital, Toledo, Ohio.University of Vermont Larner College of Medicine, Burlington.Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts.Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts.Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor.Department of Learning Health Sciences, University of Michigan Medical School, Ann Arbor. Institute for Healthcare Policy & Innovation, University of Michigan, Ann Arbor.Division of Pulmonary, Critical Care, and Sleep Medicine, University of Miami Miller School of Medicine, Miami, Florida. Division of Critical Care Medicine, Albert Einstein College of Medicine, Bronx, New York.Department of Anesthesiology, University of Colorado School of Medicine, Aurora.Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.Department of Epidemiology and Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. Harvard-MIT (Massachusetts Institute of Technology) Program in Health Sciences and Technology, Boston, Massachusetts.Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

33080002

Citation

Gupta, Shruti, et al. "Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19." JAMA Internal Medicine, vol. 181, no. 1, 2021, pp. 41-51.
Gupta S, Wang W, Hayek SS, et al. Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19. JAMA Intern Med. 2021;181(1):41-51.
Gupta, S., Wang, W., Hayek, S. S., Chan, L., Mathews, K. S., Melamed, M. L., Brenner, S. K., Leonberg-Yoo, A., Schenck, E. J., Radbel, J., Reiser, J., Bansal, A., Srivastava, A., Zhou, Y., Finkel, D., Green, A., Mallappallil, M., Faugno, A. J., Zhang, J., ... Leaf, D. E. (2021). Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19. JAMA Internal Medicine, 181(1), 41-51. https://doi.org/10.1001/jamainternmed.2020.6252
Gupta S, et al. Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19. JAMA Intern Med. 2021 01 1;181(1):41-51. PubMed PMID: 33080002.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19. AU - Gupta,Shruti, AU - Wang,Wei, AU - Hayek,Salim S, AU - Chan,Lili, AU - Mathews,Kusum S, AU - Melamed,Michal L, AU - Brenner,Samantha K, AU - Leonberg-Yoo,Amanda, AU - Schenck,Edward J, AU - Radbel,Jared, AU - Reiser,Jochen, AU - Bansal,Anip, AU - Srivastava,Anand, AU - Zhou,Yan, AU - Finkel,Diana, AU - Green,Adam, AU - Mallappallil,Mary, AU - Faugno,Anthony J, AU - Zhang,Jingjing, AU - Velez,Juan Carlos Q, AU - Shaefi,Shahzad, AU - Parikh,Chirag R, AU - Charytan,David M, AU - Athavale,Ambarish M, AU - Friedman,Allon N, AU - Redfern,Roberta E, AU - Short,Samuel A P, AU - Correa,Simon, AU - Pokharel,Kapil K, AU - Admon,Andrew J, AU - Donnelly,John P, AU - Gershengorn,Hayley B, AU - Douin,David J, AU - Semler,Matthew W, AU - Hernán,Miguel A, AU - Leaf,David E, AU - ,, PY - 2020/10/21/pubmed PY - 2021/1/16/medline PY - 2020/10/20/entrez SP - 41 EP - 51 JF - JAMA internal medicine JO - JAMA Intern Med VL - 181 IS - 1 N2 - Importance: Therapies that improve survival in critically ill patients with coronavirus disease 2019 (COVID-19) are needed. Tocilizumab, a monoclonal antibody against the interleukin 6 receptor, may counteract the inflammatory cytokine release syndrome in patients with severe COVID-19 illness. Objective: To test whether tocilizumab decreases mortality in this population. Design, Setting, and Participants: The data for this study were derived from a multicenter cohort study of 4485 adults with COVID-19 admitted to participating intensive care units (ICUs) at 68 hospitals across the US from March 4 to May 10, 2020. Critically ill adults with COVID-19 were categorized according to whether they received or did not receive tocilizumab in the first 2 days of admission to the ICU. Data were collected retrospectively until June 12, 2020. A Cox regression model with inverse probability weighting was used to adjust for confounding. Exposures: Treatment with tocilizumab in the first 2 days of ICU admission. Main Outcomes and Measures: Time to death, compared via hazard ratios (HRs), and 30-day mortality, compared via risk differences. Results: Among the 3924 patients included in the analysis (2464 male [62.8%]; median age, 62 [interquartile range {IQR}, 52-71] years), 433 (11.0%) received tocilizumab in the first 2 days of ICU admission. Patients treated with tocilizumab were younger (median age, 58 [IQR, 48-65] vs 63 [IQR, 52-72] years) and had a higher prevalence of hypoxemia on ICU admission (205 of 433 [47.3%] vs 1322 of 3491 [37.9%] with mechanical ventilation and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of <200 mm Hg) than patients not treated with tocilizumab. After applying inverse probability weighting, baseline and severity-of-illness characteristics were well balanced between groups. A total of 1544 patients (39.3%) died, including 125 (28.9%) treated with tocilizumab and 1419 (40.6%) not treated with tocilizumab. In the primary analysis, during a median follow-up of 27 (IQR, 14-37) days, patients treated with tocilizumab had a lower risk of death compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56-0.92). The estimated 30-day mortality was 27.5% (95% CI, 21.2%-33.8%) in the tocilizumab-treated patients and 37.1% (95% CI, 35.5%-38.7%) in the non-tocilizumab-treated patients (risk difference, 9.6%; 95% CI, 3.1%-16.0%). Conclusions and Relevance: Among critically ill patients with COVID-19 in this cohort study, the risk of in-hospital mortality in this study was lower in patients treated with tocilizumab in the first 2 days of ICU admission compared with patients whose treatment did not include early use of tocilizumab. However, the findings may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed. SN - 2168-6114 UR - https://www.unboundmedicine.com/medline/citation/33080002/Association_Between_Early_Treatment_With_Tocilizumab_and_Mortality_Among_Critically_Ill_Patients_With_COVID_19_ L2 - https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/10.1001/jamainternmed.2020.6252 DB - PRIME DP - Unbound Medicine ER -