Association between Early Treatment with Tocilizumab and Mortality among Critically Ill Patients with COVID-19

Shruti Gupta; Wei Wang; Salim S. Hayek; Lili Chan; Kusum S. Mathews; Michal L. Melamed; Samantha K. Brenner; Amanda Leonberg-Yoo; Edward J. Schenck; Jared Radbel; Jochen Reiser; Anip Bansal; Anand Srivastava; Yan Zhou; Diana Finkel; Adam Green; Mary Mallappallil; Anthony J. Faugno; Jingjing Zhang; Juan Carlos Q. Velez; Shahzad Shaefi; Chirag R. Parikh; David M. Charytan; Ambarish M. Athavale; Allon N. Friedman; Roberta E. Redfern; Samuel A.P. Short; Simon Correa; Kapil K. Pokharel; Andrew J. Admon; John P. Donnelly; Hayley B. Gershengorn; David J. Douin; Matthew W. Semler; Miguel A. Hernán; David E. Leaf

doi:10.1001/jamainternmed.2020.6252

Association between Early Treatment with Tocilizumab and Mortality among Critically Ill Patients with COVID-19

Shruti Gupta, Wei Wang, Salim S. Hayek, Lili Chan, Kusum S. Mathews, Michal L. Melamed, Samantha K. Brenner, Amanda Leonberg-Yoo, Edward J. Schenck, Jared Radbel, Jochen Reiser, Anip Bansal, Anand Srivastava, Yan Zhou, Diana Finkel, Adam Green, Mary Mallappallil, Anthony J. Faugno, Jingjing Zhang, Juan Carlos Q. VelezShahzad Shaefi, Chirag R. Parikh, David M. Charytan, Ambarish M. Athavale, Allon N. Friedman, Roberta E. Redfern, Samuel A.P. Short, Simon Correa, Kapil K. Pokharel, Andrew J. Admon, John P. Donnelly, Hayley B. Gershengorn, David J. Douin, Matthew W. Semler, Miguel A. Hernán, David E. Leaf^*

^*Corresponding author for this work

Medicine, Nephrology Division

Research output: Contribution to journal › Article › peer-review

368 Scopus citations

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..

Original language	English (US)
Pages (from-to)	41-51
Number of pages	11
Journal	JAMA internal medicine
Volume	181
Issue number	1
DOIs	https://doi.org/10.1001/jamainternmed.2020.6252
State	Published - Jan 2021

Funding

reported receiving personal fees from GlaxoSmithKline for serving as scientific coordinator for the ASCEND trial outside the submitted work. Dr Hayek reported receiving personal fees from Trisaq, Inc, outside the submitted work. Dr Chan reported receiving grants from the National Institutes of Health (NIH) outside the submitted work. Dr Mathews reported receiving grants from the NIH/National Heart, Lung, and Blood Institute (NHLBI) and other from Roivant/Kinevant Sciences outside the submitted work. Dr Melamed reported receiving personal fees from the American Board of Internal Medicine and ICON Medical Consulting outside the submitted work. Dr Reiser reported receiving personal fees from BioMarin Pharmaceutical, Inc, Astellas Pharma, Inc, Massachusetts General Hospital, Genentech, Inc, UptoDate, Merck & Co, InceptionSCI, and GLG Pharma, Inc, grants from the NIH, NephCure Kidney International, and Thermo BCT, Inc, and other from Trisaq, Inc, outside the submitted work. Dr Reiser reported being co-founder and co-scientific advisory board director of Trisaq, Inc, a biopharmaceutical company developing drugs for kidney diseases. Dr Srivastava reported receiving grants from NIH/ National Institute of Diabetes and Digestive and Kidney Diseases and personal fees from Horizon Therapeutics plc, AstraZeneca, CVS Caremark, and Medico Legal Consulting outside the submitted work. Dr Velez reported receiving personal fees from Mallinckrodt Pharmaceuticals, Otsuka Pharmaceutical Co, Ltd, and Retrophin, Inc, outside the submitted work. Dr Shaefi reported receiving grants from NIH/National Institute on Aging and NIH/National Institute of General Medical Sciences outside of the submitted work. Dr Parikh reported receiving personal fees from GENFIT and Renalytix AI plc outside the submitted work. Dr Charytan reported receiving grants and personal fees from Janssen Pharmaceutica, Novo Nordisk A/S, and Gilead Sciences, Inc, and personal fees from GlaxoSmithKline, Merck & Co, PLC Medical Systems, Inc, BioPorto A/S, and AstraZeneca outside the submitted work. Dr Friedman reported being a current member of the scientific advisory board for GI Dynamics, Inc, and consulting for DSMB Watermark. Dr Admon reported receiving grants from the NIH/NHLBI during the conduct of the study. Dr Donnelly reported receiving grants from the NIH/NHLBI during the conduct of the study and personal fees from ACEP/Annals of Emergency Medicine outside the submitted work. Dr Semler reported receiving grants from the NIH/NHLBI during the conduct of the study. Dr Leaf reported receiving research support from BioPorto A/S and grants from the NIH outside the submitted work. No other disclosures were reported. Funding/Support: The writing committee was supported by grants F32HL149337 (Dr Admon), K23DK120811 (Dr Srivastava), R01HL085757 (Dr Parikh), R01HL144566 and R01DK125786 (Dr Leaf), K12HL138039 (Dr Donnelly), K23HL130648 (Dr Mathews), R37AI102634 (Dr Hernán), F32DC017342 (Dr Gupta), K08GM134220 and R03AG060179 (Dr Shaefi), K23HL143053 (Dr Semler), and R01HL153384 (Dr Hayek) from the NIH and grant U-M G024231 from the Frankel Cardiovascular Center COVID-19: Impact Research Ignitor (Dr Hayek).

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Internal Medicine

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10.1001/jamainternmed.2020.6252

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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

@article{4e47b10e7301459eb6b012b5701cf79f,

title = "Association between Early Treatment with Tocilizumab and Mortality among Critically Ill Patients with COVID-19",

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..",

author = "Shruti Gupta and Wei Wang and Hayek, {Salim S.} and Lili Chan and Mathews, {Kusum S.} and Melamed, {Michal L.} and Brenner, {Samantha K.} and Amanda Leonberg-Yoo and Schenck, {Edward J.} and Jared Radbel and Jochen Reiser and Anip Bansal and Anand Srivastava and Yan Zhou and Diana Finkel and Adam Green and Mary Mallappallil and Faugno, {Anthony J.} and Jingjing Zhang and Velez, {Juan Carlos Q.} and Shahzad Shaefi and Parikh, {Chirag R.} and Charytan, {David M.} and Athavale, {Ambarish M.} and Friedman, {Allon N.} and Redfern, {Roberta E.} and Short, {Samuel A.P.} and Simon Correa and Pokharel, {Kapil K.} and Admon, {Andrew J.} and Donnelly, {John P.} and Gershengorn, {Hayley B.} and Douin, {David J.} and Semler, {Matthew W.} and Hern{\'a}n, {Miguel A.} and Leaf, {David E.}",

year = "2021",

month = jan,

doi = "10.1001/jamainternmed.2020.6252",

language = "English (US)",

volume = "181",

pages = "41--51",

journal = "JAMA internal medicine",

issn = "2168-6106",

publisher = "American Medical Association",

number = "1",

}

Gupta, S, Wang, W, Hayek, SS, Chan, L, Mathews, KS, Melamed, ML, Brenner, SK, Leonberg-Yoo, A, Schenck, EJ, Radbel, J, Reiser, J, Bansal, A, Srivastava, A, Zhou, Y, Finkel, D, Green, A, Mallappallil, M, Faugno, AJ, Zhang, J, Velez, JCQ, Shaefi, S, Parikh, CR, Charytan, DM, Athavale, AM, Friedman, AN, Redfern, RE, Short, SAP, Correa, S, Pokharel, KK, Admon, AJ, Donnelly, JP, Gershengorn, HB, Douin, DJ, Semler, MW, Hernán, MA & Leaf, DE 2021, 'Association between Early Treatment with Tocilizumab and Mortality among Critically Ill Patients with COVID-19', JAMA internal medicine, vol. 181, no. 1, pp. 41-51. https://doi.org/10.1001/jamainternmed.2020.6252

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.

PY - 2021/1

Y1 - 2021/1

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..

AB - 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..

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Association between Early Treatment with Tocilizumab and Mortality among Critically Ill Patients with COVID-19

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