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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Gupta 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.

Figures

Figure 1.. Study Cohort and Emulated Trial Flow

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ICU, intensive care unit; and IL-6, interleukin 6. To convert ALT and AST to μkat/L, multiply by 0.0167.

Figure 2.. Mortality in Tocilizumab-Treated vs Non-Tocilizumab–Treated Patients

A total of 63 tocilizumab-treated and 259 non-tocilizumab–treated patients were still hospitalized at last follow-up and thus could not be fully assessed for the primary outcome. ICU indicates intensive care unit.

Figure 3.. Subgroup Analyses Examining Mortality in Tocilizumab-Treated vs Non-Tocilizumab–Treated Patients

The hazard ratios (HRs) in the Forest plot are adjusted for the following covariates: age, sex, race, ethnicity, body mass index, hypertension, diabetes, coronary artery disease, congestive heart failure, current tobacco use, active cancer, home medications (statin, angiotensin-converting enzyme inhibitor, angiotensin 2 receptor blocker), days from symptom onset to intensive care unit (ICU) admission, severity-of-illness covariates assessed on ICU admission (fever, the renal and liver components of the Sequential Organ Failure Assessment score, the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen [Pao2:Fio2], the number of vasopressors received, white blood cell count, and inflammation [assessed by levels of C-reactive protein, interleukin 6, and ferritin]), and concurrent therapies received on ICU admission (hydroxychloroquine sulfate, azithromycin, corticosteroids, therapeutic anticoagulants, prone positioning, and neuromuscular blockade). NA indicates not applicable. aDefined as any of the following critical values or events on the day of ICU admission: arterial pH of less than 7.0, arterial lactate level of greater than 90.1 mg/dL (to convert to mmol/L, multiply by 0.111), receipt of 4 or more vasopressors, or cardiac arrest.