key: cord-0774915-un8b2tal
authors: Martínez-Sanz, Javier; Muriel, Alfonso; Ron, Raquel; Herrera, Sabina; Pérez-Molina, José A.; Moreno, Santiago; Serrano-Villar, Sergio
title: Effects of tocilizumab on mortality in hospitalized patients with COVID-19: A multicenter cohort study
date: 2020-09-23
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2020.09.021
sha: 0a83479aa168ffc29b511e295696df601d5bbbff
doc_id: 774915
cord_uid: un8b2tal

OBJECTIVES: Tocilizumab has been proposed as a candidate therapy for patients with severe coronavirus disease 2019 (COVID-19), especially among those with higher systemic inflammation. Here, we investigate the association between tocilizumab use and mortality in a large cohort of hospitalized patients. METHODS: Cohort study of patients hospitalized with COVID-19 in Spain. The primary outcome was time to death and the secondary outcome time to intensive care unit admission (ICU) or death. We used inverse-probability weighting to fit marginal structural models adjusted for time-varying covariates to determine the causal relationship between tocilizumab use and the outcomes. RESULTS: A total of 1,229 patients were analyzed, with 261 patients (61 deaths) in the tocilizumab group and 969 patients (120 deaths) in the control group. In the adjusted marginal structural models, a significant interaction between tocilizumab use and high C-reactive protein (CRP) levels was detected. Tocilizumab was associated with decreased risk of death (aHR 0.34, 95% CI 0.16–0.72, p=0.005) and ICU admission or death (aHR 0.38, 95% CI 0.19–0.81, p=0.011) among patients with baseline CRP >150 mg/L, but not among those with CRP ≤150 mg/L. Exploratory subgroup analyses yielded point estimates that were consistent with these findings. CONCLUSIONS: In this large observational study, tocilizumab was associated with a lower risk of death or ICU or death in patients with higher CRP levels. While the results of ongoing clinical trials of tocilizumab in patients with COVID-19 will be important to establish its safety and efficacy, our findings have implications for the design of future clinical trials.

There are still no treatments with proven efficacy to prevent mortality in patients with 60 severe coronavirus disease 2019 (COVID-19) pneumonia, with the exception of 61 corticosteroids in selected patient groups [1] . However, various medications such as 62 hydroxychloroquine, azithromycin, and lopinavir/ritonavir have been prescribed off-63 label worldwide. [2] Tocilizumab is an FDA-approved humanized monoclonal 64 antibody against the soluble interleukin-6 (IL-6) receptor. It is widely used in the 65 treatment of autoimmune disorders such as rheumatoid arthritis or cytokine release 66 syndrome.[3,4] IL-6 determination is rarely available in clinical settings. However, C-67 reactive protein (CRP)-an inflammatory biomarker upstream in the IL-6 pathway-, 68

is commonly used to monitor the activity of inflammatory diseases.

[5] 69

Tocilizumab has been suggested as an effective treatment for severe COVID-19 70 pneumonia due to the increased interleukin 6 (IL-6) blood levels in patients with 71 COVID-19[6] and its correlation with a more severe lung damage,[7] however, it is 72 not currently approved for use by any regulatory body in COVID-19 patients. 73

To date, very few efficacy results from clinical trials in this disease have been 74 and Related Health Problems (ICD-10) classification. [17] 102

We excluded patients younger than 18 years and those who died or were transferred 103 to another facility within 24 hours after admission to the emergency department. This 104 study was approved by the Ethics Committee at University Hospital Ramón y Cajal 105

The primary end point was the time from study baseline (defined as the first day of 109 hospitalization) to in-hospital death for any cause. The secondary outcome was a 110 composite event including admission to the ICU or death (hereafter ICU/death). 111

Patients were censored at the endpoint or at the end of follow-up (hospital discharge 112 or end of data collection in the database). 113

114 Statistical analysis 115 We tested the associations among the preadmission variables with treatment variable 116 by Chi-square tests for categorical variables and Wilcoxon rank sum tests for 117 continuous variables. We calculated the crude incidence rates of death and ICU/death 118 using Kaplan-Meier methods. We fitted marginal structural models to estimate We assumed that once a patient received tocilizumab, they remained on it until the end 124 of follow-up. This assumption helped obtain a conservative estimate of the treatment 125 hazard ratio analogous to intention-to-treat analysis in an unblinded randomized 126 controlled trial. We structured the data set to allow for time-dependent covariates to 127 change daily after admission. Propensity score logistic models predicted exposure at tocilizumab and CRP was significant, and thus we report the adjusted (weighted) 148 hazard ratios (HRs) derived from marginal structural models for the primary and 149 secondary outcomes segregated by CRP levels. 150

We planned exploratory sensitivity analyses restricted to patients who received 151 specific concomitant treatments against SARS-CoV-2. Due to the recognized 152 prognostic value of lymphocyte counts and D-dimer levels, we also performed 153 sensitivity analysis to explore the possible confounding effect of D-dimer >1000 154 ng/mL (upper limit of the normal range in the reference laboratory) or absolute 155 lymphocyte count <1000/uL (lower limit of the normal range in our reference 156 laboratory). Statistical analyses were performed using Stata v. 16.0 (StataCorp LP 157

College Station, TX, USA). 158

We analyzed 1,229 patients accounting for 10,673 person-days of follow-up who were 162 diagnosed with COVID-19 in HM hospitals between January 31 st and April 23 rd , 2020 163 and have the information needed for IPTW estimation. We excluded 99 patients 164 because they died, were discharged, or were transferred to a different hospital within 165 24 hours after admission to the emergency department (Appendix Figure 1) Individuals with baseline CRP levels higher than 150 mg/L who received tocilizumab 203 maintained a lower risk of death and ICU/death, but no significant effects of 204 tocilizumab were found among those with low CRP levels. 205

We also explored the effects of concomitant therapies against SARS-COV-2 in 206 sensitivity analyses restricted to patients who received corticosteroids (n=582), 207 hydroxychloroquine (n=1,134), azithromycin (n=812), or lopinavir/ritonavir (n=753) 208 (Appendix Table 3 generating. In addition, we could not analyze the rate of new infectious, which was 276 higher with tocilizumab in a previous observational study. [8] 277

In summary, we analyzed a large number of consecutive patients hospitalized with 278 COVID-19 and found that tocilizumab was associated with a lower risk of mortality or 279 ICU admission/mortality among patients with CRP >150 mg/L, but not among those Weighted hazard ratios derived from marginal structural models adjusted for sex, age, comorbidities 403 (hypertension, diabetes, ischemic heart disease, chronic kidney disease, congestive heart failure, lung 404 disease), need for oxygen therapy at baseline, oxygen blood saturation, and time-varying parameters of 405 severity (blood pressure, heart rate, total lymphocyte and neutrophil count, LDH, ALT, urea, D-dimer, Weighted hazard ratios derived from marginal structural models adjusted for sex, age, 416 comorbidities (hypertension, diabetes, ischemic heart disease, chronic kidney disease, 417 congestive heart failure, lung disease), need for oxygen therapy at baseline, oxygen blood 418 saturation, and time-varying parameters of severity (blood pressure, heart rate, total 419 lymphocyte and neutrophil count, LDH, ALT, urea, D-dimer, and CRP). 

Dexamethasone in Hospitalized Patients 312 with Covid-19 -Preliminary Report

Treating COVID-19 -Off-Label Drug Use, Compassionate Use

Randomized Clinical Trials during Pandemics

Tocilizumab in 317 rheumatoid arthritis: A meta-analysis of efficacy and selected clinical 318 conundrums

Therapeutic efficacy of humanized 320 recombinant anti-interleukin-6 receptor antibody in children with systemic-321 onset juvenile idiopathic arthritis

From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving 323 Upstream to Identify Novel Targets for Atheroprotection

Clinical course and risk factors for mortality of adult 326 inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

The cytokine release syndrome 329 (CRS) of severe COVID-19 and Interleukin-6 receptor

Tocilizumab may be the key to reduce the mortality

Tocilizumab in patients with 333 severe COVID-19: a retrospective cohort study

Pilot prospective open, single-arm multicentre 336 study on off-label use of tocilizumab in patients with severe COVID-19

Effective treatment of severe COVID-19 patients with

Use of Tocilizumab for COVID-19-Induced

Cytokine Release Syndrome: A Cautionary Case Report

Tocilizumab treatment in COVID-19: A 344 single center experience

Tocilizumab for the treatment of severe

COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory 347 failure: A single center study of 100 patients in

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Severe COVID-19 Pneumonia -ClinicalTrials.gov. Available at

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With COVID-19 -ClinicalTrials.gov. Available

Request Form 'Covid Data Save Lives

Marginal structural models to estimate 363 the causal effect of zidovudine on the survival of HIV-positive men

Time-dependent Confounding using Marginal Structural Models

Development and Validation of a Clinical Risk 369 Score to Predict the Occurrence of Critical Illness in Hospitalized Patients With 370 COVID-19

Baseline Characteristics and 372 Outcomes of 1591 Patients Infected with SARS-CoV-2

SARS-CoV-2 Cell Entry 375 Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven 376

A crucial role of angiotensin converting enzyme 2 378 (ACE2) in SARS coronavirus-induced lung injury

Sanofi and Regeneron provide update on Kevzara® (sarilumab) Phase 3 U.S. 381 trial in COVID-19 patients -Sanofi

Roche -Roche provides an update on the phase III COVACTA trial of

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Covid-19: Risk factors for severe disease and 389 death

Arterial review and meta-analysis

Problem of immortal time bias in 394 cohort studies: Example using statins for preventing progression of diabetes

Marginal structural models in clinical research: When 397 and how to use them?

Systolic blood pressure (mmHg), median (IQR)

Temperature (ºC), median (IQR)

Peripheral oxygen saturation (%), median (IQR)

Absolute lymphocyte count (cells/mm3)

Absolute neutrophil count (cells/mm3)

ALT (U/L), median (IQR)

Creatinine (mg/dL), median (IQR)

Urea (mg/dL), median (IQR)

C-reactive protein (mg/L), median (IQR)

/mL), median (IQR)

Abbreviations: ALT, aspartate alanine transferase; ICU, intensive care unit

All variables were available in the 1,229 subjects, with exception of IL-6, which was measured only in 88 individuals

Non-ICU length of stay (days), median (