Efficacy of tocilizumab treatment in severely ill COVID-19 patients

Zhao, Jie; Cui, Wei; Tian, Bao Ping

doi:10.1186/s13054-020-03224-7

Cited by 41 publications

(44 citation statements)

References 6 publications

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“…This is similar to the findings reported by Gupta et al ( 37 ), which showed tocilizumab use was associated with 29% reduction in the risk of mortality in critically ill patients (adjusted HR, 0.71; 95% CI, 0.56–0.92) and Somers et al ( 25 ) where tocilizumab use was associated with a 45% reduction in death (HR, 0.55; 95% CI, 0.33–0.90). This is also similar to a recent meta-analysis showing a positive association with tocilizumab on mortality in patients with COVID-19 (pooled OR, 0.47; 95% CI, 0.36–0.60) ( 45 ). The aforementioned studies are all retrospective in nature and thus inherently limited.…”

Section: Discussionsupporting

confidence: 90%

Tocilizumab in Coronavirus Disease 2019-Related Critical Illness: A Propensity Matched Analysis

Rajendram

Sacha

Mehkri

et al. 2021

Critical Care Explorations

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Objectives: The primary objective was to evaluate ICU mortality at 28 days in patients with severe hypoxemic respiratory failure due to coronavirus disease 2019 infection who received tocilizumab. The secondary objectives were to evaluate ICU-, hospital-, mechanical ventilation-, and vasopressor-free days at day 28 and development of secondary infections. Design: Retrospective, observational, multicenter, cohort study between March 15, 2020, and May 31, 2020. Using propensity score matching based on ICU admission source, C-reactive protein, Sequential Organ Failure Assessment score, vasopressor use, age, race, weight, and mechanical ventilation, patients who received tocilizumab were matched to patients who did not receive tocilizumab. Setting: Ten hospitals within the Cleveland Clinic Enterprise. PATIENTS: Adult patients admitted to a medical, surgical, neurosciences, or mixed ICU with severe acute respiratory syndrome coronavirus 2 infection. Interventions: None. Measurements and Main Results: Four-hundred forty-four patients were included: 342 patients (77%) did not receive tocilizumab and 102 patients (23%) received tocilizumab. Of those, 82 patients in each arm were matched. Before matching, patients who received tocilizumab had higher Sequential Organ Failure Assessment scores (6.1 ± 3.4 vs 4.7 ± 3.6), higher C-reactive protein (21.0 ± 10.2 vs 13.7 ± 9.6 mg/dL), higher frequency of intubation, vasopressor requirement, and paralytics. After matching, characteristics were more balanced and over 85% of patients required mechanical ventilation. ICU mortality was lower in tocilizumab group (23.2% vs 37.8%; risk difference, –15%; 95% CI, –29% to –1%), with more ICU-, hospital-, and vasoactive-free days at day 28 compared with those who did not receive tocilizumab. There was no difference in mechanical ventilation-free days at day 28 or development of secondary infections. Conclusions: Tocilizumab use was associated with a significant decrease in ICU mortality in critically ill coronavirus disease 2019 patients with severe hypoxemic respiratory failure. Future randomized controlled trials limited to tocilizumab administration in critically ill coronavirus disease 2019 patients, with severe hypoxemic respiratory failure, are needed to support these findings.

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Section: Discussionsupporting

confidence: 90%

Tocilizumab in Coronavirus Disease 2019-Related Critical Illness: A Propensity Matched Analysis

Rajendram

Sacha

Mehkri

et al. 2021

Critical Care Explorations

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“…Low-certainty evidence from observational studies suggests an association between tocilizumab and lower mortality [ 4 ] that was then confirmed in a preliminary report by an RCT [ 22 ]. This was confirmed by other previous meta-analyses, including mostly observational studies [ 23 , 24 ]. Observational studies that investigated anakinra in COVID-19 patients showed that use was associated with lower mortality [ 25 ].…”

Section: Discussionsupporting

confidence: 89%

Multistate Modeling of COVID-19 Patients Using a Large Multicentric Prospective Cohort of Critically Ill Patients

Ursino

Dupuis

Buetti

et al. 2021

JCM

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The mortality of COVID-19 patients in the intensive care unit (ICU) is influenced by their state at admission. We aimed to model COVID-19 acute respiratory distress syndrome state transitions from ICU admission to day 60 outcome and to evaluate possible prognostic factors. We analyzed a prospective French database that includes critically ill COVID-19 patients. A six-state multistate model was built and 17 transitions were analyzed either using a non-parametric approach or a Cox proportional hazard model. Corticosteroids and IL-antagonists (tocilizumab and anakinra) effects were evaluated using G-computation. We included 382 patients in the analysis: 243 patients were admitted to the ICU with non-invasive ventilation, 116 with invasive mechanical ventilation, and 23 with extracorporeal membrane oxygenation. The predicted 60-day mortality was 25.9% (95% CI: 21.8%–30.0%), 44.7% (95% CI: 48.8%–50.6%), and 59.2% (95% CI: 49.4%–69.0%) for a patient admitted in these three states, respectively. Corticosteroids decreased the risk of being invasively ventilated (hazard ratio (HR) 0.59, 95% CI: 0.39–0.90) and IL-antagonists increased the probability of being successfully extubated (HR 1.8, 95% CI: 1.02–3.17). Antiviral drugs did not impact any transition. In conclusion, we observed that the day-60 outcome in COVID-19 patients is highly dependent on the first ventilation state upon ICU admission. Moreover, we illustrated that corticosteroid and IL-antagonists may influence the intubation duration.

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“…TOCIVID-19 is the largest completed prospective study on the effect of tocilizumab using mortality as primary end-point, among published or pre-published reports. Mostly, retrospective or observational data have been reported so far, not based on prospective hypothesis testing, with prevalently positive results [ 17 – 32 ].…”

Section: Discussionmentioning

confidence: 99%

Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial

Marata¹,

et al. 2020

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Background Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Conclusions Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).

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Efficacy of tocilizumab treatment in severely ill COVID-19 patients

Cited by 41 publications

References 6 publications

Tocilizumab in Coronavirus Disease 2019-Related Critical Illness: A Propensity Matched Analysis

Tocilizumab in Coronavirus Disease 2019-Related Critical Illness: A Propensity Matched Analysis

Multistate Modeling of COVID-19 Patients Using a Large Multicentric Prospective Cohort of Critically Ill Patients

Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial

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