Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial

Veiga, Viviane Cordeiro; Prats, João Antônio Gonçalves Garreta; Farias, Danielle Leão Cordeiro de; Rosa, Régis Goulart; Dourado, Letícia Kawano; Zampieri, Fernando G.; Machado, Flávia Soares; Lópes, Renato D.; Berwanger, Otávio; Azevedo, Luciano César Pontes; Avezum, Álvaro; Lisboa, Thiago; Rojas, Salomón Soriano Ordinola; Coelho, Juliana Chaves; LEITE, RODRIGO T.; Carvalho, Júlio César de; Andrade, Luís Eduardo Coelho; Sandes, Alex Freire; Pintão, Maria Carolina; Castro, Cláudio Galvão de; Santos, Sueli Vieira dos; Almeida, Thiago Miranda Lopes de; Costa, André Nathan; Gebara, Otávio; Freitas, Flávio Geraldo Rezende; Pacheco, Eduardo Souza; Machado, David; Martin, J.; CONCEIÇÃO, FABIO G.; Siqueira, S; Damiani, Lucas Petri; ISHIHARA, LUCIANA M.; Schneider, Daniel; Souza, Denise de; Cavalcanti, Alexandre Biasi; Scheinberg, Phillip

doi:10.1136/bmj.n84

Cited by 363 publications

(475 citation statements)

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“…Figure 1 shows the PRISMA flow chart summarizing the search strategy. The literature search identified 36 full-text articles, of which 8 RCTs were eligible for inclusion in this study after full read [24][25][26][27][28][29]32,33]. A total of 6,311 patients were included, of which 3267 patients received tocilizumab and 3,044 received standard care/placebo.…”

Section: Search Results and Characteristics Of Included Trialsmentioning

confidence: 99%

“…Concealment of allocation was not mentioned in five trials and therefore risk of allocation concealment remains unclear in these trials [27][28][29]32,33]. Also, five trials had open label study design [27][28][29]32,33]. The risk of performance and selection bias was high in these trials as participants and personnel were not blinded to the assigned treatment.…”

Section: Risk Of Bias Assessmentmentioning

confidence: 99%

“…Bias due to selective reporting was deemed high in two studies because they were preliminary reports and data were not presented for some outcomes [32,33]. Risk of attrition bias was deemed high in one trial due to incomplete outcome [29]. In the rest of the studies, risk of attrition bias was low [24][25][26][27][28]32,33].…”

Section: Risk Of Bias Assessmentmentioning

confidence: 99%

“…All 8 RCTs reported the outcome of all-cause mortality [24][25][26][27][28][29]32,33]. A total of 810 deaths out of 3267 participants were reported in the tocilizumab arm compared to 893 deaths out of 3044 participants in the standard care/placebo arm.…”

Section: All-cause Mortalitymentioning

confidence: 99%

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Tocilizumab in hospitalized patients with COVID-19: A meta analysis of randomized controlled trials

Selvaraj

Khan

Bavishi

et al. 2021

Preprint

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Background: To date, only dexamethasone has been shown to reduce mortality in COVID-19 patients. Tocilizumab has been recently added to the treatment guidelines for hospitalized COVID-19 patients, but data remains conflicting. Methods: Electronic databases such as MEDLINE, EMBASE and Cochrane central were searched from March 1, 2020, until February 28th, 2021, for RCTs evaluating the efficacy of tocilizumab in hospitalized COVID-19 patients. The outcomes assessed were mortality at 28 days, mechanical ventilation, and time to discharge. Results: Eight studies (with 6,311 patients) were included in the analysis. In total, 3,267 patients received tocilizumab, and 3,044 received standard care/placebo. Pooled analysis showed a significantly decreased risk of mortality at 28 days (RR 0.90, 95% CI 0.83-0.97, p=0.009) and progression to mechanical ventilation (RR 0.79, 95% CI 0.70-0.90, p=0.0002) in the tocilizumab arm compared to standard therapy or placebo. In addition, there was a trend towards improved median time to hospital discharge (RR 1.18, 95% CI 1.05-1.34, p=0.007). Conclusions: Tocilizumab therapy improves outcomes of mortality and need for mechanical ventilation, in hospitalized patients with COVID-19 infection compared with standard therapy or placebo. Our findings suggest the efficacy of tocilizumab therapy in hospitalized COVID-19 patients and strengthen the concept that tocilizumab is a promising therapeutic intervention to improve mortality and morbidity in COVID-19 patients.

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Section: Search Results and Characteristics Of Included Trialsmentioning

confidence: 99%

Section: Risk Of Bias Assessmentmentioning

confidence: 99%

Section: Risk Of Bias Assessmentmentioning

confidence: 99%

Section: All-cause Mortalitymentioning

confidence: 99%

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Tocilizumab in hospitalized patients with COVID-19: A meta analysis of randomized controlled trials

Selvaraj

Khan

Bavishi

et al. 2021

Preprint

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“…28 Lastly, an RCT reporting that TCZ was not superior to SOC in improving clinical outcomes at 15 days was published on 22 January 2021. 29…”

Section: Tocilizumab Efficacymentioning

confidence: 99%

Immunomodulatory therapies for SARS-CoV-2 infection: a systematic literature review to inform EULAR points to consider

et al. 2021

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ObjectiveTo summarise the available information on efficacy and safety of immunomodulatory agents in SARS-CoV-2 infection.MethodsAs part of a European League Against Rheumatism (EULAR) taskforce, a systematic literature search was conducted from January 2019 to 11 December 2020. Two reviewers independently identified eligible studies according to the Population, Intervention, Comparator and Outcome framework and extracted data on efficacy and safety of immunomodulatory agents used therapeutically in SARS-CoV-2 infection at any stage. The risk of bias was assessed with validated tools.ResultsOf the 60 372 records, 401 articles were eligible for inclusion. Studies were at variable risk of bias. Randomised controlled trials (RCTs) were available for the following drugs: hydroxychloroquine (n=12), glucocorticoids (n=6), tocilizumab (n=4), convalescent plasma (n=4), interferon beta (n=2), intravenous immunoglobulins (IVIg) (n=2) and n=1 each for anakinra, baricitinib, colchicine, leflunomide, ruxolitinib, interferon kappa and vilobelimab. Glucocorticoids were able to reduce mortality in specific subsets of patients, while conflicting data were available about tocilizumab. Hydroxychloroquine was not beneficial at any disease stage, one RCT with anakinra was negative, one RCT with baricitinib+remdesivir was positive, and individual trials on some other compounds provided interesting, although preliminary, results.ConclusionAlthough there is emerging evidence about immunomodulatory therapies for the management of COVID-19, conclusive data are scarce with some conflicting data. Since glucocorticoids seem to improve survival in some subsets of patients, RCTs comparing glucocorticoids alone versus glucocorticoids plus anticytokine/immunomodulatory treatment are warranted. This systematic literature review informed the initiative to formulate EULAR ‘points to consider’ on COVID-19 pathophysiology and immunomodulatory treatment from the rheumatology perspective.

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Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19

Domingo

Mur

Mateo

et al. 2021

JAMA

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556

387

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The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group IMPORTANCE Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm.OBJECTIVE To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes.DATA SOURCES Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts.STUDY SELECTION Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. DATA EXTRACTION AND SYNTHESISIn this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I 2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. MAIN OUTCOMES AND MEASURESThe primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days.RESULTS A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). CONCLUSIONS AND RELEVANCEIn this prospective meta-analysis of clinical trials of patients hosp...

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Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial

Cited by 363 publications

References 38 publications

Tocilizumab in hospitalized patients with COVID-19: A meta analysis of randomized controlled trials

Tocilizumab in hospitalized patients with COVID-19: A meta analysis of randomized controlled trials

Immunomodulatory therapies for SARS-CoV-2 infection: a systematic literature review to inform EULAR points to consider

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19

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