Tocilizumab in COVID-19 – A Bayesian reanalysis of RECOVERY

Albuquerque, Arthur M.; Tramujas, Lucas; Sewanan, Lorenzo R.; Brophy, James M.

doi:10.1101/2021.06.15.21258966

Cited by 7 publications

(3 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our research group has previously reanalyzed the association of tocilizumab with clinical outcomes in different COVID-19 subgroups of patients while focusing on the RECOVERY trial . However, we did not collect and analyze data limited to patients using corticosteroids in different respiratory subgroups.…”

Section: Discussionmentioning

confidence: 99%

Mortality Rates Among Hospitalized Patients With COVID-19 Infection Treated With Tocilizumab and Corticosteroids

Albuquerque

Tramujas²,

Sewanan

et al. 2022

JAMA Netw Open

View full text Add to dashboard Cite

IMPORTANCE A World Health Organization (WHO) meta-analysis found that tocilizumab was associated with reduced mortality in hospitalized patients with COVID-19. However, uncertainty remains concerning the magnitude of tocilizumab's benefits and whether its association with mortality benefit is similar across respiratory subgroups. OBJECTIVE To use bayesian methods to assess the magnitude of mortality benefit associated with tocilizumab and the differences between respiratory support subgroups in hospitalized patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTSA bayesian hierarchical reanalysis of the WHO metaanalysis of tocilizumab studies published in 2020 and 2021 was performed. Main results were estimated using weakly informative priors to exert little influence on the observed data. The robustness of these results was evaluated using vague and informative priors. The studies featured in the meta-analysis were randomized clinical tocilizumab trials of hospitalized patients with COVID-19. Only patients receiving corticosteroids were included. INTERVENTIONSUsual care plus tocilizumab in comparison with usual care or placebo. MAIN OUTCOMES AND MEASURESAll-cause mortality at 28 days after randomization. RESULTS Among the 5339 patients included in this analysis, most were men, with mean ages between 56 and 66 years. There were 2117 patients receiving simple oxygen only, 2505 receiving noninvasive ventilation (NIV), and 717 receiving invasive mechanical ventilation (IMV) in 15 studies from multiple countries and continents. Assuming weakly informative priors, the overall odds ratios (ORs) for survival were 0.70 (95% credible interval [CrI], 0.50-0.91) for patients receiving simple oxygen only, 0.81 (95% CrI, 0.63-1.03) for patients receiving NIV, and 0.89 (95% CrI, 0.61-1.22) for patients receiving IMV, respectively. The posterior probabilities of any benefit (OR <1) were notably different between patients receiving simple oxygen only (98.9%), NIV (95.5%), and IMV (75.4%).The posterior probabilities of a clinically meaningful association (absolute mortality risk difference >1%) were greater than 95% in patients receiving simple oxygen only and greater than 90% in patients receiving NIV. In contrast, the posterior probability of this clinically meaningful association was only approximately 67% in patients receiving IMV. The probabilities of tocilizumab superiority in the simple oxygen only subgroup compared with the NIV and IMV subgroups were 85% and 90%, respectively. Predictive intervals highlighted that only 72.1% of future tocilizumab IMV studies would show benefit. The conclusions did not change with different prior distributions. (continued) Key Points Question Can bayesian methods clarify the uncertainty around tocilizumab's association with mortality benefit in subgroups of hospitalized patients with COVID-19 receiving corticosteroids? Findings In this bayesian reanalysis of a previous meta-analysis of 15 randomized clinical trials comprising 5339 hospitalized patients with COVID-19 treated with tocilizum...

show abstract

Section: Discussionmentioning

confidence: 99%

Mortality Rates Among Hospitalized Patients With COVID-19 Infection Treated With Tocilizumab and Corticosteroids

Albuquerque

Tramujas²,

Sewanan

et al. 2022

JAMA Netw Open

View full text Add to dashboard Cite

show abstract

“…However, subsequent meta-analyses of more recently completed RCTs including RECOVERY, or even unpublished data through searches of electronic databases and contact with experts, ultimately concluded that, in patients hospitalised with COVID-19, treatment with IL-6 antagonists, and in particular tocilizumab (with much higher certainty than sarilumab, but not siltuximab), results into a significant reduction in 28-day all-cause mortality ( 2 , 32 , 58 ), in line with previous meta-analyses of observational cohort studies ( 22 , 77 , 78 ). Specifically, high probability of reduced risk of mortality and clinically meaningful mortality benefit was observed in patients receiving concomitant glucocorticoids and non-invasive ventilation or high-flow oxygen, with no need of IMV or cardiovascular support ( 32 , 79 ). A significant interaction was seen in the subgroup analysis in regard to concomitant steroid therapy ( 2 ), while other meta-analyses confirmed the independent strong benefit of steroid therapy, particularly low-dose dexametasone (not high-dose methylprednisolone or hydrocortisone), on survival of severe and critical patients ( 80 ).…”

Section: Confirmations From Meta-analyses and Current Guidelinesmentioning

confidence: 99%

Immunotherapy of COVID-19: Inside and Beyond IL-6 Signalling

et al. 2022

View full text Add to dashboard Cite

Acting on the cytokine cascade is key to preventing disease progression and death in hospitalised patients with COVID-19. Among anti-cytokine therapies, interleukin (IL)-6 inhibitors have been the most used and studied since the beginning of the pandemic. Going through previous observational studies, subsequent randomised controlled trials, and meta-analyses, we focused on the baseline characteristics of the patients recruited, identifying the most favourable features in the light of positive or negative study outcomes; taking into account the biological significance and predictivity of IL-6 and other biomarkers according to specific thresholds, we ultimately attempted to delineate precise windows for therapeutic intervention. By stimulating scavenger macrophages and T-cell responsivity, IL-6 seems protective against viral replication during asymptomatic infection; still protective on early tissue damage by modulating the release of granzymes and lymphokines in mild-moderate disease; importantly pathogenic in severe disease by inducing the proinflammatory activation of immune and endothelial cells (through trans-signalling and trans-presentation); and again protective in critical disease by exerting homeostatic roles for tissue repair (through cis-signalling), while IL-1 still drives hyperinflammation. IL-6 inhibitors, particularly anti-IL-6R monoclonal antibodies (e.g., tocilizumab, sarilumab), are effective in severe disease, characterised by baseline IL-6 concentrations ranging from 35 to 90 ng/mL (reached in the circulation within 6 days of hospital admission), a ratio of partial pressure arterial oxygen (PaO2) and fraction of inspired oxygen (FiO2) between 100 and 200 mmHg, requirement of high-flow oxygen or non-invasive ventilation, C-reactive protein levels between 120 and 160 mg/L, ferritin levels between 800 and 1600 ng/mL, D-dimer levels between 750 and 3000 ng/mL, and lactate dehydrogenase levels between 350 and 500 U/L. Granulocyte-macrophage colony-stimulating factor inhibitors might have similar windows of opportunity but different age preferences compared to IL-6 inhibitors (over or under 70 years old, respectively). Janus kinase inhibitors (e.g., baricitinib) may also be effective in moderate disease, whereas IL-1 inhibitors (e.g., anakinra) may also be effective in critical disease. Correct use of biologics based on therapeutic windows is essential for successful outcomes and could inform future new trials with more appropriate recruiting criteria.

show abstract

“…One article was not accessible and thus it was excluded. 19 After evaluating the other 92 articles for eligibility, 42 were excluded for the following reasons: one study investigated tocilizumab combined with another IL‐6 inhibitor, 20 two discussed therapies other than tocilizumab, 21 , 22 37 were not systematic reviews, 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 and two were systematic reviews of preclinical or animal studies. 60 , 61 Finally, 50 articles met the eligibility criteria and were included in the present umbrella review 6 , 28 , 62 , 63 , 64 , 65 ,…”

Section: Resultsmentioning

confidence: 99%

Efficacy of tocilizumab in the treatment of COVID‐19: An umbrella review

Tolzali

Noori

Shokri

et al. 2022

Reviews in Medical Virology

View full text Add to dashboard Cite

Tocilizumab is an interleukin (IL)‐6 receptor inhibitor that has been proposed as a therapeutic agent for treating coronavirus disease 2019 (COVID‐19). The aim of this umbrella review was to determine the efficacy of tocilizumab in treating COVID‐19, and to provide an overview of all systematic reviews on this topic. We systematically searched PubMed, Scopus, the Web of Science collection, the Cochrane library, Epistemonikos, and Google Scholar, as well as the medRxiv preprint server. These databases were searched up to 30 September 2021, using the following keywords: ‘SARS‐CoV‐2’, ‘COVID‐19’, ‘tocilizumab’, ‘RHPM‐1’, ‘systematic review’, and ‘meta‐analysis’. Studies were included if they were systematic reviews (with or without meta‐analysis) investigating the efficacy or safety of tocilizumab in confirmed COVID‐19 patients. The AMSTAR 2 checklist was used to assess quality of the included articles, while publication bias was examined using Egger's test. A total of 50 eligible systematic reviews were included. The pooled estimates showed significant reductions in clinical failure (risk ratio (RR) 0.75; 95% confidence interval (CI), 0.61–0.93), deaths (RR 0.78; 95%CI, 0.71–0.85) and the need for mechanical ventilation (RR 0.77; 95%CI, 0.64–0.92) for those receiving tocilizumab compared with the control group. Also, an emerging survival benefit was demonstrated for those who received tocilizumab, over those in the control group (adjusted hazard ratio (aHR) 0.52; 95%CI, 0.43–0.63). In addition, tocilizumab substantially increased the number of ventilator‐free days, compared with the control treatments (weighted mean difference (WMD) 3.38; 95%CI, 0.51–6.25). Furthermore, lymphocyte count (WMD 0.26 × 10 9 /L; 95%CI, 0.14–0.37), IL‐6 (WMD 176.99 pg/mL; 95%CI, 76.34–277.64) and D‐dimer (WMD 741.08 ng/mL; 95%CI, 109.42–1372.75) were all significantly elevated in those receiving tocilizumab. However, the level of lactate dehydrogenase (LDH) (WMD −30.88 U/L; 95%CI, −51.52, −10.24) and C‐reactive protein (CRP) (WMD ‐104.83 mg/L; 95%CI, −133.21, −76.46) were both significantly lower after treatment with tocilizumab. Tocilizumab treatment reduced the risk of intubation, mortality and the length of hospital stay, without increasing the risk of superimposed infections in COVID‐19 patients. Therefore, tocilizumab can be considered an effective therapeutic agent for treating patients with COVID‐19.

show abstract

Tocilizumab in COVID-19 – A Bayesian reanalysis of RECOVERY

Cited by 7 publications

References 29 publications

Mortality Rates Among Hospitalized Patients With COVID-19 Infection Treated With Tocilizumab and Corticosteroids

Mortality Rates Among Hospitalized Patients With COVID-19 Infection Treated With Tocilizumab and Corticosteroids

Immunotherapy of COVID-19: Inside and Beyond IL-6 Signalling

Efficacy of tocilizumab in the treatment of COVID‐19: An umbrella review

Contact Info

Product

Resources

About