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Signals were broadly positive for months, but never definitive: the tocilizumab story

Cozzi-Lepri, A; Smith, C; Mussini, C; (2022) Signals were broadly positive for months, but never definitive: the tocilizumab story. Clinical Microbiology and Infection , 28 (3) pp. 371-374. 10.1016/j.cmi.2021.10.018. Green open access

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Abstract

BACKGROUND: Most COVID-19 treatment guidelines currently recommend tocilizumab in combination with dexamethasone in critically ill patients who are exhibiting rapid respiratory decompensation. OBJECTIVES: To produce a critical review and summary of the pathway which led to the repurposing of tocilizumab for COVID-19 treatment, from in vitro observations to guidelines recommendations. SOURCES: All studies evaluating the effectiveness of tocilizumab to treat COVID-19 disease published over July 2020-July 2021. CONTENT: Two large methodologically well conducted observational studies, the TESEO and the STOP COVID cohorts, showed a reduction in the risk of invasive mechanical ventilation or death in patients treated with tocilizumab as compared to standard of care in 2020. Concomitantly and up to February 2021 a number of small sample size randomized trials (RCTs) were showing discrepant results. These RCTs had a number of issues: small sample size, various designs and inclusion criteria and different dosages of tocilizumab used. The confidence interval of the meta-analytic estimate for the RCT results was consistent with the hypothesis of no efficacy of tocilizumab. In our opinion, this was mainly because the meta-analysis included small and heterogeneous studies. These results led to a delay in the inclusion of tocilizumab in guidelines which occurred only in the summer of 2021. IMPLICATIONS: Although observational studies are unable to control for unmeasured confounding, they can be put together quickly during a pandemic and promptly provide important information. The large sample size allows us to investigate effect measure modifiers and better target interventions. It is key that the effect size is somewhat large (RR>2), all sources of bias are properly accounted for and the direct evidence is weighted against these factors. It appears to us that for tocilizumab, not having dismissed the results of carefully designed and analysed observational studies in 2020 could have prevented many deaths over those months.

Type: Article
Title: Signals were broadly positive for months, but never definitive: the tocilizumab story
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.cmi.2021.10.018
Publisher version: https://doi.org/10.1016/j.cmi.2021.10.018
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Covid-19, Evidence based medicine, Meta-analysis, Propensity score methods, Tocilizumab
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute for Global Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute for Global Health > Infection and Population Health
URI: https://discovery.ucl.ac.uk/id/eprint/10139422
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