Current best evidence for clinical care (more info)
OBJECTIVES: Cytokine release syndrome with elevated interleukin-6 (IL-6) levels is associated with multiorgan damage and death in severe coronavirus disease 2019 (COVID-19). Our objective was to perform a living systematic review of the literature concerning the efficacy and toxicity of the IL-6 receptor antagonist tocilizumab in COVID-19 patients.
METHODS: Data sources were Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Web of Science, Scopus up, preprint servers and Google up to October 8, 2020. Study eligibility criteria were randomized controlled trials (RCTs) and observational studies at low or moderate risk of bias. Participants were hospitalized COVID-19 patients. Interventions included tocilizumab versus placebo or standard of care. We pooled crude risk ratios (RRs) of RCTs and adjusted RRs from cohorts, separately. We evaluated inconsistency between studies with I2. We assessed the certainty of evidence using the GRADE approach.
RESULTS: Of 1156 citations, 24 studies were eligible (five RCTs and 19 cohorts). Five RCTs at low risk of bias, with 1325 patients, examined the effect of tocilizumab on short-term mortality; pooled RR was 1.09 (95%CI 0.80-1.49, I2 = 0%). Four RCTs with 771 patients examined the effect of tocilizumab on risk of mechanical ventilation; pooled RR was 0.71 (95%CI 0.52-0.96, I2 = 0%), with a corresponding number needed to treat of 17 (95%CI 9-100). Among 18 cohorts at moderate risk of bias with 9850 patients, the pooled adjusted RR for mortality was 0.58 (95%CI 0.51-0.66, I2 = 2.5%). This association was observed over all degrees of COVID-19 severity. Data from the RCTs did not show a higher risk of infections or adverse events with tocilizumab: pooled RR 0.63 (95%CI 0.38-1.06, five RCTs) and 0.83 (95%CI 0.55-1.24, five RCTs), respectively.
CONCLUSIONS: Cumulative moderate-certainty evidence shows that tocilizumab reduces the risk of mechanical ventilation in hospitalized COVID-19 patients. While RCTs showed that tocilizumab did not reduce short-term mortality, low-certainty evidence from cohort studies suggests an association between tocilizumab and lower mortality. We did not observe a higher risk of infections or adverse events with tocilizumab use. This review will continuously evaluate the role of tocilizumab in COVID-19 treatment.
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Excellent methodology performed in this meta-analysis. Very important information from new clinical trials evaluating treatments for COVID-19 disease.
These results offer some support for further trials with tocilizumab in hospitalized patients. Until then, clinicians should use their clinical judgement in deciding whether preventing mechanical ventilation is an appropriate outcome for using this drug.
This is a reasonable systematic review of tocilizumab in COVID-19. On the basis of this evidence, I suspect few would change practice given the high costs and residual uncertainty of its effects on patient-important outcomes. Further evidence is already on the way, so this review will probably be out of date very soon (if not already).
A well done review addressing a potentially interesting intervention for COVID. It remains unclear how this synergizes with steroids. Some large RCTs will be published imminently and will add to this living review.
This is not really a primary care physician issue, of course, but COVID is very topical and it is possible patients and families may ask their trusted primary care physician about this for their hospitalized loved ones. The results in this article, however, are nothing like our experience with this drug. We didn't think it was doing anything and so stopped using it. I also heard the same from a colleague at a hard-hit NYC hospital. So, it's difficult to imagine an important clinical effect being invisible at 2 major treatment centers.
My take is that the beneficial effects of tocilizumab are marginal, as suggested by this well-done systematic review. I also wonder if dexamethasone was used and how commonly it was used concurrently with the tocilizumab in the reviewed studies . Perhaps the widespread use of dexamethasone today obviates the need for the much more expensive tocilizumab, at least in the great majority of cases.
This detailed meta-analysis finds short-term mortality risk and need for mechanical ventilation was reduced in patients given tocilizumab without adverse effects or increased infection risk. A lack of quality data precluded quantifying the long-term mortality risk. This suggests a continued role for tocilizumab in hospitalized Covid-19 patients.
This thorough systematic review up to October 8, 2020 includes 5 RCTs and 19 cohort studies of tocilizumab therapy in hospitalized COVID-19 patients. 4 RCTs supported reduced risk for mechanical ventilation (pooled RR 0.71; 95% CI 0.52-0.96). Although 18 cohorts with moderate risk of bias found reduced mortality (RR 0.58; 95% CI 0.51-0.66), 5 RCTs with low bias did not support this (pooled RR 1.09; 95% CI 0.80-1. 49). RCT data did not support any higher risk for infections or other adverse events with tocilizumab. This is a living systematic review that will be continuously updated with new evidence.