Tocilizumab in COVID-19: a meta-analysis, trial sequential analysis, and meta-regression of randomized-controlled trials

Abstract

Purpose: Interleukin-6 (IL-6) levels discriminate between patients with mild and severe COVID-19, making IL-6 inhibition an attractive therapeutic strategy. We conducted a systematic review, meta-analysis, trial sequential analysis (TSA), and meta-regression of randomized-controlled trials to ascertain the benefit of IL-6 blockade with tocilizumab for COVID-19.

Methods: We included randomized-controlled trials (RCTs) allocating patients with COVID-19 to tocilizumab. Our control group included standard care or placebo. Trials co-administering other pharmacological interventions for COVID-19 were not excluded. Primary outcome was 28-30 day mortality. Secondary outcomes included progression-to-severe disease defined as need for mechanical ventilation, intensive-care unit (ICU) admission, or a composite.

Results: We identified 10 RCTs using tocilizumab, 9 of which reported primary outcome data (mortality), recruiting 6493 patients with 3358 (52.2%) allocated to tocilizumab. Tocilizumab may be associated with an improvement in mortality (24.4% vs. 29.0%; OR 0.87 [0.74-1.01]; p = 0.07; I² = 10%; TSA adjusted CI 0.66-1.14). Meta-regression suggested a relationship between treatment effect and mortality risk, with benefit at higher levels of risk (logOR vs %risk beta = -0.018 [-0.037 to -0.002]; p = 0.07). Tocilizumab did reduce the need for mechanical ventilation and was associated with a benefit in the composite secondary outcome but did not reduce ICU admission.

Conclusions: For hospitalized COVID-19 patients, there is some evidence that tocilizumab use may be associated with a short-term mortality benefit, but further high-quality data are required. Its benefits may also lie in reducing the need for mechanical ventilation.

Keywords: COVID-19; Immunologic factors; Interleukin-6; Meta-analysis.

Fig. 1

PRISMA flowchart. Flowchart of included and excluded trials

Fig. 2

Effect of tocilizumab on mortality in included trials. a Forest plot of mortality in RCTs listed in descending order of control group mortality. Size of squares for odds ratio reflects weight of trial in pooled analysis. Horizontal bars represent 95% confidence intervals. b Trial sequential analysis of mortality in RCTs. Uppermost and lowermost curves represent trial sequential monitoring boundary lines for benefit and harm, respectively. Horizontal lines represent the traditional boundaries for statistical significance. Triangular lines represent the futility boundary. The cumulative Z curve represents the trial data. A diversity-adjusted required information size (RIS) of 5622 was calculated using α = 0.05 (two sided), β = 0.20 (power 80%). Relative risk of mortality reduction was 15.7%. The cumulative Z curve crosses neither the conventional nor the TSA boundary for benefit or harm, but did cross the boundary for futility having exceed the required information size (RIS). c Meta-regression of log odds ratio for mortality vs. risk (%)

Fig. 3

Effect of tocilizumab on risk of need for mechanical ventilation. a Forest plot of risk of progression to mechanical ventilation. Size of squares for odds ratio reflects weight of trial in pooled analysis. Horizontal bars represent 95% confidence intervals. b Trial sequential analysis of risk of progression to mechanical ventilation. Uppermost and lowermost curves represent trial sequential monitoring boundary lines for benefit and harm, respectively. Horizontal lines represent the traditional boundaries for statistical significance. Triangular lines represent the futility boundary