Association between tocilizumab, sarilumab and all-cause mortality at 28 days in hospitalised patients with COVID-19: A network meta-analysis

Abstract

Background: A recent prospective meta-analysis demonstrated that interleukin-6 antagonists are associated with lower all-cause mortality in hospitalised patients with COVID-19, compared with usual care or placebo. However, emerging evidence suggests that clinicians are favouring the use of tocilizumab over sarilumab. A new randomised comparison of these agents from the REMAP-CAP trial shows similar effects on in-hospital mortality. Therefore, we initiated a network meta-analysis, to estimate pairwise associations between tocilizumab, sarilumab and usual care or placebo with 28-day mortality, in COVID-19 patients receiving concomitant corticosteroids and ventilation, based on all available direct and indirect evidence.

Methods: Eligible trials randomised hospitalised patients with COVID-19 that compared tocilizumab or sarilumab with usual care or placebo in the prospective meta-analysis or that directly compared tocilizumab with sarilumab. Data were restricted to patients receiving corticosteroids and either non-invasive or invasive ventilation at randomisation. Pairwise associations between tocilizumab, sarilumab and usual care or placebo for all-cause mortality 28 days after randomisation were estimated using a frequentist contrast-based network meta-analysis of odds ratios (ORs), implementing multivariate fixed-effects models that assume consistency between the direct and indirect evidence.

Findings: One trial (REMAP-CAP) was identified that directly compared tocilizumab with sarilumab and supplied results on all-cause mortality at 28-days. This network meta-analysis was based on 898 eligible patients (278 deaths) from REMAP-CAP and 3710 eligible patients from 18 trials (1278 deaths) from the prospective meta-analysis. Summary ORs were similar for tocilizumab [0·82 [0·71-0·95, p = 0·008]] and sarilumab [0·80 [0·61-1·04, p = 0·09]] compared with usual care or placebo. The summary OR for 28-day mortality comparing tocilizumab with sarilumab was 1·03 [95%CI 0·81-1·32, p = 0·80]. The p-value for the global test of inconsistency was 0·28.

Conclusions: Administration of either tocilizumab or sarilumab was associated with lower 28-day all-cause mortality compared with usual care or placebo. The association is not dependent on the choice of interleukin-6 receptor antagonist.

Fig 1. Flow diagram showing the identification of eligible trials and patients.

Fig 2. Network map showing numbers of trials in each direct treatment comparison.

The node size is proportional to the number of trials that include this treatment. The width of the lines is proportional to the total number of events involved in each direct comparison.

Fig 3. Summary of the direct evidence from each included trial for all-cause mortality 28 days after randomisation.

The % weight corresponds to the contribution each trial makes to the pooled direct evidence for each treatment comparison.

Fig 4. Network associations of tocilizumab, sarilumab and usual care or placebo for patients receiving corticosteroids and either NIV, IMV or ECMO at randomisation with all-cause mortality 28 days after randomisation.

NIV: Non-invasive ventilation. IMV: Invasive mechanical ventilation. ECMO: Extracorporeal Membrane Oxygenation. Size of markers is proportional to the inverse of the variance from the net estimate. Borrowing of strength illustrates the proportion of information for each net odds ratio that is due to indirect evidence.