Intensive Care Medicine | 2021
Time for tocilizumab in COVID-19?
Abstract
Host immune dysregulation is thought to contribute to much of the harm associated with coronavirus disease 2019 (COVID-19) [1, 2]. Accordingly, significant focus has been directed toward finding immunomodulatory therapies to offset this host-mediated damage, leading to the beneficial effects of corticosteroids being demonstrated [3]. As elevated concentrations of interleukin-6 (IL-6) have been found to be an important prognostic factor in COVID-19 [4], attention has also focussed on targeted IL-6 receptor antagonism. Tocilizumab, a recombinant humanised monoclonal antibody, is one such agent. Early observational studies suggested potential benefit with tocilizumab [5, 6], though subsequent randomised control trials (RCTs) demonstrated conflicting results [7–11]. In this rapidly evolving area, much has changed since these initial trials were published. In particular, the landmark RECOVERY [12] and REMAP-CAP [13] platform trials have demonstrated benefit of tocilizumab. In this issue of Intensive Care Medicine, Snow et al. present a timely and methodologically robust systematic review and meta-analysis of RCTs analysing the effects of tocilizumab in patients with COVID-19 [14], including data from REMAP-CAP [13] and the pre-print of the RECOVERY trial [15], which has since been published in full [12]. The authors included nine RCTs (6493 patients) in the meta-analysis of their primary outcome (mortality at 28–30 days) and found reduced odds of mortality in patients treated with tocilizumab compared to standard care or placebo, but the compatibility interval could not exclude the possibility of no difference or a small adverse effect at the 5% significance level (OR 0.87 [95% compatibility interval (CI) 0.74–1.01]; moderate quality of evidence). The number of patients progressing to the need for mechanical ventilation was also found to be lower in those who received tocilizumab (OR 0.70 [95% CI 0.54– 0.89]; very low quality of evidence). This review raises several important points, some of which are discussed below. Snow et al. present results for their primary analysis using an odds ratio with random effects with sensitivity analyses using alternate methods (Table 1). What are we to make of their findings? First, if we look beyond the dichotomisation of p-values, we can see that the data is both consistent and far more compatible with benefit than with harm, regardless of the underlying statistical assumptions made. Second, the results of the trial sequential analysis (TSA) of the primary outcome cross the ‘futility boundary’ (an estimated threshold below which an intervention is unlikely to have an important effect) suggesting enrolling further patients is ‘futile’. Of note, this reflects the current parameters of the TSA (i.e., a relative risk reduction (RRR) of 15.7%, with a large typeII error rate of 20%). It is plausible that a smaller benefit exists (e.g. RRR 5–10%) which is still clinically important, however, the required information size (the number of patients needing to be included to detect an anticipated intervention effect with sufficient power) would be significantly larger than currently presented. In the RECOVERY trial [14], mortality was lower for the subset of patients who received both tocilizumab and corticosteroids (OR 0.79, 95% CI 0.70–0.89). However, in patients who received tocilizumab without corticosteroids, there was a wide range of possible effects (OR 1.16, 95% CI 0.91–1.48), though the data is more compatible with harm. Similarly, in the REMAP-CAP trial [13] (> 90% receiving corticosteroids), a mortality benefit was reported with tocilizumab in addition to corticosteroids (OR 0.70 [95% CI 0.520.96]). While these trials would *Correspondence: [email protected] 1 Department of Intensive Care, Royal North Shore Hospital, St. Leonards, Australia Full author information is available at the end of the article