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 2830day 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 [0.741.01]; p =0.07; I 2 =10%; TSA adjusted CI 0.661.14). 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. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06416-z.

“L’histoire se répète”, one size does not fit all

“…Author details 1 Departments of Intensive Care Medicine, Gelre Hospitals, Albert Schweitzerlaan 31, 7334 DZ Apeldoorn, The Netherlands. 2 Expertise Center for Intensive Care Rehabilitation Apeldoorn (ExpIRA), Albert Schweitzerlaan 31, 7334 DZ Apeldoorn, The Netherlands.…”

“…Let's look carefully at the individual COVID-19 patient in the ICU and prepare a tailored therapeutic strategy that may, or may not include the use of tocilizumab. *Correspondence: m.kuindersma@gelre.nl 1 Departments of Intensive Care Medicine, Gelre Hospitals, Albert Schweitzerlaan 31, 7334 DZ Apeldoorn, The Netherlands Full author information is available at the end of the article…”

Time for tocilizumab in COVID-19?

“…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 ].…”

“…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 0.52- 0.96]). While these trials would seem to indicate an interaction between the two drugs, this was not explored via subgroup analyses or meta-regression in the review by Snow et al [ 14 ]. It would also be prudent to note that the smaller TOCIBRAS trial [ 11 ] had a similar level of corticosteroid use as REMAP-CAP [ 13 ] and RECOVERY [ 15 ], but was stopped early for possible harm.…”