Efficacy and safety of tocilizumab in COVID-19 patients: A living systematic review and meta-analysis

Tleyjeh, Imad M.; Kashour, Zakariya; Damlaj, Moussab; Riaz, Muhammad; Tlayjeh, Haytham; Altannir, Mustafa; Altannir, Youssef; Al-Tannir, Mohamad; Tleyjeh, Rana; Hassett, Leslie; Kashour, Tarek

BACKGROUND: Cytokine release syndrome with elevated interleukin-6 (IL-6) levels is associated with multi-organ damage and death in severe COVID-19 disease. OBJECTIVES: To perform a living systematic review of the literature about the efficacy and toxicity of the IL-6 receptor antagonist, tocilizumab, in COVID-19 patients. DATA SOURCES: 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: Randomized controlled trials (RCTs) and observational studies at low or moderate risk of bias. PARTICIPANTS: Hospitalized COVID-19 patients. INTERVENTIONS: Tocilizumab vs. placebo or standard of care. METHODS: We pooled crude risk ratios (RRs) of RCTs and adjusted RRs from cohorts, separately. We evaluated between-studies inconsistency with I(2). We assessed the certainty of evidence using the GRADE approach. RESULTS: Of 1156 citations, 24 studies were eligible (5 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, I(2) = 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, I(2) = 0 %), with a corresponding number needed to treat 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, I(2)= 2.5%). This association was observed across all stages of COVID-19 severity. Data from the RCTs did not show higher risk of infections or adverse events with tocilizumab; pooled RR 0.63 (95% CI 0.38-1.06, 5 RCTs) and 0.83 (95% CI 0.55-1.24, 5 RCTs), respectively. CONCLUSION: 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.