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

ObjectivesCytokine release syndrome with elevated interleukin-6 (IL-6) levels is associated with multiorgan damage and death in severe coronavirus disease 2019 (COVID-19). Our objective was to perform a living systematic review of the literature concerning the efficacy and toxicity of the IL-6 receptor antagonist tocilizumab in COVID-19 patients. MethodsData sources were 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 were randomized controlled trials (RCTs) and observational studies at low or moderate risk of bias. Participants were hospitalized COVID-19 patients. Interventions included tocilizumab versus placebo or standard of care. We pooled crude risk ratios (RRs) of RCTs and adjusted RRs from cohorts, separately. We evaluated inconsistency between studies with I2. We assessed the certainty of evidence using the GRADE approach. ResultsOf 1156 citations, 24 studies were eligible (five 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, I2 = 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, I2 = 0%), with a corresponding number needed to treat of 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, I2 = 2.5%). This association was observed over all degrees of COVID-19 severity. Data from the RCTs did not show a higher risk of infections or adverse events with tocilizumab: pooled RR 0.63 (95%CI 0.38–1.06, five RCTs) and 0.83 (95%CI 0.55–1.24, five RCTs), respectively. ConclusionsCumulative 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

A systematic review and network meta-analysis comparing azacitidine and decitabine for the treatment of myelodysplastic syndrome

Abstract Background Hypomethylating agents (HMA), azacitidine, and decitabine are frequently used in the management of myelodysplastic syndromes (MDS). However, there are no clinical trials that have directly compared these agents. We conducted a systematic review and indirectly compared the efficacy of azacitidine to decitabine in MDS. Methods We conducted a comprehensive search of several databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus) through June 28, 2018, without language or time restrictions. Studies were screened by two independent reviewers, and differences were resolved by consensus. The fixed effect model and adjusted indirect comparison methods were used to pool relative risks (RR) of major outcomes of interest (mortality, response rate, quality of life, hematologic improvement, hospitalization, leukemia transformation, transfusion independence). Results Only four trials met the eligibility criteria. Two trials compared azacitidine to the best supportive care (BSC) and included 549 patients, and the other two compared decitabine to BSC and included 403 patients. The risk of bias was unclear overall. Compared to BSC, azacitidine was significantly associated with lower mortality (RR = 0.83, 95% CI 0.74–0.94, I 2 = 89%) whereas decitabine did not significantly reduce mortality (RR = 0.88, 95% CI 0.77–1.00, I 2 = 53%). Both drugs were associated with higher partial and complete response compared to BSC. Indirect comparisons were not statistically significant for all the studied outcomes, except for complete response where azacitidine was less likely to induce complete response compared to decitabine (RR = 0.11, 95% CI = 0.01–0.86, very low-certainty evidence). Conclusions Azacitidine and decitabine are both associated with improved outcomes compared to BSC. The available indirect evidence comparing the two agents warrants very low certainty and cannot reliably confirm the superiority of either agent. Head-to-head trials are needed. In the meantime, the choice of agent should be driven by patient preferences, adverse effects, drug availability, and cost