Placebo effects on all‐cause mortality of patients with COVID‐19 in randomized controlled trials of interleukin 6 antagonists: A systematic review and network meta‐analysis

Aim Many randomized controlled trials (RCTs) have investigated the use of interleukin 6 antagonists for the treatment of coronavirus disease 2019 (COVID‐19), yielding inconsistent results. This network meta‐analysis (NMA) aimed to identify the source of these inconsistent results by reassessing whether participants treated with standard of care (SoC) plus placebo have different all‐cause mortality from those treated with SoC alone and to reevaluate the efficacy of interleukin 6 antagonists in the treatment of COVID‐19. Methods We conducted a systematic search for relevant RCTs from the inception of electronic databases through 1 September 2022. The primary outcome was all‐cause mortality. The secondary outcomes were the incidences of major medical events, secondary infections, all‐cause discontinuation, and serious adverse events. Results The results of NMA of 33 RCTs showed that patients with COVID‐19 treated with SoC plus placebo had lower odds of all‐cause mortality than those who received SoC alone (OR, 0.75 [95% confidence interval, 0.58–0.97]). This finding remained consistent after excluding studies with no incident deaths. In addition, when we consider the impact of the widely promoted COVID‐19 vaccination and newly developed antiviral treatment strategy, the results from the analysis of the RCT published in 2021 and 2022 remained similar. Conclusion These findings suggest the potential influence of placebo effects on the treatment outcomes of COVID‐19 in RCTs. When evaluating the efficacy of treatment strategies for COVID‐19, it is crucial to consider the use of placebo in the design of clinical trials.