Systematic Review and Meta-Analysis of Ivermectin for Treatment of COVID-19: Evidence Beyond the Hype

Background: The role of ivermectin in the treatment of COVID-19 is still under debate, yet the drug has been widely used in some parts of the world, as shown by impressive market data and ivermectin-related adverse event reports. The available body of evidence may have changed over the last months, as studies have been retracted and "standards of care" (SOC) used in control groups have changed with rapidly evolving knowledge on COVID-19 rapidly. This review aims to summarize and critically appraise the evidence of randomized controlled trials (RCTs) of ivermectin, assessing clinical outcomes in COVID-19 patients. Methods: RCTs evaluating the effects of ivermectin in adult patients with COVID-19 were searched through December 14, 2021, in four databases, L.OVE platform, clinical trial registries and pre-prints platforms. Primary endpoints included all-cause mortality and invasive ventilation requirement. Secondary endpoint was the occurrence of adverse events. Risk of bias was evaluated using the Cochrane Risk of Bias 2.0 tool. Random-effects were used to pool the risk ratios (RRs) of individual trials. The quality of evidence was evaluated using GRADE. Subgroup and sensitivity analysis were performed. Findings: Twenty-one RCTs fulfilled inclusion criteria (n=2592). Of those, 12 compared ivermectin with placebo and in seven ivermectin associated with SOC was compared to SOC. Most RCTs had some concerns or high risk of bias. Ivermectin did not show an effect in reducing mortality (RR=0 . 76; 95%CI 0.44-1.32) or mechanical ventilation (RR=0.83; 95%CI 0.31-2 . 22) in COVID-19 patients. This effect was consistent when comparing ivermectin vs. placebo, and ivermectin associated with SOC vs. SOC, as well as in sensitivity analysis. Additionally, there was very low quality of evidence regarding adverse effects (RR=0 . 95; 95%CI 0.86-1.04). Interpretation: The evidence suggests that ivermectin does not reduce mortality risk and the risk of mechanical ventilation requirement. Although we did not observe an increase in the risk of adverse effects, the evidence is very uncertain regarding this endpoint.Registration Details: The protocol was register in PROSPERO (CRD42021257471).Funding Information: FAPEMIG (APQ-01154-21), IATS/CNPq (465518/2014-1). Declaration of Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.