Systematic review and meta-analysis of ivermectin for treatment of COVID-19: evidence beyond the hype
Milena Soriano Marcolino, Karina Cardoso Meira, Nathalia Sernizon Guimarães, Paula Perdigão Motta, Victor Schulthais Chagas, Silvana Márcia Bruschi Kelles, Laura Caetano De Sá, Reginaldo Aparecido Valacio, Patrícia Klarmann Ziegelmann
BMC Infectious Diseases, doi:10.1186/s12879-022-07589-8
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. The available body of evidence may have changed over the last months, as studies have been retracted and "standards of care" (SOC) used in control groups have changed with rapidly evolving knowledge on COVID-19. 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 June 22, 2022, in four databases, L.OVE platform, clinical trial registries and pre-prints platforms. Primary endpoints included allcause 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. Meta-analysis included only studies which compared ivermectin to placebo or SOC. Random-effects were used to pool the risk ratios (RRs) of individual trials. The quality of evidence was evaluated using GRADE. The protocol was register in PROSPERO (CRD42021257471). Results: Twenty-five RCTs fulfilled inclusion criteria (n = 6310). Of those, 14 compared ivermectin with placebo, in night ivermectin associated with SOC was compared to SOC and two studies compared ivermectin to an active comparator. Most RCTs had some concerns or high risk of bias, mostly due to lack of concealment of the randomization sequence and allocation, lack of blinding and high number of missing cases. Ivermectin did not show an effect in reducing mortality (RR = 0.76; 95%CI: 0.52-1.11) or mechanical ventilation (RR = 0.74; 95%CI: 0.48-1.16). 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 = 1.07; 95%CI: 0.84-1.35).
Conclusions: 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.
Abbreviations
Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s12879-022-07589-8.
Additional
Author contributions Substantial contributions to the conception or design of the work: MSM and NSG. Substantial contributions to the acquisition, analysis, or interpretation of data for the work: MSM, NSG, KCM, VSC, LCS, SMBK, RAV, PKZ, PPM. Drafted the manuscript: MSM, KCM, VSC, NSG. Revised the manuscript critically for important intellectual content: MSM, NSG, KCM, VSC, LCS, SMBK, RAV, PKZ, PPM. Final approval of the version to be published: MSM, NSG, KCM, VSC, LCS, SMBK, RAV, PKZ, PPM. Agreement to be accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature: MSM, NSG, KCM, VSC, LCS, SMBK, RAV, PKZ, PPM. All authors read and approved he final manuscript.
Declarations Ethics approval and consent to participate Not applicable, as this is a systematic review.
Consent for publication Not applicable.
Competing interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on..
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