Ivermectin for the Treatment of Coronavirus Disease 2019: A Systematic Review and Meta-analysis of Randomized Controlled Trials

  1. Yuani M Roman
  2. Paula Alejandra Burela
  3. Vinay Pasupuleti
  4. Alejandro Piscoya
  5. Jose E Vidal
  6. Adrian V Hernandez

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Abstract

Background

We systematically assessed benefits and harms of the use of ivermectin (IVM) in patients with coronavirus disease 2019 (COVID-19).

Methods

Published and preprint randomized controlled trials (RCTs) assessing the effects of IVM on adult patients with COVID-19 were searched until 22 March 2021 in 5 engines. Primary outcomes were all-cause mortality rate, length of hospital stay (LOS), and adverse events (AEs). Secondary outcomes included viral clearance and severe AEs (SAEs). The risk of bias (RoB) was evaluated using the Cochrane Risk of Bias 2.0 tool. Inverse variance random effect meta-analyses were performed, with quality of evidence (QoE) evaluated using GRADE methods.

Results

Ten RCTs (n = 1173) were included. The controls were the standard of care in 5 RCTs and placebo in 5. COVID-19 disease severity was mild in 8 RCTs, moderate in 1, and mild and moderate in 1. IVM did not reduce all-cause mortality rates compared with controls (relative risk [RR], 0.37 [95% confidence interval, .12–1.13]; very low QoE) or LOS compared with controls (mean difference, 0.72 days [95% confidence interval, −.86 to 2.29 days]; very low QoE). AEs, SAEs, and viral clearance were similar between IVM and control groups (low QoE for all outcomes). Subgroups by severity of COVID-19 or RoB were mostly consistent with main analyses; all-cause mortality rates in 3 RCTs at high RoB were reduced with IVM.

Conclusions

Compared with the standard of care or placebo, IVM did not reduce all-cause mortality, LOS, or viral clearance in RCTs in patients with mostly mild COVID-19. IVM did not have an effect on AEs or SAEs and is not a viable option to treat patients with COVID-19.

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  1. Version published to 10.1093/cid/ciab591
  2. ScreenIT

    SciScore for 10.1101/2021.05.21.21257595: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    RandomizationThe RoB 2.0 tool evaluates five domains of bias: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported results.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line AuthenticationAuthentication: AEs and SAEs were extracted as defined by authors.

    Table 2: Resources

    Experimental Models: Organisms/Strains
    SentencesResources
    Risk of bias assessment: Two investigators (YMR and AB) independently assessed RoB by using the Cochrane Risk of Bias 2.0 tool for RCTs [20]; disagreements were resolved by discussion with a third investigator (AP).
    AB
    suggested: RRID:BDSC_203)
    Software and Algorithms
    SentencesResources
    We searched the following databases until March 22, 2021: PubMed-MEDLINE, EMBASE-OVID, Scopus, Web of Science, the Cochrane Library, medRxiv.org (www.medrxiv.org), Preprints (www.preprints.org), and Social Science Research Network (www.ssrn.com).
    Cochrane Library
    suggested: (Cochrane Library, RRID:SCR_013000)
    The PubMed search strategy is shown in the Supplement.
    PubMed
    suggested: (PubMed, RRID:SCR_004846)
    Risk of bias assessment: Two investigators (YMR and AB) independently assessed RoB by using the Cochrane Risk of Bias 2.0 tool for RCTs [20]; disagreements were resolved by discussion with a third investigator (AP).
    Cochrane Risk of Bias
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    The irrational use of IVM to treat COVID-19 patients has demonstrated several limitations in management strategies: absence of transparency by some political leaders or media in order to avoid the use of drugs without evidence of efficacy and concerns about safety; lack of decisive leadership to implementing therapeutic science-based guidelines; and misuse of both effective communication and science of communication [40-42]. Similar issues were previously experienced with hydroxychloroquine and this situation likely will be repeated in the future with other repurposed drugs. To avoid it, there is an urgent need to establish collaborative efforts among scientists, practitioners, communicators, and policy-makers. A large, well-designed and -reported RCT provides the most reliable information of efficacy in the specific target population from which the sample was drawn. Similarly, a well-designed and reported meta-analysis can provide valuable and confirmatory information [43, 44]. This condition is relevant in a pandemic where timely evaluations are needed. Our study has several strengths. First, we performed a recent and comprehensive systematic search in five engines and unpublished studies and we did not restrict by language. Second, we only evaluated RCTs; several previous studies included all types of designs and their findings may have been biased and confounded. Third, we evaluated outcomes with information from at least two RCTs, including all-cause mortality, length of...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2021.05.21.21257595v2 on medRxiv
  4. Version published to 10.1101/2021.05.21.21257595v1 on medRxiv