Bias as a source of inconsistency in ivermectin trials for COVID-19: A systematic review. Ivermectin's suggested benefits are mainly based on potentially biased results

  1. Ariel Izcovich
  2. Sasha Peiris
  3. Martín Ragusa
  4. Fernando Tortosa
  5. Gabriel Rada
  6. Sylvain Aldighieri
  7. Ludovic Reveiz

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Abstract

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  1. Version published to 10.1016/j.jclinepi.2021.12.018
  2. ScreenIT

    SciScore for 10.1101/2021.08.19.21262304: (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.
    RandomizationWe included randomized controlled trials (RCTs) that recruited adults with suspected, probable, or confirmed COVID-19, or that were exposed to SARS-COV-2, comparing systemic ivermectin alone or in combination with other drugs, against placebo, standard care or other interventions, and reported on clinical important outcomes (see “Outcomes of interest” below).
    BlindingRisk of Bias: Two reviewers (A.I and M.R) independently assessed the risk of bias of all included trials using the revised Cochrane Risk of Bias 2.0 tool for randomized trials (RoB 2),[17] focusing on randomization, allocation concealment, blinding, attrition, or other biases relevant to the estimates of effect.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Risk of Bias: Two reviewers (A.I and M.R) independently assessed the risk of bias of all included trials using the revised Cochrane Risk of Bias 2.0 tool for randomized trials (RoB 2),[17] focusing on randomization, allocation concealment, blinding, attrition, or other biases relevant to the estimates of effect.
    Cochrane Risk of Bias
    suggested: None
    We conducted frequentist random-effects pairwise meta-analyses using the R package “meta” in RStudio Version 1.4.1103.[18] For the primary analysis, we assumed that interventions used in some trials as active comparators (hydroxychloroquine and lopinavir-ritonavir), are not related to significant effects in patients with COVID-19.[9] We considered those interventions as standard of care and performed sensitivity analysis to assess the robustness of results (see subgroup and sensitivity analyses).
    RStudio
    suggested: (RStudio, RRID:SCR_000432)
    We used MAGIC authoring and publication platform (https://app.magicapp.org/) to generate the tables summarizing our findings.
    MAGIC
    suggested: (Magic, RRID:SCR_006406)

    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:
    However most trials have serious methodological limitations including lack of allocation concealment and lack of blinding, and reported results varied significantly from striking benefits to null effects. GRADE assessment resulted in low or very low certainty of the evidence for all the outcomes, due to risk of bias, inconsistency, and imprecision. Visual inspection of funnel plot constructed for mortality outcome suggest possible publication bias which rises additional concerns about the certainty of the evidence on ivermectin’s effects. After excluding trials with significant methodological limitations inconsistency disappeared and results changed substantially. We found low certainty, due to imprecision, that ivermectin may not significantly reduce mortality, nor reduce invasive mechanical ventilation, and moderate certainty evidence that ivermectin probably does not significantly increase viral clearance or symptom resolution or improvement. Regarding hospitalizations, results did not change significantly suggesting that ivermectin may modestly reduce hospitalizations. However, certainty of the evidence remained low due to very serious imprecision. It is uncertain if Ivermectin reduces or increases symptomatic infections in exposed individuals or increases severe adverse events as no trials classified as “low risk of bias” were identified, or the certainty of the evidence was very low. Our systematic review has several strengths. The search strategy was comprehensive with...

    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 10.1101/2021.08.19.21262304 on medRxiv