An Updated Systematic Review and Meta-Analysis of Mortality, Need for ICU admission, Use of Mechanical Ventilation, Adverse effects and other Clinical Outcomes of Ivermectin Treatment in COVID-19 Patients

  1. Smruti Karale
  2. Vikas Bansal
  3. Janaki Makadia
  4. Muhammad Tayyeb
  5. Hira Khan
  6. Shree Spandana Ghanta
  7. Romil Singh
  8. Aysun Tekin
  9. Abhishek Bhurwal
  10. Hemant Mutneja
  11. Ishita Mehra
  12. Rahul Kashyap

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Abstract

Importance

Repurposing Ivermectin, a known anti-parasitic agent, for treating COVID-19 has demonstrated positive results in several studies. We aim to evaluate the benefit and risk of Ivermectin in COVID-19.

Methods

We conducted a systematic search for full-text manuscripts published from February 1, 2020, to August 15th, 2021 focusing on Ivermectin therapy against COVID-19. The primary outcomes were mortality, need for intensive care unit (ICU) admission; secondary outcomes were - adverse effects, need for mechanical ventilation, viral clearance, time to viral clearance, need for hospitalization, and length of hospital stay. Random-effects models were used for all analyses.

Results

We included a total of 52 studies (n=17561) in the qualitative analysis, out of these, 44 studies (n=14019) were included in the meta-analysis. In the mortality meta-analysis (N=29), odds of death were lower in the Ivermectin-arm compared to control (OR 0.54, p=0.009). Although lower odds of mortality were observed in various subgroup analyses of RCTs, they did not reach statistical significance: therapeutic RCTs: mild-moderate COVID-19 (OR 0.31, p=0.06), therapeutic RCTs: severe/critical COVID-19 (OR 0.86, p=0.56), inpatient RCTs: mild-moderate COVID-19 (OR 0.18, p=0.08), inpatient RCTs: severe/critical COVID-19 (OR 0.86, p=0.56). Ivermectin, mostly as adjuvant therapy, was associated with higher odds of viral clearance (N=22) (OR 3.52, p=0.0002), shorter duration to achieve viral clearance (N=8) (MD - 4.12, p=0.02), reduced need for hospitalization (N=6) (OR 0.34, p=008).

Conclusion

Our meta-analysis suggests that the mortality benefit of Ivermectin in COVID-19 is uncertain. But as adjuvant therapy, Ivermectin may improve viral clearance and reduce the need for hospitalization.

Highlights

What We Already Know about This Topic

  • COVID-19 is an ongoing global pandemic, for which Ivermectin has been tried on a therapeutic and prophylactic basis.

  • Results from several clinical trials and observational studies suggest that Ivermectin may improve survival and clinical outcomes with a good safety profile when compared with other treatments; however, the current evidence is limited..

    • What This Article Tells Us That Is New

  • This systematic review and meta-analysis provide a summary of the latest literature on the efficacy and safety of Ivermectin use for COVID-19.

  • Based on our analysis of the latest evidence, we found that Ivermectin’s benefit in reducing mortality cannot be concluded with confidence. However, as an adjuvant therapy it may help reduce the need for hospitalization, duration for viral clearance while increasing the likelihood of achieving viral clearance.

  • We need more high-quality data for conclusive evidence regarding the benefit of Ivermectin in reducing the need for ICU admissions, mechanical ventilation and duration of hospital stay in COVID-19 patients.

    • Article activity feed

    1. ScreenIT

      SciScore for 10.1101/2021.04.30.21256415: (What is this?)

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

      Table 1: Rigor

      Ethicsnot detected.
      Sex as a biological variableWe excluded studies focusing on pregnant females, in-vitro studies, meta-analyses, case reports and case series <5 patients.
      RandomizationRisk of Bias and Quality assessment: Clinical trials were evaluated using Cochrane risk of bias tool49 (e-table 2) and correlation of quality measures with estimates of treatment effects in meta-analyses of randomized controlled trials tool50 (e-table 3) was used for quality assessment.
      Blindingnot detected.
      Power Analysisnot detected.

      Table 2: Resources

      Software and Algorithms
      SentencesResources
      Study selection and data extraction: The extracted data was tabularized in Microsoft Excel with following parameters: author, country of study, study design, number of patients, Ivermectin regimen, concomitant treatment, efficacy outcomes and adverse effects.
      Microsoft Excel
      suggested: (Microsoft Excel, RRID:SCR_016137)
      Statistical analysis: Primary and Secondary outcomes were quantitatively analyzed by Review Manager (RevMan) Version 5.4 for windows46 and Comprehensive Meta-Analysis software package (Biostat, Englewood, NJ, USA)47 was used for qualitative-analysis.
      RevMan
      suggested: (RevMan, RRID:SCR_003581)
      The Cochrane Q and I2 statistics were calculated to assess heterogeneity between studies48.
      Cochrane Q
      suggested: None
      Risk of Bias and Quality assessment: Clinical trials were evaluated using Cochrane risk of bias tool49 (e-table 2) and correlation of quality measures with estimates of treatment effects in meta-analyses of randomized controlled trials tool50 (e-table 3) was used for quality assessment.
      Cochrane
      suggested: (Cochrane Library, RRID:SCR_013000)
      NIH quality assessment tools were based on quality assessment methods, concepts, and other tools developed by researchers in the Agency for Healthcare Research and Quality (AHRQ), Cochrane Collaboration, USPSTF, Scottish Intercollegiate Guidelines Network, and National Health Service Centre for Reviews and Dissemination, consulting epidemiologists and evidence-based medicine experts, with adaptations by methodologists and NHLBI staff.
      Cochrane Collaboration
      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 inherent methodological limitations and risk of bias conferred variable evidence grading in the findings in various patient outcomes. Mortality: Our findings are corroborated by other meta-analyses done by Padhy85 (studies N=3), Hill86 (studies N=6), Lawrie87 (studies N=5), Nardelli88 (studies N=7), Kow89 (studies N=6), Bryant et al90 (studies N=13) and the BIRD group91 (studies N=13) which found Ivermectin to be conclusively linked to lower mortality when compared to usual treatment. A network meta-analysis92 (studies N=2) reported that Ivermectin was linked to lower mortality with a very close statistical significance. Casteneda-Sabogal et al’s meta-analysis93 (studies N=6) found no conclusive association of Ivermectin with reduced mortality. Of note, the above two studies reported low or very low certainty of evidence92,93. Our sample size exceeds (studies N=22) that of all the aforementioned studies. Our pooled analysis resulting in a low mortality rate of 3.5% with use of Ivermectin reiterates its positive impact in lowering mortality in COVID-19 patients. For a valid comparison, it is important to factor in the time window during which the individual studies were conducted. Most studies recorded their data in the II&III quarter of 2020 when mortality rates with various treatments were often higher in respective countries94. Need for ICU admission and Mechanical Ventilation: Due to the small number of studies and their small individual sample size, benefit with Iverm...

      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.

    2. Version published to 10.1101/2021.04.30.21256415 on medRxiv