Ivermectin for preventing and treating COVID-19

Popp et al., Cochrane Database of Systematic Reviews, doi:10.1002/14651858.CD015017.pub3

Jun 2022

Source PDF All Studies Meta AnalysisMeta

The Publication of Fraudulent Ivermectin Meta-Analyses and Editorials by the High-Impact Medical Journals

The uses and abuses of systematic reviews: the case of ivermectin in Covid-19

Highly biased meta analysis. Authors originally wrote a highly biased meta analysis that avoided statistical significance on individual outcomes with extreme exclusions Popp, although efficacy was still seen when looking across all outcomes. Authors modified the protocol published a short time before, thereby performing a retrospective analysis, clearly designed to produce a desired outcome.

Authors indicated they would update the analysis but did not for a very long time. Authors would have been unable to maintain the lack of statistical significance with the protocol. In this new meta analysis, authors invented a new method to exclude most studies, thereby producing another retrospective analysis, again clearly designed to produce the desired outcome.

Authors included only 14 of 60 studies in the original analysis. For the update, they include even fewer studies, 11 of 87. A key method used was excluding studies without confirmation of prospective registration, however authors violate this to include the Together Trial twitter.com, which accounts for 40% of the patients in the extreme subset selected.

In the companion article for the new exclusion methods, authors note that one indicator for exclusion is if the observed risk reduction is too large medrxiv.org, twitter.com (B). The trial resulting in Paxlovid approval would be excluded on this basis.

As just one example of extreme bias, authors classify the Together Trial as low risk of bias. This trial not only has very high risk of bias, but has very high actual known bias. The trial has refused to release data despite pledging to, has reported multiple impossible numbers, and had blinding failure and randomization failure, along with many other issues Reis.

As another example of extreme bias, the authors avoid reporting on the 3 prophylaxis RCTs that all reported statistically significant improvement at the time (as of Jan 2023 there are 4, all showing statistically significant improvements), by simply deciding not to do so. Authors know that this shows statistically significant efficacy because they acknowledge reviewing our analysis. Notably, the paxlovid analysis from many of the same authors does not do this. The table shows the inclusion criteria for case results in their paxlovid vs. ivermectin analyses. Using the paxlovid criteria for ivermectin would show statistically significant reduction for both cases and clinical symptoms with ivermectin.

	Paxlovid	Ivermectin
Shared Cochrane authors	Popp, Reis, Metzendorf, Kranke, Meybohm, Skoetz, Weibel	Popp, Reis, Metzendorf, Kranke, Meybohm, Skoetz, Weibel
Prophylaxis inclusion	PrEP or PEP PCR/antigen+ @14 days and 6 months clinical symptoms @28 days and 6 months	PEP only PCR/antigen+ @14 days clinical symptoms @14 days
Matching studies	1 showing no significant effect, which was not included Pfizer	0
Matching studies with paxlovid criteria		4, all showing statistically significant improvements

The analysis is also very out of date, including trials only up to April 2022, and including only trials with >1,000 patients since Dec 16, 2021 (yet another cherry-picking mechanism).

With regards to ivmmeta:

- authors claim ivmmeta "states the FLCCC and BIRD as its resources". This is false, there is no relationship with FLCCC or BIRD.

- author's discussion of pooled estimates is disingenuous. ivmmeta reports individual outcome results which are the first item discussed in the abstract. The advantages and disadvantages of pooled estimates are clearly discussed.

- authors statement that there is no prospective protocol is highly disingenuous. The ivmmeta protocol was published in November 2020, is unchanged from the same protocol published in October 2020 used for another medication, and the same protocol is used for 42 treatments. The ivmmeta analysis has been updated regularly with the same protocol. In contrast, authors have published their meta analysis only twice, both times changing the protocol creating a retrospective analysis. Further, authors have created a new unique protocol for this treatment.

- authors claim that "there is no assessment of the risk of bias or the certainty of evidence". This is false, studies are evaluated and 29 are excluded in exclusion analyses. Authors could note that ivmmeta focuses on actual bias as opposed to theoretical risk of bias. While authors assess risk of bias, their assessment is implausible, as shown with the example of the Together Trial above. Note that not only does the Together Trial have extreme actual bias, the theoretical risk of bias is also extremely high due to the conflicts of interest and trial design.

See Popp for many other issues.

7 meta analyses show significant improvements with ivermectin for mortality Bryant, Hariyanto, Kory, Lawrie, Nardelli, Zein, hospitalization Schwartz, recovery Kory, and cases Kory.

Currently there are 99 ivermectin for COVID-19 studies, showing 49% lower mortality [35‑60%], 29% lower ventilation [13‑42%], 38% lower ICU admission [14‑56%], 34% lower hospitalization [20‑45%], and 81% fewer cases [71‑87%].

1. Bryant et al., Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines, American Journal of Therapeutics, doi:10.1097/MJT.0000000000001402.lww.com, doi.org.

2. Hariyanto et al., Ivermectin and outcomes from Covid-19 pneumonia: A systematic review and meta-analysis of randomized clinical trial studies, Reviews In Medical Virology, doi:10.1002/rmv.2265.wiley.com, doi.org.

3. Kory et al., Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19, American Journal of Therapeutics, doi:10.1097/MJT.0000000000001377.lww.com, doi.org.

4. Lawrie et al., Ivermectin reduces the risk of death from COVID-19 – a rapid review and meta-analysis in support of the recommendation of the Front Line COVID-19 Critical Care Alliance, Preprint, b3d2650e-e929-4448-a527-4eeb59304c7f.filesusr.com/ugd/593c4f_8cb655bd21b1448ba6cf1f4c59f0d73d.pdf.filesusr.com.

5. medrxiv.org, www.medrxiv.org/content/10.1101/2022.05.31.22275756v1.www.medrxiv.org/content/10.1101/2022.05.31.22275756v1.

6. Nardelli et al., Crying wolf in time of Corona: the strange case of ivermectin and hydroxychloroquine. Is the fear of failure withholding potential life-saving treatment from clinical use?, Signa Vitae, doi:10.22514/sv.2021.043.signavitae.com, doi.org.

7. Pfizer, Pfizer Shares Top-Line Results from Phase 2/3 EPIC-PEP Study of PAXLOVID™ for Post-Exposure Prophylactic Use, Press Release, www.pfizer.com/news/press-release/press-release-detail/pfizer-shares-top-line-results-phase-23-epic-pep-study.pfizer.com.

8. Popp et al., Ivermectin for preventing and treating COVID-19, Cochrane Database of Systematic Reviews, doi:10.1002/14651858.CD015017.pub2.cochranelibrary.com, doi.org.

9. Reis et al., Effect of Early Treatment with Ivermectin among Patients with Covid-19, New England Journal of Medicine, doi:10.1056/NEJMoa2115869.nejm.org, doi.org.

10. Schwartz, E., Does ivermectin have a place in the treatment of mild Covid-19?, New Microbes and New Infections, doi:10.1016/j.nmni.2022.100989.sciencedirect.com, doi.org.

11. twitter.com, twitter.com/alexandrosM/status/1557822673987612672.twitter.com/alexandrosM/status/1557822673987612672.

12. twitter.com (B), twitter.com/sudokuvariante/status/1557827663770914816.twitter.com/sudokuvariante/status/1557827663770914816.

13. Zein et al., Ivermectin and mortality in patients with COVID-19: A systematic review, meta-analysis, and meta-regression of randomized controlled trials, Diabetes & Metabolic Syndrome: Clinical Research & Reviews, doi:10.1016/j.dsx.2021.102186.sciencedirect.com, doi.org.

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Popp et al., 21 Jun 2022, preprint, 10 authors.

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This Paper Ivermectin All

Ivermectin for preventing and treating COVID-19

Maria Popp, Stefanie Reis, Selina Schießer, Renate Ilona Hausinger, Miriam Stegemann, Maria-Inti Metzendorf, Peter Kranke, Patrick Meybohm, Nicole Skoetz, Stephanie Weibel

Cochrane Database of Systematic Reviews, doi:10.1002/14651858.cd015017.pub3

Analysis 1.1. Comparison 1: Ivermectin for treating COVID-19 in inpatient settings with moderate to severe disease, Outcome Analysis 2.12. Comparison 2: Ivermectin for treating COVID-19 in outpatient settings with asymptomatic or mild disease, Outcome

C H A R A C T E R I S T I C S O F S T U D I E S Characteristics of included studies [ordered by study ID] Study characteristics Methods • Trial design: triple-blind RCT with 3 parallel arms, the 2 intervention arms were pooled for this review • Type of publication: pre-proof journal publication • Severity of condition according to study definition: mild disease, defined as not requiring hospitalization or oxygen supplementation • Severity of condition according to WHO scale: 1 to 3 • Time from symptom onset to enrolment (median): overall 4 (IQR 3 to 5.5) days • Comorbidities: any pre-existing condition, obesity, diabetes, cardiovascular disease, respiratory disease • Virus detection performed at baseline (test-positive at baseline): RT-PCR (100%) • Vaccination status: overall 91 (98%) participants without any vaccination • Inclusion criteria: age ≥ 18 years; positivity for SARS-CoV-2 (nasopharyngeal swabs) by RT-PCR; consent to participating in the study and to the processing of personal data; COVID-19 Severity Score < 3; participant able to take oral drugs Cochrane Database of Systematic Reviews • Exclusion criteria: pregnant or lactating women (pregnancy test not required, if doubt person is excluded); people with known central nervous system disease; lack of (or inability to provide) informed consent; receiving dialysis; any severe medical condition with a prognosis of < 6 months; receiving warfarin treatment; receiving antiviral treatment; receiving..

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