Ivermectin for preventing and treating COVID-19

Popp et al., Cochrane Database of Systematic Reviews, doi:10.1002/14651858.CD015017.pub2

Jul 2021

Source PDF All Studies Meta AnalysisMeta

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

This meta analysis is designed to exclude most studies. Authors select a small subset of studies, with a majority of results based on only 1 or 2 studies. Authors split up studies which dilutes the effects and results in a lack of statistical significance for most outcomes. Authors perform 16+ meta analyses with very few studies in each analysis, and do not combine the evidence from all studies. However, we can consider the probability of the observed results across all outcomes.

Authors find positive results for 11 of 12 primary efficacy outcomes with events, or 16 of 18 including secondary outcomes. One of the primary outcomes and two of the secondary outcomes show statistically significant improvements in isolation. If we assume independence, the probability that 11+ of 12 primary efficacy outcomes were positive for an ineffective treatment is p = 0.003. For 16+ of 18 outcomes we get p = 0.0007. This simple analysis does not take into account the magnitude of positive effects, or the dependence due to some studies contributing multiple outcomes, however observation suggests that a full analysis of the combined evidence is likely to show efficacy.

The study is entirely retrospective in the current version. The protocol is dated April 20, 2021, and the most recent study included is from March 9, 2021. The protocol was modified after publication in order to include a close to null result (Beltran Gonzalez "patients discharged without respiratory deterioration or death at 28 days"), so the current protocol is dated July 28, 2021.

Authors excluded many studies by requiring results at a specific time, for example mortality, ventilation, etc. required results at exactly 28 days. Authors excluded all prophylaxis studies by requiring results at exactly 14 days.

Studies comparing with other medications were excluded, however these studies confirm efficacy of ivermectin. The only case where they could overstate the efficacy of ivermectin is if the other medication was harmful. There is some evidence of this for excessive dosage/very late stage use, however that does not apply to any of the studies here.

Studies using combined treatment were excluded, even when it is known that the other components have minimal or no effect. 3 of 4 RCTs with combined treatment use doxycycline in addition, which was shown to have no significant effect in Butler. Other studies were excluded by requiring PCR confirmation.

Authors are inconsistent regarding active comparators. They state that hydroxychloroquine “does not work”, yet excluded trials comparing ivermectin to a drug they hold to be inactive. On the other hand, remdesivir was an acceptable comparator, although it is considered to be effective standard of care in some locations Fordham.

Authors fail to recognize that Risk of Bias (RoB) domains such as blinding are far less important for the objective outcome of mortality.

Authors include Beltran Gonzalez as "moderate" COVID-19, however patients in this study were in severe condition (baseline SatO2 83).

Fordham summarizes several problems:

•unsupported assertions of adverse reactions to ivermectin, and the outdated claim that unsafe dosing would be needed to be effective;

•a demand for PCR or antigen testing, without analysis of reliability and not universally available even in developed countries at the start of the pandemic;

•contradictions in the exclusion criteria, including placebo and approved SoC comparators, but rejecting hydroxychloroquine, though held to be ineffective (and an approved SoC in some jurisdictions);

•inclusion of “deemed active” comparators whilst excluding “potentially active” ones;

•exclusion of combination therapies, though the norm among practising clinicians;

•the rejection of other than RCTs when the objective is a “complete evidence profile”;

•arbitrary time-points for outcome measures, excluding non-compliant trials;

•fragmentation of data by location of care under varying hospitalisation criteria;

•the resulting focus on a small fraction of the available clinical evidence, with most comparisons based on single studies with no meta-analysis possible;

•a resulting inpatient mortality comparison with fewer patients than a June 2020 confounder-matched study;

•no conclusion on the headline mortality outcome, when multiple lines of evidence from elsewhere (including the WHO) point to significant mortality advantage.

Cochrane was reputable in the past, but is now controlled by pharmaceutical interests. For example, see the news related to the expulsion of founder Dr. Gøtzsche and the associated mass resignation of board members in protest blogs.bmj.com, bmj.com, en.x-mol.com. For another example of bias see ebm.bmj.com.

The BiRD group gave the following early comment: "Yesterday’s Cochrane review surprisingly doesn’t take a pragmatic approach comparing ivermectin versus no ivermectin, like in the majority of other existing reviews. It uses a granular approach similar to WHO’s and the flawed Roman et al paper, splitting studies up and thereby diluting effects. Consequently, the uncertain conclusions add nothing to the evidence base. A further obfuscation of the evidence on ivermectin and an example of research waste. Funding conflicts of interests of the authors and of the journal concerned should be examined."

For dicussion of issues added in the updated version see Popp.

Authors report funding from the German Federal Ministry of Education and Research, which may be influenced by gcgh.grandchallenges.org.

Bias due to funding is ignored for both analyzed studies and Cochrane. For Cochrane funders see cochrane.org, cochrane.org (B).

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. Beltran Gonzalez et al., Efficacy and Safety of Ivermectin and Hydroxychloroquine in Patients with Severe COVID-19: A Randomized Controlled Trial, Infectious Disease Reports, doi:10.3390/idr14020020.mdpi.com, doi.org.

2. blogs.bmj.com, blogs.bmj.com/bmj/2018/11/08/peter-c-gotzsche-cochrane-no-longer-a-collaboration/.blogs.bmj.com/bmj/2018/11/08/peter-c-gotzsche-cochrane-no-longer-a-collaboration/.

3. bmj.com, www.bmj.com/content/364/bmj.k5302.www.bmj.com/content/364/bmj.k5302.

4. 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.

5. Butler et al., Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial, The Lancet Respiratory Medicine, doi:10.1016/S2213-2600(21)00310-6.sciencedirect.com, doi.org.

6. cochrane.org, www.cochrane.org/news/cochrane-announces-support-new-donor.www.cochrane.org/news/cochrane-announces-support-new-donor.

7. cochrane.org (B), www.cochrane.org/about-us/our-funders-and-partners.www.cochrane.org/about-us/our-funders-and-partners.

8. ebm.bmj.com, ebm.bmj.com/content/23/5/165.ebm.bmj.com/content/23/5/165.

9. en.x-mol.com, en.x-mol.com/paper/article/947631.en.x-mol.com/paper/article/947631.

10. Fordham et al., The uses and abuses of systematic reviews, OSF Preprints, doi:10.31219/osf.io/mp4f2.osf.io, doi.org.

11. gcgh.grandchallenges.org, gcgh.grandchallenges.org/article/bill-melinda-gates-foundation-opens-new-european-office-berlin.gcgh.grandchallenges.org/article/bill-melinda-gates-foundation-opens-new-european-office-berlin.

12. 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.

13. 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.

14. 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.

15. 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.

16. Popp et al., Ivermectin for preventing and treating COVID-19, Cochrane Database of Systematic Reviews, doi:10.1002/14651858.CD015017.pub3.wiley.com, doi.org.

17. 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.

18. 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.

Important missing comments or errors? Let us know.

Popp et al., 28 Jul 2021, preprint, 8 authors.

All Studies Meta Analysis Submit Updates or Corrections

This Paper Ivermectin All

Ivermectin for preventing and treating COVID-19

Maria Popp, Miriam Stegemann, Maria-Inti Metzendorf, Susan Gould, Peter Kranke, Patrick Meybohm, Nicole Skoetz, Stephanie Weibel

Cochrane Database of Systematic Reviews, doi:10.1002/14651858.cd015017.pub2

Analysis 1.2. Comparison 1: Ivermectin compared to placebo or standard of care for people with moderate-to-severe COVID-19 treated in the inpatient setting, Outcome 2: Worsening of clinical status -need for invasive mechanical ventilation up to 28 days (primary analysis

CONSORT 2010 Statement Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMC Medicine 2010;8:18. COVID Guidelines India 2021 Covid Management Guidelines India Group. COVID Management Guidelines India. indiacovidguidelines.org/ivermectin/ (accessed 15 May 2021). COVID-NMA Working Group COVID-NMA working group. The COVID-NMA initiative: a living mapping and living systematic review of Covid-19 trials. covidnma.com (accessed prior to 1 July 2021). Cochrane Library Trusted evidence. Informed decisions. Better health. Supplementary File_Ivermectin_Risk of Bias Weibel S, Popp M. Supplementary File_Ivermectin_Risk of Bias Excel Tool (Version 1). Zenodo 2021. • Inclusion criteria: aged 18-65 years; admitted to hospital within last 7 days; presence of fever (37.5 °C), cough, sore throat, or a combination; diagnosed positive for SARS-CoV-2 by rRT-PCR • Exclusion criteria: allergic to ivermectin or doxycycline, or if here was the potential for a drug-drug interaction with ivermectin or doxycycline; had chronic illnesses (e.g. ischaemic heart disease, heart failure, documented cardiomyopathy, chronic kidney disease, chronic liver disease); had received ivermectin or doxycycline (or both) in the last 7 days; were pregnant or lactating; or had participated in any other clinical trial within last month Interventions Cochrane Database of Systematic Reviews Study characteristics ..

References

Deeks, Higgins, Altman, Chapter 10: Analysing data and undertaking meta-analyses

Deng, Yin, Chen, Zeng, Clinical determinants for fatality of 44,672 patients with COVID-19, Critical Care, doi:10.1186/s13054-020-02902-w]Dong2020

Dong, Du, Gardner, An interactive web-based dashboard to track COVID-19 in real time, Lancet Infectious Diseases, doi:10.1016/S1473-3099(20)30120-1

Dourmishev, Dourmishev, Schwartz, Ivermectin: pharmacology and application in dermatology, doi:10.1111/j.1365-4632.2004.02253

Garegnani, Madrid, Meza, Misleading clinical evidence and systematic reviews on ivermectin for COVID-19, BMJ Evidence Based Medicine

German Awmf Guideline, None

Goetz, Magar, Dornfeld, Giese, Pohlmann et al., Influenza A viruses escape from MxA restriction at the expense of e icient nuclear vRNP import, Scientific Reports, doi:10.1038/srep23138

González-Canga, None

González-Canga, Sahagún-Prieto, Diez-Liébana, Fernández-Martínez, Vega et al., The pharmacokinetics and interactions of ivermectin in humans, Journal of the American Association of Pharmaceutical Scientists, doi:10.1208/s12248-007-9000-9]Herrmann2020

Herrmann, Adam, Notz, Helmer, Sonntagbauer et al., COVID-19 induced acute respiratory distress syndrome -a multicenter observational study

Higgins, Lasserson, Chandler, Tovey, Thomas et al., Methodological Expectations of Cochrane Intervention Reviews

Hill, Abdulamir, Ahmed, Ashgar, Babalola et al., Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection, doi:10.21203/rs.3.rs-148845/v1

Huang, Wang, Li, Ren, Zhao et al., Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, doi:10.1016/S0140-6736(20)30183-5

Inthout, Ioannidis, Rovers, Goeman, Plea for routinely presenting prediction intervals in meta-analysis, BMJ Open, doi:10.1136/bmjopen-2015-010247

Ivmmeta, com Ivermectin for COVID-19: real-time meta analysis of 60 studies

Karagiannidis, Mostert, Hentschker, Voshaar, Malzahn et al., Case characteristics, resource use, and outcomes of 10 021 patients with COVID-19 admitted to 920 German hospitals: an observational study, Lancet Respiratory Medicine, doi:10.1016/S2213-2600(20)30316-7

Kluge, Janssens, Welte, Weber-Carstens, Schälte et al., S3-Guideline -recommendations on Inpatient Treatment of Patients With COVID-19

Kobayashi, Jung, Linton, Kinoshita, Hayashi et al., Communicating the risk of death from novel coronavirus disease (COVID-19), Journal of Clinical Medicine, doi:10.3390/jcm9020580

Panahi, Poursaleh, Goldust, The e icacy of topical and oral ivermectin in the treatment of human scabies, Annals of Parasitology

Prescott, Girard, RECOVERY 2021 Recovery Collaborative Group. Dexamethasone in hospitalized patients with Covid-19, New England Journal of Medicine, doi:10.1001/jama.2020.14103

Rodríguez-Mega, Latin America's embrace of an unproven COVID treatment is hindering drug trials, Nature, doi:10.1038/d41586-020-02958-2]Schünemann2020

Rodríguez-Mega, None

Schünemann, Higgins, Vist, Glasziou, Akl et al., Chapter 14: Completing 'Summary of findings' tables and grading the certainty of the evidence

Siemieniuk, Rochwerg, Agoritsas, Lamontagne, Leo et al., A living WHO guideline on drugs for Covid-19, BMJ, doi:10.1136/bmj.m3379

Singh, Ryan, Kredo, Chaplin, Fletcher, Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19, Cochrane Database of Systematic Reviews, doi:10.1002/14651858.CD013587.pub2

Sterne, Savović, Page, Elbers, Blencowe et al., RoB 2: a revised tool for assessing risk of bias in randomised trials, BMJ, doi:10.1136/bmj.l4898

Download Image

Please send us corrections, updates, or comments. Vaccines and treatments are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment, vaccine, or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.

Submit

@CovidAnalysis

FAQ

Public domain CC0 1.0