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Systematic review and meta-analysis of ivermectin for treatment of COVID-19: evidence beyond the hype

Marcolino et al., BMC Infectious Diseases, doi:10.1186/s12879-022-07589-8, PROSPERO CRD42021257471
Jul 2022  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020
*, now known with p < 0.00000000001 from 100 studies, recognized in 22 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
3,800+ studies for 60+ treatments.
Unreliable: pre-registered analysis of prophylaxis studies has not been reported and would show statistically significant efficacy; only 1 of 16 pre-registered outcomes for treatment studies was reported
Meta analysis including 25 of 100 studies (47 RCTs), with only 10 and 8 reporting mortality and mechanical ventilation results, finding lower mortality and mechanical ventilation without statistical significance. The conclusion is incorrect, despite substantial bias the results favor treatment, while not reaching the typical statistical significance threshold. This analysis is unreliable, for example consider Reis et al., authors give the study a perfect rating in risk of bias analysis, however this study not only has a very high theoretical risk of bias, but shows very high actual bias, randomization failure, blinding failure, and reports conflicting data that is impossible to be correct Reis.
See for more detailed analysis, which notes several issues including the following:
Pre-registration indicates that the authors will analyze prophylaxis studies. This is even included in the title "Use of ivermectin for prophylaxis and treatment of COVID-19...", however the paper indicates the protocol has changed without explanation to exclude prophylaxis: "...two were excluded for testing the drug for COVID-19 prophylaxis". The two excluded papers were Seet, Shouman, which both show statistically significant reduction in symptomatic cases.
Pre-registration had very different outcomes, specifying the main outcomes as:
"Number of mortality; number of patients who experienced adverse events during follow up; protection rate; % of patients progressing from mild to moderate or severe stages of disease and % of hospitalization of medical cause in patients with COVID-19 will be collected for intervention and control groups.
For treatment, mortality and severity of disease according to the WHO criteria. Change (Day 7-Baseline) Liver Enzymes; Number of patients who reported less anosmia/hyposmia; Number of patients who reported less cough; % of reduction on body temperature; Mean duration of hospitalization after treatment; follow up at day 7 asymptomatic; Hospital discharge by day 10; Admission in ICU; Survival without ICU; Successful extubation rates; Survival without oxygen; % of patients progressing from mild to moderate or severe stages of diseases; Rate of progression of the disease, or the deterioration of the clinical condition of the patients; Mean recovery time will be collected for intervention and control groups."
In the paper this has become:
"The primary outcomes were all-cause mortality and invasive ventilation support. Secondary outcome was the percentage of patients who presented adverse events at follow-up."
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 100 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%].
Marcolino et al., 23 Jul 2022, Brazil, peer-reviewed, 9 authors, trial PROSPERO CRD42021257471. Contact: (corresponding author).
This PaperIvermectinAll
Systematic review and meta-analysis of ivermectin for treatment of COVID-19: evidence beyond the hype
Milena Soriano Marcolino, Karina Cardoso Meira, Nathalia Sernizon Guimarães, Paula Perdigão Motta, Victor Schulthais Chagas, Silvana Márcia Bruschi Kelles, Laura Caetano De Sá, Reginaldo Aparecido Valacio, Patrícia Klarmann Ziegelmann
BMC Infectious Diseases, doi:10.1186/s12879-022-07589-8
Background: The role of ivermectin in the treatment of COVID-19 is still under debate, yet the drug has been widely used in some parts of the world, as shown by impressive market data. The available body of evidence may have changed over the last months, as studies have been retracted and "standards of care" (SOC) used in control groups have changed with rapidly evolving knowledge on COVID-19. This review aims to summarize and critically appraise the evidence of randomized controlled trials (RCTs) of ivermectin, assessing clinical outcomes in COVID-19 patients. Methods: RCTs evaluating the effects of ivermectin in adult patients with COVID-19 were searched through June 22, 2022, in four databases, L.OVE platform, clinical trial registries and pre-prints platforms. Primary endpoints included allcause mortality and invasive ventilation requirement. Secondary endpoint was the occurrence of adverse events. Risk of bias was evaluated using the Cochrane Risk of Bias 2.0 tool. Meta-analysis included only studies which compared ivermectin to placebo or SOC. Random-effects were used to pool the risk ratios (RRs) of individual trials. The quality of evidence was evaluated using GRADE. The protocol was register in PROSPERO (CRD42021257471). Results: Twenty-five RCTs fulfilled inclusion criteria (n = 6310). Of those, 14 compared ivermectin with placebo, in night ivermectin associated with SOC was compared to SOC and two studies compared ivermectin to an active comparator. Most RCTs had some concerns or high risk of bias, mostly due to lack of concealment of the randomization sequence and allocation, lack of blinding and high number of missing cases. Ivermectin did not show an effect in reducing mortality (RR = 0.76; 95%CI: 0.52-1.11) or mechanical ventilation (RR = 0.74; 95%CI: 0.48-1.16). This effect was consistent when comparing ivermectin vs. placebo, and ivermectin associated with SOC vs. SOC, as well as in sensitivity analysis. Additionally, there was very low quality of evidence regarding adverse effects (RR = 1.07; 95%CI: 0.84-1.35). Conclusions: The evidence suggests that ivermectin does not reduce mortality risk and the risk of mechanical ventilation requirement. Although we did not observe an increase in the risk of adverse effects, the evidence is very uncertain regarding this endpoint.
Abbreviations Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s12879-022-07589-8. Additional Author contributions Substantial contributions to the conception or design of the work: MSM and NSG. Substantial contributions to the acquisition, analysis, or interpretation of data for the work: MSM, NSG, KCM, VSC, LCS, SMBK, RAV, PKZ, PPM. Drafted the manuscript: MSM, KCM, VSC, NSG. Revised the manuscript critically for important intellectual content: MSM, NSG, KCM, VSC, LCS, SMBK, RAV, PKZ, PPM. Final approval of the version to be published: MSM, NSG, KCM, VSC, LCS, SMBK, RAV, PKZ, PPM. Agreement to be accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature: MSM, NSG, KCM, VSC, LCS, SMBK, RAV, PKZ, PPM. All authors read and approved he final manuscript. Declarations Ethics approval and consent to participate Not applicable, as this is a systematic review. Consent for publication Not applicable. Competing interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on..
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