Systematic review and meta-analysis of ivermectin for treatment of COVID-19: evidence beyond the hype
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 95 studies (45 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
[rumble.com] for more detailed analysis, which notes several issues including the following:
Pre-registration
[crd.york.ac.uk] 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."Currently there are
95 ivermectin studies and meta analysis shows:
Marcolino et al., 23 Jul 2022, Brazil, peer-reviewed, 9 authors, trial PROSPERO
CRD42021257471.
Contact:
milenamarc@gmail.com (corresponding author).
Abstract: (2022) 22:639
Marcolino et al. BMC Infectious Diseases
https://doi.org/10.1186/s12879-022-07589-8
RESEARCH ARTICLE
Open Access
Systematic review and meta‑analysis
of ivermectin for treatment of COVID‑19:
evidence beyond the hype
Milena Soriano Marcolino1,2* , Karina Cardoso Meira3 , Nathalia Sernizon Guimarães4 ,
Paula Perdigão Motta5 , Victor Schulthais Chagas1,6 , Silvana Márcia Bruschi Kelles7,8,
Laura Caetano de Sá1,9 , Reginaldo Aparecido Valacio10 and Patrícia Klarmann Ziegelmann2,11
Abstract
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.
*Correspondence: milenamarc@gmail.com
1
Department of Internal Medicine, Medical School and Telehealth Center,
University Hospital, Universidade Federal de Minas Gerais, Avenida Professor
Alfredo Balena 190, sala 246, Belo Horizonte 30130‑100, Brazil
Full list of author information is available at the end of the article
© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative..
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