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Am J Ther. 2021 Jul-Aug; 28(4): e434–e460. PMCID: PMC8248252 Published online 2021 Jun 21. doi: 10.1097/MJT.0000000000001402 PMID: 34145166 Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines This article was recently referenced at Conservative Fools with the challenge to click on it and read it. Apparently nobody did including the Ivermectin enthusiasts. The implication in the post, asking us to read the paper, is that the NIH is sitting on IVM treatment and killing Americans. Dr Fauci is suggested as the reason for withholding IVM and is responsible for Covid deaths. https://boards.fool.com/news-the-government-would-rather-you...“Note also the article was published by the NIH on June 21, 2021 so for almost four month this info has been missing from the governments official advice on Covid....”https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/The NIH and WHO both have commented on using Ivermectin for prevention and treatment of COVID. “ National Institutes of Health in the United States recently stated that “there are insufficient data to recommend either for or against the use of ivermectin for the treatment of COVID-19,”11 and the World Health Organization recommends against its use outside of clinical trials.” The following link is to papers frequently referenced (but rarely read) that prove Ivermectin cures COVID. It has been reposted often.https://c19ivermectin.comAs it so happens I caught this paper the first time around but did not quite get the connection between the paper, Dr Fauci, the NIH and the conspiracy to kill Americans until it resurfaced again as evidence that the NIH and Fauci are conspiring with big pharma to rake in profits at the price of American lives. I think I got the gist of the post right this time around-- don’t agree with the conclusion.The paper is in the American Journal of Therapeutics from June 2021.The paper is meant to look at the efficacy of IVM for both survival benefit (not dying), prevention and treatment of COVID. It is a meta-analysis. Meta-analysis is not clinical research. It’s the combining of data from multiple trials to reach a conclusion. It’s a statistical treatment of clinical trials and conclusions reached by researchers and done on real people. The title alerts us to one potential problem—there is no single hypothesis to prove or disprove. The authors have pushed multiple different considerations together which is often considered poor design. This meta-analysis statistically examines survival, prophylaxis, clinical improvement, time to polymerase chain reaction (PCR) negativity, clinical recovery, length of hospital stay, admission to hospital (for outpatient treatment), admission to ICU or requiring mechanical ventilation, duration of mechanical ventilation, and severe or serious adverse events, as well as post hoc assessments of improvement and deterioration. It's a confusing, overcomplicated design and one reason meta-analyses can be less valuable than the best designed clinical trials. If you read the paper, you can find other shortcomings that cripple the outcomes:-– no consistency in drug regimens including dosage, concomitant medications, length of treatment and no control for placebo effect—17 different protocols were used. By mixing all this data, there is no way to know with high certainty which drug or standard of care contributed to good outcomes and which were useless. -– less than half the studies were randomized.-– less than half the trials were blinded.---more than half selectively reported data and finally more than half the trial inclusions were questionable, uncharacterized sources of bias used in interpreting the results. There are too many variables and many of the papers fell short of reliable data and statistical evaluation of those results as evidenced by Figure 2. Without being the source of the data and collection, the authors were forced to contact the researchers for clarification. They admit they failed to consistently clarify questions and you can see that for yourself, in the paper, in Figure 2. All the yellow circles with question marks are data clarification failures. At this point, with such compromised data, they should have dropped it. But they forged ahead, including the fraudulent Elgazara research paper which should invalidate some of the results.In case it isn’t clear—this is bad. It makes the meta-analysis prone to errors of bias and faulty conclusions. Practically, what this means, is the end results are not high confidence or high probability in most of the findings. If you skip the statistical treatment graphs and tables and look at the discussion, you will find most of the endpoints have low confidence on the GRADE scale many of these types of statistical analyses use. GRADE scale widely used in data analysishttps://www.nhmrc.gov.au/guidelinesforguidelines/develop/ass...Grade Definition======================================= High We are very confident that the true effect lies close to that of the estimate of the effect.Moderate We are moderately confident in the effect estimate: the true effect is likely to be close to estimate of the effect, but there is a possibility that it is substantially differentLow Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.Very Low We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effectWe now get to their failure of good judgement and lack of ability to evaluate clinical trials. They managed to include a paper from Egypt stating Ivermectin was effective at reducing Covid deaths by 90%.https://www.nature.com/articles/d41586-021-02081-wThe paper summarized the results of a clinical trial seeming to show that ivermectin can reduce COVID-19 death rates by more than 90% — among the largest studies of the drug’s ability to treat COVID-19 to date. But on 14 July, after internet sleuths raised concerns about plagiarism and data manipulation, the preprint server Research Square withdrew the paper because of “ethical concerns”.Although dozens of ivermectin clinical trials have been launched over the past year3, the Elgazzar paper was notable for announcing one of the first positive results, as well as for its size — it included 400 people with symptoms of COVID-19 — and the magnitude of the drug’s effect. Few therapies can claim such an impressive reduction in death rates. “It was a significant difference, and that stood out,” says Andrew Hill, who studies repurposed drugs at the University of Liverpool, UK. “It should have raised red flags even then.”https://www.theguardian.com/science/2021/jul/16/huge-study-s...“Because the Elgazzar study is so large, and so massively positive – showing a 90% reduction in mortality – it skews the evidence in favour of ivermectin,” Meyerowitz-Katz said. Kyle Sheldrick, a Sydney doctor and researcher, also independently raised concerns about the paper. He found numbers the authors provided for several standard deviations – a measure of variation in a group of data points – mentioned in tables in the paper were “mathematically impossible” given the range of numbers provided in the same table.Why meta-analyses are weak support for drug approvalThis last quote from Sheldrick shows why a meta-analysis is never as good as a large well designed clinical trial. It effectively downgrades the primary outcome positive result of survival benefit. Here is a paper that also uses randomized controlled studies of Ivermectin against placebo and gathers data from multiple clinical trials. I put the link here to show that a meta-analysis can have a good design and clear intent. It also reaches a clear single conclusion:Ivermectin has no advantage in treating COVID infected hospital patients over placebo. They use the GRADE scale. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD...Just included as an example of a better designed clearer meta-analysis.Because the authors of the paper we are discussing failed to note the inaccurate Elgazzar statistics and conclusions seemed unreliable, we have to question how adept they are out interpreting the other 23 studies included in their data. Contact with researchers was inconsistent when questions arose but they still included the data. This does highlight one huge shortcoming of relying on the outcomes and conclusions of any meta-analysis. They are far removed from the patients, the complete picture of the trials and even the authors/researchers.The fraudulent Elgazzar paper and data were included in both arms of the primary and secondary outcomes. The Elgazzar study was large and has an outsized impact on their conclusions and should have been disqualified befor analyzing the data. The primary outcome was survival and prevention and was the only part of the meta-analysis that reached even moderate certainty. The authors note it’s difficult to interpret the findings in either the primary outcome or the secondary outcome because of lack of control—variability in the cohort, the standard of care, and the treatment regimens. Controls and design study are integral in getting an FDA decision on any drug approval in the US. Without such approval, Ivermectin will not have a broad based adoption as a component of any universally adopted standard of care. It is little use inventing conspiracy theories and protesting against Fauci and the medical community—they are not at fault. Until there is a well executed large scale study, IVM will be relegated to off label use. So far, no such data exists. More trials are underway-- not US based for the most part. Back to the paper. Primary Outcome, of survival, prophylaxis and clinical benefitThe primary outcome for the intervention component of the review included death from any cause and presence of COVID-19 infection (as defined by investigators) for ivermectin prophylaxis.Discussion of primary outcome resultsSurvival benefitThe findings indicate with moderate certainty that ivermectin treatment in COVID-19 provides a significant survival benefit. Our certainty of evidence judgment was consolidated by the results of trial sequential analyses, which show that the required IS has probably already been met. Prophylaxis and moderation of disease severityLow- certainty evidence on improvement and deterioration also support a likely clinical benefit of ivermectin. Low-certainty evidence suggests a significant effect in prophylaxis. Overall, the evidence also suggests that early use of ivermectin may reduce morbidity and mortality from COVID-19. This is based on (1) reductions in COVID-19 infections when ivermectin was used as prophylaxis, (2) the more favorable effect estimates for mild to moderate disease compared with severe disease for death due to any cause, and (3) on the evidence demonstrating reductions in deterioration.The inclusion of the heavily weight fraudulent Elgazzar study in support of survival benefit would negate their rating of moderate certainty. They did not detect the inaccurate, plagiarized and manipulated data, and that speaks to their acuity at interpreting numbers. I would be tempted to downgrade survival benefit to at least low certainty.Clinical benefit is already low certainty and might be downgraded as very low certainty. They need to run every piece of their research back through their statistical analysis and take the date from the Elgazzar paper out.Secondary OutcomesSecondary outcomes included time to polymerase chain reaction (PCR) negativity, clinical recovery, length of hospital stay, admission to hospital (for outpatient treatment), admission to ICU or requiring mechanical ventilation, duration of mechanical ventilation, and severe or serious adverse events, as well as post hoc assessments of improvement and deterioration.Conclusions for Ivermectin treatment on the above secondary outcomesSecondary outcomes provided low to very low certainty evidence (SoF Table ?Table2).2). Low-certainty findings suggested that there may be no benefit with ivermectin for “need for mechanical ventilation,” whereas effect estimates for “improvement” and “deterioration” favored ivermectin but were graded as low certainty due to study design limitations and inconsistency. All other secondary outcome findings were assessed as very low certainty.Meta-analysis of 11 trials, assessing 1533 participants, found that there was no significant difference between ivermectin and control in the risk of severe adverse events (aRR 1.65, 95% CI 0.44–6.09; I2 = 0%; low certainty evidence, downgraded for imprecision and study design limitations).This is the paper’s conclusion of IVM’s efficacy improving the outcomes of length of stay, admission to ICU and +/- the need for ventilator support. In other words, it did not work well. It was low certainty to very low certainty and that’s made worse through inclusion of bad data. OK long enough. The OPs accusations that the NIH and Dr Fauci were hiding this study and conspiring to keep Ivermectin off the formularies for standard of care and FDA approval are ridiculous. I would guess if they have read this, they would discard it as bad research with little evidence of efficacy to support either primary or secondary outcomes. Ivermectin is not yet ready for FDA approval and widespread adoption for prevention and cure of COVID.That leaves us with what is working as a national strategy—vaccinate and masks on. Just another small rabbit hole :Last Word I did find one new trial ongoing 09/08/2021https://www.wired.com/story/better-data-on-ivermectin-is-fin...ADAM ROGERSSCIENCEBetter Data on Ivermectin Is Finally on Its WayEDWARD MILLS CAME to the meeting last month with very good data. A clinical trials expert at McMaster University, Mills was presenting new results from a trial that is looking at how well half a dozen different drugs treat Covid-19—not for the people so sick they’re in the emergency room or the hospital, but in people whose symptoms haven’t gotten that bad yet. People sick at home, in other words.At his online talk, put on by the National Institutes of Health, Mills’ slides told the tale: A relatively safe, familiar, cheap drug reduced the relative risk of mild Covid getting worse by nearly 30 percent. The drug is fluvoxamine, a selective serotonin reuptake inhibitor—an antidepressant.This is a multi-site trial being done in Brazil ongoing since June 2020. The intention is to evaluate repurposed drugs like Ivermectin that have approval for another indication. This has the advantge of an acceptable established safety profile and potentially much lower costs. It’s definetly worth clicking on the link to look at the proposal.https://dcricollab.dcri.duke.edu/sites/NIHKR/KR/GR-Slides-08...The team’s results haven’t been peer-reviewed or officially published yet, but the Together trial, on which Mills is co-principal investigator, is well-designed and respected. Something quite different than most of the trials I have seen to date. What is of interest is that Ivermectin was a part of the design. In their work with it, there was no clinical data supporting:--fewer hospital admissions than placebo--fewer ER admissionsIn other words, subjects contracted COVID while on Ivermectin and required visits to the ER and admissions to the hospital. This would tend to support the low confidence of the meta-analysis we looked at. The McMaster/Brazil trial looks good and the most promising repurposed drug so far is fluvoxamine aka Luvox which is an antidepressant but also anti-inflammatory.
-– no consistency in drug regimens including dosage, concomitant medications, length of treatment and no control for placebo effect—17 different protocols were used. By mixing all this data, there is no way to know with high certainty which drug or standard of care contributed to good outcomes and which were useless. -– less than half the studies were randomized.-– less than half the trials were blinded.---more than half selectively reported data
Grade Definition======================================= High We are very confident that the true effect lies close to that of the estimate of the effect.Moderate We are moderately confident in the effect estimate: the true effect is likely to be close to estimate of the effect, but there is a possibility that it is substantially differentLow Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.Very Low We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
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