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An Open Letter on Ivermectin and Bias January 18, 2022

COVID-19 continues to pose a serious public health threat. A multitude of different prevention and treatment strategies have been employed to mitigate the effects of COVID-19, specifically to reduce length of illness, days of missed work, hospitalizations, and deaths. Ivermectin has been identified previously as having in vitro antiviral properties against SARS-COV-2. 

 

Interest in ivermectin as a treatment for COVID-19 gained traction early in 2020 as a potential inexpensive treatment for COVID-19 patients based on in vitro findings, as no vaccines were on the immediate horizon, and the institution of non-pharmaceutical measures such as facemasks  provided no clear cut advantage in stemming the wave of new infections. While Ivermectin is currently used as an anthelmintic, it had not been used previously on a large scale for viral infectious disease. Due to the dearth of available remedies, physicians across America started prescribing Ivermectin as a potential treatment due to its relatively low cost, seemingly moderate efficacy from available trials, and relatively few side effects. 

 

Ivermectin is a well established medication used to treat parasites in humans (and livestock) for decades that became a symbolic flashpoint in mid 2020, dividing the political left from right, elite class from middle class, and academics from community physicians. At $30-40 per treatment, it seemed to many medical providers like a reasonable choice as a  COVID treatment to help lower hospitalizations and deaths, while increasing natural immunity. Contrary to early support for convalescent plasma and Remdesivir (RDV) that lost traction later on, the evidence for Ivermectin has gained traction over time. For example, in spring of 2021, two separate meta analyses published in the American Journal of Therapeutics found “large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance” and “using Ivermectin early in the clinical course may reduce numbers progressing to severe disease.” 

 

By July 2021, Cochrane reviewed ivermectin for treatment of COVID-19.  Although it reported no clinically significant difference in outcomes, it did find both a trend toward inpatient and outpatient mortality reduction.  Since Cochrane’s review in July, other systematic reviews and meta-analyses have been performed, increasing support for ivermectin’s effectiveness in COVID treatment. For example, In October 2021, Chest Journal reviewed 52 studies and over 14,000 patients and found that while mortality benefit is uncertain, “ivermectin led to better clinical outcomes in COVID-19 patients and a lower incidence of adverse events.” 

 

Other systematic reviews revealed significant mortality reduction in patients with severe illness from COVID-19. Population based studies in South America comparing ivermectin with no treatment control in a prospective observation revealed a significant reduction in hospitalizations and death in those using ivermectin than those who did not. Other recent data suggest that ivermectin reduces gastrointestinal complications of COVID and ventilator free days.  An independent Bayesian analysis published in the American Journal of Therapeutics (AJT) concluded that “in our view, this Bayesian analysis, based on the statistical study data, provides sufficient confidence that ivermectin is an effective treatment for COVID-19”. Finally, two other Bayesian analyses largely support the AJT article showing the odds of reduced mortality at 97.5% (higher than 35 of 38 modalities analyzed), and 90.3% odds of reduced mortality on www.metaevidence.org.

 

Ivermectin has been prescribed safely for multiple uses over many years. Serious adverse reactions to medically prescribed ivermectin are vanishingly small. Over 3.5 billion doses have been administered with a reported adverse event rate of  0.00015% between 1992 and 2021.  According to the National Poison Data Center (NPDC), of the 1,810 calls regarding ivermectin between January to October 2021, only1% were subjectively deemed as a “major effect” with no deaths. Compare this to a 2019 report of over 70,000 reports, 1,160 major events, and 127 deaths for acetaminophen, an analgesic easily purchased over the counter in any drug store.  Aspirin is another common over the counter analgesic which has been implicated in thousands of deaths annually due to bleeding. The safety of medically prescribed ivermectin is so robust, and proclamations to the contrary so unsupported, that even authors of reviews denouncing the efficacy of ivermectin admit that it’s safety profile, both historically and in recent trials, admit that it’s safety remains robust.

 

Comparing scattered reports of a few people hospitalized for ivermectin toxicity to a 1000 fold increase of hospitalizations from acetaminophen toxicity per year neglects the scope of safety problems in comparison with other medications. According to the Food and Drug Administration (FDA) FACT project, cases of adverse reactions to monoclonal antibodies was 2.6X and COVID vaccines 3.2X greater than those reported for ivermectin. Some may ask if we should now ban monoclonal antibodies and COVID vaccines because of the number of adverse events. 


In March, 2021, the Journal of the American Medical Association (JAMA) published the results of a randomized, controlled trial, stating, “Among adults with mild COVID-19, a 5-day course of ivermectin, compared with placebo, did not significantly improve the time to resolution of symptoms. The findings do not support the use of ivermectin for treatment of mild COVID-19,
although larger trials may be needed to understand the effects of ivermectin on other clinically relevant outcomes.” The study’s conclusion was a significant impetus for the FDA, Center for Disease Control (CDC), and AMA to cast doubt on ivermectin as a potential therapeutic  despite the studies’ authors stating, “The findings do not support the use of ivermectin for treatment of mild COVID-19, although larger trials may be needed to understand the effects of ivermectin on other clinically relevant outcomes.” The authors admitted that the study was likely underpowered, despite a small reduction in deterioration of clinical symptoms in the ivermectin arm, and didn’t even address mortality outcomes. 

 

During the first COVID-19 wave in early 2020, convalescent plasma was approved by the FDA under an emergency use authorization (EUA), and supported by the NIH,  for treatment of acute, severe COVID-19 infections, based on the results of only two randomized, controlled trials. Both trials concluded no significant improvement in outcomes, with significant potential risk. In other words, the FDA approved an EUA of convalescent plasma treatments based on no scientific evidence that it works. The FDA revised the EUA in February, 2021 to only include high titer (greater than 1:250) plasma treatment, early in the course of hospitalization (before 72 hours from symptom onset). Shockingly, the FDA’s  new guidance for mortality reduction was based on a single post-hoc analysis of a single RCT with a sample size of 160 patients published in the New England Journal of Medicine.


Billboards featuring Dr. Fauci of the National Institutes of Health (NIH), social media ads, and mainstream media across America touted the benefits of convalescent plasma, and those who had prior COVID disease were encouraged to donate to “save lives”. Unfortunately for the FDA and the NIH, convalescent antibodies didn’t stand up to the crushing weight of follow up
studies that, in fact, concluded that convalescent antibodies don’t improve any outcomes. At a cost of around $5,000 per treatment, convalescent antibodies became a very expensive placebo.

 

Then there is Remdesivir (RDV). At about $3,000 per treatment, by mid 2020, it was touted by national medical organizations such as the Infectious Disease Society of America (IDSA) and the CDC as an efficacious treatment. The FDA approved RDV in October, 2020 for moderate to severe COVID in hospitalized patients. Unfortunately, only ten months after this approval, RDV’s  luster began to wilt under the heat of additional studies. An August 2021 Cochrane review revealed, “Based on the currently available evidence RDV probably has little or no effect on all‐cause mortality at up to 28 days in hospitalized adults with SARS‐CoV‐2 infection.” 


Follow up studies have confirmed that indeed the FDA approved RDV outcomes such as mortality and progression of severity for severe COVID-19 symptoms in hospitalized patients as not clinically significant, despite a mild to moderate improvement in overall symptoms. A follow up Bayesian analysis which computed a odds of clinical improvement for ivermectin at 97.5% also concluded that RDV had only a 76.7% chance of providing clinical improvement.

 

Interestingly, if we dig down into the details of those ivermectin studies showing no clinical significant mortality benefit, we find that the average RR is typically well below one, suggesting clinical improvement, but because the high end of the confidence interval (CI) is just over 1.0, the reduction are deemed “non significant” findings. For example, a recent study in QJM revealed a 23% mortality reduction, but since the upper CI limit was barely outside the window of significance at 1.19, it was deemed non significant. Another study by Roman, et. al. shows a 63% mortality risk reduction, but again, the upper CI limit was 1.13, again just barely outside the parameter signifying significance. Even the I-TECH study in Malaysia reported a 70% mortality reduction, but despite again with the upper CI limit at 1.11, again barely outside the window, the authors concluded that ivermectin has “no use” in the treatment of COVID-19. 

 

Had these intervals in these studies been reported as just under 1, the reviewers would have been obliged to report that ivermectin clinically reduces mortality rates, and the entire discussion of ivermectin would have to be reversed. Accusations of bias can go both ways, especially when reviewers have an interest in “no benefit” for ivermectin as a result of their reviews. Small, subjective tweaks in confidence intervals can turn an otherwise positive effect into a “no effect”–a wild swing. Suspicion may be warranted when many of these current CI findings for ivermectin show just a barely non significant effect. 

 

Risk of bias is important to know when evaluating evidence. However, this risk of bias (RoB) can go both ways. The chance of RoB of now dozens of studies involving hundreds of researchers and thousands of study subjects across the globe for positive outcomes for ivermectin as all either being “junk” or “fraudulent” is exceedingly low. The odds of the conclusions of these many researchers having somehow colluded to show a positive effect is simply absurd given the data available.  Why isn’t  RoB not considered in those with vested interest in COVID-19 treatment, like the “producer of ivermectin”, Merck, when in disparaging it’s off patent, cheap and generic ivermectin to support its new, very patented molnupiravir’s $700 price tag, is somehow allowed into the scientific arena and influence public perception?

Physicians have been warned by state medical boards, and have had their licenses revoked over prescribing ivermectin for COVID-19. While physicians such as myself support the use of ivermectin for COVID-19 treatment have been ridiculed and belittled by the loud chorus of naysayers (including those in news media and individuals from the NIH, CDC, FDA, AMA, state medical societies, medical boards, pharmacies, and medical news reports), those same naysayers respond with a deafening silence when the bright light of judgment is turned onto them. There is a dearth of reliable clinical outcome data regarding convalescent plasma and RDV, two currently acceptable treatment regimens approved by the FDA. Why is there no outcry over these two treatments that cost 100 times or more the cost of ivermectin while having no significant clinical different outcomes? 

 

Reports of an avalanche of calls to state poison control centers regarding ivermectin, and more specifically medically prescribed ivermectin, are simply unfounded. There exists no credible evidence that anyone prescribed ivermectin for COVID by a physician is at an increased risk of adverse events or death over any other prescribed or OTC medication. Again, where is the outrage for aspirin? Ibuprofen? Acetaminophen? Self-righteous and self proclaimed arbiters of truth opine in prestigious journals on the “worrisome trend” of 21 calls to the Oregon Poison control line regarding ivermectin toxicity. These letters do nothing to change the fact that currently acceptable drugs in our society hospitalize and kill hundreds and thousands of times more people than ivermectin has ever done, or ever will do

Others lament that ivermectin is being diverted from treating parasites in New Guinea, or how “irresponsible ivermectin misinformation” is leading people to choose to not be vaccinated and die. None of these concerns are supported anywhere in the evidence-based literature, especially in light of new oral drugs for COVID-19. Where are the indignant judgments hurled at us from academic elites discussing how molnupiravir will make people less likely to get vaccinated? Why print these obviously biased opinions as evidence based medical journals?

 

Clearly, ivermectin is held to a different standard of evidence. The same evidence used to support one drug is ridiculed when applied to another as discussed above. A letter written by Lawrence, et.al. published in Nature Journal alludes to this bias. Lawrence unsuspectingly reveals that the evidence supportive of ivermectin’s efficacy must be held to a higher standard of proof than other medical treatments by advocating for assessing individual data points (IDP) in meta analyses research.  He admits, “We recognize that this is a change to long-accepted practice and is substantially more rigorous than the standards that are typically currently applied, but we believe that what has happened in the case of ivermectin justifies our proposal”. 

 

In other words, we can’t afford to compare an apple to an apple as we have done in the past, because if we do, ivermectin “wins”. Because of ivermectin, we need to apply a much higher standard in evaluating effectiveness. Disregard the “poorly scrutinized evidence” that was seemingly ok when assessing convalescent plasma and RDV efficacy. Now it really matters because we absolutely cannot have ivermectin, a treatment that is 1/100 of the cost of other treatments, be effective. Lawrence’s admission is a breathtaking, astounding, and revealing view of the current state of confirmation bias in our current scientific establishment. The real tragedy here is that none of this information is readily available to physicians or the public. But the scathing swaths of outrage toward ivermectin from establishment science is. 

 

Confirmation bias is destroying our ability to perform science. A sort of tribal groupthink has escalated into the highest levels of scientific academia. Intellectual hypocrisy is rampant.  It must stop now. It can stop only by practicing humility and perspective seeking, then promoting curiosity as the ultimate goal of research. 

 

One way to help overcome these biases on both sides is through debate. Debate does occur through professional journals like the American Journal of Therapeutics, which I am personally grateful for. But evidence changes quickly, and this type of subject moves too quickly to be published. Debates may take place in a university, government, or medical society setting. I welcome this challenge to meet in mutual respect for the relentless pursuit of truth. 

 

Scott Hastings DO

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