Transcript
Speaker: Welcome to Critical Matters, a sound podcast covering a broad range of topics related to the practice of intensive care medicine.
Speaker: Sound provides comprehensive critical care programs to hospitals across the country.
Speaker: To learn more about our programs and career opportunities, visit www.soundphysicians.com.
Speaker: And now your host, Dr. Sergio Zanotti.
Speaker: In today's episode of Critical Matters,
Speaker: We will try to answer the question, should we use ivermectin for COVID-19?
Speaker: This is a very relevant topic to what has happened in our country for the last several months with the Delta wave.
Speaker: It's also a controversial topic.
Speaker: And considering that, I have decided to do something a little bit different for this episode.
Speaker: Instead of having our traditional expert guests with whom I discussed the topic,
Speaker: I will just share with you my thoughts and my reviews on the topic.
Speaker: We have talked about ivermectin for COVID-19 as one of the potential therapies since last year.
Speaker: However, with this delta wave, especially here in the United States, there's been a significant increase in the volume or the noise around ivermectin.
Speaker: And we have seen a tremendous rise in the number of weekly prescriptions for ivermectin in the U.S. But also we have seen, and a lot of us have felt this, at the bedside, an increasing number of news stories reporting families suing hospitals because physicians are not prescribing ivermectin to their loved ones with COVID.
Speaker: This is something that we've seen in many ICUs where families
Speaker: of unvaccinated patients have become very belligerent, stating that we should be giving their loved ones ivermectin.
Speaker: And there have been multiple news outlet reports of lawsuits being filed in Chicago or in Ohio, in Texas.
Speaker: The truth is that there's a lot of reports of these lawsuits being filed, but not one single doctor that I could find
Speaker: who did not believe that they should prescribe ivermectin has been forced by a court to prescribe ivermectin to a patient.
Speaker: So ultimately, I believe that the courts have upheld our rights to practice medicine.
Speaker: And if we don't believe that this is a drug that should be utilized, like any other drug, families can't be forcing us to prescribe it without evidence.
Speaker: So we'll talk about ivermectin in more details.
Speaker: But I think that probably where we should first go is try to understand what is the available evidence in favor or against ivermectin, and when does this discussion really start from a scientific standpoint?
Speaker: There is one study that came out early last year, published in Antiviral Research by Leon Kalli and collaborators out of Australia, that was titled, The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro.
Speaker: This is a laboratory study that basically demonstrated that very high doses of ivermectin placed in a Petri dish could inhibit the viral replication of SARS-CoV-2.
Speaker: And this was really the first scientific laboratory study that suggested plausibility to some that perhaps there is a mechanism or perhaps there is value in exploring ivermectin for COVID-19.
Speaker: What's also important to mention about this particular study, and I'll put the references and the links in the show notes, is that the doses that are utilized in these laboratory exams in Petri dishes are doses that far exceed the doses that we're able to achieve in humans with clinical dosing.
Speaker: So that is one problem.
Speaker: The other issue that I think is important to emphasize
Speaker: is that similar studies with ivermectin have been done for other viruses, including Cica, dengue, HIV, and none of these have ever resulted in a positive clinical trial.
Speaker: As a matter of fact, the only one that was pursued further after a laboratory experiment was in dengue because that is a very common disease in many parts of the world that does not have effective treatments or vaccines, and it was a negative study.
Speaker: The fact that in a laboratory controlled experiment, a very high concentration of any agent can inhibit replication of a virus does not necessarily translate in real life to an effective clinical therapy.
Speaker: But this is the study that a lot of people have quoted.
Speaker: It's the first study published and peer reviewed that suggested perhaps there's a mechanism.
Speaker: And I do believe that at the beginning of the pandemic,
Speaker: We didn't know anything about this emergent virus and disease.
Speaker: And people were desperate trying to figure out what they could utilize to treat COVID-19.
Speaker: And this and many other studies, I think, push people to evaluate or consider potential new treatments.
Speaker: Now, the same type of rationale was utilized for hydroxychloroquine that obviously in clinical trials was demonstrated not only to not work,
Speaker: but to potentially be dangerous.
Speaker: Now, when we look a little bit further in terms of, okay, what's the next level of evidence?
Speaker: And obviously at this point, with over 250 million patients worldwide with COVID, and we have seen an enormous amount of clinical trials being published with large number of patients, both pragmatic trials, adaptive platforms, and other high level randomized trials, considering the difficulties of doing these trials,
Speaker: within a worldwide pandemic, I would start by looking at PubMed, what's published, and looking at specifically at randomized controlled trials.
Speaker: I mean, ultimately, there is no reason why we shouldn't be doing randomized controlled trials with the number of COVID patients that we've seen over the last two years.
Speaker: So if you go to PubMed and you type in ivermectin plus COVID-19 and you filter by randomized controlled trials, what you get is 14 hits.
Speaker: and most of these in 2021.
Speaker: I looked at each one of these studies.
Speaker: Some of them are reporting protocols, some of them are very small, but ultimately, two stand out in terms of their size and their quality.
Speaker: And these are really what are available, peer-reviewed, published RCTs, indexed in PubMed, and they are the IvorCor COVID-19 study.
Speaker: ivermectin to prevent hospitalizations in patients with COVID-19, a randomized double-blind placebo-controlled trial, and they basically evaluated over 22,000 patients who assessed for eligibility.
Speaker: They randomized ultimately 501 patients.
Speaker: 250 patients were assigned to ivermectin.
Speaker: 251 patients were assigned to placebo.
Speaker: and all these patients were included in the intention to treat analysis.
Speaker: And what they found is that at the end, the hospitalization-free survival was really no different between placebo and ivermectin with a p-value of 0.22.
Speaker: So it was reported as a negative study.
Speaker: So this was trying to prevent hospitalizations.
Speaker: Primary outcome was the number of hospitalized patients.
Speaker: We can see that the number was low
Speaker: in both groups, 14 for the ivermectin and 21 for the placebo.
Speaker: The odds ratio went from 0.32 to 131, so obviously had a p-value that was non-significant.
Speaker: They also looked at other secondary outcomes that included time to hospitalization days in those who were hospitalized, looking at the medium, the need for invasive mechanical ventilation, time to invasive mechanical ventilation support in those who needed it,
Speaker: negative nasal swab days at day three, the number, the number of negative nasal swabs at day 12, the need for dialysis, all-cause mortality, and then any safety events.
Speaker: And once again, when you look at the secondary outcomes, not one of these really met any significance, and really the odds ratio were not there, and ultimately,
Speaker: This was reported as a negative trial, suggesting that the use of ivermectin in patients who are positive for COVID-19 but not hospitalized does not really improve outcomes in preventing hospitalizations or preventing the need for mechanical ventilation or mortality.
Speaker: The second trial that I found that was also remarkable in terms of its size and quality was published in JAMA.
Speaker: It's the effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19, a randomized clinical trial.
Speaker: This was a trial that tried to address the question of what is the effect of ivermectin on duration of symptoms in adults with mild COVID-19.
Speaker: Again, these are patients who are not hospitalized.
Speaker: And then this randomized clinical trial that included 476 patients,
Speaker: The duration of symptoms was not significantly different for patients who received a five-day course of ivermectin compared with placebo.
Speaker: The medium time to resolution of symptoms was 10 versus 12, and the hazard ratio for resolution symptoms was 1.07.
Speaker: They concluded that these findings did not support the use of ivermectin for treatments of mild COVID-19, but also, I mean, also shared that perhaps larger trials may be needed
Speaker: to understand the full effects and other clinically relevant outcomes and trying to figure out what is really the role, if any, for ivermectin.
Speaker: But I share these two studies because these are the ones that are peer reviewed, that are published, that are available on PubMed, that are considerable size, good quality, and really, they really didn't show any advantage or any effects for ivermectin.
Speaker: This particular study I just mentioned
Speaker: The primary outcome was resolution of symptoms.
Speaker: That was not significant.
Speaker: They looked at other outcomes, such as deterioration by more than two points in an ordinal eight-point scale.
Speaker: They looked at the difference between fever since randomization, escalation of care since randomization.
Speaker: They looked at deaths.
Speaker: They looked at post hoc outcomes that included
Speaker: escalation of care occurring more than 12 hours since randomization, and emergency department visits or telemedicine consultations.
Speaker: And once again, really there was no significant difference in terms of those patients who were treated with ivermectin or placebo.
Speaker: Now, another high level of evidence that we usually recur to is obviously when we're trying to figure out a new therapy is the use of meta-analysis.
Speaker: And with meta-analysis,
Speaker: There is a particular meta-analysis that I'll share first that was published in American Therapeutics.
Speaker: This was by Bryant and collaborators, Ivermectin for Prevention and Treatment of COVID-19 Infection, a Systematic Review, Meta-Analysis, and Trial Sequential Analysis to Inform Clinical Guidelines.
Speaker: This included multiple studies, most of them not published, most of them available either by pre-publication MedArvix or something of that sort,
Speaker: They looked at mild to moderate COVID-19, severe COVID-19, and mild to moderate and severe COVID-19 altogether.
Speaker: When they looked at the, they included a large number of studies.
Speaker: Most of these studies though had low volumes, but the total that they looked for in the analysis at the end was around 2000 plus patients included in all these studies.
Speaker: And they also did a,
Speaker: quality of evidence grade for the findings they did.
Speaker: And in terms of the outcome of death from any cause, they found that 48 fewer deaths per 1,000 in the ivermectin group.
Speaker: They gave that a relative effect of 0.38 for 2,400 participants in 15 trials, and they gave that a quality of evidence grade moderate.
Speaker: For the other outcomes that included recovery time to negative PCR tests in days,
Speaker: time to clinical recovery in days, time to clinical recovery in days, mild to moderate, time to clinical recovery for those severe inpatients, admissions to the ICU.
Speaker: They gave all of those positive findings, smaller number of patients, but they also gave the quality of the evidence grade as very low.
Speaker: So again, this was presented as a positive clinical trial.
Speaker: It was really a
Speaker: shared and socialized extensively by promoters of ivermectin.
Speaker: One of the complaints that some academics had about this particular meta-analysis was that they included a lot of trials that had very low quality, including a couple of large trials that were ultimately retracted for presumed fabricated data.
Speaker: So the authors have since then stated that they rerun
Speaker: all the stats and that it still holds.
Speaker: I have not seen or have not been able to find a new version of this study in the website, but this is a study that a lot of people have quoted and we also will include in the show notes.
Speaker: The conclusion though of the authors is a little bit more nimble and humble than the way this study has been quoted by many proponents.
Speaker: So they have
Speaker: Many have quoted this as incontrovertible evidence that ivermectin saves lives in COVID-19.
Speaker: Their conclusion verbatim, quote-unquote, was moderate certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin.
Speaker: Using ivermectin early in the clinical course may reduce numbers progressing to severe disease.
Speaker: The apparent safety and low cost suggest that ivermectin is likely to have a significant impact
Speaker: on the SARS-CoV-2 pandemic globally.
Speaker: So this again is one clinical trial, I'm sorry, one meta-analysis that I think a lot of people have talked about.
Speaker: One that came in sequentially after this one was published in Clinical Infectious Disease, Ivermectin for the Treatment of Coronavirus Disease 2019, a systematic review and meta-analysis of randomized controlled trials.
Speaker: They included less trials
Speaker: because they were much more selective in terms of the quality of the trials, trying to find trials that could really be studied together.
Speaker: So they were more rigorous in their selection of the available trials.
Speaker: They included a total of a little bit under a thousand patients total.
Speaker: And when they looked at the results of this,
Speaker: they found that the summary of findings on the effect of ivermectin compared with standard of care in placebo or placebo in patients with coronavirus disease, for all-cause mortality, they found that the risk reduction really crossed the line of non-significance with the confidence interval was 0.2 to 1.3, and the certainty of evidence was very low.
Speaker: So that's quite a different finding than the previous meta-analysis.
Speaker: In terms of length of stay, again, they found that certainty of evidence was very low and there was no significant effect.
Speaker: In terms of adverse events and serious events, same thing.
Speaker: The odds ratio was very wide in terms of the confidence interval and low and very low level of evidence.
Speaker: And for viral clearance, the same story.
Speaker: So they really concluded that their meta-analysis was negative and did not support
Speaker: the use of ivermectin in COVID-19.
Speaker: Now, looking at the same trials, how do people find different results?
Speaker: I think that if you look in more detail at the methodology, you will find that the second study, the one that was published in clinical infectious disease, was more rigorous in terms of the studies that they included.
Speaker: And this is always a challenge with meta-analysis.
Speaker: Obviously, it depends also on
Speaker: How do you compare trials?
Speaker: What are the trials that I include?
Speaker: And what a lot of people have argued is, do you really have patient-level data, or are you just looking at summary aggregates?
Speaker: Cochrane Library, as many of you know, is a database of systemic reviews.
Speaker: They are considered, I think, pioneers and leaders in high-quality systematic reviews and meta-analysis.
Speaker: They also have an ongoing meta-analysis
Speaker: for ivermectin for preventing and treating COVID-19.
Speaker: As of now, the main results that they have found is that among 14 studies with almost 1,700 participants investigating ivermectin compared to no treatment, placebo, or standard of care, they have not been able to find really a positive effect.
Speaker: They do mention that none of these studies compared ivermectin to an intervention with proven efficacy.
Speaker: There were nine studies treating participants with moderate COVID-19 in inpatient settings and four treating mild COVID-19 cases in outpatient settings.
Speaker: One study investigating ivermectin for prevention of SARS-CoV-2 infection.
Speaker: Eight studies had an open label design.
Speaker: Six were double-blind and placebo-controlled.
Speaker: Of the 41 study results contributed by included studies, about one-third were at overall high risk of bias, which is usually low or very low certainty of evidence.
Speaker: Ivermectin doses and treatment durations varied among
Speaker: included studies, and they identified 31 ongoing and 18 studies awaiting classification into publication of results or clarification of inconsistencies.
Speaker: So based on the available evidence, the Cochrane Library authors concluded that based on the current very low to low certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID-19.
Speaker: The completed studies are small and few are considered high quality.
Speaker: Several studies are underway that may produce clear answers and review updates.
Speaker: Overall, the reliable evidence available does not support the use of ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized trials.
Speaker: So when you look at the aggregate of the available meta-analysis and you really take the time to look at the available studies, I think the solid conclusion is that we do not have evidence to support the use of ivermectin, which
Speaker: Also, I think it's fair to say that we don't have any evidence to say that it does not work.
Speaker: But the available evidence so far does not indicate that we should expect it to be positive and that what we really need is high quality studies, which like I said before, in the midst of a pandemic with 250 million patients, this is the time to get those answers once and for all and really move science forward as we've done with dexamethasone, as we've done with anticoagulation,
Speaker: as we've done with convulsant plasma.
Speaker: And we have really been able to show with large studies and meta-analysis whether these interventions work or don't work for COVID-19.
Speaker: A lot of scientists have written about the problem with a lot of these meta-analyses that are going to be relying on summary data of unpublished trials.
Speaker: Also, what they argue is that what you put into a meta-analysis is going to determine the output, but that we have to be very careful in terms of just conglomerating a whole bunch of small, low-quality trials and expecting something reliable to come out of that.
Speaker: What can we say about the numerous trials that are being cited over and over again or talked about by proponents of ivermectin?
Speaker: And the reality is that the vast majority of these trials have not been published.
Speaker: They are usually presented as pre-peer review, pre-print, early access in the MedRx or MedRvix, I mean, websites of that nature.
Speaker: Many of these studies actually that were touted initially as positive and quoted have been investigated and have been found to either be severely flawed or have been found to be basically fake.
Speaker: and they have been retracted in some instances.
Speaker: There is a group of scientists that includes Gideon Meyerowitz, Dr. James Heathers, Dr. Nick Brown, and Dr. Kyle Shedrick, among others from Australia, the UK, who have been investigating, I mean, a lot of the studies that have been proposed in COVID-19 with the intention really of getting to the validity and the integrity of these studies.
Speaker: And in one particular review that they shared, they looked at 26 major trials that included randomized trials and large observational trials regarding ivermectin.
Speaker: What they found is that a third of these trials for the drug use for use on COVID-19 have serious errors or signs of potential fraud.
Speaker: None of the rest show convincing evidence of ivermectin's effectiveness.
Speaker: And the major problems that they have come upon, which just really requires looking at the data in more detail, asking the authors to share their original data when possible, which a lot of times does not happen because obviously authors do not respond, and that obviously raises concerns immediately.
Speaker: But the major problems in these unpublished trials included the same patient data being used multiple times for supposedly different people, fabrication and fake data.
Speaker: Evidence that a selection of patients for test groups was not random obviously introduces tremendous amount of bias.
Speaker: And in a situation where you have millions of patients with COVID-19 around the world, that should not be a problem.
Speaker: We should be able to do randomized trials.
Speaker: Numbers unlikely to occur naturally.
Speaker: These are things that you can look statistically.
Speaker: Percentages calculated incorrectly.
Speaker: When the math doesn't add up, it makes you wonder.
Speaker: And then a lot of these trials occur with local health bodies unaware of the studies without proper
Speaker: clearance from authorities in terms of whatever it might be of regulatory ethical authorities, which again raises questions on the validity and quality studies.
Speaker: So that's a problem.
Speaker: It's a problem that we have to deal with when we look at what's been published and peer reviewed.
Speaker: It's very scant.
Speaker: It's not very supportive.
Speaker: We look at the
Speaker: at the variation among the different meta-analysis.
Speaker: The higher quality meta-analysis of higher rigor are negative so far, and I think it reflects the available studies.
Speaker: There is one study that has been announced, the TOGETHER trial, which is a large adaptive platform out of the UK that has looked at repurposing different drugs.
Speaker: They have studied ivermectin with a dosing schedule of three to six
Speaker: six milligram tablets, weight dependent every 24 hours for three days.
Speaker: And they have announced that they have stopped that trial for futility in their interim analysis, that there's a manuscript in development.
Speaker: So the largest study so far, the TOGETHER trial is not published yet, but again, has been reported as a negative study.
Speaker: So when you look at the available evidence, there's really not a lot of science to support its use.
Speaker: I think that any drug potentially
Speaker: with potential benefit should be studied, but based on very, very feeble laboratory data that has occurred in other circumstances without a clinical – without translation to a clinical benefit, I think that we have not been able to find that with ivermectin.
Speaker: Yet in this last delta wave, the noise around ivermectin continues to increase.
Speaker: So we'll talk more about that in a second.
Speaker: What I do want to share also is the current guidelines from the CDC.
Speaker: They clearly say that, sorry, from the NIH, they clearly say there's insufficient evidence for COVID-19 treatment guidelines panel to recommend either against the use of ivermectin for the treatment of COVID-19.
Speaker: Results dramatically power well-designed and well-consuming technical trials are needed to provide more specific evidence-based guidance on the role of ivermectin and the treatment of COVID-19.
Speaker: Basically saying there's no evidence, let's do trials.
Speaker: The IDSA has also recommended that in hospitalized patients with COVID-19, the panel suggests against ivermectin outside of the context of a clinical trial.
Speaker: And in ambulatory patients with COVID-19, the panel suggests against ivermectin outside of the context of a clinical trial.
Speaker: Again, there's no evidence.
Speaker: Let's do the trials.
Speaker: The CDC, the FDA, and the WHO have all sent or published advisories against using ivermectin off-label.
Speaker: and especially against using ivermectin that is not designed for human consumption.
Speaker: We will address that a little bit later when we talk about safety.
Speaker: Merck, who designed ivermectin and produces ivermectin, has a very clear statement that there is no scientific evidence to suggest that it would work for COVID-19.
Speaker: People might argue that they have a
Speaker: secondary motives because they have a new drug that's very expensive that they want to use.
Speaker: And even some conspiracy theorists have said that that drug is basically ivermectin.
Speaker: That is not true.
Speaker: That has been demonstrated to be an antiviral.
Speaker: Now, again, I do believe that when you look at the science, which is what we have available, this is where we are today.
Speaker: Regarding safety,
Speaker: Ivermectin is a safe drug.
Speaker: It's been utilized for decades to treat multiple parasitic infections.
Speaker: It's usually used as a one-time dose.
Speaker: We use it for treating tapeworm, for treating other types of parasites, for even treating lice in kids.
Speaker: So Ivermectin for human consumption at the doses that have been utilized for these therapies is safe.
Speaker: However, many of the proponents of Ivermectin for COVID-19 have come up with
Speaker: all sorts of different dosing regimens that have never been studied in terms of their safety and that are associated with potential toxicity due to the higher doses.
Speaker: A lot of these toxicities are usually mild in terms of symptoms, but there have been increased calls to poison centers related to toxicity from ivermectin.
Speaker: There have been some cases of even severe toxicity, which can happen with any medication, and th is is people probably self-medicating,
Speaker: And there's also been reports of using animal formulations of ivermectin, which obviously is not safe and is not recommended.
Speaker: But I do believe that when we talk about safety, we should recognize that ivermectin at the study doses for antiparasitic treatment is a safely accepted drug.
Speaker: However, in addition to utilizing outside of the context that we know it to be safe, outside of the context of using formulations that are not for human consumption,
Speaker: and outside of the context of overdosing, there are real dangers.
Speaker: The first danger is that this use of this miracle drug, as we'll see, has been embraced by anti-vaxxers.
Speaker: And it's a way of, or a belief that if they utilize ivermectin, they don't have to accept or utilize evidence-based treatments that have demonstrated to make a difference in COVID-19, specifically vaccines.
Speaker: So that is a huge danger.
Speaker: The more we talk about a miracle drug, it gives people an excuse not to consider what the current scientific evidence would suggest is more likely to save lives.
Speaker: A second real danger that we have all probably experienced in our ICUs is that it leads to delays in care.
Speaker: People self-medicating with ivermectin for days, days, and eventually get to the hospital in very bad shape.
Speaker: They usually get care much later than they should have.
Speaker: I am sure that many of you have experienced what I have experienced, which is I saw very little people during the Delta wave in my ICU who were very, very sick, who had received vaccinations, but I definitely saw plenty of people who had taken ivermectin.
Speaker: So again, the evidence not suggesting that that's the way to prevent the disease and just leads to delays in care.
Speaker: Another very important danger, real and present danger,
Speaker: is it has created a distraction from meaningful progress in our conversation about the pandemic.
Speaker: If there is potential for drugs to work, we should do the trials based on real science, get the trials done as soon as possible and move on.
Speaker: We've done that with many drugs in the last two years.
Speaker: Most have not worked, unfortunately, but some have demonstrated to work.
Speaker: And we'll talk a little bit more about that as well.
Speaker: Finally, I think what we've seen during Delta, it's created
Speaker: an unnecessary escalation of tension and distrust between patients and families and physicians and other healthcare workers trying their best to care for very sick COVID-19 patients.
Speaker: Obviously, especially those who don't believe in vaccines, they basically will demand that we give the loved ones ivermectin.
Speaker: They will say things like they've done their research.
Speaker: And again, when you look at the evidence available for vaccines versus the evidence available for ivermectin,
Speaker: It's not, there's no match.
Speaker: The vaccines have been studied extensively.
Speaker: They have demonstrated to be effective.
Speaker: There's obviously still a lot that we don't know about the vaccines, but the amount of data and randomized trials and follow-up trials is overwhelming that they're effective.
Speaker: And we know historically that vaccinations have been perhaps alongside hand hygiene, two of the most impactful interventions in public health
Speaker: and in medicine in terms of saving lives.
Speaker: Yet that is not true for the use of ivermectin and COVID-19, but there still seems to be a tremendous amount of noise around this, and we'll talk about that next.
Speaker: So one of the unique aspects of the COVID-19 pandemic has been the infodemic, and the amount of information that has been shared has never been
Speaker: so big and has never moved so fast.
Speaker: Information spreads like a virus, right?
Speaker: So does misinformation and disinformation.
Speaker: So information is facts or data that are based on scientific evidence and real, real, real, real data, right?
Speaker: So for example, we report the number of patients we have in our ICU who have COVID-19 based on positive tests, and we can report the number
Speaker: or percent of those who are in our ICU who are unvaccinated versus vaccinated, that is information.
Speaker: When we present the results of multiple randomized trials, such as what we did for dexamethasone and COVID-19, and then show the aggregation of those trials in well-designed, prospectively agreed meta-analysis, such as the prosperous meta-analysis, we show that there's an impact on mortality, that is information.
Speaker: There's also misinformation.
Speaker: which is information that is believed to be true, but is shared and ultimately ends up being false.
Speaker: Perhaps there were people who believed that hydroxychloroquine would work and they were sharing that as a potential therapy for COVID-19.
Speaker: But as soon as we did the trials and found that not only it doesn't work, but could be dangerous, we kind of retracted that.
Speaker: That's misinformation.
Speaker: So information that is shared with good intentions, but might be incorrect.
Speaker: And finally,
Speaker: There's disinformation, which is information that we know, that somebody knows is false, that they share with alternative motives or just to create more confusion among the public.
Speaker: And there's been plenty of that.
Speaker: Obviously, a lot of that has been shared through social media.
Speaker: What's important is that misinformation and disinformation or the lack of spreading good information all can be deadly.
Speaker: and we need to critically assess information before we share it.
Speaker: That's our responsibility.
Speaker: But also when you look at how these things propagate, a lot of these videos or social media posts or headlines might show up in a fringe kind of extreme social media platform.
Speaker: They're then picked up in more mainstream social platforms, a local
Speaker: newscast might pick it up and then a national newscast and all of a sudden these things go viral and people are sharing and re-sharing some of these videos, some of this information that again might be completely wrong and can lead to problems such as death when we're talking about a severe pandemic such as COVID-19.
Speaker: When we look at the themes of misinformation and COVID, by far the most prominent one is miracle cures.
Speaker: And that obviously is where ivermectin falls.
Speaker: There's tremendous amount of misinformation and disinformation regarding the benefits or the evidence behind the use of ivermectin.
Speaker: Another important aspect of this infodemic is that something that says that we have a simple solution to a terrifying worldwide complex problem is always going to travel faster
Speaker: than somebody that says that this is a negative study or this doesn't work, right?
Speaker: Positive studies are gonna definitely move a lot quicker.
Speaker: When you look at any of these ivermectin meta-analysis, those that are positive, such as the first one I shared, despite being published in much lower quality and lower impact factor journals, have a lot more tweets and shares
Speaker: than those who are higher quality, higher rigor.
Speaker: And I think it just speaks to what people want to hear is that something works.
Speaker: Before we dive deeper into what happened with ivermectin specifically and the role of some of our colleagues in that, there are some tips that we can all apply and share with others for navigating this epidemic.
Speaker: So number one, assess the source.
Speaker: When somebody sends you something or you see something,
Speaker: Try to figure out who shared that information with you and where did they get it from.
Speaker: Even if it's a friend or a family, you still need to kind of vet their source.
Speaker: Where did this come from?
Speaker: A lot of times you eventually get to a source that is a fringe source or something that does not really have a lot of reputation or that really just shares a lot of misinformation and you can immediately kind of assess the quality of where that came from.
Speaker: Go beyond the headlines.
Speaker: Headlines may be intentionally sensational or provocative.
Speaker: I have seen in
Speaker: large clinician kind of forums, people go crazy around headlines regarding some of these lawsuits, talking about how now the judges are dictating what we do as doctors.
Speaker: And all you have to do is read the whole article.
Speaker: And what you find out actually is that the judge is not dictating to doctors what they're doing.
Speaker: What the judge said originally in an Ohio case was that if a doctor prescribed the ivermectin,
Speaker: and has privileges in the hospital, the hospital should give it.
Speaker: So they basically are upholding and defending the right we have as clinicians to prescribe sometimes off-label medications if we believe they're going to help our patient.
Speaker: So go beyond the headlines.
Speaker: Read the actual article before you share it or before you comment on it.
Speaker: Identify the author.
Speaker: Search the author's name online to see if they're real or credible.
Speaker: People present themselves as accomplished scientists,
Speaker: world-renowned, and all I have to do is Google search some of these authors and find what they published before.
Speaker: And what you find, for example, with a lot of the proponents of ivermectin is that they publish a lot of opinion pieces in low-quality journals, but they really haven't published any randomized clinical trials or they really haven't participated in high-quality science.
Speaker: So identify the author, and that sometimes helps you understand also where they're coming from.
Speaker: Check the date.
Speaker: Is it up-to-date and relevant to current events?
Speaker: Has a headline image or statistic been used out of context?
Speaker: So people are still sharing sometimes data on stuff that we were talking about in May of last year that has been debunked.
Speaker: I recently got, for example, a protocol for anticoagulation that was from June of 2020, which is way before we had published studies on perhaps the role of anticoagulation
Speaker: COVID-19 in critically ill patients.
Speaker: So again, check the date because people keep resharing things that might be outdated.
Speaker: And we have learned with COVID that information moves very, very quickly these days.
Speaker: So you really have to figure out where this came from.
Speaker: Examining the supporting evidence.
Speaker: Credible stories back up their claims with facts.
Speaker: If you look at some of these claims and you actually go and look at the references, start pulling the references, you will find that often in disinformation or misinformation pieces, there's a lot of websites that are not official.
Speaker: There's a lot of pre-peer-reviewed studies, quote-unquote, that have not been published.
Speaker: There's a lot of...
Speaker: data that really comes from very, very questionable sources.
Speaker: So pull the references, look for the studies that people are quoting, and when you read the studies, a lot of times you'll find that maybe an article took the study totally out of context.
Speaker: It might be a very small study, which obviously has tremendous biases.
Speaker: And again, these are usually, if anything, if they're positive,
Speaker: They just indicate that we need to study the topic more, not that we should be utilizing something based on a small end with a tremendous potential for bias.
Speaker: Check your own biases.
Speaker: Think about whether your own biases could affect your judgment on what is or is not trustworthy.
Speaker: So if you believe that ivermectin works, anything that's positive will confirm your bias.
Speaker: And if you believe that it's probably not going to work, you're going to give a lot more credence to negative studies.
Speaker: So for example, based on what I've seen so far, my bias is that ivermectin is unlikely to work based on its track history with other viruses, based on the fact that the available evidence does not suggest it works, and based on what I've seen over and over again, and the fact that people are just using anecdote, but every time that we try to study it, it really hasn't panned out.
Speaker: However, I always tell myself,
Speaker: If I see well-designed studies that show that in certain situations it might be, it will work, I have to be able to check my bias and change the way I'm thinking.
Speaker: And there are some people who just are unwilling to change the way they think no matter what, and that is something that is very, very dangerous.
Speaker: And finally, turn to fact checkers.
Speaker: Consult trusted fact checking organizations
Speaker: There's an international fact-checking network, global news outlets focusing on debunking misinformation.
Speaker: Look at guidelines.
Speaker: We're clinicians.
Speaker: We are experts in critical care.
Speaker: The depth of expertise in our current society is a problem.
Speaker: We should be able to trust colleagues who dedicate their lives to science.
Speaker: Nobody has all the answers.
Speaker: But I think that there's a lot of sites like the NIH guidelines where a lot of clinicians are looking at all the available data and trying to give us the best available recommendations.
Speaker: They have all they recommend is based on references.
Speaker: You can check those references.
Speaker: And I think that we should really trust the experts because that's how we got where we are today in society, by creating expertise, by creating studies, and by following the science.
Speaker: So don't forget that.
Speaker: is also an important tip.
Speaker: So let's get back to ivermectin and how did ivermectin become this wonder drug that all of a sudden everybody is talking about, especially those who are sick and refuse vaccines?
Speaker: Well, there are a couple of prominent groups that have pushed narratives against vaccines in favor of certain unproven therapies, but there's one in particular
Speaker: that I think has been very prominent in the critical care world.
Speaker: It's a group of colleagues that they call themselves the Frontline COVID-19 Critical Care Alliance.
Speaker: And they have been promoting prevention and treatment protocols for COVID-19, often without good science.
Speaker: But they are strong believers in this.
Speaker: And they're people who have really, they have this frontline COVID-19 Critical Care Alliance or
Speaker: The FLCCC Alliance is also confirmed not only by clinicians, but they also have media experts and news reporters that have really organized a very deliberate campaign to promote some of their protocols, but ultimately to really promote ivermectin.
Speaker: One of the leaders of this group back in December of 2020 actually testified
Speaker: to members of the Senate Homeland Security Committee and quote-unquote said, Ivermectin is effectively a miracle drug against COVID-19.
Speaker: He stated that the data showed profound efficacy of the drug in all stages of the disease.
Speaker: And his conclusion was that if everyone were to have access to this drug, Ivermectin, the pandemic would end, the economy can reopen,
Speaker: and social interaction activity can resume and life can normalize.
Speaker: So those are extraordinary, extraordinary assertions that really require extraordinary data, which, as I've shown you so far, is nonexistent.
Speaker: Now, when you go to their website, there are three things that they talk about, I think, prominently or that they have multiple times have said is, number one, that they are high-quality scientists.
Speaker: who are just trying to really promote what's best for patients, that they have no financial skin in this game, that they really have no financial interest.
Speaker: And number three, this and other groups have promoted perhaps that there is some conspiracy among expert institutions, among pharmaceuticals to push unproven, very expensive drugs and kind of
Speaker: eliminate the evidence of drugs that would not make them a lot of money.
Speaker: So let's look at those three things.
Speaker: So in terms of the science, they tout themselves as being respected scientists and believers in science, yet they don't talk about vaccines.
Speaker: They do very little mention of things that have been shown to not work that they promoted initially.
Speaker: Vitamin C is something that they promoted for a long time before COVID.
Speaker: Some of these members, large randomized studies have shown it's not effective.
Speaker: They don't talk about those studies.
Speaker: They usually criticize any study that is negative against what they believe.
Speaker: So that's a problem.
Speaker: The fact that they are pushing ivermectin stronger and stronger now really probably relates to the fact that it's been embraced by a large group such as anti-vaxxers, extreme fringe right-leaning groups, also conspiracy theorists,
Speaker: So obviously it's giving them a captive audience, a large audience of support.
Speaker: They talk about the fact that they don't make any money from this.
Speaker: We don't know that, but the first thing that you'll encounter on their website is a big asking for contributions and donations.
Speaker: We also know that large captive audiences are very valuable financially these days, and they have a following, almost a cult-like following of people who are against the establishment.
Speaker: And number three, they've also...
Speaker: kind of push this idea that everything is a conspiracy, that we're just trying to use what's expensive.
Speaker: Well, vaccines have been around forever.
Speaker: They've been demonstrated to save lives.
Speaker: The evidence for vaccines is extremely powerful.
Speaker: They don't talk about that with a lot of emphasis to kind of minimize that.
Speaker: Before vaccines, they talked about ivermectin as a bridge to vaccines, but now they're not pushing their followers to get vaccines.
Speaker: That is a little bit, I mean, concerning.
Speaker: And finally, in terms of the science, when you look at what they tout, they talk about ivermectin for COVID-19.
Speaker: There are 65 trials, 655 scientists, 40,000 patients, 32 randomized controlled trials, 86% improvement on prophylaxis, 66% improvement on early treatment, 40% improvement on late treatment, 57% improvement on mortality.
Speaker: Again, you go to their medical
Speaker: ivmmeta.com where they do their ongoing meta-analysis and you find retracted studies, their forester plot makes no sense, the way they calculate things is unclear, and really just very quickly you can poke holes into the rigor of their science.
Speaker: Same thing when you look at their protocols and extensively reference, but a lot of the references are articles they wrote themselves, which are opinion pieces or tweets, or they reference
Speaker: what has happened observationally in places like Paraguay last year when they don't mention what has happened more recently in Paraguay in those same places.
Speaker: Same thing with India, they attribute these declines in rates to the use of ivermectin.
Speaker: Ivermectin has been utilized probably in many places for some time now for COVID without any real effect.
Speaker: So again, they cherry pick the observational data and they really promote a lot of data that has not been published as proof
Speaker: that they work.
Speaker: And most of what you'll find is news reports of lawsuits, news reports of where people can get ivermectin.
Speaker: But again, the science does not seem to be there.
Speaker: Most of their social interactions are on fringe social media platforms, just basically talking to an audience that wants to believe them.
Speaker: So unfortunately, if they were true scientists,
Speaker: they probably would have done a study by now.
Speaker: They probably would have promoted the use of vaccines, and they probably would have been more interested in finding answers than in telling us why their answer is absolutely correct.
Speaker: So what are some of the conclusions that we come, kind of my perspective on ivermectin?
Speaker: They're currently
Speaker: is no credible scientific evidence to support its use in COVID outside of the context of a well-designed clinical trial at the present moment.
Speaker: Could that change?
Speaker: Perhaps.
Speaker: But as of what we have right now, the plausibility is low.
Speaker: And the studies that have been done are either super, super low quality, really, I mean, laughable almost, or the ones that I've done that are published that have good quality have not really shown any signal.
Speaker: With 270 or 250 million COVID patients around the world, if it really worked, shouldn't we be able to figure it out?
Speaker: The second issue in terms or the second conclusion I have is that there's a deliberate, organized, and well-funded campaign to promote misinformation and disinformation regarding COVID-19 right now.
Speaker: A lot of this is centered around ivermectin because ivermectin has become a flag for a lot of the groups that feed into this
Speaker: into this campaign, the anti-vaxxers, those that are against the established expertise, those who really are trying to minimize COVID-19 as a worldwide problem.
Speaker: And we have to not be naive and recognize that there are colleagues who are part of those campaigns.
Speaker: Their motives are unclear, but it would be nice for them to share more information of why they believe this to be the way
Speaker: and why they're not doing randomized trials like they would do for any therapy that we're trying to figure out.
Speaker: They know better than anybody that the way for trials, the way for therapies to be accepted is with good science.
Speaker: The argument that they know that it works for a fact so it would be unethical, they don't have that equipoise is BS.
Speaker: That's an excuse basically to keep promoting misinformation.
Speaker: Families and patients are victims.
Speaker: They're victims of this deliberate campaign of misinformation and disinformation.
Speaker: And when we encounter them at the bedside and they bring these things up where they didn't get vaccinated or they want us to give ivermectin, we should be compassionate and explain in simple terms why we do not use ivermectin if we don't use it to treat COVID-19 at this time.
Speaker: I think that it's very easy to lose empathy and to become antagonistic
Speaker: But if your loved one was dying, you would probably hold on to anything that looks credible and that really gives you hope, right?
Speaker: And if you were to Google ivermectin or treatment for COVID-19, you probably would see these fringe websites pop up immediately, which tell you probably all the things that they have done in the back burner to have their search optimization pushed up.
Speaker: And finally,
Speaker: we have ongoing trials such as the COVID out trial, active six trial, and a UK based principal trial.
Speaker: They're actually trying to, in a serious, rigorous way, evaluate, is there a role for ivermectin and COVID-19?
Speaker: I anticipate that we will have results of those trials soon.
Speaker: Hopefully they'll provide more evidence, but I also think that that's the way forward.
Speaker: If there are drugs that people believe could work,
Speaker: we should be trying to organize ourselves to do the trials.
Speaker: This is the time to do trials for a pandemic because we have the patients.
Speaker: Now, granted that we are seeing the number of patients with COVID-19, especially during this Delta wave in the United States go down, and that's a positive trend.
Speaker: I do think that there are lessons to be learned
Speaker: from this infodemic and especially from the ivermectin story during this delta wave that we need to be able to apply to other situations in the future.
Speaker: Recently there was a family member that was demanding a patient get ivermectin and one of the colleagues just asked me, why would we just not give it, wouldn't that be easy?
Speaker: It's not going to hurt the patient.
Speaker: But I think that we have to be careful in terms of letting families dictate what we should do based on bad information
Speaker: or based on campaigns that are predatory and target people like them.
Speaker: Because where do you draw the line?
Speaker: Are they going to tell you then give somebody full dose anticoagulation when they're bleeding?
Speaker: Are they going to tell you what people should get or should not get?
Speaker: So we have to be able to draw the line but be compassionate.
Speaker: But we also have to remain humble and recognize that we don't know everything and that we can only act based on the best available information.
Speaker: And we should make the effort
Speaker: to look for that information and those sources ourselves to try to understand a little bit better what the situation is.
Speaker: I like to finish the podcast usually by asking our guests a couple of questions.
Speaker: We talk about books and some of the things that they hold dear that other people don't believe.
Speaker: But what I wanted to finish with is maybe a book recommendation.
Speaker: There's a recent book I read by Adam Grant called Think Again, The Power of Knowing What You Don't Know.
Speaker: which I think is really a phenomenal read for what we've been through with COVID in terms of misinformation, disinformation, and how we behave throughout the last two years and a lot of what is happening right now with colleagues in terms of treatment options for COVID.
Speaker: One of the things that he argues in this book is that often people are either in a preacher, prosecutor, or politician mode.
Speaker: So a preacher is somebody who has found the truth and is only trying to bring people to see their truth.
Speaker: So there is no question that this is the truth.
Speaker: And a lot of the proponents of ivermectin have become preachers, right?
Speaker: When asked in interviews what would make them think differently, they clearly have stated that they know that ivermectin works, that people are trying to suppress it, and that there's nothing that would make them think differently.
Speaker: Well, for a scientist and a clinician,
Speaker: That is probably not the best position to be in.
Speaker: Another mode is prosecutor.
Speaker: Well, all you try to do is bring down the ideas that oppose yours, right, as a prosecutor and bring up all the flaws.
Speaker: So a lot of people on the other side of the camp, the people who don't believe in ivermectin, have become prosecutors.
Speaker: And every trial that is negative or every trial that is possible that's retracted, we kind of prosecute that idea and keep trying to confirm what we believe, which is it doesn't work, right?
Speaker: So we have to be careful with that.
Speaker: I mean, there's things you need to prosecute, but you should also prosecute your own ideas and just try to figure out, okay, what would make me think differently?
Speaker: Or what would be the evidence that I need to change the way I think or think again?
Speaker: And then fine, there's politicians who are just trying to accommodate the louder voices or whoever suits their benefits.
Speaker: And that might be some hospitals or some clinicians who, if somebody wants ivermectin, they'll give them ivermectin if somebody wants
Speaker: to not use ivermectin, they won't use ivermectin.
Speaker: But again, these are very common and we probably all have played these roles in different points of our life or the pandemic.
Speaker: But ultimately, we want to be a scientist.
Speaker: And scientists, when you look at what they know or what we know, you can think of concentric circles.
Speaker: The smallest circle is the things I know I know.
Speaker: A little bit larger is the next circle, which is things I know.
Speaker: The third circle, which gets a little bit larger, is the things I think I know.
Speaker: And then by far, the largest circle around all those is the things I don't know.
Speaker: So as a scientist, we start with being humble and recognizing that there's too much we don't know.
Speaker: We have a constant sense of doubt.
Speaker: If I believe something works, I should be doubting.
Speaker: How could it not work?
Speaker: Or what would convince me not to work, that it doesn't work?
Speaker: If I believe something does not work, I should be doubting myself in terms of how could this actually work and what situation might it work?
Speaker: What are the things that would make me think it works?
Speaker: And that should lead to curiosity, which either leads to us investigating the literature ourselves or scientists designing clinical trials that ultimately leads to discovery, which is the way that we advance forward.
Speaker: So I would like to leave you
Speaker: with a quote from this book, Think Again by Adam Grant.
Speaker: And this is open quotations.
Speaker: When we're in scientist mode, we refuse to let our ideas become ideologies.
Speaker: We don't start with answers or solutions.
Speaker: We lead with questions and puzzles.
Speaker: We don't preach from intuition.
Speaker: We teach from evidence.
Speaker: We don't just have healthy skepticism about other people's arguments.
Speaker: We dare to disagree with our own arguments.
Speaker: Thinking like a scientist involves more than just reacting with an open mind.
Speaker: It means being actively open-minded.
Speaker: It requires searching for reasons why we might be wrong, not for reasons why we must be right, and revising our views based on what we learn.
Speaker: So my final ask is for all of you to be scientists and take care.
Speaker: We'll talk in the next episode of the podcast.
Speaker: Thank you very much.
Speaker: Thank you for listening to Critical Matters, a sound podcast.
Speaker: Make sure to subscribe to Critical Matters on Apple or Google Podcasts and share with your network.
Speaker: Sound's transforming the way critical care is provided in hospitals across the country.
Speaker: To learn more, visit www.soundphysicians.com.
