Well, welcome to today's talk it's thursday the 24th of june (2021). Now the best
meta analysis so far on the efficacy of ivermectin has been published so we're going
to look at that now. I know looking at these studies aren't for everyone it's
it's a bit scientific and it kind of journal reading stuff so i'm going to give
you the the the headlines and the or the bottom line really on this. Now now
this study shows that Ivermectin probably
reduces deaths by 62% and possibly reduces
transmission by 86 percent, and you notice i said probably reduces deaths by 62
and possibly reduces transmission by 86—so that's the result from this meta analysis
which we're now going to look at in detail. And i'd love you to to stay it is
pretty interesting actually.
Now this is the publication here just came out on the 17th of june so it's a few days old now “Ivermectin for the prevention and treatment of covid19 infection” we see the authors there and Tess Lawrie of course we've had the enjoyment of interviewing twice on this channel and during that time Tess did give us a lot of this information that's in this before it was published. But the big difference now it's published it's in this it's in this journal the american journal of therapeutics and and it's peer reviewed so this is peer reviewed and this is particularly important because a meta-analysis as you know is looking at the results from many different trials combining those reanalyzing that data and reinterpreting that data and that is intrinsically quite a complicated thing to do, so you need good quality peer review to make sure that this technique that this methodology was correctly followed. And given it has been published i think we can asses that it was correctly followed. It certainly looks good to me in fact parts of it are beyond me actually but i think i've worked out most of it and we'll go through it now so “ivermectin for the prevention treatment of covered 19 infection a systematic review meta-analysis and trial sequential analysis to inform clinical guidelines”…so background to this now the the anti-parasitic agent ivermectin with antiviral and anti-inflammatory properties has now been tested in numerous clinical trials so here they're clearly saying that it's got antiviral and anti-inflammatory properties, the question is to what degree are they efficacious? Now 2018 application for ivermectin used for scabies gives a direct cost of $2.90 for 112 milligram tablets—i mean this is an incredibly cheap drug. It's off license, it's generic, it can be manufactured in huge amounts in india—remarkably low cost. So if it did work it would be really good because it's a very very cheap intervention low-cost therapeutic, because that's particularly useful in countries where they've got very limited resources. Now most trials were registered self-funded and undertaken by clinicians, so these are not trials done by large pharmaceutical organizations they're not trials done by governments, they're trials mostly done by the actual clinicians the doctors and their assistants who were actually working in the field. And very often they've done this research as well as their day job, so they were largely self-funded by the clinicians themselves rather than officially sponsored. Now we this is we assess this is the team from the meta analysis “efficacy of ivor mectin treatment in reducing mortality and chemo prophylaxis as a prevention of covid19 and preventing cross-infection spread of infection”… now data sources that they used in this up to the 25th of april 2021…now this is quite important because recently there's been some international studies which indicate possible to probable preventative effects in mexico, peru, a couple other places i can't remember from around india of course, but from from around the world that indicates possible to probable prophylactic effects in terms of preventing people contracting covid 19 in the first place , but you've got to have a cut off somewhere, and this one was on april the 25th. Because this is a complex analysis to calculate and indeed to write up so the team these are direct quotes in italics system sifted four studies extracted data and assessed risks of bias meta-analysis were conducted and certainty of evidence was assessed. That's what they do now we're gonna look at what they did in a minute but just interesting to note here they use what's called the grade approach and the grade approach here is on the this is on the cochrane training site and it's the grade approach so let's look at what this is: so that's the cochrane training site there that's a good article in bmj on the grade approach grading of recommendations assessment development and evaluations the grade approach. Now i obviously knew about this but when you look at this there's actually whole training packages and textbook sort of things on it so it's a whole field in its own right actually so for the serious students plenty there on that on that cochrane review training site. Needless to say we're not going into it but the point to notice is it's it's this method is reproducible and transparent framework for grading certainty and evidence. So how sure are we that the evidence is giving evidence for what it says it's doing? This is about validity the degree to which something does what it says it does. So if it says beans on the tin and you open the tin and it's got peas inside that's a non-valid claim isn't it? But if it says beans on the tin you open the tin that's what you get you get beans and that's a valid claim. It really is as simple as that, but of course there's degrees of validity in this in these meta analyses. 100 organizations officially endorsed grade and as we saw the cochrane the main uk one uses that methodology. Now, what this does it it is reproducible, now it's not saying it's completely objective, it's not a mechanical process, it's not—there is subjective assessment in it, but the subjective assessment is carried out by people with a lot of research analysis experience and the peer reviewers in this case will have carried out their own grade analysis. One would like to think and come up with the same conclusions, otherwise it wouldn't be a proper peer review. So basically grade has four levels of certainty of evidence how sure are we what is our certainty and it can either be very low low moderate or high so very low level of certainty, low level of certainty, moderate level of certainty, or high level of certainty—that's what this grade thing does now things that would decrease confidence making things either sort of go down from moderate to low to very low risk of bias. In the study, imprecision in the studies, inconsistency in the studies, indirectness (that something isn't actually assessing what it's supposed to assess)—and publication bias (things that are published and indeed not published), that's the hardest one to assess, so that would tend to put things down into lower categories. But increasing confidence is a very large magnitude of effect, so if lots of people survived in one group, and lots of people died in another group, for example, clear dose response gradient, so the more of the good thing the the more the better effect. And the third criteria there is residual confounding is likely to decrease rather than increase the magnitude of the effect. So anything that gets in the way, that clutters up the result is likely to decrease rather than increase the magnitude of effect. Of course if you've looked at previous videos on there you'll recognize these from the austin bradford hill criteria, so it's not entirely new, but it's been revamped and and updated so that's kind of what they're doing. So recognize methodology that can be analyzed and reproduced by others’ data sources: 25 randomized controlled trials, number of patients in in the studies collectively 3,406 participants, right. Ivermectin reduced risk of death compared with no ivermectin. Now the meta-analysis here was 15 trials that contained the mortality data and in these 15 trials there was a total of 2,438 patients, and the average risk ratio was 0.3, in other words 62% reduction in deaths. If you were given the ivermectin your chances of dying were 0.38, 62% reduction in the probability of dying. So that is kind of the headline figure that we gave at the start, and it's it's it's quite a reasonable figure. Now the level of certainty here is moderate certainty evidence. So that's the second highest or third lowest level of evidence depending on how you look at it, so if that's the lowest second, third, fourth, there you go. So that's where it is, it's at the moderate level of certainty. Now when we talked to tess about this, actually we did, i was quite impressed with the fact that she was very conservative. She wasn't making assumptions about how valid her data was, or how certain she was, and it appears the peer reviewers agree with that. So moderate certainty evidence, a bit disappointing to be quite honest if i'm being honest. I am disappointed that it wasn't high level, but of course we know that these were mostly based on small-scale studies carried out by the clinicians themselves, self-funded, and of course clinicians are good at clinical work they are not necessarily absolutely brilliant at organizing clinical trials. It's not really their day job. But because there is no big pharmaceutical companies or governments involved in this, this is what we've got. So it's not surprising really, that's kind of where we ended up. So we can have moderate certainty that this is an accurate reduction in deaths of 62 percent, the average risk ratio 0.38.
Now i'm not going to go into these, to tell you the truth i don't fully understand them, but these are other ways of assessing the validity of that data other than the grade so the dersimonian-laird method and the biggerstaff-tweedy method, so basically it checked out, in other words what the team authors are saying here as well as using grade they triangulated the grade results—grading of recommendations assessment development and development and evaluations—they triangulated those with other methodologies and they got the same, at least the same direction of results. So so that's good, they've used different methodologies, and tell you what, if you actually look through this paper, it really is it really is quite a a detailed impressive piece of work. But it's a very detailed study with lots of fairly precise methodological information in it, so that was that result: 62 percent protection.
So ivermectin versus no ivermectin in hospitalized patients: the ivermectin group, the total mortality was 2.3 percent, the patients died; the no-ivermectin group, 7.8% of the patients died in hospital. So we see quite a nice bit of clear water between those two figures, really indicating the likely, with moderate certainty, likelihood that ivermectin is being efficacious. So the 62% protection, 2.3; versus 7.8.
Now, moving on to ivermectinus prophylaxis, which we've recently seen for example in india, peru , mexico. Did we look at study in chile as well? We looked at a few studies about this, and it does look remarkably promising from population-based data, but we're only going from what is three trials analyzed by the trial authors. In this one, the average reduction in transmission was 86 percent in prophylaxis reducing covid 19 infection, but this was low-certainty evidence. Now the reason it was low certainty evidence— of course, it wasn't very low, it was low—is due to study-design limitations, and “few included trials”. But what they did find clearly favored ivermectin used to bring about improvement in patients’ condition and prevent deterioration, that was another thing the trial or the meta-analyses authors concluded.
Adverse events, rare among treatment trials, evidence of no difference was assessed at low certainty. In other words, they couldn't really tell from the data they had they couldn't really give a definitive answer to the severe adverse events, how different they were between the two groups. But again, other studies, and we know ivermectin's been used extensively for parasitic infections which we've looked at, but this is only looking at what this is looking at, so evidence of no difference was assessed as low certainty, so they couldn't say for sure there was no difference, which is is the honest opinion, now the conclusions from the study authors now put these all in inverted commas because i think it's quite important to to get them right these are all direct quotes “moderate certainty evidence finds that large reduction in covered 19 deaths are possible using ivermectin”. Okay so that's one conclusion. Using ivermectin early in the clinical course may reduce nbers progressing to severe disease. Certainly consistent with what dr nair was doing in india when we interviewed praveen now a few weeks ago. “the apparent safety and low cost suggests that ivermectin is likely to have a significant impact on the sars coronavirus 2 pandemic globally” is the conclusion of the study authors. So that's that it's not as convincing as we would like, but largely due to the limitations and the clinician-run nature of the trials, but the team clearly the meta-analysis team clearly feel that they have collected enough evidence to indicate efficacy and clinical use. Now of course i'm not prescribing anything, this is purely for educational purposes. Read the paper yourself and see what it says but that that was what they say the apparent safety with low cost suggests that ivermectin is likely to have a significant impact on this highest coronavius 2 pandemic globally. And it would certainly have been good if we did have an effective prophylactic agent because that could have curtailed things things like the delta variant couldn't it? Because the vaccines don't work straight away whereas the the idea is that a therapeutic would work within probably within oh i don't know within a few hours anyway within a few hours.
Now let's just compare this with other agencies at the moment for balance. Now this is from the national institutes of health from the united states of course and they have their statement here any national institutes of health covered 19 treatment guidelines and fairly well known now they say there is insufficient data for covid-19 guideline pane,l to recommend either for or against the use of ivermectin is their conclusion. Now, of course we know that the world health organization has come out against ivermectin except in clinical trials, whereas national institutes of health in the states has kept this neutral response, and that has been their position since february i think yeah 11th of february, that's been their position since then. So direct quote “there's insufficient data to recommend either or against the use of ivermectin for the treatment of covidd 19. Okay, now the reason that they give for this that they can't be more definitive, is the sample size of most of the trials were small. Okay, some were a few hundred, but yeah, we accept that point. “various doses and schedules of ivermectin were used”—well, of course, this was done by different clinicians around the world. Some of the randomized controlled trials were open-label, in other words, there could be placebo effects. They weren't all double-blind, which of course is a legitimate critique. Patients receiving various concomitant, potentially confounding, medications such as doxycycline, hydroxychloroquine, azithromycin, zinc and corticosteroids, so these could have confused the picture, meaning that it's hard to say whether it was these or the synergistic or the inhibitory effects of these with ivermectin that gave the results. So they are saying they are confounding, casting uncertainty on the dependent variable which is the potential efficacy on the severity of covid 19 in the study. Participants were not always well described. Okay, again, fair critique and the study outcome measures were not always clearly defined, again, now, had these trials been done by a large pharmaceutical group who are used to doing this, or had that been done by government with large sponsorship, then these probably wouldn't have occurred, but again this is largely clinician-led research, so again these limitations aren't surprising. But it is frustrating that this definitive answer is just that little bit out of reach, although this 62% efficacy is probably the best thing we've got so far. So that was the national institutes of health on that one.
Now, the sort of definitive guide for these things in the uk is the cochrane library: “trusted evidence, informed decisions are better health” is their motto. So “ivermectin for preventing & treatment of covid 19,” this was written on april 2021. Now, what they've written here is a very detailed proposal for the study, not the study itself. Now, this proposal for the study is probably the best proposal i have ever read for a meta-analysis. It really is quite excellent. So it's got ivermectin… people that are doing it, objectives… “this is a protocol for a cochrane review intervention, the objectives are as follows”. But this is what they plan to do, so description of the condition which is very well and concisely done. Description of the ivermectin which was well done… how the intervention might work, all well done. But it's all saying what they plan to do, so the objective is to assess the efficacy and safety of ivermectin, and compar it to standard care placebo or any other proven intervention. Again, we will include randomized control trials, so it's not done yet. So this was back in april and this is the cochrane institute, which is like the new uk national flagship, so you've got to—i mean, they've given themselves a very complicated job, but you would have thought given the evidence that we appear to have they might have given this a slightly higher priority. But let me show you the state of play: so cochran reviews on this subject, zero. Cochrane protocols, that's what we've just looked at one, so they've got the protocol which is good. They're aware of 112 trials. They've written no editorials, no special collections, and no clinical answers. In other words, that is completely useless at the moment, which is a bit surprising, as i've said. So the evidence from this meta-analysis, again, i would reinstate release date demands, some form of response from dr fauci or chris whitley, because there's sufficient evidence there to merit a response, even if it's to say this trial's rubbish, forget it, and we're not going down that route. But as we've said before the silence is deafening.
So they there you go. I must say i've been looking forward to this matter of analysis for a long time and i'm a bit disappointed, but having having read it i can understand why the result is more limited and less definitive than we would like. So there we go, that is my understanding of the ivermectin situation at the moment: 62% probable reduction in death with moderate certainty evidence; and with low certainty evidence 86% protection against spread and effectiveness as a prophylactic agent, and that's basically the best we've got at the moment. But this is by far the best meta-analysis so far that i'm aware of so that really is our current definitive state of knowledge on this subject. Remember that was educational purposes only, don't take any medicines based on what i say. It's always a difficult subject, but more to come on this, and that there are other trials ongoing and planned. And i'm hoping that quite a few countries like india mexico chile peru are going to start writing up definitive papers on their population level studies, which of course involve millions of people and the effect particularly on prophylaxis. So we look forward to more definitive answers in the future, so on that slightly frustrating. End. Thank you for watching this video.
