Ivermectin discussion with Dr Tess Lawrie

oh welcome to this talk we're going to be talking to Dr Tess Laurie about Ivermectin and of course you would never take any medication based on what we say on this channel this is for academic educational interest if you want to take some medication go to your own doctor or prescriber and get them to prescribe it for you so enjoy this educational discussion with Dr Tess Laurie right welcome everyone it is now the 5th of April and and we last uh talked to Dr teslori on the 5th of March so coincidentally a full calendar month now I'm delighted you've come back after the uh I kept you for an over an hour last time Tess so it's really kind of you to come back we appreciate it and I know lots of viewers I've been looking forward to an update background here is um you're a medical doctor you've worked In Obstetrics Gynecology in South Africa you've got a lot of experience on the ground but you're also a research Doctor so you you you're really doctor doctor test lawyer sir so it sound it sounds like you've got a good background for this and for a while you've been specializing in in this research and you're currently working with the in fact I think you're in charge of the evidence-based medicine uh um is it Consortium or consultancy consultancy yeah evidence it's my writing I can't even read it every space medicine consultancy and you basically put together data you make recommendations to the Cochrane which has got major implications for for UK policy you make recommendations to the World Health Organization so we don't make recommendations we provide the evidence for the recommendations to be made right right so you provide the evidence and then they can basically do what they want with it yes yeah yeah and you usually up until some provisos at the moment that's usually been fairly positive I think yes yeah there's usually a correlation between there's a correlation team the evidence and the recommendation that gets me what one would hope so yes the evidence the evidence is always good but the background here is there's this drug called Ivermectin and it came out what mid 70s I think was it yes yeah and it's brilliant at treating parasites it's been used uh for several billion doses have been given the the doses are known it's on the World Health Organization list of essential drugs for its anti-antiarasitic properties which are all all well proven and well established and it's been um it's been a major benefit to humankind I think it's fair to say as a result of it anti-parasitic properties but then recently anti-viral properties have also been identified and uh in in vitro it's clear that there are anti-viral properties and and by extra but by continuation when the current pandemic which of course is caused by a virus SARS coronavirus II RNA virus that ivomechan also seem to have antiviral properties against SARS coronavirus too and we looked at evidence from that last time so um that there is there is in vitro and in Vivo evidence for the efficacy of ivomechan against that size coronavirus to from from your from your studies test is that basically yes yes and resonatingly it seems to have an event because it is you know 90s in terms of its uh various mechanisms of actions so uh there's much that can be studied going forwards as well just to you know look into how this um amazing drug seems to work so so antiviral property Survivor Mexican have been known since the 1990s is showing many different mechanisms of action which could all be in play now given that with SARS we have inflammatory responses as well as viruses load to deal with and viral proteins and um and you know so it's so it seems to have uh and I'm sure more research will show as well many different mechanisms of action which makes it really useful because it means it's not strain specific or you know and it's not a stage of the disease specific it's easy to work across all stages this is a big thing of course with covid-19 is that we have the viral stage at first and then we have the inflammatory stage when the body in most individuals has been able to eliminate the virus and and of course the the one of the main treatments now the dexamethasone which is the steroid anti-inflammatory I think most people would consider that to be contraindicated in in the viral stage of the illness but of course can be absolutely life-saving as data is clearly shown in the inflammatory stage but but the the the indication here is that either Mexican could potentially work in both stages of the illness yes excellent yeah so um up to up to when we talked on the 5th of March test can give Just A A Brief Review of where we left it off there the the data you've been looking at and uh and uh the the conclusions from that data yes so um on the um at that time we had done our systematic review um and we had included 21 trials and 13 of the trials had contributed data to the permit analysis on deaths um and we found uh 68 reduction in deaths in fact let me show you this guy can I share screens please please yeah yeah so yeah just so well the first review that was done was Andrew Hill's review uh and that was the 18th of January um and he found six randomized control trials to include in his analysis with 1255 people um and it showed a clear reduction in deaths um 75 with ibamctin and he also looked at um vowel clearance and he found there was a clear reduction in Barrel clearance as well with adamation um and um this was this a study and review was funded by the World Health Organization and unity and um the gist of it was that um that they were still waiting for more data so they didn't want to make a decision on this evidence well we did our review and and we found that um very similar findings we found a 68 production of deaths but we included 13 studies in our analysis and this is what I showed you last time um the risk ratio of 0.32 indicates a 68 reduction and it and the effect lies clearly to the to the left of the line of no difference which is um clearly in favor of Adam Neptune and the confidence so that that up and sorry that up and down line there test Warner that that's the line of no difference yes yes so if a study if so each of these lines represents one study so study finding so if you look at this um uh data from the Earl gazaar study you can see if you look at just that study well the effect seems to lie to the left in favor of I haven't met him but it does touch the line and it crosses over which means that in actual fact there could be it could be no different or it could even lie somewhere over here but true effects of the true effect layer of it here well then they put favor the control group so it's only when you do if you look at any one individual study because these studies are not powered to assess a big difference in deaths um you you know also in mild disease for example you wouldn't text you would need thousands of people to establish a clear difference in deaths you need to be able to pull data so when you pull data from all these studies you can see this most of them lied to the left of the line and then the overall summary uh it's the overall effect estimate and in this case it's an average across these studies which gives us a risk ratio of an 0.32 corresponding to a 68 introduction in this which is a thing this is the this is the forest plot test is it yes yes um now you can see from this uh from this number here this I squared equals 57 and P equals 0.02 this suggests there's a significant difference um across these studies you know there's a there's a there's a bit of inconsistency across the studies and when we'd expect this because I haven't met is going to work differently and different um severity of disease for example or different you know these studies use different doses of ivamectin some of them compare are compared to an active art for example what we discovered when we did our sensitivity analysis which is a kind of it's analysis to check um if there are if there are reasons for um full heterogeneity for the inconsistency for example um so we removed this study Fonseca and when we removed that study um we found that this number disappeared sorry I think I've just switched sides um yeah we found that that the heterogeneity disappeared when we removed this study now this study was done amongst very ill patients and they didn't find much of a difference between ivometon and the control arm but the control arm received hydroxychloroquine so basically there's a comparison between two fairly active treatments um I know that you know there is a current perception that from uh wh and so on that hydroxycline doesn't work but um but that's not necessarily um true and um there are many many um reasons to believe that it that it is active so in actual fact and here the study did compare automation with something that's an active treatment and so one would expect perhaps that they wouldn't they wouldn't have picked up much of a difference between the two in any event once we've established we know the reason for the for the inconsistency they can put the study back in and say okay well this is the situation we have a bunch of studies and aren't exactly um the same but but we don't need to worry because we know that in actual fact worked this including the Fonseca study would do would actually underestimate the effect not over estimated you know what it would do is suggest that there isn't a difference in actual fact um the favorable result shows that there is so we're not worried about making you know it's it's not um you know it's not overestimating the effect it's not saying that there is an effect when there isn't one so the 68 really is the minimum effect that these studies would indicators yes the minimum average does it does appear to be there so you know we carried uh looking at trials and we found um by the 31st of March we found uh three new studies and you randomized controlled trials and two of them had data on deaths so we included these status so the one is um Lopez Medina and there was it was conducted in a mild disease it was only one death in the control arm and none in the automation arm and the other study is Gonzalez and in this day this was also severely sick patients there were five deaths in the Ivermectin arm and six in the control arm and when we look at our overall summary now we have 62 percent reduction in deaths and um with a with a confidence interval of 27 to 81 so we're still in you know we it's uh it's just saying the same thing um so the minute the minimum from this data the the Ivermectin reduces deaths is 27 and it may be as high as 81 I mean yes yes and it's really just it's going to keep on blockchain because it really you know the more studies you do and depending on the patient group you're looking at it's going to change so you know once just rearranging the dhas on the Titanic really there's no you know we know it works and um and uh this estimate will keep on changing depending on on you know which studies we look at what does they're using who they you know who their patients are and so on and that this methodology that this meta-analysis tested this is this is sort of tried and trusted research uh methodology is it yes yeah and this is um uh the software that we use uh for Jane Cochrane reviews so um it's standard software it's sand methodology um if this had been a Cochlear review then uh then this is the the analysis we would have done in fact we have done we do have a copying review and um it just isn't published So the plan is to publish the full Cooper interview even if it's on a frequent website in the next couple of weeks let me say it in the next four weeks so that I don't you know give myself enough time but um it's quite a hefty document and it's basically it was prepared for submission to park rain and then um and the thing is what you need to remember is with coconut views there's a protocol it goes with it so many reviews are done and you're not quite sure why they grouped their studies the way they did or you know whereas our review has a protocol which is basically a recipe for how you're going to do it and um and we've we've got that protocol and we've done it according to the protocol and uh so there's no um surprises and it's not you know it's not as if we sort of grouped the studies differently or you know done anything different with them we said how we would do it and this is and this is the product of that um recipe so so basically since we've talked last time what what what what's happened I mean what what's what's the story with the World Health Organization in the Ivermectin uh that their current uh recommendations or views or dictates or whatever you want to call it um well do you want to do this first sorry yeah depend on uh with this um yeah let's do this first sorry so the World Health Organization um has um revealed the recommendation on our connection and it's not in favor of having maintenance against animation they base their decision on this um on this well on on a systematic review done by a group at McMasters University and the only Forest plot in the guideline recommendation that I can comment on is this one here because this is the only one in the guideline foreign Health Organization recommendation is made on these few studies where whereas you had how many was it twenty twenty we've got 24 hours now and in three analysis we've got 15 right but they seem to only have found five in this meta-analysis but I'll show you later on they seem to have referred they refer to seven but in this analysis which is of death they they have five studies and that group then you can see according to high risk of bias and low risk of bias yes now I I'm I have not seen a protocol for this review and I have not um I'm surprised that they have grouped in that way in terms of high-risk advice and low risk of bias I've never seen that done before necessarily usually we do that in a sensitivity analysis for example I'll just go back here this is our sensitivity analysis and what we did is we've just removed the studies that we assessed as being a pirates of bias to check whether our findings are the same so we've removed four studies from this analysis um and we found actually when we remove the high risk of Webster the high risk of Bio studies we have a 72 reduction in deaths and a confidence interval of 15 to 90. so it's quite a broad confidence interval but it's still in favor by the nation it's consistent with the overall thing so we'll just put those studies back in and not worry about them too much and um but that's not what's happened here here they've separate to them and to higher skin low risk I have concerns about business group anyway because Gonzalez and Lopez are both high risk of studies in our analysis and the and I and I recently I had the the Lopez Medina study evaluated by some job applicants who applying for a systematic review job and they and they all came up with us being Irish goodbyes so it's not just our group who finds the study to be a high risk of buyers it seems to be widely be regarded quite widely as as being of high risk and and yet this is what the World Health Organization are basing their thinking on yes Gonzalez and it's some it seems like they've randomized them and then on different clinical criteria so we have queries about this that the study that need to be answered to both of these in our review would be classed as high risk of bias um and the and and and so the overall um they don't have a lot of data here they've only got 31 deaths in all it's still clearly favors I ever met and but they've they're lots of I have lots of questions about this which I hope to get answered you know I've emailed the authors of the systematic review and I will be emailing who as well before studies here Charles these were in Andrew Hill's original analysis so they were good enough in the original analysis that whn unitated but somehow they're not in this analysis um they actually yeah the only five in this analysis which is very strange they were six in the original analysis so and the other thing is they've used fixed effects now this isn't um fixed effect model this is surprising because this is usually assumes that the trials are all very similar and the data are consistent uh whereas that's not the case in this analysis the data aren't consistent it's a fair amount of inconsistency although they haven't actually reported their I squared and um and also with which is the heterogenicity of the studies yes and also we know that these studies are all quite different you know some of them are on lowest patients some of them are the highest patients uh they're you know they give different doses of treatment so it's surprising that they didn't uh use random effects we certainly pre-specified in our protocol that we would use random effects because we were expecting quite a lot of heterogeneity inconsistencies within this the trial designs and and uh patients so well anyway you can see they still get a 72 reduction in deaths with the confidence interval of 25 to 83 percent so even assuming that this is a good methodology which I think we've established isn't particularly good it's still showing a 72 reduction in deaths and they're still recommending against it can you help me out here snap Dash they haven't even bothered to remove the brackets from the from the titling here and so on so um yes carry on um so then in terms of the the summary of findings now there's also conflicts with what they're present in the figure and as I said it could just be a factor in that they haven't provided all their working so somewhere in in the background there must be a full set of forest plots but that's it's not available in the guideline document and the systematic review in which its phase doesn't seem to be published at the moment so we just don't know where these dates are coming from what is very peculiar here is that whilst in the previous figure in the previous Forest Park they report risk ratios here it seems like they've done a completely different analysis in their reporting odds ratios now that's a different thing it's a different thing it's a different calculation so and then they get 0.19 which is even more um efficacy so it's 81 reduction in deaths and the confidence interval is 0.09 to 0.36 which suggests the confidence of 64 to 91 so it's a very tight confidence interval yes and this is based on data from 1419 patients and seven studies so in the figure we've shown five studies here they refer to seven studies it just doesn't make any sense does it it just doesn't make any sense and this is the World Health organizer this is the world house this is the World Health Organization we're talking about and then an acid effects we've got um standard of care if you don't get ivomex and you just get standard care Alternative Care which is basically nothing um at the moment it would be the oxygen in the dexamethasone yes yes yes yeah yeah sorry I just mean you know just yeah generally we don't have any specifically no no specific antivirals yes um do you have a risk of death across these studies in their data of 70 per thousand and if you could either make and you have a risk of death of 14 per thousand so the risk difference is 56 fewer deaths per thousand according to the analysis which shows and then the confidence interval is six it's 44 fewer to 63 fewer so um so it might be as many as 63 fewer deaths per thousand if you were to get animation according to the analysis nevertheless so so that they've basically done this we believe highly flawed meta-analysis this meta-analysis has shown high levels of efficacy for Ivermectin they've recommended against Ivermectin I mean am I missing something here well it comes down to their grading so what they've what they're saying they're grading is that even though they have an iteration walk with one man showing and 81 risk of death I mean 81 reduction in death and that narrow confidence interval of 64 to 91 um they say they've graded the evidence it's very low due to Serious risk advice and very serious imprecision now we just looked at that risk ratio uh or odds ratio uh confidence interval and it was notable for its Precision actually uh 64 to 99 is a very precise estimate even more precise than much more precise than our original one based on all those studies because you know um there's just a mismatch they've got a precise estimate which they're downgrading twice for for being emphasized and then the inter they're interpreting it to say the effect of iron metal mortalities is uncertain um so and in actual fact this is very unsuit and I use the word very uncertain in their documentation but it's missing from this um from this interpretation so so there's just something very strange going on here their grading needs to be checked and is this open to Peru is this open to a peer-reviewed it doesn't it doesn't seem like it no um I mean to to do a peer review process you would need full data yes and and that just doesn't seem to be available it's at least not in the public domain it's not the public domain and there's no there's no evidence at the moment which studies what seven studies these are I try to add and subtract the study to see if we could get 1419 and I just ran out of time and patience um it really needs to be transparent we need to know what studies what data they've included in actual fact why with such a great uh precise estimate um is this and and due to serious so serious risk advice leads to downgrading of one because you with when you're grading data evidence from randomized controlled trials you start up with a presumption that it's high quality evidence or high certainty evidence and then you downgrade it for various criteria so for risk of bias for serious risk advice you downgrade by one for very serious risk of bias you don't grade back to for imprecision you downgrade by one for very serious and precision your downgrade by two so you can see here they've downgraded for serious risk advice which is minus one which will take you to moderate certainty and then they've downgraded for very serious imposition by two which takes you down low to very low so they've got very low um certainty evidence when an actual fact even if they decided Well they would prefer to have more events to be sure um and and decide to downgrade once film Precision they'd end up with low certainty evidence which means that either Neptune May reduce the risk of of deaths substantially for example just like this one here do you see here they've got low certainty evidence this is this is the data for serious Adverse Events they've got low certainty evidence and they've interpreted that I haven't met and may increase the risk of serious Adverse Events now this is a bit of an anomaly as well because if you look here they've downgraded twice due to very serious imprecision so the same is for the mortality but in this instance there is very serious imposition you can see here the confidence interval spans from favoring Ivermectin to favoring the control group and it crosses that line of one you can see the number one would fit in the middle here yeah so um so in actual fact there is no clear difference from these data and from this estimate you cannot say whether ivomechan um causes more serious Adverse Events or whether the control group because whether the control um uh medicine cause more serious Adverse Events so in actual fact this is another um misinterpretation of the data what this should say is I haven't mentioned may make little and no difference to the risk of serious Adverse Events it's not as if it's a new drug it's a well-known drug yes and um and nobody knows that better than the who because they stress that over and over in their guidelines on Adam action for neglected parasitic diseases and things well the explanation you've just given tests I I could follow that I I could see that you were pointing out that you know you as an expert in this I even I could see you that the anomalies you were pointing out and the anomalies that were fairly glaring to me there and there's a lot of questions that need to be answered um so I just want to say this is the document um right and you can see it was updated on the 31st of March in the document they say who recommends against other Nation for code 19 except in the context of a clinical trial and and here where they talk about certainty of evidence um it's as I was just as I was describing that evidence was rated as very low certainty primarily because of very serious imprecision for most outcomes now this is simply not true for deaths hmm and it says the aggregate data had wide confidence intervals and or very few events well for deaths it certainly did not right and yet this is what governments around the world are now following yes and then I just you know they have this handbook for guideline development which is what IU I'm used to using in the documents that I prepare and they have something on imprecision they have a description of imprecision just so that you're aware that this is actually you know a documented there is a method to this and so it says four guideline development groups if the confidence interval for the pooled estimate of effect crosses the threshold established for making one decision versus another I.E in favor in the body of evidence is imprecise for the particular article in question and the quality of the evidence is lower than it would be otherwise going to the uncertainty in the result so as I showed you that effect estimate lies clearly to the to the left of the line in favor of our connection it's note and precision

Channel: Dr. John Campbell

Views: 319,648

Keywords: physiology, nursing, NCLEX, health, disease, biology, medicine, nurse education, medical education, pathophysiology, campbell, human biology, human body

Id: D2ju5v4TAaQ

Length: 30min 38sec (1838 seconds)

Published: Wed Apr 07 2021