Cardiology Controversies 1 with Mark Rishniw

(upbeat music) - You're listening to the Animal Heart Speed. My name is Kieran Borsche. - Hi, I'm Joseph Donatoz. This is the world's only podcast dedicated to veterinary cardiology. - Hi everyone, welcome to the Animal Heart Speed, your veterinary cardiology podcast. Today is the last episode of season three. - I'm not believing. - Time flies. - Time flies. - It was a great, great season with great guests as you all know. And now we have a grand finale with another very special guest. We have today with us Dr. Mark Rishniew. He truly did the internal medicine residency and the cardiology residency. So he's truly double-bored. Which is already quite amazing. And Mark does a lot of work at VIN, the veterinary information network. But I'm sure Mark is better known by his research. And I have to say that I love Mark papers 'cause Mark is one of our critical thinkers in our community. I think Mark research really tries to questions our beliefs and our dogmas. And that's pretty cool really. Well Mark, thanks very much for joining us today. He's a great pleasure to have you here with us. - Oh, thank you very much for inviting me, I feel. Rather on it after looking through the list of people that I've come after. And I don't know if the grand finale is because I'm gonna go out with a bang or it's just be like, "Okay, we're done and this is it, we're finished." (laughing) - No, it's very exciting. - And I'm glad you're not calling it, one of the icons 'cause to me that sounded like, "Oh, this is your life type of episode," which is sort of a very nice way of saying, "Have you got your orders, your affairs in order "and have you arranged a grave plot because you're "no longer long for this world?" - I'm really hoping that's not the impression that all of our guests have had for season. (laughing) - That would be, what a terrible impression to leave on such legendary cardiologists. (laughing) - No, thanks so much for joining us. Welcome, welcome to the Animal Hormone. - So we thought the perfect topic for you would be to discuss controversies, in veterinary cardiology. Again, some of you are most recent research or your research in the past maybe five, 10 years. As a dress, again, many of our beliefs and dogmas in veterinary cardiology. So we'd like to delve into some of those papers you have published and have your opinion on them. Both of us are very biased towards fueling cardiomyopathy. So if you don't mind, we'll start with fueling cardiomyopathy. You wrote two really interesting opinion papers on javmen, on fueling cardiomyopathy and starting. So you have one about screening for subclinical cardiomyopathy in cats. And so can you tell us more about what you think we should be doing? Should we be screening cats that are apparently healthy for subclinical asymptomatic cardiomyopathy? And if so, what's the role of anti-proBNP on screening cats? Is it worth it or is it a waste of money? - I've reached an age now where I can actually write opinion pieces. I feel like I've got the street credit a little bit, even if I haven't done a lot of work with cardiomyopathy's per se, but at some point, I have an opinion and it's going to come out. So the question about screening cats becomes one of a population medicine issue. And it's because you don't screen a cat, you screen cats. And just like if we went in for HIV screening or whatever, at the blood bank, you're going to give blood then they'll test it for it. They don't care whether you're infected. They care whether there's a possibility of an infection that might get out into the blood sample you're providing and getting transfused into somebody else. And so it's done on a population basis. And so we have to think about what are the criteria for effective screening programs? And so then it becomes an issue of, you know, is it common enough? Can we intervene by knowing what the status of that individual is? It's no point in screening an animal for the sake of knowing that it's affected by something or other. If at that point you can't do anything about it. It's a bit of sort of useless knowledge and it can actually, and in humans, they've shown that that can actually worsen outcomes because people then become obsessed, worried, concerned and actually change behaviors and things like that. Based on the results of the test, ideally the screening test should be either sensitive or specific. The best test would be both, but we rarely have screening tests like that. The only one I can routinely think of is heartworm antigen testing in dogs has very high sensitivity, very high specificity. You've got to apply it to the right population so you need to find animals that are likely to be affected by the condition you're screening for. And then finally it's got to be easily or rarely available, cheap, easily performed, easily interpreted. Which immediately puts echocardiography out the door because whilst you can talk amongst cardiologists that yeah, we can all do echoes and most of us can identify hypertrophic cardiomyopathy when it's present or at least have a fairly reasonable idea of it, we probably see less than 10% of the cats out there that would be candidates for such a test. And so we're screening a very select population with echo because simply people cannot afford it and there aren't enough qualified people to perform the test. So and even then, you know, between the three of us, we could probably get into arguments about whether this particular cat is affected or not based on some equivocal results. But it's one of the challenges, isn't it? Particularly with HCM in cats. - Absolutely, full stock. - Absolutely. - It's interesting what you said about the impact of a screening result on an individual and in humans, my understanding is this whole branches of medicine dedicated to sort of genetic cancelling, for example, and support around the result of screening tests. - Absolutely. And if you've got genetic testing and that disease process is well enough understood. So for example, if we take hypertrophic cardiomyopathy. So firstly, you might spring for medical legal reasons. So kids who are gonna go play sports. You don't want a kid dropping dead on a basketball court 'cause they had an unrecognized cardiomyopathy and when he do an acute sudden death situation. So there's a medical legal reason, you know, for the school or the institution or the sports team to look for that sort of thing. And secondly, cardiomyopathy has been fairly well identified and different genetic variants have been reasonably well enough identified and characterized to know that with this condition, these are the likely outcomes. These are the preventative measures we might be able to use to intervene or at least counsel, as you say, as to what to expect. We basically look at cat hearts and go, yep, but stick dumb. What that means, even the characterization of cardiomyopathy in breeders as tightly and well characterized as main coons is still poorly understood. There's no natural history of that disease that I know of that's ever been described for that one breed with that one mutation. Nobody's looked at a large population of these cats and said, here's what their outcomes are. How many of them die suddenly? How many of them develop congestive heart failure? What's the time period over which that's likely to occur? All those sorts of things, there's just no information. So we're simply saying, yep, you're going to think hard, no, you know, yeah, you might have, I'm not really sure. Totally. And so what we want really to identify are stage B2 cats, right, because those are the ones we strongly believe or that we know are more likely to progress and develop an event, develop clinical science and then of course, we need to understand how prevalent, how common are stage B2 cats in a general cat population. I think there are some figures out there. We look at our data recently and around 10% of the cats we saw with murmurs, so that's already bit biased, were stage B2. I think the Coutier study from JVM in the general cat population is just Lew and Coutier, I think they were around 10%. And so that also creates another problem, right, Mark? Because then we are talking about the relatively small percentage of cats that we want to identify in the general cat population. It's going to be very hard for one test, even if the test is really good, to catch those 10% that we might be more interested in. So when I looked at this for the paper, about screening cats, I used the data from Joey Wei-Hung's group out of Taiwan. And he was a lovely study looking at screening apparently healthy cats. And from, it was a small number of cats that when I sort of picked through the data, and I got numbers about what you got. Somewhere around 10, 12% of those cats would have been considered to have moderate to severe. And I hate the term B2. And we can talk all about the mentholature and I talked to it. Absolutely, we want to hear why you hate that class of cats. But let's wait a bit longer. Yeah, I was going to say, what is a B2 mark? It's a bomber as far as I know it's a bomber. So it's okay, a big left item. So we want to try to get to it. Because they take out the two raised heads because they pay for when they call it moderate to severe. Some of those cats, they based on LV age and LV age severity and not necessarily on LAS size. And so some of those cats might not have had a big left atrium. But yeah, let's start to start. Yeah, we're like five minutes in and we're already talking over each other and arguing about it. So I think, you know, so I use that same sort of probability and that's probably too low for an epidemiologist to think that it's worthwhile implementing a screening test unless the screening test is near perfect. Because certainly if you're down in the single digit percentages, most of the results you're going to get are not going to be truly positive or falsely positive. Now having said that and the part of the argument or part of the reason for my paper then was because both the Taiwanese group and again, and Mark Kittleson with their book argued that anti-probe MP is not a good screening test and on its face value, it really isn't. But you can't look at sensitivity and specificity. What we need to be looking at is positive and negative predictive values. It's sort of a reverse of that equation where we're saying, I've got an animal in front of me. I've got an imperfect test because there are no perfect tests. What's the likelihood? What's the probability or the chance that the cat that I've just tested either has the disease if the test is positive, has the disease if the test is negative or doesn't have the disease if the test is negative or it might have the disease if it's negative as well. There are both positives and negatives, false positives, true positives, all that sort of stuff. We're sick of those two by two's. But ultimately that's the question. For a clinician and this arose because a lot of practitioners would be running these tests and of course I'd X offer the test as a part of the panel and so forth and make it freely available and everybody's going to run it and then nobody really knows how to interpret it. There are a lot of false negatives. There's no doubt. If you look at the test sensitivity, there's a lot of cats you're going to miss. And if you're faced with a case where you're going to anesthetize this cat and you just would like a little more security about the knowledge or the idea that it's not going to die under anesthesia. It's not going to die in the immediate postoperative period because or going to congestive failure shortly thereafter because you missed substantial heart disease. Does the test help you do that? And my ultimate argument became well, if you run the test, you're going to miss about half of the cats that have moderate to severe disease in your patient population because its sensitivity is quite low. So you're going to get a lot of false negatives. The test will tell you the cats clear. In fact, it was diseased. However, the percentage of cats in your cat population that are likely to have moderate to severe disease is relatively low. So most of your negative tests are going to be true negative tests, which is where the importance of pre-test probability comes in, doesn't it? Absolutely. That's all it is. Now, some people could say, well, assuming that you may as well just not bother testing and assuming that the cat's going to be test negative anyway, which is true because it's a relatively low percentage. My thought then went to the other side of the equation where yes, you're going to get false positives and you'll get as many false positives as true positives, but it's still a small percentage of the total cat population. And if you identify, so you're going to have to echo a bunch of cats and it turns out, I think you're going to echo about three times the number of false positive cats as true positive cats to get that second level of confirmation. Because now you've got a positive test. I need to send it away to see if it really is a true positive because the cat still needs a stand all or it still needs to have a surgery, whatever. At that point, you're going to pick up those true positives. You'll have missed half of them, but you'll have saved half of them potentially. And so my argument always has become both to the Taiwanese group and people who have argued that the test is worthless is, would you rather prevent an unexpected death in half the cats or none of the cats? Because if you don't test them, they're all at risk. If you test them and you miss half, you've still effectively had a better outcome for half of them or potentially had a better outcome. Another half that you did manage to identify, what's the cost? It's the cost of finances for echoing a whole bunch of cats that you thought had disease that turned out not to have disease. But I guess without the screening using the anti-probe MP or imperfect is, if you wanted to be as sure as you could be, you're going to echo way more cats who don't have disease. You're going to spend way more money, but also you're going to impact the well-being of those cats. You're going to attend to the vets. They're going to be laid on their side. They're going to be sedated. If you can avoid that in some individuals, is that utility of the anti-probe MP is a screening tool worthwhile? Yes. I think from that perspective, especially at a first opinion practice, and you also talk about screening a lot of cats that don't have disease with echo and the cost and the potential physical inconvenience. There's also inconvenience of the owner having to take the time off, to take the cat to the vet to get screen, finding a cardiologist, traveling that distance, having the money, and in this country, you're paying probably $7 or $800 to get a full cardiac workup. Money that could have been spent on the actual procedure that you were intending to perform as a first opinion practice. And the thing that's gotten me all riled up more recently is the unbelievable wait times that people report for routine cardiac consultations with cardiologists, at least in the U.S., anywhere from six weeks to three to four months to see a cardiologist. Now if I've got a dental schedule for this cat for this week, how am I going to explain to the owner? You're going to wait six months to get in to see the cardiologist because they're doing a bunch of meaningless echoes, occupying their time unnecessarily on stuff that doesn't need to be referred because you thought I need to refer this cat for an echo or this dog for an echo. And that's my most recent, and it's a longer term thing that I'm more concerned about is how do we do more pragmatic first opinion cardiology? And part of its own fault, we've taught students that by having echo and cardiologists in referral centers and in universities that it's got a murmur, it's got this, it needs an echo. And honestly, that's our bad management of cases, not to explain. It really doesn't undoing this to teach you, undoing this because it was referred in and the owner wanted it done. But honestly, we could have come up with the same answer without all this and you need to be more confident in your ability to make those calls without necessarily echoing. So yes, if every cat that's going to go in anesthesia needs to get an echo, it's never going to be a screening procedure, unless as Adrian mentioned, it becomes an AI thing where anybody, Joe with the probe from down the road can put it, can sort of shine the probe at the cat somewhere and it'll tell you. Again, even as you said, even the perfect screening test would never be good if you just start using it in everyone and you do not tailor the population, you're going to use it. Absolutely. What's the predestines probability and so on. So I think if then our general practitioner is start tailoring or using the test in middle laged water cat because cardiomyopathy is an a our an agent dependent penetra. So it's more likely that older cats will have the disease or mild cats are more likely to have the disease. And so then I think hopefully that this. certainly the sensitivity and the specificities of the test will improve because we are already selecting which cats are probably more likely to have to have to have the disease. Same in the predictive value will improve. Yeah, also. So if you're testing, obviously if you're testing breeds that are predisposed, but we know are predisposed. Yeah, sure. Siblings. Siblings. Well, and again, there's not a lot of evidence of just your domestic moggy. You know, it is a strongly inheritable trait. I think there's the one case report that Mark Kraus put out back in the 90s or case series of one family of cats that appear to be affected. But yeah, and I know that Virginia and Rosie's data are all, you know, they should be able to look at some of that. And I don't know that they've ever suggested that it's got a strong heritability amongst your average cat. Mark, you said there's little point in screening if we're not going to intervene. And obviously that pre-annacitated situation is a particular set of circumstances because we're talking about giving some drugs or modifying the cardiovascular system in some way as to cause the push them, you know, is to push the cardiovascular system. Do you think our requirements for screening or our interest in screening is going to change if we find that anti-hypertrophic drugs become more easily accessible and usable in veterinary practice? Oh, absolutely. Yeah. No, so at that point, there is an intervention. So right now, if I can identify a cat that's got moderate to severe disease, already I might be looking at intervening with something like a platelet inhibitor or whatever, although we can, you know, I know that just say we wanted to talk about that paper as well. And but yeah, certainly if something like fellison comes out, then it will impact that ability to intervene, hopefully positively, in a population of cats that are at risk and might have more advanced disease where we want to, you know, and again, it depends on which population that that drug is going to be applied to. Currently, you know, it's three football teams of cats in that study that came out. And we're making treatment decisions and everybody's calling out like should this cat be on on this drug? And I'm like, you know, that's, let's turn it around and ask if that had been done in humans, would you be asking for that drug to be given to your children based on the number of cases that were involved? And I'm guessing most people would say no, and I know that the FDA wouldn't even come close to approving something like that. Yeah, it's early days, yeah, isn't it? Yeah. So and we've been there before. We would have built ties back in the early 90s. Yeah, yeah, show. Totally, totally agree. And then Keir and Spont is of course a very good point. And again, that's why and we talk about that a bit later. That's why people are interested. That's screening much of our disease or the related cardiomyopathy because there's an intervention, right? There's you can start Pymobend and then we can discuss when do we start Pymobend and so on. And so we don't have that yet in cat or hopefully that that will be changing as there are certainly several drugs out there that might might be useful. But even without the drug and you also raised that that that point on your on your opinion paper from the rush diet to show that in half of the cats that are present with HCM, they had an antecedent events. There was something that happened in those cats that pushed them into hard file. I've flew it steroids surgery. A lot of the same when you looked at TMT, the HCM control group, 30% I think had an antecedent event. So we can push we can push these cats over the edge. And so it's really, it would be really important to identify those with a big left edge on the tar on the edge for something bad to happen because those will be the case that the vet then will avoid giving too much fluid or maybe will change their sedation protocol or will not will not give steroids and so on. So I think it's still very useful to find those B2 cats. So I really liked again your conclusion on that pipe because again, anti-bropy NP might not be perfect but at least we would identify half of the cats and that's already better than nothing. And again, that's based on the Taiwanese diet and kutus diet where they screen the whole general population. If we would target those cats and we would just select which cats we might run anti-bropy NP, the test performance might even be better. So yeah, I liked it. And I liked it on Europe, but you gave examples in humans like for screening for prostate cancer I think. Yeah. So I mean, I looked at I tried to find evidence of tests that had similar performance characteristics. And what I found was that the early PSA tests in screening for prostate cancer and the pap smears looking for cervical cancer have about the same sensitivity. It's about 50% and a sensitivity, a specificity up in the high 80s, 90s somewhere up there. I've never heard Medicos back in the day saying we shouldn't use these tests because they're imperfect. These are the best tests we have. And they're better than nothing. Now since that time newer tests have come out that will allow better screening that have much higher sensitivity. So those tests have gone by the wayside. That's fine. That's progress. That's medicine. But until a better test exists, we do with what we've got. The worst thing I think that happened was that you know, the diagnostic labs put these tests on routine panels. And so now you're applying them to animals that are clear say says after the target population. And so the performance of the test goes way out the door. And in fact, I'd recommend for first opinion practice. Like if this cat is not one that you're worried about, just put a black marker, get a sharpie and cross it out because it's a rubber. Redact it. They're a heaps of examples on there from human medicine about, you know, these whole body CTs. Oh, I'm going to have a whole body CT because I'm 50, you know, and finding adrenal nodules in a healthy person. And okay, what do we do with that? You know, do we go sticking needles in it? Are we going to buy out? See it? Are we going to repeat the CT? It's a such a challenge, isn't it? To find these unexpected positives because we don't know how to interpret them. Exactly. So Mark, you mentioned about B2, cut him up, C and Clipidacar. I don't think Mark said that. No, I'm like that. Okay. You mentioned about what some people refer to as B2, cutting up a thing. The stage formally known as B2. And an intervention that many listeners are going to be thinking about is giving an anti-play letter, such as Clipidacar to reduce the risk of arterial thrombomellism. And I've always had a bit of a sneaking feeling about this that we're really over-treating, to prevent ATE. But the balance argument for that, for me, has always been, what, ATE is really bad for the cat. So is it worthwhile over-treating a population to prevent the cats who do go on to be at risk of ATE? What are your thoughts on that? So, and I agree. I think ATE is devastating for the cat and devastating for the owner or the caregiver. It's a horrible, horrible disease. And so I don't have a problem in over-treating. And the point of that paper was not about that we shouldn't be treating them. Because, as you say, that is the counter-balancing argument, is that if I can reduce one more miserable experience, it might be worth it if the drug is cheap, effective, and easily administered, and so forth. I wanted to look at the moment. We don't really have a strong predictive indicator other than left-atrial size of cats that are likely to be the targets for intervention. Because we know that cats with big atria from a whole host of other conditions don't develop thrombone. And so big atria aren't the best predictor. That's all with God. And years ago, we did a study where we looked at clotting profiles in four different groups of cats. So we had healthy cats. We had cats with left-atrial enlargement. We had cats with left-atrial enlargement and spontaneous echo contrast. And we had cats that had already undergone an ATE event. And the clotting profiles of those final two groups, those with smoke and those with a big left, those that already had an ATE event, were virtually identical. Whereas those that just had big atria looked sort of like healthy cats. So we thought, well, maybe smoke might be a good predictor of likelihood of developing a saddle thrombus. Nobody's ever actually gone back and looked at that prospectively, but it would be interesting. Other things, if I'm pretty much in, there's a number of different parameters that people could look at or indices or variables that I could look at as to target that population more effectively. The reason I sort of wrote the paper was to look at, well, what is the actual benefit across a cat population that we are over treating? And it turns out it's not huge in absolute terms, but that's because not a lot of cats that could get ATE actually do. So again, we're dealing with a relatively small percentage of cats that develop the thrombus. So we might be treating ATE cats to prevent it in one. And I think in my paper, it turned out to be like 33 cats or 30 odd cats for every cat in which you might actually prevent an event or delay an event. There's numbers, big numbers, they really do make you think a little bit about that. Yeah, now there is a caveat to this and that is that I didn't have data for cats with just severe subclinical disease because they're the cats that we're really interested in because once you've had, once you've gone into failure, you're probably on the pit of girl anyway because we know you've got bad disease. But let's look at the cats that have really bad ATE but still seem to be ticking along. I looked at the overall prevalence of cardiomyopathy in cats and so it became a little, so it may actually be a little higher, but even if we double it or triple the number of, or the percentage of cases that we're going to prevent it in, it's still quite a few that we're administering the drug to that may not have needed it. That wasn't the point. The point was of that paper to say that if a client finds it difficult to administer this drug, which is a very difficult drug to get compliance with, it's not a sin to omit it. Don't feel guilty and don't make the client feel guilty that they chose not to or couldn't get this pill in because if you try to pill, you know, again, it's easy for us to sit there in our cardiology office and prescribe six drugs to a cat that be given three times a day. Try doing that to your own cat and just give him sugar pills, let alone a pill that makes him froth vomit and hate you for the rest of their lives. So now I had a labrador. I could have given that dog toxins that it would have wolfed down. It doesn't matter hydrogen peroxide, sure, give me another squirt. Yeah, no. So the point was to make people realize that you're not being that the client isn't being malevolent or unfair to their poor cat by not being able to give this drug because the absolute benefit might not be as great as we expect it to be. And so you have the choice if you can give it great give it no big deal if you can't this still pretty good chance that cat may have never needed that drug to begin with. And so yes, some some of those cats are going to have a catastrophic catastrophic event and they're going to get saddle thrombi and everybody's going to be really upset but. You know don't don't kill yourself over it and don't kill the owner over that was the point of that paper. And again, it's really interesting, Dayton is a really interesting exercise what you you did and I wish we all did that more commonly with drugs we give with stuff we do to see exactly what the impact of what we are doing in terms of numbers so that that's really cool. And as you both said, I totally agree and the other thing that I think in humans is a big deal the risk of bleeding as soon as you do dual therapy there's a huge risk of bleeding so you also need to balance that which is something we don't really see in cats. So I think the problem really is indeed compliance how easy to give a tablet and so on but my approach as you guys were saying is. It's such a horrible terrible how outcome that I would rather have every cat on that drug understanding that I may be over treating some because again as you showed curing many of these cats will be will be put to sleep when they are diagnosed with a T such such a such a bad outcome but yeah again another really cool paper mark. So I think I think we need to move on to start talk about dog stuff and another another fight that you have been involved with is about how do we define how should we define stage B2 mitrovov disease but before I say stage B2 can you tell us why do you hate. Why do you don't like the staging. So you probably remember and one of my favorite papers and I'm still you know several generations after I die maybe I'll be adopted is to rename murmurs and just call them what they are but it makes a sound very intelligent and pseudo scientific to give it a numerical value. The problem is that those numbers are misinterpreted by both the user and by the person to whom they're conveying that information so if I say a one out of six murmur you might know what it is but again you might know what it is to you and it might be different to me right and a client has absolutely no idea what I want out of six murmurs is that good or is that bad. Whereas if I said you've got a barely detectable or soft murmur there is no confusion or much less confusion about that classification using a word to say what we mean and as Adrian pointed out we need to be as clear in our information transmission as possible. So I you know I went on this kick of like why are we using these numbers and are all the numbers necessary and do people think that they mean the same things and if we reduce the number of categories maybe more of us can agree on any one category and there's less confusion and discord so that's where that all started and we still fight that battle every day and people still like a numerical scheme. The same applied to well from the point of view of why not be to it's why not a b b c d and e whatever again those are those are code that we understand there are shorthand but the rest of the world does not and if our goal is to inform the un informed public or clientele then we need to use words that we need to use. Then we need to use words that make sense and secondly saying congestive heart failure or c h f tells me exactly what it is when people start using stage c then they have to go back and redefine it for us well why did you use stage c if you then have to tell me what stage c means so the nomenclature is more of an issue van the principle of staging. Not completely so i've had arguments and discussions with Adrian and Yens and a number of others and there's a group of us that have started to look at staging a little differently and why my concern has come at the consensus committee writing a set of guidelines that were. Often based in very little information and a lot of big opinions and compromises on those opinions because they. Involved a number of people with very differing opinions about something but they they are then adopted as written and become a template for the way we should treat this disease and again going back to primary practitioners and first opinion practice who i deal with daily multiple times a day explaining what do you mean well the the cardiologist that it was a b two okay that's meaningless. What was b two b two was an arbitrary designation based on a clinical trial the epic trial. And not only was it based on the epic trial it was based on arbitrary criteria that were adopted by the epic trial because there was no strong prior evidence to suggest that the criteria that they used had a certain probability of an outcome. So and I asked Adrian about and Dave Dixon had told me this too that the original that the. Left ventricular normalized dimension was based on a study that they did where they divided the outcomes into terraces between different sizes of left ventricle and the dogs in the upper terraces how to worse outcomes. than those in the lower two-terraceiles. Well, that's a very mathematical way of addressing the data, but that's not biological, because it could be that it's only the last 5% percentile of those dogs that actually had the worst outcome, but as a group when you combine them with the upper 30% of dogs, then you've effectively applied that value at that cutoff to what was only a problem in dogs with substantially worst disease. So it's not a biologically determined cut point, if you like, of 1.7 or whatever. And we've shown that 1.7 can be quite normal in a whole bunch of dogs and breeds, and especially breeds that get congestive, get mitral bowel disease. The bigger problem that I had was that those were the inclusion criteria for that trial. They weren't the trial population criteria of the studied population. And my example of that is, if I asked all of our, if I selected a told everybody in the veterinary cardiology community that you can all try out for a basketball team, because you're all cardiologists and we need a basketball team. And then I select Adrian and everybody over 6'3" to play on that team, and they do really well. Does that mean that me at 5'6" would equally do as well, because the entry criteria allowed me to participate, even though I wasn't chosen, right? And it's the same thing. When you look at the data and the guys out of Texas did that with the radiographic evaluation paper, where they looked at what would be the vertebral hard size of dogs that were actually included in the epic trial. And it was like 1.6 or 1, sorry, 11.5 or 11.6, way above the 10.7 cutoff that was allowed, right? But all of a sudden, B2 says a 10.7. Well, no, that's what you could have been enrolled with, but that's not what you were enrolled with. And so my point is that, and we've never actually seen the epic data, but I have superimposed that over, superimposed the survival curves over some other curves of dogs and natural histories of mitral valve disease, they tended to behave like moderately diseased, some clinically affected dogs. They weren't mildly diseased, even though there was effectively what we called a mild B2 category. The dogs in epic look pretty much like what our classifications of moderate and severe disease look like, rather than mild. But the mild dogs again, being put on PMO because that was the entry criteria. So I think it would be reasonable to go back and readjust this scheme to actually include dogs that really were in the epic trial and not go based on the paper from, well, they said anything over 1.6 and 1.7 was good. No, they said that, but that's not what the dogs were. What is clear is B2 is a very heterogeneous group. And so there are early B2s and certainly way more advanced B2s. And just by looking at one internal diameter, one linear dimension, it's difficult to, certainly, classify cats, the dogs that are mildly affected and dogs that are more badly affected. And you have suggested other scores, another way to look in two days. And more recently, you present some date on your Minerva score. So why are these scores better? How do these scores differ in our ability, in our capacity to detect more than two versus early B2s? I started working with Thomas of Atsozi and Orel Dominek on this when they came out with their mind study, which was brilliant, because they actually started looking into this idea of some classifying preclinical disease into what would be more biologically relevant categories. And that is based on the idea that rather than B1 and B2, because B2s are continuum from barely over that threshold to, I can't believe you're not yet in heart failure at the other end. This allowed you to start to say, well, no, these dogs, if they're, and as Adrian pointed out, looking at his mitral valve clinic data, it's a benign disease. And if you have relatively mild disease, even if you are technically a B2 dog, you are most likely to die of something other than your heart disease. And yet that dog would be automatically prescribed Pymabendin. And we don't know that those dogs do better given Pymabendin than the dogs that don't get given Pymabendin just because they're barely tipped over that line. Nobody's actually done the work to show that I've got, I had some data from the original Mind Study that suggested there was really no difference in their outcomes, but it's not a lot. I thought about what would I do as a clinician and why? Well, if it's mild disease, I'm not going to really worry about it because I know the disease is slowly progressing. It may never get to a point where I'm having a concern. And I can appease the owner not to be spending a lot of time and money and monitoring and so forth. Because it gets to a more advanced level, now I, my probability of developing disease at some reasonable time point goes up. So if we, when we looked at the data from Michaela and Luca, which were dogs that had never actually been on Pymabendin. So this is a pretty nice natural history study. There was a much higher probability once they were beyond mild of actually going into heart failure or dying from heart disease. And so now I've got a population. It's like a screening test, if you like. Now I've got a population which I can target because you've told me that you're going to, you've got a pretty good shot at progressing. So if I can delay that progression at that point, I'm good. You know, I may have bought you some extra time at the severe size, you know, so what we call is mild, moderate and severe. And I might change that to advanced because I've talked to some people who are not better in areas. And for them, severe sounds like, oh, you're telling it's going to die. Well, no, I'm telling you that we're saying it's important, aren't they? Absolutely. Language is everything. So if we say advanced pre clinical disease, these are dogs where you're worried. And you should be because they've got less than one year on average before they go into heart failure. But I want you to be paying attention to that dog as an owner because it's not going to be long and I want to be there and I want you to be there when it does start to go into failure so that we're not spending thousands of dollars in ICU rescuing it, but we can treat it maybe as an outpatient because it's just to develop mild signs of congestion. And we've gone on top of it before it started blowing bubbles. So those were the sort of the management reasons why I wanted to divide them up. And the other one was that as I explained to people, if Pima Benden was the price of aspirin or Tylenol, I've seen a menophan or paracetamol, whatever you want to call it, we wouldn't be having this conversation. You can throw it at every dog under the sun. I don't care. But when people are spending hundreds to thousands of dollars a year on a drug that's not necessary, that worries me. And I've got no skin in the game. So I don't care. Drug companies aren't paying me. They're not hiring me. They don't want to talk to me because I worry about those sorts of costs to people who have limited resources. And I'd rather spend them on things that might matter. If you've got a thousand bucks to spend on your dog with my full valve disease, let me do it when it really needs to be spent. Mark, that's amazing. We've got so much more to talk about that I think we might have to make this the first two-part episode of season three. So thank you so much for all your perspectives and to everybody listening, please come back and join us for part two of Mark's episode. You have been listening to the animal heart beat. Thanks very much for our listeners. Keep in touch by finding us on social media or sending us an email on [email protected]. Please remember to like, follow and share to help us find new listeners and make sure to check out our previous episodes wherever you get your podcasts from or on our YouTube channel.