Hello guys and welcome to this webinar, an update on the treatment of mitral valve disease. I'm with myself, James McMurray. So I'm an RCVS Advanced practitioner in small animal medicine and veterinary cardiology.
And I work out of, that's now referrals in Manchester, and certainly I see quite a lot of patients who have mitral valve disease at our clinic, whether they present through our emergency service, in full congestive heart failure, or because of some of it. Clinical, symptom, or whether these are patients who were referred over to me on an outpatient basis for further investigation of incidental heart murmurs. So what I want to do today is just update you on what's new in the literature on the treatment of my valve disease, and this is really going to be a webinar which is aimed at you guys in a primary care practise.
So it's to hopefully give you as much information as you can, in shortest time as possible on how you can successfully sort of diagnose and manage these patients in your clinic based on the latest evidence. So we're gonna start out by defining mitral valve disease. Then we're gonna talk about the importance of staging mitral valve disease before we then go on to the treatment of pre-clinical disease, then congestive heart failure, whether that's in hospital or at home, and then touch a little bit on the end, about additional therapy, on top of that.
So let's get straight into it, defining mitral valve disease. There's quite a few different names for this disorder, and, depending on the age of the publication you read or the age of the clinician you speak to, they might use different terms, but essentially they are all really very much interchangeable. And so I like to use mitral valve disease, but otherwise we can use degenerative, mitral valvular disease or myxomatous mitral valve disease.
When we're thinking about patients with cardiac problems and using the term heart disease, it's important to be aware of what that specifically refers to, and heart disease, can be defined as any disorder that affects the heart, OK? Now it's important to remember that that's very different from heart failure. So heart failure is the inability of the heart to keep up with the demands that are put upon it, and specifically the failure of the heart to pump blood with normal efficiency.
So we get into the differentiation of those a little bit more later on and and the differences in treatment but certainly be aware and certainly make your clients aware that there is a big, big difference between heart disease and heart failure. A little bit more background info now on mitral valve disease. So we're interested in it because 10% of all dogs that present to vets have heart disease.
So that's quite a large number, and of those 10% of dogs, about 75% of them have mitral valve disease, so it's, it's the most common heart disease of dogs that we see. The disease itself has a very long pre-clinical course, meaning that over a period of often many years, these patients remain clinically silent, you know, they have asymptomatic disease, but simply an incidental heart murmur. And, and what happens is over time there is progressive, change in, in many of these patients and often increases in volume of the classic systolic left apical heart murmur over time, progressive cardiomegaly before they eventually develop congestive heart failure.
So there is really quite a long pre-clinical course for these patients. And as we get to later on, there are some drugs that we can use to prolong that pre-clinical course, so it's certainly worth identifying these patients as early as possible. Progressive heart enlargement is one of the, main things that we look for, to indicate that the disease itself is progressing, and again we'll we'll touch on later on how we diagnose carddiomegaly.
But other things that we can use as well to tell us that a patient's mitral valve disease is progressing, are, or other indices as well. So one of them is, the mitral. E-wave velocity, which the discussion has really beyond the scope of this webinar, but it's something we can measure in echocardiography.
But otherwise, increasing anti-probate BNP levels on blood tests can be used, sometimes to track progression of mitral valve disease, but also increases in resting heart rate, as well in these patients. The disease affects the mitral valve, as its name suggests, but it is basically a degenerative valvular disease of the atrioventricular valves, and in approximately 30% of patients, it not only affects the mitral but also the tricuspid valve. So it's always worth bearing that in mind and not forgetting when we're auscultating these patients, not only to listen to the left side of the chest over the mitral valve area, but also the.
Side of the chest as well for the tricuspid valve. Sometimes we will hear a right-sided heart murmur, and it certainly could be because that patient has tricuspid valve disease and leakage, or it could simply be because we've got a very loud mitral valve, murmur on the left side and it's radiating over to the right, and really echocardiography is the only way we can differentiate those two. This is a disease that is certainly more prevalent in younger, sorry, in, smaller breeds of dog.
So the prevalence is much higher in breeds of dogs that are below 20 kilogrammes in weight. So any dog that presents with signs of congestive heart failure that's sort of over. 20 kg, it's probably not that likely they've got degenerative al disease and perhaps more likely it could be DCM or something else.
So it happens in smaller, typically terrier breeds, and the prevalence as well is much higher in males, about 1.5 times higher in males than females. And the prevalence certainly increases with age.
So we tend to think of mitral valve disease as being a disease of smaller, older dogs, and it's so frequent that 85% of small breeds have valvular lesions, by 13 years of age. So it's definitely very, very common. Larger dogs certainly can get mitral valve disease.
And when they do, it is unfortunately more progressive in these individuals than it is in the smaller breeds of dog, and, and they more rapidly progress through the pre-clinical period to congestive heart failure. And when they do go into heart failure, these guys actually do tend to develop myocardial dysfunction, which causes, systolic function problems in these patients, which is something that we don't tend to see in the. Breeds of dog with mitral valve disease, who tend to maintain myocardial function and systolic function, you know, until right at the end, of their, mitral valve disease.
So it's much more of a problem in larger breed of dogs, mitral valve disease, when, when it's there. . It's important to remember that even though this is a very, very common heart disease, not all patients with mitral valve disease do progress to congestive heart failure.
In fact, most don't. About 70% of all patients with mitral valve disease do not actually progress to heart failure. So These patients are the ones that we obviously don't get too worried about, and a lot of sort of work at the moment that's going on is trying to confidently identify the sort of 30% of patients who we think will or do have progressive disease and deciding what we can do with medical therapy in those patients to help delay progression.
There are definitely, breeds that are overrepresented, and of course we all know about Cavalier King Charles spaniels, but also Daxis, Yorkshire terriers, Chihuahuas, and miniature and toy poodles as well are very much overrepresented for the disease. With regards to the pathophysiology, I'm gonna keep it incredibly brief, and simply state that the cause of mitral valve disease remains unknown, although inherited components have been identified in some breeds, and essentially changes in the cellular constituents and intracellular matrix of the valves and the cordi tendina lead to Changes in the valvular structure, and the way that those valves close or or co-opt, and as the disease progresses, the defective coaptation gets worse and it leads to regurgitation of blood through the valve when it should be closed, and that regurgitation of blood. Into the left atrium causes increased cardiac work and progressive volume overload of the left atrium, which leads to progressive eccentric hypertrophy or enlargement, if you will.
Of the left atrium, and it primarily is a a disease that affects, the left atrium, when we talk about cardioomegaly, mitral valve disease. However, further on into the disease process as well, we do develop left ventricular, cardiomegaly and dysfunction as well. But yeah, certainly bear in mind it's not just the disease of the valves, but also the cordi tendin themselves.
That attach the valves to the papillary muscles, so they also are affected. So yeah, eventually in end stage margin viral disease, ventricular dysfunction, becomes evident as well. So now we're gonna talk about the importance of staging mitral valve disease, .
And that's because a lot of the recommendations that we're going to make about treatment are based on the stage of mitral valve disease. So if there's sort of one thing you can take home from this webinar, it is remembering these stages of mitral valve disease, and the importance of the stages, and or what the actual stages are themselves. So, the staging of mitral valve disease was first mentioned in this ACVIN consensus statement from 2009, so this is A a paper that's put together by sort of the top specialists, in this field, and they come together and make some decisions about mitral valve disease, the diagnosis and the treatment of it and put For some guidelines about what they think is sort of best practise based on the evidence, at the time.
So this is, this is relatively old from 2009, but it is open access through the Journal of Veterinary Internal Medicine. I highly recommend you check the paper out. And this paper first.
Brought forth this, staging system that we now use for mitral valve disease and actually now also use the feline cardiomyopathies as well. So these guidelines were then updated just last year, where the same consensus statement was simply revised based on, you know, the latest information, and the staging system has stayed sort of exactly, the same. So again, this is, Open access this paper and and I recommend you getting hold of this as well through the journal of Badminton and medicine.
So this is a diagram that was made up on the staging of mitral valve disease, and it's the kind of thing that I think we should become really familiar with when we are talking about mitral valve disease. So the beauty of this staging system is it describes all stages of mitral valve disease and helps us understand how patients progress through mitral valve disease. And at which points we are, you know, going to see clinical signs, and at which points we're going to use therapy and and what sort of therapy that we're going to use.
So what they've done is gone for an AB CD kind of approach to the staging system. And when we start out at stage A, these are patients that are at risk of mitral valve disease. So you know, these are patients of certain breeds and ages, for instance, middle to older age, cavalier King Charles spaniels, you know, those patients are at risk of mitral valve disease, therefore technically have stage A mitral valve disease, and these are patients that we're going to sort of monitor for the development and.
Of a heart murmur. So in stage A they won't yet have a heart murmur because they don't yet have heart disease, but they certainly are at risk of developing it later on down the line. We then move on to stage B.
So stage B are the patients who do now have heart disease. So heart disease, in manual heart disease is typically going to be, diagnosed based on the presence of, the classic. Left apical systolic heart murmur.
So these patients have disease, they don't have failure, and so, you know, they don't really have any clinical signs, but they do have heart disease. And then they are further subdivided into two stages, stage B1, which are those patients with disease but no cardiogaly. And then those patients that are stage B2 who have the disease but now have progressed to develop cardiomegaly.
So the B2 patients are an interesting group that we're, we're most interested in, because those are the ones that are most likely to progress to congestive heart failure, and patients who are stage B1 who have disease but know cardiomentally are much less likely to progress to develop congestive heart failure. So a lot of work has been done on the patients with stage B2 disease, and we'll get onto that. Later on with several studies and treatment recommendations, but these are an important, stage to be aware of and sort of understand, you know, that these are basically patients with pre-clinical mitral valve disease that do have heart enlargement.
They then progress from stage B2. To stage C, and stage C is congestive heart failure. C1 are the patients who are currently hospitalised because of their heart failure, and C2 are those that are sent home on heart failure treatment.
As patients, progress through stage C, they're gonna be on various medications to control their heart failure. But at some point, as the underlying disease worsens, they will become refractory to standard therapy for their congestive heart failure. And once you're essentially refractory to standard therapy, which we, we get on to later on, but it's essentially a daily furosemide dose of more than 6 to 8 migs per gig, and then we're classed as having stage D disease, which obviously is, is the most severe category.
And once patients are in stage D, you know, the prognosis, gets significantly worse, and we start to think about, optimising dosages of medications and adding in, other medications as well to help try and improve outcome. Within stage D, we then have the patients that are hospitalised who are D1 and the patients who are home at D2. So that's the staging system and as I say, use that for mitral valve disease, but we also use it now for cardiomyopathies in cats.
It's really, really, really, really, really, really important to be familiar with this, simply because it allows us to very easily make recommendations based on the patient's stage, you know, and also for us to communicate . As veterinary professionals with each other, you know, and very easily if I say to a colleague, oh, I've got this patient with this patient with stage B2 mitral valve disease, they're gonna know exactly what I mean, they're gonna know they've got disease and not failure, and that they have cardiogaly, and that therefore they're probably going to be on the medin or peopleendin, which we'll get onto later on. So it's just really, really, yeah, important to get to grips with this staging system if you're not already using it in your practise.
So we're gonna quickly rattle through now a little bit about the history and physical examination findings in our patients with mitral valve disease, and essentially, all of our patients with stage B disease are going to have incidental, left apical systolic heart murmurs, but no other, clinical signs or generally many other physical examination findings. Whereas our patients with congestive heart failure who are in stage 3 and above, and, you know, these guys are definitely going to have clinical signs, and those clinical signs most classically, are gonna be. Significant exercise intolerance, and tip at rest, OK, those are probably our best indicators that we have from the client's history that their pet might be in congestive heart failure.
And I always at this point sort of reiterate, the, the lack of usefulness really that a cough gives us in demonstrating that a patient may have congestive heart failure. So essentially this paper that's on the right, and a few others that can go with it, looked at, patients with, naturally acquired mitral valve disease, . And looked at how many of them coughed and, and how many patients coughed because of other diseases, and essentially a cough has been identified as a poor indicator of congestive heart failure and a better indicator of primary respiratory tract disease.
So essentially just because a mitral valve disease dog isn't coughing, it does not mean they're not in heart failure, and just because a mitral valve disease dog might be coughing, it doesn't mean they are in heart failure, OK? But other physical examination findings that'll tell us that patient might be in heart failure, will be pale, mucous membranes, often with a prolonged capillary refill time because of poor peripheral perfusion. Tachypnia is really, really common.
Tachycardia as well, and in, in the patients as well who've got congestive heart failure, they're obviously going to have this characteristic, left apical systolic heart murmur of mitral valve disease, but it's going to be pretty, pretty loud because one thing we know about mitral valve disease is that the intensity or volume of the murmur generally correlates pretty well, with the severity, of the heart problem. So, generally to be in congestive heart failure, our patients often have a grade 4 or above, systolic heart murmur. And those patients that present with breathing difficulties but a grade 1 or 2 out of 6 heart murmur, you know, probably don't have respiratory difficulties because of a heart problem, but because of a, an airway problem instead.
We may hear lung crackles in these patients because of pulmonary edoema, but the absence of lung crackles certainly does not exclude pulmonary edoema. They may have ascites because of right-sided congestive heart failure. Normally, mitral valve disease starts on, on the left side of the heart with the mitral valve.
And causes left-sided heart failure, but certainly can progress, and affect the right side of the heart if the patient has concurrent tricuspid valve disease or develops, pulmonary hypertension. Reduced pulse quality may be seen as well, and cachexia, which is obviously, loss of lean muscle mass, secondary to chronic cardiac disease can be seen and hypothermia as well is often associated with poor peripheral perfusion in patients with congestive heart failure. So this is where we now start to talk a little bit more about staging and being able to identify cardiomegaly.
Simply because of its importance in differentiating patients with stage B1 and stage B2 disease. So I'm just gonna quickly go through how we can do that, because if you guys, are doing some basic echocardiography in your practises, there's a couple of really simple measurements that you can take to be able to diagnose cardiogaly in. Practises and be confident about the need of putting, you know, a patient on a certain medication for that stage of disease.
If you're not doing echocardiography, you know, I'll just highlight the importance of using echocardiography, but also discuss what, radiological parameters, we can use to diagnose cardiogaly in these patients. So with radiography, we've all been using, I imagine the vertebral heart score for years to diagnose cardiomegaly in our patients. And we've traditionally said something along the lines of a vertebral heart score over 10.5 is often consistent, with cardiogaly.
Based on some work back in, in, well, a couple of decades ago really, by Jim Buchanan, but essentially, there's some new papers that have come out, more recently, that have looked at the vertebral heart score and related it, to patients who have, echocardiographic cardiogaly. And there's some sort of slightly newer. Cut-offs that we can use to help be a little bit more specific about the patients that probably do and probably don't have, cardiogaly and those patients that that need an echocardiogram.
So this paper was from earlier this year. And it basically looked at vertebral heart score in mitral valve disease dogs and what they found is that when you diagnosed echocardiographic cardiomegaly, sorry, let me just reverse that statement the other way around actually, when you had a patient who had a vertebral heart score of more than 11.7, essentially all of those patients had echocardiographic evidence of cardiogaly.
So that's really useful in primary care practise if you've got a patient, and it's got a it's got a mitral murmur and you're saying to the owner, we, we need to sort of decide if this patient's got CB1 or B2 disease because of cardiogaly. Ideally, we recommend X-rays and ultrasound, but if they can't afford the echocardiogram, then you can simply. Form of vertebral heart score on that patient with a right lateral radiograph.
And if their VHS is over 11.7, you can be pretty confident that that patient has, significant cardiogaly and definitely has stage B2 disease, which we'll get on to, you know, later on when we talk about the treatment of B2 patients. Conversely, any patient who has a vertebral heart score of equal to or less than 10.8 quite infrequently had echocardiographic cardioomegaly.
So, again, if you have a patient who can't afford an echocardiogram, if you do have vertebral heart score and it's less than 10.8, it's highly unlikely that patient's going to have echocardiographic cardiogaly and therefore it is unlikely, To meet, you know, the, a diagnosis of stage B2 disease and need therapy for it which we'll get to a bit later on. So what this study told us is that unfortunately there's quite a large grey zone, and any patient who has a VHS between 10.8 and 11.7, we can't be sure about whether or not they've got echocardiographic cardiogaly, and those patients really would benefit from having an echocardiogram.
So just to show you the VHS technique in case you know you aren't familiar with it, essentially we obtain a right lateral radiograph, and this is one of a cavalier with quite advanced mitral valve disease. And just looking at the radiograph, I can tell this patient's got a left atrial bulge, so in this region here, you can see the left atrium. So I also can see that there is an elevated trachea that almost runs parallel with the vertebral bodies here, rather than being divergent from it, which you would normally expect.
So I'm pretty sure this patient probably does have cardiogaly, but we're going to do a vertebral heart score, and, the first measurement that we take is from, the bottom of the carina, which is this little black area here which is the bifurcation. Of the left and right main stem bronchi. So we draw a line down from there to the apex of the heart.
We then put another line perpendicular to that, that measures the width of the heart. From its most cranial border here, back to the level here where the cordial vena cava actually inserts into the heart. Now you can't see the corrdal vein at caver here very clearly, but you can, in the next couple of slides in another patient that I'll show you.
So you take, these two measurements that have to be perpendicular, as I say, and then you line them up with the, thoracic vertebrae. So you find the 4th tho thoracic vertebra which is 1234, this one here. And there's the body of the vertebra there, so you put this long line in line with that, 4th, vertebra here, and then you take the shorter line and you put that in line as well, and you basically count the number of vertebral bodies.
That each line measures. So we've got 6.4 for the longer measurement, 5.8 for the shorter.
We add those together and it gives us a vertebral heart score of 12.2. So this patient definitely has cardiomegaly, from its radiographs and, you know, this is a value that's over 11.7, so with a high degree of certainty, this patient would also have echocardiographic carddiomegaly.
And therefore we can quite confidently say that this patient probably has, well, it does have stage B2 mitral valve disease, you know, and likely it's gonna warrant, long-term therapy for that as we get on to the latest slides. I think that we can use, alongside the vertebral heart score, which is something that's relatively new. Is the vertebral left atrial size, the VLAS, so this has been, .
Sort of covered in a couple of papers really, the first paper looked at establishing reference intervals in healthy dogs for the VLAS, and what we found in this paper that was published in July 2020, is that a median value of 1.9 was identified with a reference interval of 1.4 to 2.2.
So we'll get on to the measurement of VLS in just a second, but what they found is that there was a positive correlation between the VLAS and the vertebral heart score. And that there was excellent intra observer and inter-observer agreements, so it's quite reproducible, the VLA LAS just as the vertebral heart score is. So there was another paper then also published in 2020, that looked at the utility of the vertebral left atrial size to be able to stage patients with mitral valve disease, and what they found in that study is that a VLAS, A cutoff of 2.5 can be used to identify dogs that would benefit from echocardiography, to see if they have, stage B2 disease with a sensitivity of 100%, and a specificity of 78%.
So basically, Perform a VLAS on a patient, if the VLAS is over 2.5, they certainly could well have echocardiographic cardiogaly and should have an echocardiogram. So just to show you how to .
Measure the DLAS, so this is actually a patient, not with mitral valve disease, I'm cheating here a little bit, but actually with DCM, but it was just a really nice, image to use. So the first thing that we do is we identify the carina again as we did last time, so that's that, circle there. We then identify the cordal vena cava so you can actually see it really clearly on this film, which is why I picked it.
So this structure here is the caudal vena cava, OK, this is the dorsal border and this is the ventral border. OK. So we identify the carina and the cordial vena cava, and then what we do is we draw a line from the ventral aspect of the carina to the dorsal aspect of the caudal vena cava at this level here where it meets.
The base of the left atrium. So, so this is the left atrial bulge here, OK, and this is the level here where, basically the cord of vena cava sort of, passes across the left atrium. So this is the distance that we're going to measure with our callipers.
And then very much like the vertebral heart score, we then align this with the start of the 4th thoracic vertebra, and, we measure the number of vertebral bodies. And in this patient, we've got 1, 2.8, so VLAS of 2.8.
So if this patient Was a small breed terrier that we thought had mitral valve disease, you know, this VLAS is over that cut off of 2.5, and to this client, we should be probably recommending echocardiography to be sure that it has echocardiographic. Cardiomegaly to see if it may meet the criteria for stage B2 disease.
Really, so I hope everybody found those couple of techniques useful. It's certainly something that we probably VHS we've all been, trained on how to do at university, but it's perhaps not something that we're using on a day to day basis when we're performing thoracic radiographs on our patients, but really, really useful and certainly the VLAS can be useful in addition to that too. So moving on to echocardiography.
All I really want to do is, I, I, I, I can't talk about this in any great depth. But I think just to highlight the importance of echocardiography, in patients with, with pre-clinical, mitral valve disease. So firstly, echocardiography is the only way to diagnose mitral valve disease.
You know, a patient who's got a classic mitral valve murmur, who has left atrial cardioga on an X-ray, more than likely does have mitral valve disease, but you can only make the definitive diagnosis on echocardiography, so it's really important to point that out. . Secondly, when we are looking at staging patients with microbial disease and and making treatment decisions, certainly echocardiography is, is the most sort of accurate way of doing that.
It's definitely the most sensitive and arguably the most specific way of doing that. And some of the studies that we're gonna touch on a bit more in the, in the final section on sort of treatment, in particular this EPIC study which I'm sure everybody will have already heard of, a lot of the, the inclusion criteria for patients who were entered in these studies were based on very specific echocardiographic measurements and therefore we know that based on the evidence, if our patients meet these specific echocardiographic criteria, we can be more confident that they're going to benefit from the use of these various medications. .
So the two criteria that we used in the EPIC study, which was looking at the use of peerendin in preclinical mitral valve disease, which was published a good couple of years ago now, and basically they looked at the LA to AO ratio, which you've got a picture of here on the right. And, and what we used is, a cutoff of equal to or more than an LAAO of 1.6, to diagnose left atrial cardiomegaly.
And then the other measurement they used was the normalised left ventricular internal diameter in diastole. And what they used as a cutoff for that is an LVIDDN of equal to or more than 1.7, which is shown how to measure that on, on this slide.
So basically it's an M mode measurement that's actually not particularly difficult, image to acquire, and it's not a particularly difficult, measurement to make, but essentially what we're doing is measuring the diameter of the, left ventricle in diastole. And then we're normalising that to the patient's body weight and it gives us, this number. And as I say, with using a cutoff of 1.7, we can use that to echocardiographically diagnose cardiomegaly very accurately in these patients.
And in this patient here who weighed 15 kgs, and had an LVID. 4.2 centimetres.
When we plumbed those numbers into the equation that gives us the normalised left ventricular internal diameter and diastole, it gives us an end result of 1.89, as you can see, which is over the cutoff of 1.7.
So this patient has evidence of echocardiographic cardomegaly. OK? And So essentially, the, the, the summary there is that radiography can be used to diagnose stage B2 disease when the cardiogala is particularly significant.
OK. However, when the cardiomegaly is more mild and is. Not as as sort of significant on radiography.
We should really be using echocardiography in all patients in which there's any uncertainty, to, to definitively diagnose cardiogaly before we look at any definitive therapy for those patients, OK? Brill, just a little tiny bit on cardiac biomarkers. All I really want to say is that the NT Pro BMP is probably the one that most people have heard of and or are using.
The take home messages really are that this, biomarker can't be used to make a diagnosis of mitral valve disease, OK? It's basically a marker for stretch of the heart and essentially cardiogaly, but it cannot diagnose, cardiac disease, OK? It can be used to look for evidence of cardiogaly and certainly a progression of cardiomegaly, but it's nowhere near as sensitive or specific, as an echocardiogram.
So as a cardiologist, I very rarely, if ever, measure NT Pro BMP in my patients because that test is not going to tell me anywhere near as much, or anywhere near as accurately, as much information as an echocardiogram is. So it can have its utilities, but certainly don't think that an NTro BNP has any benefits over an echocardiogram other than it is cheaper, and easier to perform. Do be aware of the specific sample requirements for whichever lab you're using, and, when you're performing a quantitative NT pro BNP, there are a cut a few sort of cut-offs that we can use to help.
Really guide us on, on whether or not that patient probably has progressive disease and and probably would benefit from an echocardiogram or radiographs. So an NT Pro BMP of over 1500 moles per litre is associated with an increased risk of heart failure in the next few months. So these patients likely would benefit from imaging to see if they do have cardiogaly.
Progressive increases in the NT Pro BMP as well of more than 60% between visits as well has been associated. With an increased risk and the need to image, and in a patient who has respiratory signs, so we're really talking about, you know, dyspnea, tachypneia, an NT pro BMP of less than 900, is pretty good at excluding congestive heart failure, whereas over 2500, it is often pretty consistent with congestive heart failure. Now, that's great looking at anti-Pro BMP in a patient with dia.
Dysmia, but these are all being sent externally and quantitatively, which take days to come back. So in those situations, if we worried about heart disease, we would take an X-ray and look for radiographic cardiogaly in those patients to see if it looks like it is. Cardiac in origin or respiratory tracts.
OK, so we've talked quite a bit about how we stage mitral valve disease, and what I'll now do is go through the different stages of mal mitral valve disease and sort of update you on what the treatment options are. So stage A disease is those that are at risk. Essentially, there's there's no treatment recommendations, we just need to monitor these patients to see if they do develop heart disease.
So yearly auscultation, for instance, in all cavaliers is recommended. And breed screening as well, obviously, for those at-risk breeds. Any, individual, that develops a, migual valve murmur that is less less than 6 to 8 years of age, should also not be bred from as well as a recommendation from patients in stage A.
And, and all of these, recommendations that I'm going to go through are all really lifted straight out of the ACVIM consensus statement, . Because there is pretty robust evidence behind all the recommendations. So patients with stage B1 disease, so they have mitral valve disease, but no cardiomegaly.
These patients don't need any therapy, they don't need any dietary modification, and simply monitoring is the key, OK? So. What we're saying here is just because a patient has a mitral murmur, it does not mean they automatically warrant chronic pemobendin therapy, OK?
Only those with stage B2 disease need that patients with stage B1 disease do not benefit from Piemobendan, OK? So there is no need to prescribe it. Instead, what we need to do with the B1 patients is simply monitor them to see if they do progress to stage B2, at which point then we would put them on PMmobendin therapy as we get onto the next slide.
So for patients with stage B1 disease, no therapy needed, but simply monitoring for progressive cardiogaly either with radiographs or echocardiograms every 6 to 12 months, OK? So now we get on to the more interesting patients, so patients with stage B2 disease. So stage B2 disease as we've already said, is a mitral valve disease with cardiomegaly.
So the EPI trial, which I've already, mentioned earlier on, looked at these patients, and they basically compared two populations of dogs that were either put on Pima Bendin or put on a placebo. And what they did is they looked at the outcome between the two groups, Pemo versus nothing. And, What they basically found, I just sort of fast forward a couple of slides, is that emobendin therapy delayed congestive heart failure or sudden death by a median of 15 months when compared to placebo.
OK. So patients with stage B2 disease, Definitely benefit from chronic Pendin therapy to help prolong their pre-clinical period and delay the development of congestive heart failure, OK? Now a couple of sort of slightly Slightly picky things to bring up are that this epic trial, as I said, had some specific criteria to diagnose sort of cardiogaly and the patients had to meet these specific.
Parameters, but they also had to be over 6 years of age between 4 and 15 kgs, and have a murmur of grade 3 or more. So technically any patient who is younger than 6, or heavier than 15 kgs or has a lower grade murmur than a grade 3, even if they have e cardiographic criteria, technically we'd say they don't meet the EPIC study criteria might not benefit from premobendin therapy, but I think that's been incredibly Pedantic really. And I think any patient with mitral valve disease, who does have, either, sorry, does have a combination of an LAAO over or equal to 1.6, an LVIDDN equal to or over 1.7, or radiographic evidence of cardiogaly, which in the EPIC study they used to cut off of 10.5.
A patient who meets these criteria is likely to benefit from chronic pin bending therapy. So essentially, Any patients that we're concerned might have B2 disease screen them for cardiogaly if they have cardiomegaly, certainly if it meets these epic criteria, then they need to be started on Pendin therapy. Off the back of the ACVIM consensus, they obviously, were aware that not every client can afford an echocardiogram.
And if radiography is the only thing that is available, if they have a vertebral heart score of equal to over 11.5 or a VLAS of equal to or over 3.0, if they couldn't afford an echocardiogram, those are into themselves.
Were enough of a criteria to say that they likely had echocardiographic cardiogaly and probably would benefit from chronic pending therapy as well, OK? So with the, the pin bend and we're gonna prescribe this at a dosage of about 0.25 mg per kg twice daily.
Do make sure that the owners are aware that this needs to be given on an empty stomach, so an hour before food to increase the bioavailability. And the drug itself is often very, very well tolerated, and, as a result of the EPIC study we're now using this, very regularly in on stage B2 patients. Is there any evidence about any other drugs at this stage of disease?
Well, essentially, no, there isn't. So some people, and certainly in the consensus statement, do advocate the use of ACE inhibitors, in quite advanced stage B2 disease just prior to the onset of heart failure. However, there is certainly no evidence, to support that in the literature, no strong evidence at least.
And the very, recently published delay study, from 2020 actually looked at, Benazapril, which of course is an ACE inhibitor, given in combination with sorron lactone. In patients with B2 disease, and compared that with patients who received placebo, and essentially there was absolutely no difference in outcome between patients who had spironolactone and benazepril versus those just with placebo. And so neither group had pumabendin in that study, but essentially it kind of tells us that really, an ACE inhibitor in, in stage B2 diseases is unlikely to be beneficial.
Do be aware that any patient we diagnosed with stage B2 disease, we should also screen for comorbidities, such as chronic kidney disease, because that might change, our treatment options as they progress into heart failure. And of course, systemic hypertension. Any patient who has mitral valve disease and systemic hypertension should have their, systemic hypertension treated to help reduce the afterload on the heart and therefore reduce cardiac work essentially.
So if all of that seemed a little bit confusing and convoluted, because it's not the easiest thing in the world to explain, there is some great information that's available, through the cardiac, education group. So this is an online resource that's, open access, to vets or, to clients, and they do some nice sort of flow diagrams like this, where you, you've got a patient that's got an asymptomatic left apical murmur, you can kind of decide, based on your investigations, whether or not that patient actually needs vet medic or not and whether they just need to recheck at a later date. So I highly recommend, using their website as a resource.
OK, moving on to stage C, so we're now talking about how we're gonna treat our congestive heart failure patients with mitral valve disease. Essentially, these patients are more than likely gonna go on what we call quad therapy. So quad meaning a combination of four drugs, and these 4 drugs are furozamide, yabbendin, benazepril, and spironol lactone.
So there is evidence for each of these drugs that they are beneficial in patients with congestive heart failure. And as a result of that, if my client doesn't have any cost constraints or any problems with polypharmacy, you know, so getting multiple tablets into their pet, and this is the combination of drugs that I will use for outpatient treatment of all of my stage C mitral valve patients. So ruzamide.
You know, obviously it's a loop diuretic, so we're gonna start that normally at 1 to 2 migs per gig twice a day, and then what I tend to do is get that congestion under control, recheck them 1 to maybe 2 weeks later, and at that point often down titrate the dose a little bit, see if we can just reduce that, and still keep, the congestion under control. And often these patients, yeah, therefore, do end up staying on 1 to 2 weeks, but keep twice a day for quite long periods of time before they, sort of further, you know, decompensate at a later date. That me in, we've sort of already talked about, so, Peavendan is an INodilator, and it's definitely, beneficial in patients, with congestive heart failure, .
Benazapril, is an ACE inhibitor, tend to start back at 0.25 to 0.5, migs per gig, once daily.
And we tend to stick with that dose, to be honest, until patients progress to stage D, at which point we may look at increasing that dosage. Spironolactone, so this is an aldosterone receptor antagonist, otherwise it can be described as a potassium sparing diuretic, but it's a pretty lame diuretic. In actspironolactone itself does does various other things to help, patients with congestive heart failure, rather than its effect as a diuretic.
Tend to start this at about 22 to 4 migs per gig once daily. And again, they tend to stay on that dosage pretty much the whole way through stage C disease. It's only really, the uzamide dose that we tend to, you know, slowly over time up titrate as their stage C disease progresses.
What about patients who can't afford all of those drugs? OK, so I call them the stage C on a budget patients. Well, if we look at the results from the quest study published in 2008, this is a study comparing the outcome in patients with stage C mitral valve disease who are either put on ruzamide and Pendin versus ruzamide and benazepril.
And what the study found, is this Kaplan Meyer curve, on, on the right, will sort of show you, when, when it looks at, Composite endpoints of the study is that patients that received Peabendin and rosemide had a significantly longer time period, before intensification of their treatment was needed compared to those patients that were on Benazepril and rosemide. So as a result of this, if you've got an owner who really can't afford quad therapy, and that combination of drugs, the best combination probably to get as much bang for your buck, is a combination of, of, of peabendin and rosamide alone, and probably dropping the benazepril and soronolactone is, is the most sensible thing in those patients if they can't afford all 4 drugs. What about the patients who are stage C and hospitalised?
So the cornerstone of treatment with these guys is, is suzamide therapy, and this is going to be given parentially. The best way to do ruzamide is IV, and we should have an IV in all of our, stage C hospitalised patients if possible, so we can administer ruzoammide via this route and obviously, any drugs, during CPR should these patients. And we tend to start with initial bolus of 2 migs per gig IV or if we can't get an IV because, the patient is too dyspic to handle, then IM, you know, is appropriate.
And we can either use this bolus space approach of 2 mg per kg IV. RIM sort of hourly until the respiratory rate starts to improve, or a total dose of 8 mg per kg is reached over a period of 4 hours. So the vast majority of stage C mitral viral disease patients will improve with simply this approach, the 2 migs per kg hourly bolus.
However, if they do not, for whatever reason, then the next thing to do is to consider the use of a rosemide CRI. So a constant rate in infusion of rosemide, at a dose of 0.66 to 1 mg per gig per hour after an initial 2 migs per gig bolus has been given.
What we know about the use of a CRI, over bolus is, is that, It basically it's slightly more effective as a diuretic, and this has been looked at in healthy greyhounds, but also, in, in, in patients hospitalised with congestive heart failure and essentially a CRI has been found to confer a shorter hospitalisation period. Better levels of diuresis, but along with that does slightly increase the risk of that patient becoming azodemic as a result of the increased diuresis. So, we do need to make sure that when we are using fruzamide bolus and rosemide CRIs, our patients have free access to water.
To help them cope with the progressive dehydration that they'll develop. And at no point, even when we make these patients dehydrated and or razotemic, at no point should we really be giving them intravenous fluid therapies, because it's simply going to counteract the effects of the diuretic drugs that we are giving. And Alongside furozamide, in our hospitalised patients who want to start immobendin therapy as early as we've got the diagnosis, and that can either be orally, the standard dosages of 0.25 mg per kg twice a day, or the first bolus of pumabendan can be given intravenously.
The, the intravenous preparation of vet medicine is really expensive, so I certainly very infrequently use it, and I think the oral version is fine. The sort of exceptions to those scenarios are the patient that is so dyspneic, you can't really medicate them, in which case I'll give them their first bolus of Pin bend and IV or in the patient that's got really advanced right-sided heart failure signs, so, that cavi that's coming in with, a big belly of acitic fluid, you know, they are gonna have, really pretty significant, gastrointestinal tract edoema, because of, their right-sided congestive heart failure, and as a result of that, they're not going to be able to absorb any drugs that are given orally as well as a dog who has a normal GI tract. So my worry is that if you've got a patient with advanced right-sided heart failure, you know, as per the patient presents to the ascites, that actually the bioavailability of that drug might be much lower than you'd expect and actually giving it orally might be, nowhere near as effective as giving it intravenously.
Any patient that is particularly, distressed would could or would probably benefit from a little bit of anxiolysis or, or light sedation, and I tend to use butorphenol at about 2.2, sorry, per gig IV or IEM. Butorphenol doesn't, reduce cardiovascular function, .
But by being able to reduce some of the anxiety these patients feel, you reduce the amount of catecholamines that they're releasing in this sort of increase in sympathetic tone, this fight or flight, you know, sort of situation that they find themselves in, and actually it can be beneficial at limiting the negative effects of, of the congestive heart failure. So, certainly, you know, but orphanol, oxygen supplementation are used very, very regularly in the particularly, dyspneic. Mitralal disease patients.
There's then various other drugs as well that we can consider using ACE inhibitors, dibutamine, nitropluide, but all of these are really beyond the scope of today's lecture, . So I thought I'd just go on to a a a a slide I'd like to call the who are the new kids on the block. Well, if this was the 1990s and we were talking about music, it would be these guys, but of course it's the year 2020 we're talking about veterinary cardiology.
So in fact these are the new kids on the block, and these are the various different versions of, Terazamide, which has been licenced through vetoquinol, in the form of UCA. So I wanted to just to, to briefly touch on Terazamide because. Terazammide is something that is is a newer loop diuretic that maybe you guys have heard about, maybe you guys are using, but I'd like to give you some insights on, on where we as cardiologists tend to, to use this drug.
So it's a potent loop diuretic, many times more potent than furosemide, something in the order of 10 to 13 times the potency, so you use 10 to 13 times less dosage of this drug. And it's useful, certainly traditionally we've, we've used it, patients that are resistant to furosemide, who have been on high doses of rosemide and don't have good control of their congestive heart failure. And the drug has another advantage over furosemide that it has a much longer half-life.
So the drug itself, when administered orally, is effective for about 10 to 12 hours. So this is, a graph of time versus diuretic excretion rate, and as you can see, the terrazamide single dose, keeps the patient's sort of level of, of diuretic excretion within the effective range for much, much longer than furozamide, which is a much shorter acting drug, OK, . So the longer half-life means that you can dose less frequently and actually it's licenced for just once daily use, to razamide instead of twice daily with rozamide.
And it also has a higher oral bioavailability as well when compared to rosemide as well. So it's licenced at 0.1 to 0.6, migs per gig orally once daily.
And what we tend to do is, if we're starting terrazamide as as the patient's first loop diuretic, we'll start at the low end of the dose range and slowly up titrate, and we find that most dogs are stabilised at a dose of less than or equal to 0.3 migs per gig per day. So we can use this as a first line choice of a diuretic and up until sort of very recently, there wasn't a huge amount of evidence for its use in that situation and then as cardiologists, we were using it a lot more as a rescue therapy, in stage D patients that were no longer responding to furosemide, as I'll get to in another couple of slides.
But there actually have since been. A couple of studies, the test study and CARODM study, which have both looked at comparing terrazamide and rosamide in patients, with congestive heart failure because of mitral valve disease. So the test study, which was the first one is what we call a non-inferiority study.
So it basically looked at patients with congestive heart failure, . And it was not at the point of first diagnosis, but they were already diagnosed with heart fail, already on diuretic therapy, and it basically compared switching, a group of patients onto terrazamide versus keeping the other group of patients on their rosemide, and basically what it found is that terraamide was not inferior or non-inferior to furozamide in that study, and that actually when they looked at the Kaplan Meyer curve. Comparing the percentage of dogs not reaching the end point of the study, which was significant worsening of heart failure, cardiac death, or, or, or euthanasia because of cardiac disease, that actually it appeared that the the terrazimide group, actually.
Had a two-fold reduction in the risk of reaching the composite end point of that study as this line at the top shows you the fruit of the terrazamide patients versus the lower lying rosemide patients. So essentially this initial study said terrazamide is at least as good as furosemide and maybe in the longer term, it can be more beneficial because the less patients will die as early on because of their heart failure. There's then the more recent CA DM study, which was published in August 202,020.
And basically this again was a non-inferiority study comparing, patients with newly diagnosed congestive heart failure and putting half of those on, terrazamide and half of those on rozamide. And again this study found that the two, the terrazamide was non-inferior to furosemide, it's at least as good, and that actually when we looked at . The probability of the two different treatment groups reaching the composite end point of the study, again, they found that dogs receiving terrazamide had a longer time to endpoint of this study and were less, likely to experience, death, or euthanasia, than the patients that were receiving frozamide, again, as this Kaplan Meyer curve sort of demonstrates here on the right.
So essentially, there is now a decent amount of evidence out there to say that. Instead of starting our newly diagnosed stage C patients on terrazamide, on Frozamide, as we always have done, we can consider starting them on terrazamide as their first line loop diuretic, because it's certainly a non-inferior drug and actually, over time may be more beneficial than rozanide in these individuals, but there's still, more evidence that we need from the literature. OK, so just gonna quickly touch on stage D patients.
So these are individuals who are refractory to standard therapy, essentially patients who still don't have control of their congestion on a dose of more than 6 to 8 migs per gig per day. And a lot of these patients, have essentially ruzamide resistance. And in these individuals, there's a few things that we can do.
To try and optimise their therapy, one thing that we can do is try and increase the rosemide frequency, so not necessarily increasing the dose, but just increasing, the frequency, that the rosemide is given throughout the day. So as this sort of graphing you right helps helps to demonstrate. And if we just increase the dose of furosemide, yes, it increases the diuretic excretion rate, but it doesn't, increase the duration of time at which that's within the effective range.
But actually just by giving the rosemide more frequently, we're then gonna spend longer within the effective range in that individual patient. So consider it firstly, maybe increasing the frequency of rosemide to 3 times daily, but not necessarily increasing the total daily dose. Another thing that we can do as well is consider switching from Frozamide to terrazamide.
As I say, it is a more potent diuretic. It does have a longer duration of action and a higher bioavailability. So when we do this, what we often do is we look at the total daily dose.
Of rosemide and then we divide that by 10 and that dose is the new dose of terrazamide. So if you're on 6 migs per cube per day of rosemide, gonna divide that by by 10. That patient on 0.6 megs per per day of terrazamide instead.
So that's something that that I've been doing for a little, little while and, and it certainly seems beneficial in quite a few of these stage D patients that seem refractory to frozenide. There are other drugs as well, that we consider adding into stage D patients, but I think these, are the ones that really would definitely definitely benefit from seeing a cardiologist. They really do need an echocardiogram to look for evidence of, problems such as pulmonary hypertension or, arrhythmias and systolic dysfunction and.
Ruptured cordi tendon, all these sorts of things that really significantly alter the prognosis, you know, and treatment options, but otherwise, additional, sequential, diuretic, therapies such as the addition of hydrochlorothiazide is often used in, in, in, in these patients, . Really, no, we're just gonna finish up, because I'm quite aware that we're running out of time, on monitoring of these patients in your practise. So once you've diagnosed them with a certain stage of disease and put them on the appropriate treatment, we're gonna monitor stage A dogs with auscultation, as mentioned earlier.
We're gonna monitor stage B1 dogs who are not on any therapy with serial echoes and radiographs. To see if they develop, progressive stage B2 disease and warrant Pendin therapy. We're going to monitor stage B2 patients, not with serial echocardiograms and radiographs, but simply for signs of heart failure.
There's not a lot of point in repeating radiographs and echoes in these patients because even if their cardioga progresses, until they develop congestive heart failure, it's not going to change the choice of drugs that we use, they're just going to remain on their Pendin. Patients with stage C and D disease, we're just gonna monitor closely for clinical deterioration. So the history from clients, physical examinations, blood tests, potentially echoes, particularly in those stage D patients.
And an important thing to always remember as well is that anytime that we introduce a diuretic or an ACE inhibitor, or increase the dose of a diuretic or ACE inhibitor, it's very sensible to recheck the renal values and electrolytes, 7 days later. Because obviously, diuretics can, can cause, low levels of our electrolytes, and potentially can cause a degree of pre-renal azotemia because of dehydration. But also ACE inhibitors not infrequently can increase your urea and, sorry, your, your creatinine by up to sort of 20-30%.
You know, if that pushes a patient into an azotemic state, it might mean we have to back off from the dose of that ACE inhibitor or even discontinue it altogether. Just a tiny bit on monitoring at home. It's simply just to mention the importance of sleeping and resting respiratory rates.
So this is something I, I recommend all of my clients become familiar with performing. So what they need to do is measure. The number of breaths that their pet takes in a minute when they are asleep or almost completely asleep.
There's absolutely no point doing this when the patient is sort of conscious and alert, because it is, it's far less representative. But there's a couple of really good studies that looked at sleeping and resting respiratory rates, and what we found is that if they are consistently below 30 breaths per minute, That patient does not have pulmonary edoema. So if it's a stage B2 patient and it's resting respiratory rate's consistently below 30, we know it's not progressed to stage C.
If it is a stage C patient that's on treatment of his heart failure and it's resting respiratory rate is consistently below 30, we know that they're doing well on therapy and don't need any dose increases. I always tell my clients though to, monitor the progressive increases in the sleeping respiratory rates. And when they're consistently between 30 to 40 breaths per minute, I recommend you contact a vet, as we might need to up titrate the dose of their diuretic.
If they're pet's resting respiratory rate is persistently above 40 breaths per minute, I recommend they seek immediate veterinary attention because that patient likely has pretty significant pulmonary edoema. What about the cough? Well, treatment of the cough is, something that I sort of touched on earlier.
Remember that, cough is not a good indicator of congestive heart failure. So if you diagnose stage C disease in a patient that is coughing, use their resting respiratory rate to guide how well they're doing with therapy, not whether or not their cough improves, in its severity or frequency. Generally, if a patient has stage C disease and a cough, I'm a bit reticent to use anti-ussives, but if they have stage B2 disease and a cough, definitely the treatment of that cough, can be beneficial for that individual the use of anti-ussive therapy, but again, the discussion of that is kind of beyond the scope of this lecture, .
Finally, just going to briefly mention surgery for mitral valve disease, just in case there's people out there, who have, clients that certainly have some cash, to splash, really. So, mitral valve disease surgery, was first, described in 2012, and it was being performed, by a group, of, of cardiothoracic surgeons in, in Japan. In dogs, and it was published in a paper that that identified that patients had a very sort of good outcome following my actual surgery, with patients having 93% survival at 3 years post-surgery, and these were patients who had, basically advanced stage B2 or stage C mitral valve disease.
This surgery is now available in the UK at the Royal Veterinary College, and, the surgery itself is generally performed on patients with stage B2 or stage C disease, certainly if it's sort of early or well-controlled stage C disease. And the survival to discharge rates are currently 100% for patients with stage B2 disease and 87% for stage C. Now bear in mind this is unpublished data.
But, that, that's the information that, that, that I've got from the RBC. Patients who are most suitable for referral for microval surgery are those that, as I say, are late B2 disease or well controlled early stage C disease that don't have significant comorbidities, without evidence of severe pulmonary hypertension, and those that are generally less than 10 years of age. So mitral valve surgery, essentially.
Is an open heart surgery, that allows, Essentially repair of the valve so that we correct the regurgitation, really dramatically reduce the volume of regurgitation and as a result, it can be curative in in in in the vast majority of these patients, meaning that they are able to come off of, cardiac medications even if they were previously in stage C disease. So it's, it's a wonderful option. If our client can afford it, and it certainly is expensive, and, and the last time we checked, the cost of the procedure was capped, which is good, but it was in the order of, 17,500 pounds, and the waiting time was in the order of several months.
So it's an option that's out there, for some patients whomaritual valve disease, but it's certainly, not for everybody. This is a picture provided to me by Poppy Bristow, from the RVC. It's an intraoperative, image of the mitral valve undergoing, repair.
And that's pretty much it, really. So the summary would be the importance of staging mitral valve disease so that we can, make very informed decisions about the best treatment options based on what is really quite robust evidence that's out there in the literature. So I hope you guys have found that, useful and you have a couple of, sort of top tips that you can take away with you.
As this is a pre-recorded session, there won't be any questions at the end, but I've just popped my email address on that final slide there should you want to send over any questions to me via email. All right, well, everybody, thank you once again for listening and do take care.