Dr. Vik Khangoora with Inova Fairfax Hospital, in Falls Curch, Virginia, describes the clinical classification of pulmonary hypertension and the pathogenesis of PH-ILD.
Thank you everyone. All right. So we're almost there. You guys are hanging in there. Um I have the, the non envious position of following uh a cadre of very, very talented speakers. I was sitting there taking notes on how, how well they did. I want to start, you know, doctor. So I was criticizing the lungs for getting away of his echoes. But um if it wasn't for the wimpy, right? Ventricle, we wouldn't be in this predicament. So really, it's your fault. Um So no relevant disclosures. We've, we've hammered this point home already. I think a number of times, but we talk about group three ph we're talking about diseases of the lung, right? The lung, pereny diseases of um of oxygenation. So, you know, for the, for the purpose of this talk, we're gonna focus on ph uh and interstitial lung diseases. I'm gonna touch if we have time, uh I will touch very briefly on COPDPH. But um I think again, we're gonna focus on uh pulmon hypertension in the context of interstitial lung disease. So, you know, initially, when we started to discover that patients with ILD were developing Ph, we thought this is for sure, just a consequence of that lung disease. But what the data showed us is actually, there's not necessarily a correlation between the amount of lung disease and the amount of ph that a patient has, right. The hemo para parameters don't always correlate. In fact, what we see is this really complex interplay. What's my mouse here? Yeah. So it's a very complex interplay of a lot of things, you know, including tissue destruction, inflammation, fibrosis, hypoxemia, and these things lead to, you know, vasal constriction, proliferation, remodeling, but it's sort of a two way road there, right? That in fact, you get this disease in the vasculature and this disease in the prana and then they sort of feed each other to some extent. And then, you know, we touched on briefly how, you know, even within group one pah that not all those phenotypes are created equally. Well, the same thing goes for group three, right? If you take patients with ch you know, connective tissue disease, now you're adding another layer of complexity, right? So now in addition to everything else, you've got, you know, you intertwining this fibrosis that's occurring this vasculopathy. Now, you've got this autoimmunity and this varying amounts of inflammation that are also occurring and further exacerbating the picture as I mentioned before. This is a paper from 2007. Um actually, uh Steve Nathan published um looking at FEC and mean P A pressures in patients with IP F. Um And you can see it's a total scatter plot, right? That actually the degree of restriction does not necessarily correlate with the degree of uh A P A pressure elevation. When we look at the epidemiology, you know, it's again listed as common in the guidelines. But overall really quite rare, you know, when you look at the, the registry data and the and the studies looking at prevalence, um it really varies depending on when you're capturing those patients. So if you're capturing patients early on at the diagnosis of their ILD, then the you know prevalence of PH is quite rare. If you capture them somewhere in the middle, you know, through their course, it's somewhere between 30 46%. I mean, if you look at patients that, you know, are found to have Ph at the time of transplant referral, it's quite high up to 86%. So, you know, really depending on where you capture these patients. Um you see varying prevalence. Um Our goal is obviously to capture patients earlier here. And the same thing that, you know, as we see that Ph develops, you know, more and more as patients progress in their ILD and their symptoms also evolve, right? So we have symptoms that are primarily driven by their ILD initially. But then as that ph starts to kick in, we start to see symptomology that's driven by the development of pulmonary hypertension as well. And then you know, late in the disease starts to develop um uh you know, signs and symptoms of RV, failure with dizziness, syncope, et cetera. Again, hoping to catch patients before that, before that point. Um you know, if we look at and again, hammering home, you know, correlation between me P pressures, um you know, and, and, and disease. If you, you know this study, uh looking at uh the mean P pressure values among 79 patients with IP F, you can see for most patients, they sort of live in this, you know, mild ph range of 25 to 30. But if you look at that in survival, really just having PH at all in this cohort, you know, correlates with very poor survival, right? So having no ph even versus mild PH was found to, to have a really strong association with poor poor outcomes. And in fact, in patients with group three, ph, we compare that to the other uh you know, forms of uh uh pulmonary hypertension, whether it's group one, group three, you know, group, group, uh group four there. Um that they also do worse. I mean, it sort of makes sense a bit, you know, they have got both lung disease and ph as we talked about, there may be this sort of two way street there, between, between the two. So as you guys can, uh it's my pointer here. See, uh there we go. So you can see here the group three patients, you know, and this is about, um, I think this is about 100 and 100 and nine patients with group three here, 100 and 64 with group one. And this is a retrospective study in total. I think it was about 360 patients. And you can see their survival is terrible. I mean, their one year survival was 70% their, their, uh, you know, five year survival was only 37% here if you break it down. Um by the type of uh of, of uh lung disease that they had patients with IP F uh did the, did the worst there. And as you know, hammering home that point that really having any ph uh portends poor prognosis in this population. Uh was this, it was this nice study published last year by Dr Paka. So this was a retrospective study of 317 patients out of Europe. Um And you can see here even having borderline or mild ph uh was associated really poor prognosis uh in patients with, with lung disease if you break that cohort up a bit. Um you know, between COPD and ILD. Now, uh you could see really in the COPD group, it's primarily the folks that have really severe pulmonary hypertension and what you see uh you know, really poor poor survival. But in patients with ILD, otherwise you can see any Ph right, even borderline pulmonary hypertension, uh portends a really poor prognosis. And, you know, we talked about how not all phenotypes are created equally, you know, and connective tis disease is a sort of a different disease. I mean, I think even within CTD, we talk about scleroderma, which in itself pretends even worse prognosis, um we can't treat all of these patients necessarily equally. Uh This was a small study about 100 patients out of the Middle East, looking at those with connective tissue disease, ILD versus those with IP F. And then uh how survival was impacted with the presence of uh concurrent ph. You see patients with IP F and PH did substantially, substantially worse there. And so, you know what we think again, initially for patients, their ILD is really driving their outcomes and their symptoms, but they hit this sort of inflection point, right where now their ph starts to really drive both their symptoms but also their outcomes. So as their PV R rises, their RV function decreases, that starts to become the primary driver. And we know that these patients also walk much less and there's plenty of data out there. And uh you know, um doctor, you know, talked about six minute walk test as a uh as an endpoint in studies. And there's a good reason for that there's good correlation with outcomes there. And we see that patients with ph and ild, that they tend to walk less, they tend to have higher mortality, they tend to have lower oxygenation. Um, and so when you have a patient who's seeing you in clinic and they've got lung disease and you're noticing, you know, uh, they're really getting really Toni, they're really not walking as far. They're oxygenating much less than I would expect. Although their lung disease re is relatively stable, that should really start to ring some alarm bells for you that ph is starting to occur. And then um I, you know, I think there was a touched on this briefly but looking at the P A to aorta ratio, I mean, you know, we're pulmonologists, we love looking at pictures, right? We, we have to get AC A T scan. So we're getting the cat scan and there's always, you know, there's some clues there. So this patient has, you know, some, some ILD that there some some fibrosis, but you could see that P A is massive and so that P A to aorta ratio of greater than one, you know, should really again, start to, to increase your suspicion that these patients could be having pulmonary hypertension. So what are some other things that are occurring that might, you know, alert you to the presence of ph and lung disease. And it's really challenging because again, you're seeing these patients that have lung disease, so they have a good reason to be short of breath, right? Um But there are certain things that you can look at that might also start to raise a suspicion for Ph, so again, shortness of breath is disproportionate to the extent of ILD. You know, they're really, I mean, this is complex, of course. Right. Uh, I, I especially think about our patients with connective tissue disease. Um, uh, you know, who sometimes have, uh, you know, whether it's myos or scleroderma things that impact their exercise. So it's difficult to, to, to sort through. But, you know, ones that you look at their cat scan and you're not that impressed, but they're very, very Disick. Listen, you know, hearing a loud P two obviously JVD A powder jugular reflux, lower extremity, edema, signs of RV, dysfunction there uh on clinical exam having ad LCO that's disproportionately low compared to their FEC not walking very far. We talked about six minute walk test already but not walking very far. Desaturating just at room air. Of course, we can see that with severe ILD as well, pulse rate recovery. And actually Steve studied this uh uh previously as well, but having a low pulse rate recovery, actually following your six minute walk test, not being able to have that cardiac recovery should really start to, to, to make you concerned for ph we talked about imaging and of course serum bio markers, you know, we're all checking B MP S PRO B MP S and then marrying that with our echo findings. So there was a Delphi consensus. Uh Doctor Raha leading this this publication here published last year, you know how when should we screen these patients? So what are the things that we should be looking for? So, as discussed in the previous table, we got to take the whole picture, right? We've got to look at walk tests, biomarkers, chest imaging, we need to look at all of this and then come up with a clinical suspicion and that's where sort of the art of medicine still remains, right, where it's where experience comes in doing this over and over and over. But when your clinical suspicion is high, even though considering an echocardiogram, if you have no suspicion, of course, probably not a good reason to do echo again. I think the caveats here, patients with like scleroderma, for example, um uh looking at that Dlco potentially, but based off the echo then looking at your echo findings. Well, how does the right heart look doctor? So we went over very nicely echo findings that should raise suspicions of pulmonary hypertension. You know, one thing I wanna highlight here is that if you look at the boxes, nearly all of them, say right heart catheterization. And I think the the point to hammer home here is that, you know, you need to diagnose with the right heart cath. Number one and number two, you know, if you have even the smallest amount of suspicion that this patient might have ph I would, you know, uh whether it's on echo or whether it's clinically, really, you should be strongly considering uh a right heart cath. And really, it's when they have neither, when you're not clinically suspicious for PH, they have no echo findings. A P that you can probably avoid that. And he touched a little bit about, you know, uh the, the reliability of RBS P. Uh this is a paper uh from 2008 looking at in patients with IP F, you know, how accurate is the RBS P when compared to the pulmonary arterial systolic pressure. And we see only about 40% of the time is that accurate? So, again, right. Heart Cath, OK. And let your, you know, your, your cardiologist have B payments to make. So, you know, uh refer them over there. Um You know, hemodynamic definitions. I'm not gonna spend a ton of time here because this is up for lots of debate, I think. Um you know, the, we know that the, the, the new definition as per the guidelines last year for precapillary ph is, has already been discussed, you know, there is also a statement on what Ph and chronic lung disease, uh you know, should be what are the definitions there. And so we have that here. And again, I'm not gonna spend a tremendous amount of time on this because, you know, it's not something you guys really, you, you guys really need to memorize. Um But, you know, there's a lot of sort of debate. Um And we still really don't know what that definition should be. In fact, the coo consensus conference had suggested that maybe we should be classifying severe ph by these criteria. I mean, P A pressure of greater than 35 of PAP, greater than 25 and a cardi index less than two and a PV R greater than six. And then the compare registry data suggested maybe actually a PV R five is where the cut point should be. That that's where we see an inflection in terms of worse survival compared to less than five. But actually eight has an even lower P value. So, you know, again, there's quite a bit of debate um about, you know, what, what does P how should we define? Uh Ph and ILD? And I think, you know, when we see these multiple and changing definitions, that kind of underscores the concept that pulmonary vasculopathy in the context of ILD is really a continuum, right? That when we are talking about these definitions, that is a snapshot in time of that patient. And so, you know, I, I think the reason why we struggle so much to find these hemody a cup points because it's not, doesn't necessarily capture every, every patient. Of course, I think the thing that I find still the most challenging in this group and I, I suspect that my colleagues there feel the same way is when we have these patients who have maybe some group one and maybe some group three and we don't know what, which one it is, you know, and it's, it can be difficult, right? Especially in our patients with connective tissue disease, right? Who let's say you have a scleroderma patient with significant fibrosis, they have ph as well. How much of this is group three? How much of this is group one? I will say maybe to some extent with some recent approvals and therapy that doesn't matter as much. But um there are some things that might point you towards group one versus group three. You know, we talked a little bit about this before but you know, say you have very mild restriction on your PFTs but very severe elevation in your P A pressure is a very high PV R low cardiac index. You know, you don't tend to see like near systemic P A pressures and someone who's got IP F without a group one component. So there, there are signs there that, that might suggest more of a group three versus a, a group one. pardon me, group one versus group three. phenotype there, lots of drugs, right? We've already been over. This started with EPO lots of drug approvals for Ph and we uh we really were hopeful that we could, you know, find something that worked for our patients with group three. And for many years, you know, this is uh I have a couple of slides here, looking at the number of cli clinical trials or small trials, not, you know, looking at, um, multiple drugs that, you know, used in pah, in terms of group three. And, you know, for many years we were trying and trying and trying and some have worked and some haven't. Um, I'm not gonna go through all of these because it would be exhausting. We would never get out of here. We'd be talking about dinner rather than lunch. Um, but I'm gonna, I'm gonna highlight just a few here. So, you know, one thing is that, er A is probably not a no go. Right. So we've got data off of a few, few trials including artemis IP F that endo receptor in attack is probably not the best idea uh potential for harm there in patients with, with ILD and PH, we're gonna touch really briefly on the rise I IP study. Um, you know, the I know, pulse phase two looked good. The phase three data has disappointed and then we'll touch base about the increase trial, which is, um you know, been a landmark landmark study for us. So let's touch really briefly on the rise. I IP you know, um so this was a randomized control trial. Uh phase two study looking at Rio sig wat, which we know is approved for group one and the only drug approved for group four ph in the context of uh ILDPH. And so this was enriched primarily with IP F patients here. You could see a relatively mild ph with MP A pressure of 33 and FEC there, uh which again, not, not all that low, uh, of around 75 76% between both groups, but unfortunately, r IP, despite previously looking at res, so it didn't do so well. Uh We see that death's both in the main phase but more troubling I think is actually the long term extension phase were quite high. So in patients, in fact, were on placebo previously and I crossed over to uh to, to drug, um you know, had a, had a much uh much, much greater um incidence of death there. So, you know, rightfully, so the DS MB there uh terminated, uh terminated that study. Now, the question is why did rise fall here? Um You know, there's uh been a, a post analysis looking at this. Um One of them was shown here. So I'll, I'll sort of walk you through this, this graph here. So they had high res CT data available for 65 of the 147 patients. So about 45% of the patients in the trial. And they said, well, let's look at the CT data and see if we can sort of figure some stuff out here. Um The uh the, the pink at the, the pink or red at the top there, that's the amount of emphysema present uh proportionally to the fibrosis that's present and seen on the CT uh the sort of darker uh deeper, more vibrant colored grafts. So those are the patients that, that passed away. Um And then the, the shaded ones are those that, that, that survived. And so actually, when they looked at this, what they found again, we have incomplete data, only 50% of the patients there, that mortality was much higher in the patients who had combined pulmonary fibrosis and emphysema. And so, is it maybe the emphysema portion of this? That's, that's driving outcomes. In fact, you know, nearly 30% of patients um uh that with CPFE died compared to 13% without, without CPFE. So, you know, I don't think we'll ever see another riolo in uh uh at least oral riolo and ILDPH study again. Probably. Right, rightfully. So, but there is uh inhaled Cylon cycle stimulator trial going on um uh for, for pulmonary teal hypertension, which we may may ultimately see, but we must never give up, we must never surrender. And luckily, uh if you know, uh f folks didn't and we got the increased trial. So the increased trial looked at inhaled tra prost and PH due to ILD. And so this is a randomized control trial 16 weeks, um which looked at inhaled tra prostin. Uh The primary end point was the peak six minute walk distance um between baseline and uh and week 16 in week 6, 16 and then they collected a bunch of secondary um exploratory end points as well. All patients uh on drug therapy were started at three breaths and then uh uptight treated to no more than 12 breaths, uh four times a day. So as, as much as they, they tolerate it there, so pretty well matched study you could see in terms of the etiology of Phild, I IP making up about 40 to 50%. Uh CPFE actually making up about 25% of the patients uh connective tissue disease, about 25% as well in terms of background therapy. And the reason I bring this up is uh for those of you, which some of you may be uh familiar with the end stage trial looking at uh OE and uh and sildenafil uh background therapy for antifibrotic was, was really in about 20 to 30% of uh of patients there. So the study met its primary end point. In fact, there's a difference there of 30.31 m between the treatment group and uh and placebo. So this is um at week 16, but there are a number of secondary endpoints as well that were, that were compelling. Um One including um you know, uh occurrence of clinical worsening between the, between the two groups, mostly driven by uh hospitalizations transplant and a uh decrease in six minute walk distance, greater than 15% there. Also B MP levels. Uh So we found that actually beneficial effect on B MP levels and patients treated with inhaled trapo as well compared to placebo. And so luckily we got approval, March 31st, 2021. Yay, hooray, we have something that we can use for Phild and we all rejoiced. So what was interesting though was the one of the post talk analysis that was done for Phild and you know, they collected FEC data uh in these patients and then they looked back, they found that actually those on inhaled terrain, a slight increase in their FEC whereas those on placebo had a decline as we would expect. In fact, if you separate these groups out by I IP or IP F, that difference still remains. And so this sort of, you know, stimulated a lot of a lot of interest. So what happened when you flipped patients who are on Placebo onto open label extension? So here we can see, oh, here we go. All right. So here we can see patients that were on Placebo before at week 16, flipped open label extensions. So all these patients are now getting drug therapy and you can see there is an improvement in their FEC as well. So this really kind of raised this intriguing concept that maybe there's a link right between pulmonary fibrosis um and the pulmonary vasculature as we talked about before. It's kind of a two way street we think, right, that vascu you know, vasculopathy may be driving fibrosis and fibrosis, driving vasculopathy. And so then the question came, you know, by treating one, can we potentially affect the other? And then the end-stage trial for many years ago, which looked at an intent and SENNA suggested also that potentially on FEC there's a benefit of adding senna to patients on anti fro therapy. So, you know, the Teton study which is currently uh ongoing is looking at the use of INHS in the context of ILD to see, you know, is there potentially a benefit uh for patients outside of just their ph but in fact, uh on their, on their ILD as well, uh some additional post talk data. That was interesting. I think doctor owing is actually on this paper as well, so she probably speak to it more, more than I can. But um you know, the six minute walk distance, um you know, when we, when patients were flipped over actually didn't improve, which I thought was kind of intriguing. Um Now, maybe they didn't lose as much as we thought they would lose. I think a lot of times we think if patients untreated, maybe they would lose somewhere around 30 or 40 m over this this time period. So maybe it stabilized them to to some extent. But what I I think this might reflect is that actually delaying therapy um has a long term effect on patients, right? And we've seen this in other PH trials as well that patients, even after they're flipped over to drug, some of them never really quite catch up. And I, I think this hammers home, the point that, in fact, you know, early drug therapy and capturing these patients sooner, getting them on therapy sooner does have long term ramifications in terms of um of how they do. And in fact, when we look at, you know, what was the dose that was achieved early on in the study? Um and how that impacted folks. Um there was also uh some interesting data there. So, you know, this study looked at actually what was the the peak dose that patients could achieve by four weeks into the study? So how high could they get? And they stratified these patients into a high dose? So uh inhaled toros greater than equal to nine puffs, um a low dose of less than nine or placebo. And what they looked at was what was the clinical change uh that occurred? Was there clinical worsening or clinical improvement that occurs uh by week 16? And so, as you could see here on the graph, those that are on the, the high dose group had, you know, more clinical improvement and less clinical worsening than those in the low dose or placebo group. So, you know, again, I think we, we've sort of come back to this multiple times but early recognition and early therapy in these patients, you know, again, I think has, has more long long term effects um than, than we oftentimes appreciate. So again, we've got multiple definitions for PH. Now, I will say the increased study used a MP pressure cut off of 25 and a PV R of three. And so based on that data, I think that's the threshold that we generally use now to determine whether or not we're gonna treat someone. So with the MP pressure grade then equal to 25 and a PV R more than three, I think that's where you're talking about inhaled trapo for patients. You know, we have to make sure we're assessing for comorbid factors. We know a lot of our patients with like IP F have, you know, uh risk factors for um diastolic dysfunction as you say, scleroderma patients. Um And so we have to make sure we're, we're not missing anything else. Um These are patients who may want to consider an early referral to ph uh oral D programs as well as a transplant referral as Doctor Levine very nicely said we know that these patients have really high mortality, very, very poor outcomes, right? Compared to their IP H um uh um uh compared to IP H patients. And so I think really or early transplant referral uh should be, should be really be really be considered and patients that don't tolerate or can't get inhaled your process. No, there is some data suggesting that maybe PD fives are beneficial in these folks. Um not not really um robust data enough for us to, to say, say that to with any degree of certainty. But I think a lot of us will say that we oftentimes use PD fives uh in this patient population, any patient that presents to you that's got severe ph really should be seen by PH program. And um you know, uh in case to case basis, be considered prosto noid. Um Again, a lot of these patients have some group one and group three disease together, but uh severe Ph we should try to treat aggressively here and then contraindicated therapies involve rein and uh and Rio based off the, the rise I IP study here. So things to look out for, you know, theoretically, we all worry about this worsening oxygenation with BQ mismatching doesn't always really seem to bore out, especially in a lot of the studies, but something to keep in mind, a cold heart failure, as I mentioned, PV OD specifically, particularly rather in our scleroderma population, um, and then extensive prantal disease. And by that, I'm really talking about sort of COPD, which I'll touch on very briefly. I know we're running short on time here. Yeah, before you go on any further, I just wanted to ask about one of those slides. Right. Not this one, that one. So one of the things in the guidelines from 2020 22 from, er SESC, which were frustrating, continue to be frustrating is that you know, they make a difference between, you know, group three disease ILD, not COPD and they really want your PV R to be more severe before they say might merit therapy and an expert center. So how do you guys, so how do you respond to the guidelines where those guidelines say that the PDR should be in excess of perhaps five or six wood units versus the three that you share with us here. Do you guys just have a lower, just a lower threshold for pulmonary vascular resistance to treat in the setting of Phild? Just because of, you know, how much work you've done in that over the X many years and see that it's better to treat it earlier rather than later. Yeah, I think our, our general approach, the stat is to be more aggressive up front, right? And I think even when we look at the data on borderline ph right, patients that are just sitting around that borderline 25 millimeters of mercury, the PV R just around three, that they also have much worse outcomes in patients with a mean P pressure less than 25. And so our, our general approach is just have been to be aggressive up front. I think the general movement, right? In ph therapy is that more aggressive therapy? It was just interesting that Steve Steve wrote, wrote those guidelines. So I was curious, thank you. So again, I, you know, we're running a little short. So, you know, we know that elevated PV R in patients with CCOPD um is associated with worse, worse outcomes, lots of trials as well, looking at treatment and, and COPD. Um PH as well. There are a couple of me analysis that were published in the last couple of years trying, you know, looking at all these, all these studies and suggest that, you know, if we use PAH therapy in these patients, maybe there is some beneficial effect particularly on walk distance here. Um The the therapy used almost, you know, almost always was senna. Um There are a few trials looking at uh Bosentan uh as as well. Um The perfect study looked, you know, piggybacking off of the, the, the great things that happened with increase um aimed, aimed to see if we could actually use inhaled toro and COPD. And unfortunately, this was uh this was stopped early. So um the, the data safety Monitoring Committee there um ended the ended the study early. Uh we don't really have a whole lot of information on that just yet. But um you know, uh so far COPDPH is remains, remains elusive uh for us again, you know, whether it's group one or COPDPH, uh oftentimes difficult to discern and you know, what, what you really have to do is put this contextually, right? So patient to patient, you have to look at how much lung disease do they have? What is it, what are their hemodynamics, you know, um and, and put it in contextually there. So in summary, you know, the pathobiology of Phild involves a complex interplay of many things, right? So, uh it's not, not just straightforward, you've got fibrosis, you've lost vasculature and, and that's it that there's oftentimes disease there that's feeding uh feeding each other. Uh you, when we're talking about diagnosis, you can't hang your hat or I, or I guess turban in my circumstance on any one thing here, you've got to put everything together, right? Ct echo heart cath biomarkers, you know, pulmonary function tests, differentiating between group one and group three can be challenging, I think particularly in those circumstances, that's where you really should be talking to your ph experts. Uh inhaled prosol is our only drug approved for Phild. And you know, we should really be strongly considered using that when indicated we should be avoiding Rio syd and endothelial receptor antagonists for, for these patients. And then uh you know, again, uh potentially soil on a case case by case basis. And then Doctor Levine mentioned this. Doctor Wing mentioned this as well, but just like we do in group one pah, these patients should be monitored very closely, right? So we're talking every our bias is usually every three months and some patients every six but usually every three months, we're evaluating these patients in clinic, getting walk tests, getting echoes, um getting, getting B MP S um making sure that we're, we're capturing uh worsening and, and again, referring to, to transplant uh on a timely basis. OK. That's all I've got. I love the thing of Frodo. It's finally over. Thank you very much, Doctor Kangara.
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