Dr. Jean Elwing with the University of Cincinnati, in Cincinnati, Ohio, examines the current available therapies for pulmonary arterial hypertension and summarize risk assessment.
So this is one of my favorite conferences every year and it's just such a nice group of people that I've gotten to love and such a great venue. Um Really, really nice here this year. So um looking forward to talking to you about management. So I do have a few disclosures listed here and I do wanna know who is a fellow in the audience, who's fellows. OK. I'm gonna pick on you. Um and then um nurse practitioners, OK? Nurses, art pharmacists. Got it. OK? Awesome. So we're gonna go on a Whirlwind tour because we've got a lot of meds to choose from. Now, we're gonna talk about available therapies, summarize treatment approaches and discuss outcomes. All right, this is a complex disease. We are not talking about only smooth muscle cell proliferation. We've got internal medial advent tis changes and we're trying to use mainly pulmonary vasodilators to address them. So obviously, we have more work to be done. All right, going back to the three pathways. This is our classic picture. Most of the time people are still using it as we just learn from Mike, we're gonna have a new pathway and we'll have to probably get rid of this one. But what I wanna do is just equal the playing field here. I wanna make sure each one of you knows our choices. OK? Three main pathways. The first one I'm gonna talk about is nitric oxide. I first learned about nitric oxide from my geriatric professor uh when I was a resident and he, it was the molecule of the year and it is a potent vasodilator. And what we're trying to do with our PD fives is stop the breakdown of the downstream products, the cyclic GMP. And by doing that, we're hoping to vaso relax and maybe affect the smooth muscle cells and that proliferation, maybe. Ok. These drugs were approved short term, six minute walk distance trials. Why do we care about six minute walk? We'll learn later. It tells us a lot about outcomes. You know that 30 m is indicative of outcomes so important. So in this pathway, we have another drug. This is our Ria sig wt it also was shown to work on pah patients and CTF patients, chronic pe patients again proven by a six minute walk distance trial. These are nice short trials. We can get people out of trials and get them on more drugs if we need to. All right now, we're gonna change gears to that endothelin pathway. Endothelin is a potent vaso constrictor. We wanna block it. We have been working on these drugs. These are our one of our first oral drugs we've used with Bosentan. And first we studied it in sicker patients and guess what, six minute walk distance improved. And then we said, hey, could this actually work in less sick patients, less symptomatic patients? And the answer is yes. But we had to follow something a little bit different than walk distance. And we were really flirting with these longer trials, then delayed a clinical worsening. Ok, longer trials, you have to have events and when you're less symptomatic, it takes longer to get there. So just know that that's a very different clinical trial experience for a patient and the P I. But we showed that even less symptomatic patients had benefit from an er, a endothelin receptor antagonists and then came Amberin and more recently, masin Amberin again, six minute walk trial, masin longer trial. And that was disease progression. Ok. So you can kind of see how we are progressing through evaluating drugs. All right. Our last and are actually first group of drugs were in the process cycling pathways. We don't have enough process cycling in the system when we have pulmonary arterial hypertension. So we're trying to add it. Ok. Our first trial was an IV therapy trial. We are still in a daunting situation where we ask people to do continuous IV therapy. Can you imagine when they first used it? I can't imagine those patients and how they felt agreeing to a continuous IV infusion that could make you extremely sick if you got too much or too little. But that was a short term six minute walk trial that showed a survival benefit. And then we studied it again in scleroderma and we had improvement in those patients short term trial, six minute walk benefit as well as hemodynamic and symptoms. And then we came back and studied it in a different formulation. A longer formulation called Ter Prostin also showing us benefit in the short term parameters. OK? But you know, not everybody wants to do IV therapy. We talked about Mike's present presentation on America. You know, twisting arms is a lot of, you gotta do a lot of arm twisting to get people to do infusion therapy when they're busy and they've got a lot of other things to take care of. So we looked at in infusion therapy kind of medications inhaled and orally and we were able to show that we could benefit benefit patients even when we gave them these drugs in different ways. Ok? So now that everybody's on the same page, this is what we got. These are our medications, we will have another dry powder inhaler to add to this list soon. And next year, we should have a biologic to add to this list. We'll talk about that next year. So, uh, we're gonna talk about what we've got. All right, lots of drugs, the more drugs, sometimes more difficult it is like which one do you choose? How do you choose them? How do you put them together? Do they all work together? Do they actually harm you if you use them together? Well, a couple of them, couple situations, we've proven that they don't work well together and if we use things in the same nitric oxide pathway, a dentist and PD five will actually cause you to have very low blood pressure. So we're gonna concentrate on, er, sesc most recent guidelines because they have the prettiest pictures. If you look at this, you'll be like, man, whatever that artist was they hired, I want them to do my guidelines. All right. So we have the ph patient America comes in, we think she has pulma tension, we work her up and we risk assess, we wanna know the likelihood that she will not survive in that first year. The more sick she is, the harder we hit it. It's pretty common sense, right? But we are not always doing it and I'll show you that later. All right. So we're gonna go through this huge road map with the case. All right, we're gonna talk about a 36 year old female and I want you to take this little purple book here and write down a couple of things. She's having shortness of breath that's slowly progressive. She's not having chest pain, she's not feeling lightheaded or dizzy and she has decreased exercise tolerance to the point where she's not exercising anymore. What function of class do you think that is two? Yes. Ok. So you wanna put that? She's two and I want you to write down her blood pressure and her pulse, her blood pressure is 10 4/72. He's like, oh, that's ok. It's actually a risk factor. And we'll put that in our risk calculation. Pulse of 88. She's 95% on room air. She doesn't have HDR or JB D, which is good. We talked about those downstream signs of right heart failure. Lungs are clear because lungs are supposed to be clear when you have pulmonary arterial hypertension because you don't get fluid in your lungs. And we're not talking about ILD because we're gonna talk about that later. Um, abdomens mildly descended and extremities are having a little bit of edema but no clubbing, no sinus. So she has pretty good forward flow. All right. So you want to in your mind, try to figure out how sick is this lady? How suspicion of how suspicious of Pah are you? Are there any big risk factors? I didn't tell you that she has a history of meth or she has lupus. I just tell you she's not feeling as good as she was in the past. How fast is disease going? What is our functional class? We decided to are vitals? Ok. We wrote those down and any signs of right heart failure, just trace edema. Ok. So, what's our next step? We're gonna look at some data because we wanna figure out is this a young person that's tolerating severe pulmonary hypertension or is it a lady that may have untreated asthma? Right. So, so many reasons you can be short of breath. Our lab show Gratin which was within an acceptable range 0.9 but her B MP is much higher than it should be. She's a young woman that has no other things going on. She should not have a high BNP. She can walk 375 m. What do you think about that? I want you to write that down too. 195 BNP and six minute walk of 375. What do you think of 375? Way too low if you look at your health app, what is your six minute walk? You can check your six minute walk on your health app and I bet most of you are 500 m 600 m walking really fast. We practice that a lot of work. So um mildly decreased DLCO, we expect that in our pulmonary hypertension patients. So not an unusual finding. We do some tests because we want to figure out what else could be causing your symptoms. We wanna be cute. We wanna rule out a cutter chronic pe looking for chronic pe in our patients when we're working them up for Ph AC T because we wanna know if they have ILD and we've got to get our echo to see what our pressures are and what our right heart is looking like because we don't want to meet America's heart here. We wanna meet it mildly uh mildly change so we can intervene quickly and reverse that change. Ok. So one of the fellows, what do you think about this heart on this echo? What do we think about this? What's that? So, yeah, so you got this septal flattening too big of right ventricle. Um That's supposed to be a circular left heart. So that's your heart cut in half. It's a parasternal short. It's telling you nice side by side with the right and left ventricle is doing and how they're interacting with us. Are they playing nice? Is that right heart? Letting the left heart fill or not? In this case, the right heart is being a little bit of a bully. It's pushing in on the left heart. We see that the tr jet here is that's a pretty good tricuspid jet, nice envelope. So pressures are estimated in the 50 range and we have too big A RV and two bigger right atrium here. All right. So of course, we can never get out of this game without AC TP A. She had one. We have no clots. We saw it on RVQ already and we get our right heart catheterization and on our right heart catheterization, anybody won tway shows simple, not complicated, normal wedge this is not her left heart because we believe it, it's at end exhalation. It's a good wave form. We checked it with our pas A and we even got an led P that proved it. So, what about, does she have pulmonary hypertension? Ok. She has precapillary disease and you're gonna say she has pah, because we went through the whole work up. Right. We've got PAH group, one functional class two slowly progressive, but a high B MP and a right atrium and a right ventricle that are bigger than they should be. All right. So now it's time to take what we know and do a initial risk assessment. Some people are showing these to their patients. You gotta gauge this when you see high risk, 20% chance of not making it through the first year. You're meeting somebody, you gotta take it with a grain of salt and you gotta say, OK, this is population data. This is not you. I'm not saying you're gonna, you're gonna 20% chance. You're not gonna make it through this year because it's based on groups of patients. But it tells me your risk. How likely am I gonna have to ramp up therapy to get you under control? All right. So now I wanna have all those things you wrote down and I want you to tell me which category you think she's in? Is she low, intermediate or high risk? I didn't make you write down the right heart numbers. But her, her human dynamics are actually in the low risk category. She had a good cardiac index and her radial pressure was in, in the normal range. So where do you think she lands somewhere in between? What look? Yes, exactly. So we are gonna have to say we're somewhere in the middle there. Nobody's gonna fit these manmade rules, right? We've got to go with what we're, what we're feeling most represents the patient. Ok? He was like, I don't like that. I want a number. So I wanna calculate my reveal score and reveal. Tells me about modifiable things like your functional class, your vital signs, your walk distance. But it also tells me about some things that I can't modify. I can't modify how old I am, what sex I am, why I have Pah. And that's really helpful because that kind of gives you a backbone. Your port of pulmonary hypertension patients get three points because they are so darn sick. So we're gonna calculate or reveal. It's gonna give us one point because she doesn't really get a lot of points. She felt pretty darn good. And she's a young woman and she's gonna get to intermediate score. All right. So they kind of, they're kind of tracking. All right. So going back to this guideline, there's two sides of this guideline you can see here, this is our traditional PAH approach. And over here, the European said, people with a lot of co morbidities. We could put the brakes on, pump the brakes a little bit, go a little bit slower. You might have an opinion on that. I think the most important thing is when you believe somebody has PAH, treat them like they have pah, if you don't believe they don't have P A, if you don't believe they have Pah, don't treat them that way because you're not gonna have any benefit. So that's the big thing. Figure out what you think they have and then go full court press because I already told you if they're in that high risk category, population based data would suggest that they have a high likelihood of having a very bad year. So she's low intermediate. We're gonna give her a combination of therapy. Nobody gets monotherapy if you really believe they have Pah in our current era. All right. So you saw, you assessed her, you gave her drug based on two big studies. One hasn't been published, but you'll see it soon. It's called the A Dewey. But the one that drove this is what study it's up there. The ambition study. Ok. The ambition study was an ambitious effort by Pharma to say two drugs are better than one upfront. We were doing one drug waiting and adding before that, that was very much unlike what the heart failure people know works for patients. So ambition, lot of data on these slides. Hopefully they are available to everyone. Mike at the end. Ok. Ok, good. So you'll have all the references. Ambition again. One drug versus another drug versus both together in the category of, er, A PD five. Amberson was the, er, A, the PDE five was Tadalafil. What did they look at? Look at, not walk, they looked at clinical worsening. These were drug naive patients, brand new babies and you gave them Amer and 10 plus Tadalafil 40 Amer and 10 or Tadalafil 40. And they pulled the, the monotherapy and compared them, they were a little bit worried giving two drugs with adverse events that we'd have problems. But the side effects were pretty much what we would expect and not to the point where patients could not tolerate them. So they did tolerate this combination and they found a significant reduction in worsening. All right. So no events, your combination therapy, people up here, your pooled monotherapy people down here and separation is happening pretty early on in weeks, 1218 weeks, you're separating and you stay separated. So monotherapy is not the name of the game. We can't be starting people on. So NFL and say, hey, find that number to your local ph doctor and get an appointment. That's not the answer. The answer is try to get people upfront drug. So 18% of the people on combination therapy had events versus 34 and 28%. We're not saying one is better than the other. It's just, both are the pathways we need to address secondary end points decrease B and P higher satisfactory response in terms of improvement and better walks. All right. So are we gonna stop there? Oh heck no, we don't even know if this worked. So we gotta go back re risks assess and see how well we did. Ok. We do our risk assessment again. Reveal 2.0 now we're at eight shoot. She's not better functional class. Now two B she's trying to flirt with a functional class three. Her walks 350. Remember it was 378. Now it's 350. Her B and P was 150. Now 450 I go and write her cat. Aren't that changed? But I'm worried she's not doing well. We are not putting the stop on her progression. So now we're gonna do something easier. We're gonna look at really easy to assess parameters. Things all of us can do very quickly and cheaply as compared to our human dynamic assessment, we wanna look at her function class, her walk distance and her B and P and they're right up there. So we're gonna get a point. Now, this is the four strata model and we're gonna get a point for each one of the parameters in low risk two for intermediate and then the intermediate high three and high four. And then we add it up and we divide it. We can't get much easier than that. So then we'll get a score and we say, hm, she's got a three, she's got three parameters divided. So six divided by three, her answer is two. So she ends up being intermediate, low risk, not good enough. Just because, because you have a low in, it doesn't mean it's enough. So it means we gotta add something or we gotta change something. This is different in the algorithm that was in the past and I'm gonna tell you why. OK. So what can we add? We can add something in the process cycling pathway because I told you three pathway, we're not assessing that or we could switch that PDE five to a Guana cycle stimulator, Ria Sig. So what is that based on adding something in the pros cycling pathways based on the Griffin study, the Griffin study showed us that people on background therapy could have this selective IP agonist, selective prostacyclin agonist added that's oral and we can affect the time to worsening. The primary end point in this study was composite of death or worsening and overall cec decreased morbidity and mortality by 40%. It actually didn't get the mortality side, it got the morbidity s side and we don't study drugs to mortality that would be completely inappropriate and we all wouldn't do those studies. We'd reject them because we, that would not be something we wanna do. So if you take out the people that were like her on two background, we still had a 37% reduction. So it worked not only in monotherapy patients, but also combination therapy and we found that those high B and P patients had a high correlation between that uh that result and their morbidity and mortality. So what I pulled out of this study is I wanted to show you not only it works in the population, but it works in the population early if you can see in the right upper side here. So even the people that were less than six months out had that separation of their worsening, their morbidity early on about three months. And those people who are on both drugs, dual combination had the same thing. So it doesn't matter. Works on everybody. What about a RNA tram, the oral ter prostin ST uh therapy. So that was studied in monotherapy in combination therapy in those six minute walk studies. But this was an open, this was a long term event driven trial. Freedom ev looking at adding this to one drug, a monotherapy study. So you're like, well, our little lady didn't have one drug. She had two drugs, but I'm gonna tell you about that. So in the one drug group, we slowed disease progression. The median time to clinical worsening was 46 weeks with trip with trin and 37 weeks when you had placebo. So you had an event much quicker if you didn't get or prono. So that was important. And then 27 or 26% receiving oral trapo experience to clinical worsening event versus 36 on placebo. So a greater number had events and they had them quicker. Now when you went to open label, so you had an event or the study closed, you could go to open label, you could get on dual combination then. And so even the dual combination therapy patients had further improvement. So we can use it in our monotherapy patients. But we've also shown open label. If you're on two drugs in the background, it still works for you. So important information. So what about that replace study? The replace study is taking patients who are stable on PD fives, stable but not reaching goal. They're still in the intermediate risk group and switching out that PD 5.5 of them and changing it to Ria Siga. So what did that do? Twice as many people had improvement? Ok. So what did they track? They tracked walk function class and B and P sounds familiar, right? It's how we track and we judge risk on follow up. And uh this was a really powerful study and that it taught us that maybe we don't always have to add, but we could in some patients switch. So I'm just telling you that looking at those parameters, we would track risk with, we can improve them twice as often if we switch, not everybody, but at least it's an option for some of our patients? All right. So you're like, oh, that sounds good. But what are my other options? Because I tell you the one thing about the guidelines is they're European guidelines and you guys all know that there's holes in that we're missing a couple drugs. What about an inhaler? Um So the triumph study showed us in pah patients, we could add an inhaled trop prostin, inhaled prostacyclin and get improvement in exercise capacity. And I mentioned this earlier, but I just wanna make sure that, you know, when you're looking at guidelines, they are wonderful tools, but they may not fit your patient community always perfectly. You might have a community that can't do infusion very well or you might have a situation where you are living in a country without all the drugs available or more than the drugs available that are listed. So what did we see that when you look at patients who improve their walk distance by 50 m or more? Three times as many were able to achieve that when they were exposed to inhaled terrain versus placebo? So these are a little bit older studies but important to know that what the backbone of our therapies in the US are. Ok. You're like, you know, that sounds great, but my patient is not going to do something four times a day when they work at the grocery store as a checker, they can't do it. And that's actually a story from one of my patients. Um I saw him at the grocery store. Um so there is a dry powder inhaler and that came to market recently, it is the same compound but in a dry powder formulation and this was a switch study where patients were on nebuli therapy, switching to dry powder. And in three weeks, they, they were able to make that switch and maintain their therapy. And then following them open label, they had further improvement in their walk distance. So nice option for people. This is new, not available to be prescribed yet, but a different type of inhaler. And if any of you are a little bit older, you might remember that was the four L like inhaler there where you put the pill in it, squished it and you took a puff. So inspire was a study that looked at a different way to deliver dry powder toros and they did not only switches from people who are un nebuli, they also looked at people who were naive and they found that patients could remain on these drugs and they had maintenance of their walk distance. You know, this was not a new drug and we had to go through all the same things we normally do. This was a safety and a tolerability study. So now we're gonna go back to our lovely lady, we're taking care of. What do you guys think about her New Echo? Do you like it. Is it any better? Is it reassuring? Ok. So not nearly as good as we'd like us to, I'm encouraging the fellows, fellows. Do you have anything to say? You like it? Is it, are you happy about it? Are you, you're gonna say you should be unhappy? OK. So we are not where we wanna be. If we get all the things we want. Her echo is gonna look good. She's gonna walk more than 44 m. Her BNP is gonna be 15. We're definitely not there. OK? Despite three drugs. So we do her C over again. Uh Her PV R is 8.8. Her cardiac index is not, it's not worse but not better. Where is she in this spectrum? Where do you guys think she is now? She is progressing up this PB R chain and she is somewhere in between three and trying to flirt with four. So definitely not where we want her to be. We're gonna do that mini uh four strata again and we're gonna calculate out and she's gonna be somewhere in between intermediate high and high risk. What do I wanna know? I, I trust everybody to a point. Are you actually taking your drugs? Is there a reason you're not taking them? Are they making you sick and then you're not using them? Are you using any recreational things that make your pulmonary vascular resistance go up like methamphetamines, cocaine. And if not, did I miss something. Did I miss Lupus, did I miss something that's driving your pulmonary vasculature to do this. So we're gonna look at everything again and then we're gonna say, I'm really sorry to tell you that we need more drug. I'm gonna tell you, we're gonna give us, give you your, our strongest drug. And what is that? That's still are IV therapies, Ivy. But first of all, why do we love it? Because it's the one thing in a short term trial that saved people's lives in 12 weeks. Think of any other drug out there that can improve mortality by 20% in 12 weeks. Nothing. I mean, we can put a stent in, we can do that. We can treat an arrhythmia, uh but not a drug like this. Why the heck would we still be giving IV infusion 24 hours a day that has a 2 to 5 minute half life. The only reason is it works. We do have our other options. IV Toroidal, which showed us improvement in walk distance, but it didn't meet the survival in the short term. Uh So people walked better, they felt better. Uh But it missed it. Here is our survival. 0.0511 we can use it subcutaneously. It is painful. 30% of people can't use it long term because of pain. But it's an option for people that are not great IV therapy candidates or people that live at a distance and over a long period of time, it does have better survival than we would expect so important. Um Also a very valuable drug to add because of those the patient populations that really do well with sub Q. All right. So I talked about that strongest drugs. Are we getting them to the masses? Well, in the rebel registry, about half of people in the six months when they were functional class four before they died or right at the time of death did not get them. These are 55 centers that treat pah. So 55 centers that treat pah, aren't getting them to the folks. What do you think about the place in North Dakota or West Virginia that has no one to treat them? That would be maybe 5% if they're, if they have the resources to travel. So, what I wanted to point out on this slide is ph related deaths function last 46 months before they passed away. So we have some lead time, right? Who's on triple therapy? This is old but not that old. This is 2013. We had all our drug pathways then 20%. Ok. Now I'm gonna tell you something a little later. Why? That's so important. All right. How do we get our patient to improve? Well, we have to watch her like a hawk because she did not do what we wanted her to do. We wanted to give her two drugs and have her functional classic one plus and be able to do everything she wanted. We gotta get our labs, our exam or functional class or walk distance B and P echo, right Heart Cath and really use them together. If one is not tracking, we gotta figure out why six minute walk distance is going down. Everything else is going in the right direction. You broke your ankle, we'll give that to you. Your right heart cath your cardiac output is not going up like it should. Let's look at your heart a little bit more closely in an older person. Let's see if you have coronary disease or infiltrative disease. Something is not right. We gotta make sure it's all meshing and we gotta follow people in a way that makes sense. Not too much, not too little. We can't test people a billion times because they get user fatigue. Our patients are with us for years, decades. They will get tired of this. So the right amount and then we can say to the patient, if you do all these things, I know they're hard. We have shown that we can impact your survival. So if we go back, we see that this is 2010, I highlighted in the bottom corner in all of these three year survival. About 65% French registry. They sorted them out. You saw this a little bit ago. Con Gals did the best our connective tissue disease closer to 60% in three years. That's a bad survival for anything. Reveal showed us the same thing. This is about a decade ago, 60% 3 year survival, seven year, 50% survival. All right now, a little bit after that, the French said if I get you to low risk doesn't matter. So these are assessments at baseline if you met low risk criteria, which at that point weren't all those noninvasive, they did include right heart cath. But look at those, those people in the green on top for low risk criteria, they had a beautiful life expectancy, right? And we're not just saying those were the well people because I'm gonna show you that later. Those could have been sick people. All right. And this is looking at separating it out using the three strata and the four strata. The people who have low risk features at baseline and a follow up have good outcomes and look at the change. You can really bump up that survival if you get more people to low risk. And what if you change to low risk? So this is our people who are stable at low risk and these are the people we bump to low risk about the same. We have an opportunity in that first three months to change their life forever. We may not be able to do that later. Sometimes when the cat's out of the bag, we cannot get it back. All right. Now, I promised to tell you about this. I want you, this is what I want you to concentrate on. These are your triple combination therapy patients. These are people with zero low risk features. These are sick people. One follow up later. No more red on triple combination. So is triple combination therapy worth it. It is in the right patient. You don't want to give it to your low risk patient because they will all, they will quit it in a second because all they'll get is side effects. But people who need it, it's still the way to go. Ok. So what about long term if I throw Debbie's transplant in there, I can get people 90% on triple therapy at 10 years based on the French registry. If I don't throw a transplant in there, still pretty darn good. 80%. So again, what they need as quickly as they need it to get these kind of outcomes. All right. And how do we make that happen? Well, the patients at the center, but it's everyone in this room, it's the nurses, it's the pharmacist, it's the fellow seeing the patients because guess what if you don't recognize it, you don't tell us about it. We don't follow it. We don't treat it. It is everyone together and being able to communicate with our counterparts and other specialties. So they know the severity of illness our patients have and how not to exacerbate it. All right. So, in summary treatment depends on the right diagnosis which we heard from Mike, you gotta get the right thing to treat, to be able to be successful. Therapy is initiated for best outcomes. And now now that we understand what our targets are, where we're going, how we can get there, we have a much brighter future for our patients. As I mentioned, we're gonna have the new dry powder inhaler and as of next year unless the bottom falls out of things which we don't expect. Um We have the biologic I mentioned which Mike mentioned also in the stellar trial Satter such, so we are gonna have our first real new baby um for a long, for many years. So it'll be exciting time and we're gonna be talking to you about it um over the next year or so. So anyway, with that, I'll end and thank you all for your attention.
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