Welcome, everybody, to the session on Therapeutic Dilemmas in Pulmonary Arterial Hypertension. These are the three sessions listed here for you. My name is Purash Giri from Loma Linda University Medical Center. These are my disclosures. Today I'm going to be talking about one, two, or three upfront therapies for severe PAH. Our goal is to calculate risk on a patient and then use that to assist with therapy decision making. Let us start with a case. A 55-year-old female was diagnosed with methamphetamine-induced pulmonary hypertension seven years ago. She was treated with sildenafil and diuretics, but she was lost to follow up. She was admitted now, is admitted now, to the ICU with dyspnea and exertion at rest. She's requiring high amounts of oxygen, inotropic support on diuretic drip. She's hypotensive, tachycardic, and has evidence of right heart failure. Pertinent labs include acute kidney injury, elevation of N-terminal proBNP. Her hemodynamics show severely elevated right atrial pressure, pulmonary artery pressure, as well as pulmonary artery wedge pressure, which subsequently improved with diuretics, revealing significant pre-capillary disease, low cardiac index. And she was started on triple therapy, including a parenteral prostacyclin. Her echocardiogram had shown significant RV dysfunction. So you can use your audience response from your chest app to answer this question. Have you encountered such a patient in your practice? You get 15 seconds for that. I'm not entirely sure the app is working well. Is it? No. We've got 100 percent. Yeah. All right. And then, based on above history and findings, what is the risk of mortality for this patient in the next year? Low risk, less than 5 percent. Intermediate, 5 to 10. And high, more than 10 percent. Let's see if it works. All right, so most of you picked high risk. So risk assessment requires assessment of multiple parameters. No one single parameter can singularly predict outcomes. Pulmonary hypertension registries have used a combination of these parameters to come up with risk scores. In this table here shown are a few pulmonary hypertension registries. The first column is the reveal registry using 12 to 14 variables. And all of these risk registries can be summarized. Their assessment of mortality can summarize as such. One year mortality, less than 5% is low risk, more than 10% high risk, and intermediate is in between. For our patient, as you all guessed correctly, the risk was 14 and high risk. And it's important to calculate just risk in this way formally because this study had shown that there was only 40% concordance between gestalt risk and formally calculated risk. So you all did quite well, and give yourselves a pat on the back here. So now that we know how to assess risk, let's go to selection of therapy. So what is the risk of mortality at baseline would be the first question I would ask myself. And the second is what is the risk of mortality after therapy? Shown in the graph to the left are survival curves, five year survival curves from the Swedish registry. They used the following variables that are shown in the blue box here to assess risk at baseline. And patients at low risk did significantly better than patients at high risk. Said in other words, if patients come to us in advanced disease state, they do poorly. However, PAH mortality can change with therapy. We wouldn't know that at the onset before therapy is initiated. But in the graph to the right, you can see there's red, yellow, and green curves. But I would draw your attention to the blue line, which depicts patients that were intermediate or high risk to begin with at baseline, but improved to low risk at follow up. And you can see that these patients' survival is similar as if they were started off as low risk patients. So response predicts response in PAH. The World Symposium guidelines give us this algorithm and they emphasize risk assessment for initial treatment strategies, which I will focus on in the next few slides. At follow up in three to six months, if the risk is anything but low, the guidelines recommend escalation of therapy. And Dr. O'Dease and Dr. Elwing are gonna be talking about this in their part of the lecture. Our goal is to bring that curve down to low risk, attain and maintain low risk status. Recently published 2022 ESC-ERS guidelines similarly stress using risk assessment for initial therapy decision making. And they can be summarized as such. If you are low or intermediate risk, initial oral combination therapy with an endothelial receptor antagonist and a PDE5 inhibitor. If you are high risk, initial combination therapy that includes a parental process cycle. If you're a patient with multiple cardiopulmonary comorbidities, then treading a bit cautiously with initial monotherapy is recommended. So why is combination therapy recommended? So we have 14 FDA approved therapies to choose from listed here. Second, there is no one single dominant pathway for PAH. Survival is improved, but still poor with monotherapy. And a large percentage of the randomized trials have at least one arm with combination therapy, yielding us a lot of data with combination therapy. Listed here for you are randomized control trials and a select few non-randomized control trials. The trials that are colored in black and red are single monotherapy or sequential combination therapy. We will not discuss those. What we'll discuss today is the ones in blue are upfront combination therapy and some select randomized trials that evaluated initial combination therapy as well. So the first of the trials is the BREATHE-2 study. Patients are randomized to ipoprostenal plus bosentin versus ipoprostenal plus placebo. These were prevalent patients. And the primary endpoint of total pulmonary resistance decreased, but there was no difference between the two arms. There was a few liver enzymes elevation in the bosentin arm. Functional class improved, but there was no difference between the two cohorts. Fast forward 11 years, the AMBITION study was published. It's a landmark study. Around 500 patients randomized to ambrescentin plus tadalafil combination upfront versus monotherapy with ambrescentin and tadalafil. These were newly diagnosed patients. And the primary endpoint of clinical deterioration depicted here by a person jumping from the frying pan to the fire was significantly lower in patients that got initial double therapy. So were the secondary endpoints. And in the combination therapy arm, the risk of time to first clinical failure event was half compared to the monotherapy arm. In a subsequent analysis, this was driven primarily by hospitalization, linking morbidity to mortality in PAH. Then the TRITON study was performed. The rationale for the study was that although AMBITION combination therapy patients did better, as you can see in the curve, they continued to decline over time. An addition of a third drug to two drugs in the GRIFON study reduced the risk of morbidity and mortality by 40%. So the TRITON study had masetentin, tadalafil, and celexipag versus masetentin, tadalafil, and placebo. These were, again, newly diagnosed patients. There was no difference in the primary endpoint, pulmonary vascular resistance, or secondary endpoints. Some trend towards improvement in some exploratory analyses. Coming back to this slide, the chronological order of listed studies, now we'll talk about the green ones, the non-randomized data. This paper published in 2014, small study, ipoprostanol plus placentin plus sildenafil. These are newly diagnosed patients. Really sick, NYHA function class three, four, and cardiac index of less than two. And you can see that there was significant reduction in the primary endpoint of pulmonary vascular resistance as well as secondary endpoints. And this is pretty impressive. The predicted equation survival for these patients is shown by the red line. And these patients with therapy, all patients were alive at three years. This next study focused more on risk reduction and right heart function assessment. 52 patients randomized to ambrosentin plus tadalafil plus subcutaneous triprostanol versus oral therapy. These were, again, newly diagnosed patients. And they were high risk using the revealed risk score of more than nine. Again, as a recurring theme, their PVR reduced significantly, so did the secondary endpoints. And 81% were able to achieve low risk status, which is very impressive. And in stark contrast to another study, I'll present in the next few slides. In this graph is shown a change in PVR on the x-axis and change in RV end diastolic area in the y-axis. So larger decrements in resistance and RV size were seen in patients that got triple therapy, represented here by blue dots, compared to monotherapy represented by red triangles. Linking afterload reduction to improvement in functional class and survival. This initial treatment strategy, study assessed initial treatment strategy and long-term survival. This was a much larger retrospective study. A newly diagnosed patients, functional class three and four, triple therapy versus dual or monotherapy. The authors assessed the number of low risk criteria at baseline and at follow-up. And the lowest criteria were assessed using the parameters listed at the bottom. And if you had zero low risk criteria, that means you're high risk. And high risk is depicted by the red color out here. I'd focus your attention to the third bar diagram from the left. These are patients that got triple therapy. You can see there's a whole bunch of red there. And our follow-up in those patients to the bar to the extreme right, there's no red color. So the risk reduction was significant. And the mortality was significantly better in patients that got triple therapy. Now if you parse the data out into high risk and intermediate risk patients, high risk patients did better with triple therapy upfront. But what is interesting is that intermediate risk patients did better as well. Timing of therapy matters and morbidity predicts mortality. In this study, patients that had a morbidity event prior to three months, as depicted by the blue lines, had a higher mortality compared to those that did not. And also the functional class of these patients that are in placebo arm of randomized control trials never quite catches up to their treatment cohorts, suggesting that aggressive therapy is warranted upfront. However, on the flip side of things, like in medicine, anything you give has benefit might have a risk as well. There's cost to the system, cost to the patients, cost of parenteral therapies, quality of life concerns. Patients will come to me and say give me the pill, give me the inhaler, I don't want the pump doc. And there are really quality of life issues. As well as adverse effects and complications of advanced therapy. Second, upfront triple therapy may be unnecessary if you're able to achieve low risk status with dual therapy, as the data shown earlier. Third, the tools we use to assess risk may need refinement. Currently 70% of our patients fall under the intermediate risk category. So there may be a few patients in the higher end of intermediate risk spectrum that might benefit from aggressive therapy, termed as orange patients by the authors here. And the Compera data used four strata model to delineate this intermediate group better. And it's shown here as light yellow and dark yellow curves. And you can see the survival is separate for the intermediate high, intermediate low risk at baseline as well as in follow up. And at the last point, minority of our patients achieve low risk status. This data from the Italian registry gave upfront combination therapy to patients and only 34 patients. Remember 80% in the retrospective study that I mentioned earlier had reached low risk status. And if you pay attention to the high risk category, nobody reaches low risk status at all at follow up. So triple therapy in pH, yay or nay? Yay, functional class of patients never catches up. The placebo patients never catches up. Morbidity predicts mortality. Very few patients reach low risk status. All arguments to be very aggressive upfront. High intermediate group may need a little nuanced approach. And retrospective studies show afterload reduction and survival benefits. But on the flip side of things, randomized controlled trials evidence data is lacking. The Triton study was negative and should provide us caution. There are costs, quality of life, effects associated with pH therapy. It's risky to assume that they are safe and efficacious in patients with multiple comorbidities because they were excluded from randomized controlled trials. And retrospective studies are by design flawed in the retrospective nature and have biases associated with them. There are multiple drugs been evaluated currently for pH. One of them is Cetateracept. In addition of that drug, reduced pulmonary vascular resistance in patients that were currently on background triple therapy. Half of them were on triple therapy. So maybe in future we'll have four drugs. But now coming back to our dilemma, one, two, or three. And I'd stick my neck out and say triple therapy in patients that are severe and high risk, certainly including a prostacyclin. Monotherapy in low risk patients. Dual therapy for almost majority of patients that are low intermediate risk. In intermediate high risk patients may benefit from a nuanced approach. And our goal is to attain and maintain low risk status. Pull that needle down. Coming back to our patient. She did well for a few years after triple therapy. She never came back to low risk status. She stayed on intermediate, came down from high risk. After five years, she needed bilateral lung transplantation. These are her hemodynamics, two days post-operatively. And her echocardiogram, eight months later, shows normalization of RV function. Thank you very much. When do we use that triple therapy and how do we do it? Do we do it orally, inhaled, or we do it parenterally? My name is Dr. Jean Elwing and I'm from the University of Cincinnati Thank you so much for inviting me to join you guys. I do have a few disclosures listed here. Objectives really are to understand that risk assessment driven treatment strategies, discuss goals, and then review the prostacyclin pathway therapies. It is much harder than it used to be. We've got a lot of colors and a lot of different delivery systems here. It's great to have choices, but you really need to know the personality of these drugs to be able to pick and choose what will be best for your patient. And of course, your patient has to agree. So I'm gonna introduce you to Susan. She's 36 year old, who comes to your office as an add-on for a little bit of shortness of breath at 4.15 on Monday after you've already seen 20 patients. So you're ready for it. She says her progressive shortness of breath has been pretty gradual and it's really with more than routine exertion. No chest pain, no lightheadedness. She just can't exercise anymore. She is nervous and COVID really was hard on her and she's on some Boost Bar. Vitals wise, and I want you to pay attention to this because you're gonna need to remember this, blood pressure 104 over 72, heart rate 88, respiratory rate 12, and she's 95% on room air. She doesn't have JVD, no hepatic jugular reflux, but she has some mild heat, but she could just be nervous and her heart pounding really hard. But you notice her B2 is accentuated, she has a two out of six murmur, lungs are clear, abdomen's a little bit distended, and she has trace edema, which is very unusual for her. So what's your next step? Okay, you're gonna see her as a pulmonologist, you're gonna start your workup. Maybe she's just anemic, right? No, she's not. Her creatinine's good, her hemoglobin's 11, but her BNP is 195. That is not normal for a 36-year-old healthy woman. You walk her in clinic and it's 375, is that normal? Does anybody think that's normal? Absolutely not, she should be like 500 feet, she was just exercising, or 500 meters. Pulmonary function tests, isolated low DLCO. Now are you getting a little bit worried about pulmonary vascular disease? I'm sure all of us are. We start our workup, a VQ, no perfusion defects. An echo, LV looks good, but we gotta look at the right side, right? Annihilated RV, septal flattening, and increased pulmonary pressures. All right, here's our echo. And all of you can see that this is not normal. The right side is enlarged, right atrium's very enlarged. Here we have our flattened septum. We can put our whole left ventricle right into our right ventricle, because it's much bigger. And we have elevated tear jet velocity, consistent with elevated pulmonary pressures. So now, we gotta go back and look if we can find out anything else. She had an autoimmune workup in the past. It was negative, she does not have HIV. She doesn't have liver disease. You found this old CT, it looks good. There's no PEs on that. So we go on and get a right heart cap. Mean pressure, 38, wedge of 10. Her PBR's 5.6. So we sealed the deal, right? We have a patient with PAH, and we said, she's idiopathic. But now we wanna risk assess her. And this is from the new ERS guidelines. All right, we're kinda in between, low and intermediate. She's a very smart lady, and she asks you, really, what is her risk? And you're like, well, you're kinda halfway, halfway here. She's not having any right heart failure symptoms. Progression has been slow for her assessment. She's functional class two. She's not passing out. She's walking 375 meters, and her BNP is 195. Her TAPSE has a little bit of pericardial effusion, I'm sorry, her ECHO has a little bit of pericardial effusion, and her hemodynamics are intact. So she wants a number. So you say, okay, I'll do a reveal risk score. Reveal 2.0, and we calculate, it's seven. So she's in intermediate risk, all right? What we just heard is, maybe more aggressive would be better, so we're gonna say, let's try to be as aggressive as she will let us be, and what will fit in guidelines. So let's go to the guidelines. She's at low intermediate risk, all right? She's functional class two, score reveal 2.07. So we start her on dual upfront combination therapy, as discussed, ambition style approach. Monitor her very closely. This doesn't work every time. We have a lot of people that respond very well, but she didn't. She comes back, and her walk is 350, and her BNP is 450. You are very uncomfortable. She initially felt somewhat better, and now worse. So where do we go here? This is the hard point. We're worsening, so we've gotta do something. We're not at low risk. We're actually getting worse. So now, by the guidelines, we drop into this re-evaluation intermediate risk, and it's recommended either to switch to a quantumly cyclic stimulator, or to add a prostacyclin receptor agonist, okay? But you saw that data that you presented from the French registry, that I can change her trajectory dramatically, even in the intermediate risk patient. We offered her IV therapy. How many people in the room would offer her IV therapy? So a lot of us would. She said no. She's like, in no way. I read those guidelines. Smart lady, she's Googling everything. So we said, okay, let's talk about what information we have. So let's start with the orals. Looking at Griffin, assessing CelexaPEG. Of course, this was an event-driven phase three randomized double-blind placebo-controlled trial, and it's pills. Sounds good, right? More than 1,000 people were in the study, and overall, CelexaPEG decreased morbidity and mortality by 40% versus placebo. And what I'm showing you here is the graph looking at the newly diagnosed patients, and the patients who were diagnosed more than six months ago. So same signal in both groups. So yes, this sounded like it might be a good idea for her. We also talked about FREEDOM-EB, an event-driven phase three randomized placebo-controlled trial. 26% of the people receiving oral triprostanol experienced a clinical worsening event versus 36% of those on placebo. And patients who were less sick had the similar kind of response as those that were more advanced in their symptoms with pulmonary hypertension. So another option for her. Again, pills. She's like, I don't know if I wanna do pills. Tell me something else. Okay. We could do inhaled. But remember, it's four times a day. We talked about Ilapros, too, because she wanted to know everything. Six times a day. She said no. She couldn't do six times a day. We talked about inhaled triprostanol. And in this study, the TRIUMPH-1, the addition of inhaled triprostanol, was associated with improvement in six-minute walk distance, even when people were on background therapy, sultenafil and bocentin at that time. So yeah. And we looked at some other endpoints. And 31% of patients on inhaled triprostanol versus 12% met an endpoint of more than 50 meter improvement in 12 weeks. She said, can you give me something simpler? And we talked to Breeze. Breeze is a recent study, single sequence study, taking people from inhaled triprosinone to dry powder inhaler triprosinone. And those patients had stability with the transition and then an open label they had improvement in their six minute walk distances, you'll see here. No serious adverse events. And then she said, well, what's on the horizon? Well, another inhaler, Utrepia, studied in the INSPIRE trial, an inhaled triprosinone study looking at either transition from nebulized triprosinone or new starts, well tolerated, and stability of six minute walk distance was shown in those patients. She actually decided to go with an oral therapy. Okay. She tried. She came back, her walk distance is worse. BMP is worse. What do we wanna know now? Is she actually taking her medicines, right? We look at her Epic, she's filling them, we talk to her. Is side effects problematic? Are side effects problematic, limiting her ability to use her medications? Sometimes that happens. No. So you're gonna recather, you're gonna get a repeat echo. And things are worse there too. So we don't have an option anymore. We have to go big or we're gonna have major problems. So she is now in that stage where she has to go to infusion therapy or she's gonna have a difficult time with her pulmonary hypertension. So you look at her new echo. You can see an increased pericardial effusion. You see that D-shaped septum and her pulmonary pressure estimation is even higher. Okay. Where is she at in the spectrum of disease now? You know, she started in that functional class two stage. Now she's moving down the spectrum of disease and sometimes we can't rescue people. Very important that sometimes we can't catch up. And we've been telling her this, but she was really not ready. But now she is. Okay. Now she wants to know about her options. We say, I would recommend IV therapy and we would recommend that based on the initial study for iproprostanol that showed in 12 weeks in 81 patients we had improvement in survival in addition to improvement in walk distance, quality of life and hemodynamics. She also wanted to learn about subcutaneous therapy. So we talked about the initial studies and this long-term study with more than 800 patients showing us that as compared to historical controls, iproprostanol had an improvement in mortality estimates. How do we give this subcutaneously? Well, we had previously this small pump that was previously used for infusion insulin, but now a Rimmunity pump, which is a small hockey puck-like pump that is paired with another device to program it. So we showed her those options and we told her Rimmunity now is the pump that's available. And she's like, okay, but what about an IV? Has it ever been studied IV? It has a longer half-life, I kind of like that. Well, looking at the trust study, 44 patients were treated with IV iproprostanol and they had improvement in their walk distance. She really wanted to know about her functionality. She actually decided to go with IV iproprostanol with close monitoring. Okay, she was agreeable, she started on therapy, she gradually improved over time and she achieved low risk status, which we were worried she would not be able to do. Because remember that French registry data is actually from people who were started on triple therapy with a parenteral prostacycline from the beginning. We are actually letting her worsen and add on. And many of our studies showed us that we can't catch up, but she was able to at least at this point. So again, showing you that as we have patients treated and they improve their risk status, their survival improves. You know, survival's not everything, but at least gives us time for our patients to be optimized and improve overall. So how many people like her don't get parenteral prostacyclines? How many people have met a PAH patient dying in the ICU that maybe is on suldenafil? I'm sure all of you, right? It's tragic, we have all these wonderful medicines, so many we can't decide which one to use, and there are people out there still not getting medications or even offered medications, right? So about 50% of the people in Reveal that were end stage, functional class four or within six months of their demise were not on infusion therapy in expert centers. So yeah, some of it is personal choice, but a lot of it is us interacting with the patient and taking the time really to show them how these medications can have a positive effect on their outcomes. So with that, I say thank you, and I'm happy you all are here today to listen to this interesting case. I'm Ron O'Dease, I am a cardiologist, and I take care of PAH patients like my colleagues and many of you out there. I've been asked to talk about triple PAH therapy and specifically transitioning between different therapies. So these are my disclosures, and we're gonna talk about how and why, but first I wanna just isolate the why just in one slide. And it could be because of drug interaction, it's something that's often overlooked in these days, maybe not as common as it was back in the day when we had a problem, if you will, with the interaction between Bosentan and Sildenafil, which are often used in combination. So there's some studies addressing this. And then the idea that there's a tolerability issue, and that tolerability in the pumps that Dr. Elwing was describing is a significant one, not only because of the quality of life with the pump itself and the catheter, but also some oftentimes recurring and life-threatening catheter infections. Catheter integrity, where catheters break or they get pulled out, sight pains if you're talking about subcutaneous parenteral therapy, tape allergies for either of the therapies, and on and on. So many of us who are in the trenches who deal with these pumps every day realize that sometimes it's a formula that just doesn't work, and it's not because of patient preference or clinician preference, but it's because the build-a-better-mousetrap didn't work in this case. And then probably more commonly, we see patients that are doing well on parenteral therapy and then ask if they might be able to switch over. When we first saw this, it was after epiprocinol was approved, and then oral therapies came along, and patients said, well, I've been on parenteral therapy. Back then, it wasn't necessarily because you were a high-risk patient, but it was because that's all that was available other than a clinical trial. And so the question was, can I, and if so, how? And then finally, probably the most important is what to do when your patient is already on triple therapy, but they're not doing well. Is there any room for improvement? And if so, what are you going to do to switch over from one drug to the other? And then maybe because we can't. I think that patients in particular, they see a new product or a new development, and they just say, well, can I? Well, why? Well, because I want to. Hopefully, physicians aren't saying that for the same reason. This is just a quick slide, an overview of the development of the drugs and the timeline with which we've developed now all these different drugs, and the reason why I'm here talking to you about this today, because there's so many different targets and molecules that are within those targets. So now for the how, and we've already talked a little bit about the 22 guidelines, but if you look at any guideline, there really isn't any information on how to switch, what the equivalences are, what the process, what the timeline is. Luckily, a group of experts did my work for me, albeit it's five years old now, and probably seven-year-old data, because by the time it got to publication five years ago. But nevertheless, they saved me from having to go through 610 studies that filtered down to, even 41 would be a lot for anyone trying to get their hands around it. And so I'm not gonna try and cover everything that is out there, and I apologize if you saw a deficiency of one molecule or one modality that you didn't get reviewed for how I think is best to transition. We'll talk a little bit about this one, this ERA to ERA transition. This came about because there was a company that was working on an ERA that patients were on, and had to withdraw from development. And so the bulk of patients were from Cetaxanthin to Ambrosanthin, but there were some patients that were on both Cetaxanthin as well. And the transition was successful. In 35 of 36, one patient had liver function, and that was sort of the primary endpoint to see if you could get patients away from having liver function abnormalities. Several studies on PDE5 to PDE5 transition, mainly sildenafil to tadalafil. One question that I might ask all of you, and maybe you don't know the answer, because I don't think there really is one, what's the dose equivalent of a daily dose, 20 TID sildenafil to the approved 40 daily of tadalafil? Here is the data from the six minute walk that was the primary endpoint that led to approval for sildenafil. And you can see that the difference between 20, 40, and 80 was I think 45, 46, and 49 meters. It was not statistically significant, and the FDA didn't feel that there was a need to approve anything other than the lowest dose. And here are the differences between the two and a half, 10, 20, and 40. It turns out that the 40 had a statistically significant, better six minute walk distance than the other doses, but more importantly, it was the only one that actually had a P value statistically significant in clinical worsening. So if you look back then at the sildenafil study, the 20, 40, and 80, and you look at PVR here for the 20, and for the 40, and for the 80, this PVR drop was twice that of the other low doses. And despite that, the FDA, as you may know, is not thrilled about hemodynamics. Although, I find this in a dose-dependent way fairly compelling to suggest that maybe 80 actually is more potent than 20. But it remains that sildenafil 20 is the dose, and I know many of us are able to get higher doses approved and some go even higher than that. I'm going backwards. But that's where we're at. So let's talk then a little bit, and there'll be some time for questions if you have questions for all of us at the end. We've designed it so that we should have at least 10 minutes at the end of our hour. Let's talk about perineural to perineural. This is probably the most sensitive area because a patient that is on a perineural therapy is sick enough to be on a perineural therapy, and oftentimes there are reasons to switch from one to another. So if you look at the label for remodulin, the sort of basic idea here is that you have a starting dose of one and the other is just being weaned down, and you go like this, and you get off of your drug. Fairly straightforward, but they don't really tell you much about actual doses in the labels when you look at this. There's one comment in this label that says in a long-term open extension, the 860 patients that Dr. Elwing presented, 29% achieved a dose of at least 40 nanos, and 40 is sort of the key. I'll tell you why in a second. But they were as high as 290 nanogarons per kilogram per minute. So there's no dose range in the label for IV prostanoids in general. If you look at maximum IV prostanoid doses in one study, you can see that they range, and many of them sort of cluster around the 40 to 60. And I think what we learned over time in coming to conferences like this and chatting in the hallway or whatever, and obviously the trial and error of up titration and inadequate low dose efficacy, that we came around a cluster of somewhere between 40 to 60 nanograms per kilogram per minute. Now, some of them are higher and need higher, and some of them actually can't tolerate higher than 25, but that's just about what we think is the clutch area. Triprostanil itself, we think that there's a dose equivalent but what about the same way we looked at sildenafil-tidalafil, there's no good head-to-head data to compare. So there's a survey that we did years ago where we looked at the expert centers across the country that were using EPO versus triprostanil, and you can see here that there are some similarities and that these clusters of the EPO maybe are a little bit lower than the clusters of the IV triprostanil. 1,000 patients on EPO, 300 patients on triprostanil. And so we get an idea that maybe they're close to one-to-one but that you're gonna have a little bit of leeway there. Maybe a couple comments on parenteral to inhaled because when inhaled came out in 2009, it was considered a potential alternative to IV or sub-Q therapy. And again, for reasons that are fairly obvious when patients wanna come off pump, they would rather go to a QID inhaled contraption than an IV, especially if the IV or the sub-Q wasn't working. So Vinicio published this data looking at a bunch of different patients and line item listed all their doses to start. Some of them were at very high doses and some of them were at very low doses. Their functional class was two to three, so that's one key point here, maybe a pearl, that when you're talking about doing and messing with a patient who is on a parenteral therapy, especially if you're backing down from a parenteral, that you probably don't wanna do it in a class four patient. You probably wanna do it in a fairly stable patient so these patients had fairly good walks and BNPs. So just some notes from this particular trial, the starting dose varied. Some did prefer to wean dose down on the parenteral and make sure that the patients tolerated it well. There were no functional class four patients, as I mentioned, the six minute walks were fairly good. And most were already on background therapy as well, so we weren't weaning them down to just the one drug that they were on. But if you look at some of the things and the outcomes with these patients, their functional class, their BNPs, and their cardiac indices trended worse. So the inhaled therapy in intermittent doses compared to a relatively high dose or moderate dose prostacyclin probably doesn't have the same hemodynamic efficacy and may not have the same clinical efficacy. So you gotta be careful there. Myalgia, nausea, headache trended better. Three that had cough, three that had syncope though that make you a little bit worried. We published a study, a very small study, but this was done in a protocol driven fashion in the hospital overnight where we had specific inclusion and exclusion criteria. And we started up with this timeline and made sure that we had a certain target by the time the evening came along and we went home and then came back on day two and wrapped it up. And so one of the criteria we had was a PBR had to be less than six to start. We actually had nine included in the study, but three actually failed because their PBRs were too high. And so what we point out here is the hemodynamics were fairly variable. The change in PBR over time in that one to one and a half days, some of them were okay in terms of their drop. Some of them really had an improvement. But overall, and there's that variability we see that is maybe sometimes a placebo effect. But nevertheless, we had the same strategy to lower the patients. And a lot of my colleagues and mentors had warned me that you can do pretty well when you're weaning down on a peroneuroplastocyclin until you get down to the last 10 to 20 nanograms. And that's why we did this as a protocol-driven inpatient study because I wanted the catheter in place and I wanted to make sure that when we got them down off the final drop of that therapy, that parental therapy, that they were actually going to be stable. We did cardiopulmonary exercise testing, one of my favorite things to do. And the baselines were all less than 40, which was a good sign that we had room to catch them if they fell. And there wasn't much worsening here and that was really sort of our safety endpoint, the same thing with the walk. Prostanoids to non-prostanoids, you can see here that you're dealing with some successes but also some failures. And so this second pearl here is that you gotta be careful and you got to be especially watchful for these patients because when patients get worse, they may not get worse immediately. We've talked about in other instances where the FDA made United Therapeutics do a withdrawal study so that patients on the prostanoid molecule would be withdrawn to placebo. They would be not transitioned but they would be withdrawn into a placebo and they were watched over time. And there were some patients that did well until week two where they finally started to do worse. So even if you're in the cath lab or in the CCU overnight with a catheter and you're weaning your final drop and everything looks okay and the patient gets up and walks out the next day, you don't know if she's gonna be alive in two weeks. So the third caution about watching out for these patients is they don't get worse until they're worse and then maybe it's too late. This was a study that was fairly recently published on transitioning prostanoids to CelexaPak. So you're still active in the prostacyclin area with an IP agonist but you're coming off of a perennial. So what I thought was a little bit funny was this sort of diagonal line that just basically said it's linear and it's a fairly pedantic approach at doing this. So what I also thought was interesting here is that we're talking about 40 nanograms and some sort of dose equivalent here which I'm not sure makes much sense. There is a transition study from parenteral to oral to prosanil in the same way along the lines of CelexaPak. You start off with a high dose. If this is median dose, a mean dose or a median dose, you start off low on the oral and then high on your parenteral and then you do the reverse and you get to that point by week 24 here. So a lot of these studies were short term like hours overnight when we had the catheter in place. A lot of these studies were longer term and a slower transition and some were inpatient, some were outpatient. There is a conversion dose. It's based on pharmacokinetics for this molecule for triprosanil going from parenteral to oral and you can see the formula there or you can use this wheel and calculate the weight and the current dose of the patient and figure out what the oral equivalent in TID dosing is. So with that I just want to say that the how and why of transitioning can be incredibly variable and the individual need for that patient really needs to be weighed carefully. I haven't said this yet but obviously this should be done in an expert center, a center that knows about IV and sub-Q prostanoids, a center that has lots of patients with these, they know how to troubleshoot, they know the risks and benefits when they're advising their patients of whether or not they should do the transition. There are many reports in the literature as we just saw, mostly case reports and retrospective reviews, very few protocol driven studies. A transition from parenteral prostanoids is dangerous even in the best of hands. Worsening may not be initially obvious. Once it is, it may be too late. There are no official guidelines on what drugs to use yet and I say yet meaning that I'm not aware of any plans in the near future to have this hit guidelines. Guidelines are evidence based but expert consensus could be useful as well. So thank you for staying and I think we have time.

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