So now we'll move to Fundamentals Part Three with Lauren Eyadiel covering novel agents and 4-pathway combination therapy.

Lauren Eyadiel: Thank you John. so now we're going to move into this third fundamentals section, where we'll really be kind of clarifying where new agents are going to fit, as well as what does the future for care and our patients with PAH look like.

[1:10:25]

So let's first talk about our guideline directed therapy. I think in PAH we are all familiar, right, with our 4 pillars of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction. So we can think of these as kind of 4 pathways. We're going to be targeting 4 different pathways with these kind of cornerstone therapies.

So as Brian discussed, we have our endothelin receptor antagonist or our ERAs. There are ambrisentan bosentan and macitentan. Our PDE-5, as well as soluble guanylate cyclase inhibitors, so our PDE-5 are tadalafil, sildenafil and then riociguat is our SGC stimulator. Then we have our prostacyclin pathway modulators. and what we're kind of going to kind of turn towards and focus a bit more on in this section is really the addition of our fourth agent, our activin modulator, sotatercept.

So we know after the discussion that we've just had and in the patient that we just talked about, that, when we add on to sotatercept as a quadruple therapy option for our patients with PAH, it improves exercise tolerance, their hemodynamic parameters, as well as their functional class. So how do we really take all of these great things and all of these pieces that are blocking all those bad, upregulated stuff that we saw in that slide earlier in patients with PAH?

[1:12:08]

So we start with kind of a combination initial dual therapy. And then we can kind of add on to that. So thinking about 2 together, right. and those are our ERA and PDE-5 inhibitors based on the SERAPHIN and AMBITION trials. and then we can think of adding. Going to the triple therapy option in our patients who have persistent symptoms, persistent abnormal hemodynamics.

And really, truly as you've seen earlier, those risk calculators are really guiding us in what we're going to do from a therapeutic perspective. This is different than a lot of risk calculators that we have. Think about patients with atrial fibrillation, that we're doing a CHA2DS2-VASc score, right? It tells us to anticoagulate or not to anticoagulate, but it doesn't tell us how we're going to anticoagulate. Whereas our risk calculators in the PA space really give us a better idea of what therapies are we going to be targeting.

So as a triple therapy we would add a prostacyclin modulator or a prostacyclin pathway agent. And these tend to be oral, inhaled or parenteral IV. And we want to do this when the risk for our patient based on the calculator rises or the patient has a plateaued response to the dual therapy with ERAs and PDE-5 inhibitors. Then our quadruple therapy, where we're adding on our activin/TGF-beta modulator, sotatercept, is really focusing on addressing proliferative remodeling in patients who have a persistent disease burden.

So in the trials for sotatercept, the STELLAR trial to be specific, it has been shown to improve 6 minute walk distance, reduced risk for clinical worsening – very important to our patients. They probably care far less how far they can walk in 6 minutes than they do about how they feel, even though we know those things kind of meld nicely together.

so as we start and escalate therapy for these patients, we really want to make sure that we are following them, okay, every 3 to 6 months with a goal of getting to low risk. We are not giving up. We are grabbing in our toolbox. We are looking for alternative tools, and we are digging deep until we get these patients to the low risk profile.

[1:14:44]

So as we look to the future, what treatments are on the horizon for patients with PAH? So we have a lot of new targets in sight. If you remember that complicated or busy, so to speak, slide from earlier, that really talks about the pathophysiology of PAH. This is a complicated disease process. And if you remember back to the very beginning of our presentation, 50% of patients have idiopathic disease. So in those cases we need to target as many of those abnormal pathways that are leading to dysfunction as we can. Because as Brian mentioned, our goal is to not need lung transplant. Lung transplant is there when the patient fails all these therapies. But the more that we can do from a medical therapy perspective and reduce the need for transplantation, the better off these patients are.

So some of these new targets include hormone-based circulating hormone therapy, epigenetic alterations, growth factors, vasoactive factors, inflammatory mediators, ion channels, mitochondrial metabolic adaptations, oxidative stress modulators, as well as stem cell therapy.

So for now we're going to focus kind of on the quadruple therapy while we remain incredibly optimistic for the future in patients with PAH and some of these new targets, as Brian mentioned earlier, you know, ten years ago, we didn't really have much of anything. So it will be very interesting to see where we land in ten years.

[1:16:13]

So when we think about some newer agents on the horizon, we have some that are under investigation as well as some that are already approved, specifically our sotatercept. But some investigational agents that have been looked at, that we'll talk about in a bit more detail, are inhaled imatinib, frespaciguat, oral ralinepag and inhaled seralutinib. And so these agents are either ongoing investigation or have had a trial terminated thus far.

So Sotatercept is our fourth agent in our quadruple therapy, and there's still trials ongoing, even though we already know that this is showing improvements for our patients with PAH. So let's look a little bit closer at some trial data.

[1:17:06]

So in the IMPAHCT trial looking at inhaled imatinib for patients with PAH, this trial was really looking at patients who were already on a background of both dual and triple therapy – so these are patients that had a good background of underlying medications – to determine, did the patients have improvement in the primary endpoint of a change in pulmonary vascular resistance or 6 minute walk distance at 24 weeks. In addition they had multiple secondary endpoints. Unfortunately, though, this trial was terminated due to not providing efficacy across the tested dose even though this medication was well tolerated by the patients. So from a clinical perspective, this is really interesting mechanistically, but not practice changing at this point. so it just kind of reaffirms our need and the importance of having a really good robust endpoint for these patients with PAH and in these trials that what we think might work actually does work.

So let's look a little bit closer now at the prostacyclin adjacent kinase target in the PROSERA trial.

[1:18:22]

So the trial looked at inhaled seralutinib for patients with PAH on stable background therapy. And so this was a phase 3 trial looking at patients who were already on therapies and their primary endpoint was 6 minute walk distance at 24 weeks. So same duration but a more narrow initial endpoint. and then their secondary endpoints are listed there.

So at this time, we don't have the finalized results of this trial but for now, it's very important that we continue to remain anchored in the pathways that we know work. Dual therapy, triple therapy, and then the addition of sotatercept in patients for quadruple therapy. and so it may be true in the future that this comes up as another data driven therapy. But we do need to keep in mind as well, it is subcutaneous and would require an injection.

[1:19:27]

So speaking of medication delivery, let's talk a little bit about living with PAH. The adherence to these therapies as well as quality of life for our patients. So while we know that dual, triple and quadruple therapy are helpful, right, we know that they improve outcomes in these patients, they will only work as good as the patient that takes them, right? If our patients are not adherent and not following through with their therapies, then the medicine doesn't work, right. that seems really simple and really basic, but I think it's really important for us to be reminded of, especially as we're thinking about risk calculators, escalating therapies and things like that. Our primary goal there is to really make sure that they're doing what they're already prescribed before we start adding on additional agents.

So we have multiple tools, the SF-36, the CAMPHOR and the emPHasis-10 that are specific for our patients with PAH that help predict adherence as well as quality of life metrics. so you can see here kind of exactly what these tools are using.

But all of this to say in the PA space what really defines us from other disease states is we have risk calculators that we're using that are driving our therapies. And then we also have these patient outcome tools that we should be using with these patients in follow up to ensure not only are they adhering with their therapy, but also that they are having improvements in their quality of life.

[1:21:13]

So shared decision making. Hugely important, right? So, this is last but certainly not least within the space of this talk. and so it's like a corner piece in a puzzle. A puzzle is not complete without the corner piece. And so our multidisciplinary teams are really important in ensuring comprehensive care for our patients, right. So making sure that there aren't gaps along the train. You can imagine many of these agents and many of these therapies are cost prohibitive for patients. And that's where our pharmacists, our nursing coordinators, our PH coordinators come in and help, really, help the patients access the therapies to help them feel better.

So this coordination really does improve both patient adherence as well as patient outcomes. And that's very important when we think about medication titration, drug titration, teaching on how to administer medications appropriately. Right. Someone's giving themselves a subcutaneous injection and it hurts and they pull it out and the medication squirts on them, then that's not going to be effective, right? So we really want to offer patient education in a way that they can understand.

So when I treat patients, you know, I see myself as a consultant in their care and that it is absolutely my job to give them all of the information that they need in a way that they can understand to make the decision that is best for them. And so I would encourage you, as you approach your patients, to ensure that you are giving strong education in a way that they can understand, and then working together for which therapeutic agents are feasible as well as reasonable for them to adhere with. We don't want our patients not eating to take their medication, so we really need to partner with them as well to ensure that they have access to all that they need to improve.

So based on registry findings, strong team communication as well as shared decisions result in greater patient satisfaction. Not surprising right? But also lower rates of hospitalization in patients with PAH.

So in addition to that, when we integrate nursing as well as pharmacy, medication discontinuation goes down by 30%. So I think that this is really important to think about and hone in on, that we make sure that we apply the corner piece of that puzzle when we are caring for our patients with PAH.

John, I think I'll hand it back to you.

[1:24:09]

John Giacona: Excellent. Thank you Lauren. So moving to our last skill building and feedback session.

[1:24:17]

So, like usual, we'll start with a patient case. So we have Carla, who's a 62 year old woman. Her chief complaint is ongoing shortness of breath and fatigue despite aggressive therapy. Carla remains symptomatic. Her 6 minute walk has plateaued, and she reports occasional nosebleeds and mild dizziness. She's on a 4-drug regimen: macitentan, tadalafil, selexipag and sotatercept. Her past medical history: she has pulmonary arterial hypertension Group 1, diagnosed 3 years ago, she has hypertension, mild CKD, her EGFR is about 65. On physical exam, we see mild jugular venous distension, trace edema and accentuated P2 on heart sound. Recent findings: her NT-proBNP is 620, which is down from 880 but above goal, and her 6 minute walk is 310, which has been stable.

[1:25:15]

So with Carla in mind, we'll move to poll number 9. So based on Carla's findings, what is the next best step?

1. Continue current regimen and reassess in 12 months
2. Optimize supportive care and address quality-of-life factors
3. Discontinue sotatercept due to side effects
4. Add riociguat to replace PDE-5 inhibitor

Excellent.

[1:26:01]

So let's take a brief moment to discuss an important topic. And so in this patient, right, sustaining stability in managing her adverse events and obviously she has advanced pulmonary arterial hypertension. So, kind of a brief summary of what's happening. She's stable but she's very symptomatic on 4-pathway therapy. She's experiencing some some adverse events from the sotatercept. She has telangiectasia, increased hemoglobin for example. That could be some of the adverse events. in this case, she's had a plateaued 6 minute walk. And that may indicate, you know, need for rehab management of some of the AE she's experiencing or adherence reinforcement.

So what are some things that we can do? It's important that we continue 4-pathway regimen and monitor her adverse events. we can integrate exercise, rehab, mental health and adherence support, all of those factors that Brian and Lauren had mentioned using nursing and pharmacy support. Being really proactive in managing adverse events, is important in helping patients achieve functional goals. Coordinating follow-up every 3 to 6 months. As you guys have paid attention to, every time we have one of these little discussions, it's important to continue follow up with our patients and having more frequent touch points with them. and it doesn't have to be with you every time, it could be with nursing or it can be with pharmacy, as long as it's your team is reaching out. and then as always, encourage shared decision making and realistic goal setting, especially in a patient with advanced pulmonary arterial hypertension.

[1:27:36]

And so I'm going to bring back Brian and Lauren. And so with patients, Brian and Lauren, with patience on 4-pathway therapy, what do you define as treatment success and how do you approach a patient such as this one?

Brian Rose: treatment success in this instance is not only objective findings like the 6 minute walk test, like biomarkers, but also how the patient feels. You know, if she's able to go and do her activities of daily living, she's in with minimal to no symptoms. That's treatment success with this 4-pathway therapy. if we're not doing those things, then we have to evaluate is this a patient that needs further escalation of non-medical pathway? is this someone that needs to be evaluated at a tertiary transplant facility? Or is this somebody that we may need to start talking about palliation for? That, in my mind, is how I would define treatment success and whether we are truly being successful with what we're doing or have we kind of reached the end of the road as far as these 4 pathways will take us?

Lauren Eyadiel: I agree, Brian, I think that treatment success is individualized. Like once you meet that metric of quadruple therapy, that's kind of where the guidelines leave us, right? Like the guidelines kind of leave us a little bit hanging there as to where we go from here. And so I think treatment success could look different for different patients and where they have different goals. I think when we think about mild adverse effects from sotatercept, most of the time I would treat through that. Like are there other things that we can look into that might be impacting the hemoglobin, or are there other other contributors that might be leading to that adverse effect being more pronounced? And can I target that in different ways to make sure I am keeping that fourth therapy for them? So, you know, I think that each patient is different, right? The more severe the adverse effect, the more likely we would have to, you know, de-escalate therapy. But from a mild adverse effects perspective, I think I would treat through. What about you, Brian?

Brian Rose: Absolutely. you know, this is where you definitely weigh the clinical benefit. You know, I want to see that objective data. I want to know how the patient's feeling. I want to know how their day-to-day life has improved with adding a medication like sotatercept. And not just sotatercept, but any medication, any of these medications, is that risk-benefit ratio in favor, that they're getting benefit from this? If the answer is yes and it's minimal side effects, well, you know, there's an argument to be made to continue it. If not, we have to go back to the drawing board and reach back into that toolkit and and see if there's something different we can do and attack this disease process from a different angle.

John Giacona: Excellent. And you guys kind of touched on strategies to help sustain adherence and motivation. I guess specifically, what kind of communication, do you guys have patient education that you have at the ready for patients to help them understand, you know, what's going on with their management goals? Do you guys make that a point every time you you see them? What we're looking for, what is success from the patients view as well?

Brian Rose: Yeah. There's a lot of societal information. There's a group known as PHA or the Pulmonary Hypertension Association. There's excellent, excellent, patient education handouts and, you know, things for families to be able to go home, you know. I tell the patients all the time, like, look, I can prescribe all these fancy medications, and we can do this and we can do that, but if they're not able to go home and talk amongst themselves and say, “Okay, this is what's wrong with me, this is the disease, this is what I have, and this is what we're doing about it, and these are what these medications are helping me, or this is the way in which they're helping me,” then I didn't do my job. So, you know, figuring out whatever medium that is that the patient needs to get that education more than just with their visit with me.

The other thing that I feel very strongly about is I show them their risk calculator. I show them where they are. you know, those risk calculators are in color. so you've got green, yellow and red, and patients really kind of take on that. That's something they all can understand. and I think it goes back to that ownership of disease. and I think this is not just applicable to pulmonary hypertension. You know, we see this in, you know, cardio-kidney-metabolic, in your world, John, when you use heat maps and things like that. Really, truly whatever it takes. So I tell patients this is not a one size fits all plan, this is very much a tailored to fit approach.

Lauren Eyadiel: I agree, I think too, the better they understand the disease itself, the better they're going to adhere. You know, when we talk about like these different pathways, they don't need to know necessarily that it is a PDE-5 inhibitor. But they do need to know it helps dilate or open up the blood vessels in the lungs, and that their pressures are very high in the lungs.

The other piece that at times with the right patient that I’ve found to be incredibly helpful is, is showing them their they're imaging, right? Like so showing them their ECHO, letting them see the change that is happening from one to the other. showing them the numbers. in EPIC hyperspace, if that's your medical record, and I'm certain in other medical records, you can create graphs of different things. So oftentimes you can create a quick graph with just the click of a button, biomarkers to demonstrate that, even if the patient isn't saying that they feel a whole lot better, and they don't like giving themselves this injection, etc., that their biomarkers are coming down, right. And so kind of giving them a visual of, of what the treatments and the therapies are doing, I think can really spark ongoing adherence and motivation to modify their disease.

John Giacona: Thank you both so much for those. I mean, those were incredible tips. I did not know that there was a Pulmonary Hypertension Association that had all that patient education. That's great. a lot of times these, you know, maybe it isn't necessarily considered rare, but unique diseases have patient oriented groups like that. And that's really great.

Brian Rose: The other thing that I will also say is all of the manufacturers of the medications for pulmonary hypertension have very agnostic patient-education websites that are really focused on disease state and education more than it is about, you know, their drug that they manufacture. So I think the industry buy-in as well on making sure that the awareness and the education is there, has become a great resource. so really, by whatever medium the patient needs, I think it's there, whether it be, you know, handouts or, you know, these websites have great video, and patient stories which I think is also really good. You know, patients often want to be able to see or hear from a patient like themselves, that look like them, that talk like them, to be able to feel a little bit more comfortable.

John Giacona: Yeah. That's great. I really like your idea of of showing them the colors on their risk risk calculator and risk score. It's kind of like showing, you know, coronary artery calcium image to a patient to try and get them to adhere to statin therapy. So I think that's great, really putting them in the driver's seat. So thank you both for that.

I'll bring you guys back because we'll have some Q&A. but I'll go ahead and move to the polling and then and then ask you guys to come back.

[1:37:19]

So for the audience, here's poll number ten. How would you respond if Carla says, If I'm on all these treatments, why don't I feel completely better?

1. Some patients don’t respond fully, so this may be your baseline
2. You should rest more; your body may just be tired
3. These medicines help slow progression and improve your heart function over time — we’ll keep working together to help you feel your best
4. We’ll consider stopping one of your medicines to simplify things

Excellent.

[1:38:11]

Moving to poll 11. So take a moment to reflect on what this case brought up for you. What's one area you'd like to strengthen in your PAH care?

1. Early identification of when to add novel agents
2. Improved AE monitoring and lab follow-up
3. Enhancing patient education and self-management
4. Expanding collaboration across multidisciplinary teams

Excellent.

[1:39:01]

So we have some take-home points before we go into our posttest assessment. So obviously these are truncated of all the great things that Lauren and Brian taught us today. But right, pulmonary hypertension comprises multiple etiologies, including PAH, which is Group 1, a rare but high mortality form requiring targeted therapy.

We talked about echocardiography as a screening tool, and right heart catheterization is required for a definitive diagnosis and hemodynamic classification.

Risk assessment via 4-strata model from low to high directs therapy and the goal of maintaining low risk status in all of our patients.

And importantly, we talked about this a lot, combination therapy targeting 4 pathways: endothelial, nitric oxide, prostacyclin and activin pathways – are important in our patients.

And then we have Lauren talked about some of the ongoing trials that are exploring additional mechanisms that are beyond the already established pathways that these are going to be coming down the pipeline and so things to look forward to.

[1:40:05]

And so going into our posttest assessment, posttest question 1.

[1:40:10]

Posttest 1

So we're revisiting this. Your patient with HFrEF and right ventricular dysfunction experiences exertional dyspnea. You suspect pulmonary hypertension and a right heart catheterization confirms that diagnosis. How would you classify this patient's pulmonary hypertension and qualify their mortality risk?

1. Group 2, low mortality risk
2. Group 3, low mortality risk
3. Group 2, high mortality risk
4. Group 3, high mortality risk

Very consistent. Very consistent.

So looking at the sort of rationale. So the answer is C, which is a majority for both pre and post. So the answer choice is C, group 2, high mortality risk. So pulmonary hypertension associated with left sided heart disease, in this case this patient has HFrEF, is classified as group 2. We need to remember that pulmonary hypertension associated with pulmonary disease is group 3. And so the presence of right ventricular dysfunction indicates that this patient has increased mortality risk due to it being an indicator of poor prognosis.

[1:41:46]

 So moving to our posttest number 2. So according to results from the STELLAR and SOTERIA studies, treatment with sotatercept in patients with pulmonary arterial hypertension receiving background therapy has been shown to:

1.  Improve exercise capacity without affecting long-term clinical outcomes
2. Provide short-term hemodynamic benefits that diminish over time
3. Show no significant benefit compared with standard dual therapy
4. Sustain improvements in exercise capacity, functional class, and risk of clinical worsening

Excellent. Very consistent. We did have some improvement. So the answer is D. So, sotatercept did show and produce durable improvements in exercise capacity, functional class and clinical outcomes in patients with PAH. And they were on background therapy. So this really supports that its used as an add-on therapy, add-on pathway targeted therapy. so very good job.

[1:43:13]

Moving to posttest 3, an individual is newly diagnosed with PAH. Their REVEAL 2.0 score is 8, which puts them at intermediate risk. They are nonvasoreactive and have no comorbidities. Which of the following would be the best initial treatment?

1. Oral monotherapy with PDE-5 inhibitor or ERA
2. Oral dual therapy with both PDE-5 inhibitor and ERA
3. Oral dual therapy with both calcium channel blocker and ERA
4. Triple therapy with oral ERA, oral PDE-5 inhibitor, and parenteral PCA therapy

So we kind of had a mix on our pre-test. Most of you put B for pre-test. And posttest very similar, but more people. So the answer is actually B. And so we can talk a little bit about the rationale.

So patients without cardiopulmonary comorbidities, we evaluate them with the 3 risk, the 3 strata. Patients with low or intermediate risk should initially receive an ERA with a PDE-5 inhibitor, and those with high risk should initially receive ERA with PDE-5 inhibitor plus IV or subcutaneous PCA therapy. Patients of any risk category who have cardiopulmonary comorbidities should initially receive oral monotherapy with a PDE-5 inhibitor or an ERA.

[1:45:09]

Moving to posttest 4. After this education, how confident are you in your ability to integrate quality of life, mental health and shared decision making into your treatment plans to improve patient adherence and outcomes?

1. Not confident
2. Somewhat not confident
3. Somewhat confident
4. Confident
5. Very confident

Excellent. It looks like we improved confidence. That is a very good outcome.

[1:46:04]

Moving to poll 12. Do you plan to make any changes in your clinical practice based on what you learned in today’s program?

1. Yes
2. No
3. Uncertain

[1:46:53]

And please take a moment to enter one key change you plan to make in your clinical practice based on this education.

Excellent. Thank you guys for staying engaged. So now we'll move into our Q&A session.

[1:48:17]

And so I will ask Brian and Lauren to join me again. And I will kick us off. So, we have some questions in the queue. So I'll start with the first one. I think this is good, and it's important to help guide therapy. So can either of you describe and explain what nonvasoreactive means?

Brian Rose: Sure. So nonvasoreactive is something that will come forth through the right heart catheterization. Now, I do want to point out that we're talking about a very, very small subset of patients that actually respond to vasodilator challenge and are deemed “vasoreactive” at time of right heart catheterization. very small subset. A lot of folks don't actually even do the vasodilator challenge during right heart catheterization. It's a mixed bag. But what we do is, there's 3 different vasodilators that are used. You can use adenosine, you can use epoprostenol, or you can use nitric oxide, inhaled nitric oxide. And if those patients respond at time of right heart catheterization, you can treat them with calcium channel blockers. Again, I want to really underscore this is a very, very small subset of patients that have pulmonary arterial hypertension. But this is a group that you will encounter. it's just becoming exceedingly rare.

John Giacona: So thank you for that, Brian. The next question, from an audience member, is what is cut point for RV dysfunction on ECHO for catheterization referral?

Lauren Eyadiel: I think that this question is more complex and more nuanced, really, because I think it depends very much so on the patient in front of you. If you have a patient with connective tissue disease who has symptoms and their ECHO still looks normal, I think that there may be a real indication in that space knowing what we know about associated PAH to evaluate with a right heart catheterization. I would have a much lower threshold to refer for right heart catheterization and initiate early therapy in a patient with known connective tissue disease than maybe someone who is idiopathic, right?

So in terms of RV dysfunction, you know, the question is why was the ECHO gotten? Was the ECHO gotten because the patient was short of breath? Then if there is any RV dysfunction present, I think that it's very reasonable to move forward with a right heart catheterization. But certainly in patients who have severe RV dysfunction and normal LV function, then we really need to figure out is that RV dysfunction, is their pulmonary hypertension really at that point related to a HFpEF physiology vs a PAH physiology. And in that case, our only ability to figure out the difference between those 2 things is really utilizing right heart catheterization, specifically exercise right heart catheterization. Brian, any other thoughts there?

Brian Rose: I agree, I think that that is a definitely a very nuanced question. You know, I don't want people to come away thinking that the only thing you need to look at is RV dysfunction and say, now I need a right heart catheterization. yes, if you've got somebody look at the context and why the ECHO was gotten to begin with. if someone was short of breath and they have scleroderma, for example – I hope they don't. You know, I hope folks are looking at the possibility of them having pulmonary hypertension long before we start to see RV dysfunction on their ECHO. Otherwise, we're a little bit late to the party. but, you know, if I have somebody, for example, that I'm managing for heart failure and despite really having them optimize, maybe I'm doing a reevaluation for device therapy, let's say, and I repeat their ECHO and I've got pretty significant right-sided disease. Right ventricles enlarged, systolic functions reduced, pretty significant tricuspid insufficiency, right atrium is big. Then I'm saying, wait a second, am I missing something here? That's definitely someone that's more than appropriate to to say, okay, I need some hemodynamics here to really help determine am I purely dealing with heart failure or am I kind of missing the boat here altogether?

John Giacona: Excellent. so this is a unique question that came through. So based on the disease being slow progression, how would you recommend treating a patient diagnosed with the disease in their 90s?

Lauren Eyadiel: So I would say it depends on the patient and it depends on how severe their symptoms are and their ability to tolerate the medications. I think that we're really talking about a risk-benefit here. So if a patient is coming to you in their 90s with profound symptoms from PAH, we should really be trying to get them on therapy. We we are not necessarily treating to the endpoint of thinking that lung transplantation would be in their future. That's off the table. but in my realm as well, I wouldn't withhold Lasix from someone who was 90. So, yes, these are more expensive, more nuanced medications. but I wouldn't let someone be volume overloaded. And so I think that the age is important as we consider it, consider trajectory of disease, but really their clinical picture and their symptoms should really drive your decision making. So if that patient is completely asymptomatic, you know, and their REVEAL calculator reveals intermediate risk, then certainly you could go with dual therapy and see if that makes them feel better, while giving extreme caution towards side effects and seeing them back with closer monitoring than maybe a younger patient. What do you think, Brian?

Brian Rose: I agree, I think, you know, very similar to patients with heart failure, function is everything. You know, I tell patients there's 90 and then there's 90. You know, I've seen 90 year old patients who walk in, they’re on a few medications, they're in better shape than some of the 40-year-olds sitting in my waiting room. So I think, what their baseline function is, is extremely important.

the second is, and you alluded to this is, you know, I wouldn't withhold medication in this instance. I mean, if this is somebody that's pretty functional, that we're making a new diagnosis, I absolutely am going to start this person on oral therapy. Yes, escalation of therapy may warrant a little bit earlier discussion about palliation, especially if they're kind of in that higher risk per se. but we've got good data, like in the heart failure realm, there was good data that just was recently published on utilizing SGLT2 inhibitors in very elderly patients that show clear benefit. So I think you can surmise that we do need to treat these patients, depending on what their other comorbid situations look like. You know, if I see somebody who's 90, who's bedbound, who is not functional, I'd be a little bit more apprehensive.

The other thing I think that I would want to draw attention to here is the polypharmacy. If you've got a 90 year old who's on a bunch of medications, and we're going to start some fairly potent vasodilators, this is somebody I'm going to probably keep my ear to the ground with some adverse events, probably more so than the average person.

John Giacona: Yeah, those are really good points, Brian. That actually segues into another question, from the group. So are there specific – you had mentioned comorbidities – are there specific comorbidities that affect how you treat each patient with pulmonary hypertension?

Brian Rose: Absolutely. you know, these are patients that, you know, you're never – very rarely do I see the patient who's, you know, middle aged female with connective tissue disorder, who's coming with PAH, who's on no medication. I mean, sometimes we get patients that are like that, but the vast majority of folks are coming with other comorbid conditions. You know, these patients can have coronary artery disease. they can have valvular disease that isn't driving their pulmonary hypertension. They don't have any left sided disease. They purely have truly PAH. they can have sleep apnea. They can have obesity. They can have multiple other things going on, that we have to mitigate as well. and we have to manage, you know, I'm coming back to talking about heart failure, but you've got somebody with an ejection fraction of 20 and you put them on 4 pillars and do all these things, but if they're morbidly obese and they have untreated sleep apnea, you know, how much are you really going to achieve? You know, if you've got somebody here with PAH and they've got untreated sleep apnea and, you know, they've got untreated diabetes and untreated, you know, poorly managed coronary disease it really is going to hinder that clinical benefit scenario. you know, are you actually making their pulmonary hypertension better? Maybe. Maybe not. Or are you really needing to stop that? You know, take a step back and focus on some of their non-PAH related comorbid conditions and really get a handle on those?

Lauren Eyadiel: I would say as well, in the scenarios where we know the underlying cause of disease, so where we know that this patient has connective tissue disease, what if they have that very rare variant of being HIV positive and having that disease or having methamphetamine exposure, any of those things, right? We also really need to focus on treating the underlying cause in parallel with treating their PAH. We can't go full force with their PAH without treating that underlying etiology as a companion. And so, you know, just like Brian was saying, it's really uncommon, if ever, that someone comes in with an isolated one thing. And so it's very important that we think of the disease within the scope of the patient and then really honing in on focusing on that shared decision making for the patient and what is going to bring them benefit and improvement in quality of life, as well as disease modifying.

John Giacona: Excellent insights. So another question from the group. At what point in the patient's follow up is it recommended to start rehabilitation?

Lauren Eyadiel: So I have never had a patient come in and say that they hate doing rehab or they don't enjoy pulmonary rehab. I think if you have the patient with PAH that is coming in and presenting with syncope, like we need to address and disease modify before we send them to rehab. We want them to be able to exercise. But I think that pulmonary rehab is positive for many reasons, right? It allows for supervised exercise. There is education, like the education piece I think is so huge, especially with inhaled therapies and parenteral therapies and subcutaneous therapies. There's a reinforcement there. as well as giving these patients a construct, patients who are short of breath, whether it's cardiac or pulmonary, all of the above, giving them really a construct for what does exercise look like and what does safe exercise look like and how to push themselves and things of that sort. What are your thoughts, Brian?

Brian Rose: I tend to agree. you know, I've never looked looked at a patient and thought to myself, man, I wish I didn't send you to pulmonary rehab so early, you know? This is probably just as important as any of the medications that we're going to prescribe for this disease. and I don't want to just say this is exclusive just to PAH. If the person has group 2 disease or they have group 3 disease, they need to participate in pulmonary rehab as well. They have absolute indications to go to pulmonary or cardiopulmonary rehab. to me, that is just one part of the treatment algorithm that probably doesn't get assessed enough.

In the context of the participant's question of kind of when along this treatment pathway do you do it, I tend to kind of do it out of the gate because I know in my institution, between patients that need pulmonary rehab and folks that have heart failure and post CABG and post valve surgery, it can take a little bit of time to get these patients in. so going ahead and kind of initiating that early, I think is is key. but I definitely don't withhold that. if somebody's still in kind of that intermediate or high risk, you're still going to start therapy on them. but look at pulmonary rehab as a therapy as well to initiate early.