John Giacona (UT Southwestern Medical Center): So I'm your moderator. I'm Dr. John Giacona. I'm an assistant professor in the Department of Applied Clinical Research in Cardiology division in internal medicine at UT Southwestern Medical Center.

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And here are my disclosures.

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So again, thank you guys for logging on for the live stream. We're all really pleased that you're joining us for this virtual experience, and we're really looking forward to providing you with timely updates in cardiology practice. This program has been specifically developed to provide NPs and PAs, clinical nurse specialists and other advanced practice providers with education tailored to your unique needs and responsibility in the cardiology setting.

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So here I'll go over today's agenda. the presentations today will cover pulmonary arterial hypertension, hyperlipidemia and ATTR-CM. And so we're really delighted to share with you our esteemed faculty for today's program.

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And today we're offering six hours of credit in the three topics provided by Partners for Advancing Clinical Education in partnership with the Academy of Physician Associates in Cardiology.

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And so for today's materials, including the downloadable slides and the evaluations to claim credit, we click on the links in the resources section of your player. and if you do require technical assistance, there's a request support icon at the bottom of your screen. So please click on that if you have any questions.

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And so throughout today's sessions we have polling questions. So we ask you to actively participate in today's program by voting on the polling questions throughout the presentation. They're sprinkled in, in different sections. and when a new polling or survey question pops up on your screen, please select your answer and then click submit.

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And so again here are our commercial supporters. Decera Clinical Education thanks all of them.

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And so we'll get started with our first presentation, which is Leading with Impact: NPs and PAs at the Center of Pulmonary Arterial Hypertension Care and Transformation.

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And so I'm really pleased to introduce our first speakers. and so I'll start. Brian Rose is an assistant professor at Methodist University PA program in Fayetteville, North Carolina. He's at First Health of the Carolinas, Reid Heart Center and Pinehurst, North Carolina.

And joining him is Lauren Eyadiel. She's an assistant professor, Department of PA Studies at Wake Forest University School of Medicine and the Advanced Heart Failure, Heart Transplant, and Mechanical Circulatory Support Section, Atrium Health Wake Forest Baptist, Winston-Salem, North Carolina.

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And here are their disclosures.

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And the learning objectives for their section. And so I won't read them all to you but we will be going over all of them today.

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So we have our first poll. For those providing patient care, how many patients with pulmonary arterial hypertension do you provide care for in a typical week?

1. 1-2
2. 3-4
3. 5-6
4. 7-8
5. > 8
6. Not applicable

All right. Thank you for thank you for answering.

[0:03:47]

Poll 2

Going to poll number two. For those who practice in academic or community settings, please indicate your practice setting.

1. Academic
2. Community
3. Not applicable

All right.

[0:04:13]

So we have our first pretest question. So 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

All right. Thank you guys for answering.

[0:04:57]

We'll move to pretest number two. So according to the 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

Thank you guys.

[0:05:44]

Moving to pretest number three. So this individual is newly diagnosed with pulmonary arterial hypertension. Their REVEAL 2.0 score is 8, which is 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

Thank you very much.

[0:06:46]

We have our last pretest question. So how confident are you in your ability to integrate quality of life, mental health and shared decision making into your pulmonary arterial hypertension treatment plans to improve patient adherence and outcomes?

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

Excellent. Thank you guys for answering.

So at this point I will pass it off to Lauren. She will start with Setting the Stage: The Unique Role of APPs in Optimizing PAH Care.

[0:07:32]

Lauren Eyadiel (Wake Forest University School of Medicine): Thank you so much John. I do think it requires a PhD to be able to pronounce my last name. So very impressive work there. So my name is Lauren Eyadiel and I'm going to really kind of set the stage for us as APPs in the PAH care space. We really sit at the center of PAH care transformation between our day to day decisions, as well as kind of our shared decision making with our patient. this is super imperative in our patients’ outcomes, their adherence to therapy, as well as their quality of life.

So one of our goals today is really to connect guideline-based recommendations from the bench to the bedside. So to begin, let's get started with why is this even important and why is this a unique role for APPs.

[0:08:26]

PAH Epidemiology & Etiologies

So when we think about the epidemiology and the etiology of PAH, we know that over the past 30 years, the global prevalence of the disease has increased by about 100,000 patient. this is also based on registry data, so there's a chance that this is really also underestimating the number of individuals who are living with and suffering from pulmonary arterial hypertension.

So when we consider the causes of pulmonary arterial hypertension, if you look to the right side of this slide, we can think of these in some big buckets, like associated, which means this type of PAH is associated with an underlying disease, a known underlying disease. And this accounts for about half, about 50% of patients with PAH.

Then we have patients who have idiopathic PAH. And alarmingly this is about 46% give or take of patients with PAH. And so there is a large group of people who have PAH that we really do not understand or know why this happens to them.

But when we think about associated PAH, this is by far most commonly caused by connective tissue disease. So in your patients, even if you are practicing in a more generalist setting, in your patients who have connective tissue disease, it is incredibly important that you have a high index of suspicion that these patients may go on to develop PAH. So for patients with connective tissue disease and who have associated PAH, this accounts for about 50 to 67% of all associated PAH. So this is something that is really, really important for us to consider.

in addition, PAH is more common in older adults between the ages of 50 to 65, which is interesting, because in a prior registry, this actually showed that there was a younger age of onset. I think this is likely really related to techniques where we can better identify and diagnose patients in this space.

[0:10:52]

So with the who and the what in mind, for patients with PAH, let's kind of talk a little bit about what competencies define the power of the APP impact in patients with PAH. So when we think about key competency domains these are separated into five subsections: patient centered care, interprofessional collaboration, systems based practice, your medical knowledge and your ability to practice based learn or learn on the job and grow, and then your professionalism and communication.

So these are tenets that really exist for APPs in all areas of practice, but are uniquely important in the PAH space as this disease has significant complexity and a bit of a unique need for really multidisciplinary approach where you have pharmacy, you have cardiology, pulmonology, oftentimes rheumatology when we think of connective tissue disease as well, involved in the patient's care. So we really want to focus on making sure that the patient is central to their care model, and that we are using shared decision making in them to provide the best outcomes. in addition, centering our care on the patient is really important for their adherence with these morbidity, mortality and quality of life improving therapies.

We also always, as we practice, want to use our guidelines. So in the PAH space we're talking about the ESC ERS guidelines from 2024, that really guide and define what a PAH Center of Excellence looks like.

In addition, we want to continue to grow our knowledge. We are all lifelong learners in this space. And so that's very important. And as with any multidisciplinary care, our communication amongst other providers is very important in the team based care.

[0:12:44]

So when we think about guideline-based management of PAH, we have this here on this slide formatted as kind of this nice table, looks very stepwise right. But I would like for you to think of this more as kind of a flow chart that is surrounded by the clinical care team. So that last point on this chart, really think of that as more of an overarching thing that is really almost supporting the patient through the entirety of the guideline-based principles and care.

So we cannot treat something if we don't know the diagnosis. Right. So the most important thing for us to do initially is to confirm the diagnosis. And we do this using right heart catheterization, which Brian will talk with you a little bit more about what these diagnostic criteria look like, but that is our gold standard for diagnosing group one pulmonary arterial hypertension. Then we use risk scores such as the ESC, ERS, four-strata risk stratification and the REVEAL calculator to guide our therapy. That helps us decide exactly what we're going to do and what risk level the patient is that defines what level of therapy is needed.

We start with combination therapy, utilizing an ERA, an endothelin receptor antagonist, as well as a PDE-5 inhibitor, and then escalate our care into triple and quadruple therapy in patients who are higher risk profiles. We have some novel pathways we're going to talk more about as the intensive goes forward this morning. So stay tuned. Hold on to your hats. We've got lots of great news in that space. And then it's very important, as with all disease, that even once we get our patients well controlled, right, we're continuing to follow up with them every 3 to 6 months to ensure that they're not having decline, and ensure that they are on optimized therapy.

[0:14:45]

So what is a PAH Center of excellence? So PAH happens in rural settings and urban settings and across all areas where APPs practice. So when the diagnosis is made for PAH it is recommended that patients are referred to a PAH Center of Excellence. When they are referred to these centers it has been shown to improve outcomes for these patients. And that's really because these centers of excellence are defined by the guidelines as comprehensive care models for patients with PAH. It's very similar, in a sense, to sending someone with advanced heart failure to a tertiary care center where advanced heart failure therapies like LVAD and transplant are an option.

That said, if you look at this map to the right side of your screen, you will notice that there are many areas that do not have access to a center of excellence. In the state of North Carolina we have one singular center, right? But if you look through the Midwest there, it could take someone a significant amount of travel to reach a PAH center of excellence. So there are lots of barriers in access for our patients to these spaces and so we need to all know about and know how to manage patients with PAH in the event that they can't make it to a PAH center of excellence and really cultivate relationships with our local centers of excellence or our regional centers of excellence in some spaces. Unless, of course, you're in the northeast, it does look like there's quite a few up there. but we need to cultivate relationships for shared care models to really improve outcomes for our patients.

So now I will hand it over to Brian, who's going to really kind of get into the nuts and bolts of pulmonary arterial hypertension.

[0:16:39]

Brian Rose (Reid Heart Center): Thank you, Lauren. again, I would just like to underscore the thanking the planners for inviting me to talk about this topic that's very near and dear to me. so I want to kind of get down into the nitty gritty so to speak, talking about pathophysiology and the importance of symptom progression reversal for these patients, which Lauren kind of already touched on in terms of risk stratification, what we're shooting for.

[0:17:12]

So hopefully this may be review for a lot of folks, but it's really important that we're all talking the same language when we discuss pulmonary hypertension, and we use the World Health Organization or WHO classification groups. So group one, which is really what we're talking about today, is pulmonary arterial hypertension. and when we get into discussion of hemodynamics based on the right heart catheterization, which you see here, that is what really defines pulmonary arterial hypertension and distinguishes it from the other groups among other factors. So I'm going to kind of hold off on what those exact hemodynamic parameters mean and why they're important to us until later in our presentation.

Group two, which was discussed during some of the pretest, is due to left heart disease. And this can include both valvular heart disease as well as heart failure with reduced ejection fraction or heart failure with preserved ejection fraction.

Group three is pulmonary hypertension that is due to intrinsic lung disease or hypoxic lung disease.

Group four is due to what is called CTEPH, or chronic thromboembolic pulmonary hypertension, or blood clots in the pulmonary arterial system.

And group five is what I like to commonly call the catchall group. It's etiologies that are not really clear or multifactorial mechanisms.

[0:18:57]

So our focus today, like I alluded to, was on on group one or pulmonary arterial hypertension. So what's really happening here is we're having narrowing of the pulmonary arteries leading to increased RV overload, which results in right ventricular failure. And there's multiple different reasons this can happen. it can be due to genetic predispositions. There's some environmental exposures and underlying conditions. And what the World Symposia did last year as well as the ESC guidelines, which Lauren alluded to, is to try and tease out subcategories within group one.

So we talked about idiopathic pulmonary arterial hypertension. And a subset among those folks are responders to calcium channel blockers, and that would be indicative during right heart catheterization. There are patients that have heritable pulmonary arterial hypertension. Associated with drugs and toxins like methamphetamine use which we see, I practice on the East, the eastern United States, we don't see a whole lot of methamphetamine use, but colleagues that are practicing on the West Coast, where there is a methamphetamine epidemic, so to speak, see this quite commonly.

The associated subset of patients, which Lauren showed in that pie chart earlier can be due to connective tissue disease, HIV infection, portal hypertension, congenital heart disease or schistosomiasis. There’s also patients that have PVOD involvement and then also persistent PH of the newborn.

[0:20:56]

So I alluded to what is going on in terms of RV dysfunction and patients specifically with left heart disease, once they have RV remodeling and RV dysfunction, that is associated with a worse prognosis in that group. And what exactly is going on is the increase in the pulmonary congestion, the vasoconstriction, and then you get vascular remodeling as a result. And remember left heart disease, this is not only patients with heart failure – so HFrEF, HFpEF – but also those with left-sided valve disease, aortic stenosis or regurgitation, and mitral stenosis or regurgitation.

[0:21:50]

In patients with group three or pulmonary hypertension associated with lung disease, you can see remodeling of the airways, the lung parenchyma and the vessels. And one way I tell my patients to think about this is it's almost like a garden hose mentality. You've got something going on in the lungs, and it's like someone's turned the garden hose on and put a kink in it. So in this instance, the lung disease is causing the kink. It's causing that backwards remodeling of the airways, lung parenchyma and vessels. And this can be due to chronic obstructive pulmonary disease and emphysema, patients with interstitial lung disease like pulmonary fibrosis. And what we see is that as patients develop more remodeling of their vessels, their pulmonary vascular resistance increases significantly and those patients do worse over time and have a high incidence of morbidity and mortality. And these are patients that we can often see in clinic that may that have intrinsic lung disease. COPD is fairly common. We see lots of patients in our offices with COPD. But these are patients that will have a significant amount of hypoxemia at rest or with even mild levels of exercise.

[0:23:20]

So distinguishing the type of PH is important. But I want to back up for a second and really point out that we have to have a high index of suspicion for these patients. So being able to detect symptoms or being able to detect pulmonary hypertension early based on symptoms is key. So some of the early symptoms that patients will have, classically dyspnea with activity. They can have fatigue and rapid exhaustion, dyspnea with bending forward or something called bendopnea. Palpitations, hemoptysis. Exercise-induced abdominal distension and nausea. Weight gain due to fluid retention. And syncope, both shortly after or during physical exertion.

Some of the later findings that we will see once they've had that pulmonary remodeling is exertional chest pain, and this comes from dynamic compression of the left main coronary artery. Patients can have hoarseness or dysphonia due to compression of the left laryngeal recurrent nerve. This is something called Ortner's syndrome. Shortness of breath. Wheezing. Coughing. Atelectasis due to compression of the bronchi.

[0:24:46]

So some of the clinical signs of PH: central, peripheral or mixed cyanosis; an insinuated pulmonary component of the second heart sound; an RV third heart sound; a systolic murmur of tricuspid regurgitation; or diastolic murmur or pulmonary regurgitation. Similarly, signs that point to an underlying cause of pulmonary hypertension. So patients that have digital clubbing, signs of cyanotic congenital heart disease, fibrotic lung disease, bronchiectasis, PVOD, or liver disease. Auscultatory findings like crackles, wheezing, murmurs can point to underlying intrinsic lung disease or heart disease. patients that have a prior deep venous thrombosis or venous insufficiency, we get suspicious for CTEPH. Telangiectasias. Sclerodactyly, Raynaud's phenomenon, digital ulceration, GERD, we worry about connective tissue disorder.

So those are signs. What about when things are maybe a little bit more advanced? So signs of RV backward failure. So, distended and pulsating jugular veins, abdominal distention, hepatomegaly, ascites and peripheral edema. Now, these are signs that obviously have some overlap with other underlying conditions as well. So I do want to point that out.

What about signs of RV forward failure? So peripheral cyanosis, dizziness, pallor, cool extremities and prolonged capillary refill.

[0:26:37]

So this is a busy slide, but let's break this down. So when you have a patient who you're suspecting pulmonary hypertension in, your echocardiogram is your first line. It's a quick, inexpensive, easily accessible test for most patients. And we're able to use the ECHO to give us some clues. Now remember, this is not definitive for determining someone has, let's say, pulmonary arterial hypertension but this is a good way to further that index of suspicion and really make sure, are we working this patient up properly?

So the ECHO is allowed to give us information like TAPSE, which is looking at excursion of the tricuspid annulus; the right atrial area; something called the eccentricity index; the RV, RV LSS and RV FAC. So we're able to hone in on that right ventricle by looking at the estimated pulmonary arterial arterial systolic pressure. What's the RV function doing during systole? What's the size? What's the severity of the tricuspid regurgitation? Is there pericardial effusion or is there evidence of shunting?

Similarly we have to work up the lungs as well. We have to make sure that the patient doesn't have CTEPH. If we're going down the rabbit hole to diagnose pulmonary arterial hypertension, we must make sure that there's no CTEPH. And we do that by VQ scan.

We will get a lot of serologic testing specifically to look at connective tissue disease, HIV, etc. if we suspect portal hypertension we'll get an abdominal ultrasound. We need pulmonary function testing with diffusion capacities to be able to look at their lung function. Are we dealing with someone that has hypoxic lung disease? Is there an intrinsic lung disease like ILD or pulmonary fibrosis?

But ultimately we have to get the right heart catheterization for confirmatory diagnosis by getting those critical hemodynamic parameters.

[0:29:08]

So as I alluded to previously we’re able to distinguish some of the classification based on right heart catheterization. So pulmonary hypertension, just a patient that you get an ECHO on and it shows an elevated pulmonary artery systolic pressure, let's say estimated at 45%. We take that patient for right heart catheterization. What defines PH on the right heart catheterization is a mean pulmonary arterial pressure of more than 20mm of mercury. That is true for all classes of pulmonary hypertension. Group one through five, you must have that mPAP of more than 20.

Now, when we add the pulmonary arterial wedge pressure and the pulmonary vascular resistance is where we start seeing differentiation. So precapillary pulmonary hypertension or truly group one, PAH, is the mPAP more than 20, a wedge less than or equal to 15 and a PVR of more than two Woods units. When we have isolated post-capillary, pulmonary hypertension, we have the mPAP more than 20, but our wedge is more than 15. So these are patients that are classically group two in etiology and their PVR is less than two. However, you can have patients that have a combined pre and post-capillary component. And that's where their wedge is more than 15 but their PVR is more than two. So they've had some of that backwards remodeling.

And lastly, just for the sake of completeness, but you know, a little bit outside of the direction of this talk, is exercise induced PH, and we calculate that based on the mPAP and cardiac output slope.

[0:30:59]

So the seventh World Symposium gave this algorithm for pulmonary arterial hypertension. So we have good clear cut therapies for patients that have group one PH. And this includes patients that have idiopathic pulmonary arterial hypertension, hereditary, connective tissue disease, among others. So we do our initial risk assessment. We work the patient up as we saw a few slides ago and we determine their risk because their risk helps us identify what therapies they need.

So patients that are not deemed at high risk, based on whatever risk assessment model you use, will get combination therapy with an ERA and a PDE-5 inhibitor. But those that are deemed at high risk will look at utilizing an ERA and a PDE-5 plus either a subcutaneous or IV prostacyclin.

[0:32:08]

Treatment based on risk stratification is key, as I said previously, and you can pick. There are a lot of great risk stratification markers to use not only at time of diagnosis, but also at time of follow up, because every time we evaluate a patient with pulmonary arterial hypertension who is on therapy, we're wanting to make sure we have achieved low risk. If we have not, we're looking at ways to escalate their therapy to achieve low risk, because by achieving low risk, we're improving their outcomes. We're improving their functional class and we're improving mortality.

[0:32:52]

So in summary, we have to have a high index of suspicion, a thorough and complete diagnostic evaluation that ranges all the way from a thorough physical exam to an echocardiogram, serologic testing, VQ scan, and ultimately right heart catheterization. We have to exclude thromboembolic disease. This is a critical pitfall that people can fall into is they think that they have a case of pulmonary arterial hypertension, but in reality it may be CTEPH, in the right patient with the right risk factors.

We need to evaluate potential causes and contributing issues. Remember, the vast majority of patients that have pulmonary arterial hypertension have it associated to another underlying cause.

The right heart catheterization is required prior to initiating PAH therapy. We must get those critical hemodynamic parameters in order to decide on therapy, and not only to decide on therapy, but to make sure that we are treating the patient correctly, because not doing so can lead to potential harm.

We have to do some baseline functional evaluation. We need to know what the patient’s risk is, what their risk profile is not only at time of initiation of therapy, but also on subsequent follow up. Do we need to be escalating therapy?

And lastly, if we do identify a patient that has a heritable cause, we need to make sure that there's genetic testing and counseling available not only for them but for their family members as well.

And with that, I will pass it back to Lauren.

[0:34:45]

John Giacona: So actually I will I will take it back.

Brian Rose: Okay.

John Giacona: Thank you so much. Thank you, Brian, and thank you, Lauren. That was amazing. so we'll take a little halfway section here, to talk about a case study.

[0:35:02]

And so here we have Angela. She's a 48 year old woman. Her chief complaint is worsening shortness of breath and fatigue over the past three months. She reports new ankle swelling and disrupted sleep. She also reports great adherence to her current therapy, but feels that it isn't helping like it used to. Her current therapy is here. It's macitentan 10mg and tadalafil 40mg. Her past medical history: Idiopathic pulmonary arterial hypertension, WHO group one diagnosed 18 months ago, no significant cardiopulmonary comorbidities. On physical exam, she has mild right atrial dilation, right ventricular enlargement, TAPSE 15, trace pedal edema, accentuation of P2 heart sound. Recent findings: she had an NT-proBNP of 780, which is up from 420 previously. She has a six-minute walk test of 320, which is down from 385.

[0:36:04]

So with that in mind, we have our our poll number three. Which mechanism is most likely the primary driver of Angela's disease progression?

1. Increased endothelin-mediated vasoconstriction and vascular remodeling
2. Reduced nitric oxide production leading to impaired vasodilation
3. Decreased prostacyclin synthesis reducing antiproliferative signaling
4. Progressive right ventricular remodeling secondary to vascular change

Excellent. Thank you very much for taking the time to answer.

[0:37:00]

 So, we can discuss a little bit from pathophysiology to practice. So what's happening with this patient is obviously she's experiencing endothelial dysfunction. and that can be characterized as vasoconstriction, proliferation and remodeling, as Lauren and Brian talked about. she's also experiencing progressive right ventricular strain, which is showing up and manifesting as functional decline and increasing in her symptoms. non-adherence worsens vascular remodeling and outcomes.

And so what are some things that we can do? again, many of these were discussed by Brian and Lauren, and I'm about to bring them back in to discuss, but we can repeat right heart catheterization and reassess her hemodynamics, which is recommended by the 2022 ESC/ERS guidelines. We can evaluate for add on therapy, right. We might be able to add on sotatercept. We can reassess every 3 to 6 months or should be reassessing every 3 to 6 months, and using patient-first communication and shared decision making, specifically when we're talking about potential non-adherence to medications.

And so I'm going to bring our faculty back in so that they can kind of talk about how we how we approach patients who are feeling discouraged and how we can get them back on track with their treatment. So Lauren and Brian, would you guys like to join me back in and kind of discuss how you would approach this?

[0:38:21]

Brian Rose: Absolutely. unfortunately, this is, you know, a conversation we have more often than we probably would like with these patients. you know, pulmonary arterial hypertension at its core is a progressive disease. it is something we always have to be very attentive to, which I think this case really underscores the need for continual risk stratification. You know, this patient is getting clinically worse, due to a multitude of reasons. but, you know, it's very important to stay positive when people – and this predates me, but if you talk to a lot of the original, you know, the OGs of of pulmonary arterial hypertension, you know, 10, 15 years ago, there was not a lot of therapies. I mean, we wouldn't be talking about a lot of these therapies. now our toolkit is getting pretty full. so patients that do have clinical worsening, we do have options. And I think that's important to underscore we have options to change therapy. You know, the goal here is to make sure that they feel better, and that they're more functional. and that we also have a way to measure that. So being able to let them know that there are options, and sometimes it's not a failure if we have to change course. those are critical discussions that I have with my patients often. Lauren?

Lauren Eyadiel: I think too, kind of a real focus on empowering your patient, you know, these are funny named medications, medications that are hard to understand, but it's really our job, as the providers, as the APPs in their care, to really be able to explain it in a way that they understand so that they kind of have an underlying understanding and why this medication is important. Why do I need to take it when I need to take it? You know, especially with parenteral therapies, a lot of times it's a bit more difficult, right, to get people on board with that, or inhaled therapies that require multiple times of daily dosing. And so I think really empowering your patients to take some ownership of that and have good understanding of their disease process, as well as these kind of funky-named therapies that might be difficult for them to understand. really kind of getting that down at the level that our patients can understand and then be empowered to adhere with therapies.

John Giacona: Thank you both for those incredible insights. I mean, I completely agree, non-judgmental language. And being a hypertension specialist, we often talk about, you know, adhering to therapy and hypertension worsens with age and so similar, very similar sort of patient focused, patient centered language, comes in all in all of our cardiology discussions. So thank you both for that.

For the sake of time, I will move on to our next section. so that will be poll number four.

[0:41:37]

So for the audience, how would you respond to a patient like Angela who says, I've been taking my medicines, but I feel worse. Does this mean they're not working?

1. It might take more time for your medicines to work, so let’s just keep monitoring
2. Your symptoms suggest your PAH may be progressing — we’ll review your results and adjust your plan together
3. That can happen sometimes; you should probably rest more and see if things improve
4. You may need to stop one of your medicines if they’re making you feel worse

Excellent. Thank you all for for for responding.

[0:42:27]

So last poll for this session. Poll five. 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 in your pulmonary arterial hypertension care? Is it:

1. Patient education and adherence support
2. Earlier diagnostic or RHC follow-up
3. Integrating QoL and mental health screening
4. Enhancing communication and shared decision-making

Excellent. Thank you.

[0:43:17]

So we'll move on to the next session, which we're going to ask Brian to come back. And this will be Fundamentals Part Two: Guideline-Concordant PAH Management with Multitherapy and Risk Reduction Strategies.

Brian Rose: Thank you John.

[0:43:36]

so our goal here, as I think I gave away earlier, is to achieve and maintain the lower risk status because we know that this improves survival, improves quality of life. We see improved exercise capacity through the six minute walk and functional classification. And if we repeat their hemodynamics with right heart catheterization, those improve too. And when we do this, patients feel better. They have fewer and lesser symptoms. And we prevent that clinical worsening, as we had with Angela, which required escalation of therapy, unfortunately sometimes hospitalization, lung transplant, as I'll touch on later. And ultimately, like I said, this is a progressive disease and it can lead to mortality.

[0:44:29]

So this is a very busy slide. for a lot of us, this may take a trip back into biochemistry a little bit. but let's break this down a little bit further. we have four distinct pathways in which we're able to target pulmonary arterial hypertension, three of which are a little bit on the older side, and one is the newer kid on the block.

the first is the endothelin receptor pathway. And this is obviously where our ERAs work and live. The nitric oxide pathway, which is where our PDE-5 therapy comes from. Prostacyclins. And lastly, our newest pathway, which we’ll dissect a little bit later.

[0:45:22]

So, as I alluded to previously, we've got patients on multiple medications. But do we see any benefit compared to monotherapy? Well, yes we do. So this is the AMBITION study. And this looked at combination versus pooled monotherapy. So these were patients that were either on macitentan or tadalafil monotherapy versus those that were on dual therapy with macitentan and tadalafil. And what you can see here is significant differences in combination therapy versus monotherapy in terms of percentage or likelihood of having an event. And we were able to see statistical difference with NT-proBNP and patients achieving a clinical response as well as six minute walk distance.

[0:46:29]

Selexipag, which is another therapy, is a prostacyclin, oral prostacyclin. And the GRIPHON trial, shown here, was a phase 3 randomized trial of a little over 1100 patients with pulmonary arterial hypertension that received up to the maximum dose of 1600 nanograms twice a day versus placebo. And what you can see here is again, we're looking at event differences. So compared to placebo there was a significant difference in events.

[0:47:25]

Sotatercept, which is the newer medication that is out, in the PULSAR trial, looked at patients that were on stable background therapy and found changes in their pulmonary vascular resistance as early as 24 weeks.

So this is an exciting new frontier for patients that didn't have a lot of options. Now we're able to tackle pulmonary arterial hypertension through multiple angles. And not only are we saying, all right, are we making a difference in the way patients feel and their six minute walk? But are we actually seeing hemodynamic changes? Yes we are. As early as 24 weeks in this instance.

[0:48:31]

Again, the STELLAR trial, sotatercept, looking at patients that were on stable background therapy, again compared to placebo. These are patients that are on good therapy. When we add this to their therapy, we see significant improvement in their six minute walk test as well as differences in time to death and clinical worsening.

[0:49:01]

So this is a picture of the REVEAL 2.0 risk calculator. And I personally use this model at my patient's initial visit when I'm trying to decide on therapy, when I've gathered all that clinical information and diagnostic workup that we talked about previously and decide, okay, what's their risk? Are they low, medium or high risk? If they're low risk, I'm going to put them on a dual therapy with ERA and PDE-5 inhibitor and monitor their clinical response. If they’re intermediate risk I'm going to add that activin signaling inhibitor, like sotatercept, to intensify their therapy. If they’re initially high risk, I'm looking at potentially a fourth agent and considering sotatercept.

And then I'm going to reevaluate those patients every 3 to 6 months either utilizing the same risk calculator, there's also what's called the REVEAL Lite, which is a simplified version of the REVEAL 2.0. Or if you're choosing to use a different risk stratification model, like the ESC/ERS-4 risk stratification tool, you can use that as well.

Escalation is success, not failure. The goal here is symptom reversal and survival improvement.

[0:50:42]

And this is a good schematic of what that would look like. So, you know, I'm seeing my patient back. I've done this REVEAL Lite. I determined that my patient is a six, and I decide, where do I need to go on this graph? Or have I achieved that? Have I achieved that low risk status, or do I need to escalate things further?

[0:51:08]

So these are our current therapies. We have prostacyclin analogs that come in IV, inhaled and oral, as well as subcutaneous. Prostacyclin receptor antagonists. Selexipag, which I described previously, is oral and IV. ERAs, macitentan, which we mentioned earlier. These are all oral therapies. PDE-5 which we know very well. Tadalafil and sildenafil. I'd be remiss if I didn't mention that macitentan and tadalafil come as a combination therapy medication. we have riociguat, which is an oral medication as well, and we use this a lot in CTEPH for patients that may not meet criteria for surgery or pulmonary balloon angioplasty. And lastly, that activin signaling inhibitor pathway, that fourth pathway which we saw earlier is sotatercept. And this is the new kid on the block. And this is subcutaneously administered.

[0:52:17]

These are some of the adverse events. you know, these medications are not necessarily without their fair share of adverse events, so I'm not going to go through these ad nauseam. but definitely these are things we counsel our patients on initially, make them aware of, they know to report these symptoms. And sometimes we're able to mitigate these and patients are able to tolerate them. But again, our toolbox is very vast now as opposed to ten years ago. So sometimes we will have to adapt and adjust medications.

[0:53:02]

So this is a kind of a larger schematic of what we've been talking about. So we get that diagnosis. We get a negative vasoreactive testing on that right heart catheterization. So these are patients that we're not going to treat with calcium channel blocker. We want to risk-stratify them. If they're not low risk, we're automatically going higher than dual therapy, with those patients with intermediate or high risk, with efforts to achieve low risk. And being able to reevaluate these patients on a regular basis, apply that risk stratification tool is key, because we've got to have some sort of objective finding to say this patient is getting better or this patient is getting worse, I need to do more.

And again, this just focuses on, whether or not the patient has any cardiopulmonary comorbidities or they do have cardiopulmonary comorbidities at present. in these instances, patients that do have comorbidities despite their risk categories, we would treat them with an oral mono therapy with PDE-5 inhibitor. and really those patients have individualized therapy.

[0:54:48]

All right. So, incorporating the patient's perspective into PAH management is the true center of treating this disease process. This is a true partnership between the provider and the patient. So utilizing that shared decision-making on what therapies we're going to pick. I inform the patient and say, based on your risk we need to be using two agents or we need to be using three agents, and these are the these are the tools that are available. And more importantly talking about those adverse events, things to look out for, things to report. Having good follow up and a good open line of communication.

But also understanding what your patient's goals are. What are the patient's goals for their treatment? And this goes back to what we touched on earlier was understanding this disease. This is something a lot of not only patients haven't heard of, a lot of providers haven't heard of this either, or they've heard of it very peripherally. So understanding what the patient's realistic goals are. But also you as the provider, what are your goals for this patient?

[0:56:06]

So what about when things don't go well? and I think Lauren later on will probably have a really good discussion about this because you are at a transplant facility. I am not. I'm more at a regional facility. So I'm often referring patients to someone like Lauren or to a lung transplant specialist in these instances where things aren't going well. Our standard of care therapies are not improving.

So when do we consider transplant for these patients? And I don't want to just say that this is just lung transplant. Sometimes these patients need heart-lung combo transplant. So patients that are truly in stage disease if you will, refractory to medical therapy, like I said. We're seeing these patients back and despite escalation we're still in that high risk or we're still in that intermediate risk and they're having functional limitations. Patients whose survival is expected to be less than two years. these are patients we want to consider a transplant evaluation.

One of the unfortunate things about transplant, whether we're talking cardiac or lung transplant or dual, is, and Lauren I think would agree with me on this, a lot of patients never even get to the point of getting an evaluation. They never even get to that point where they can see a specialist that can determine if this is a good option for them.

Lastly, it's important to note out some absolute contraindications versus relative contraindications. these are important to me because I don't want to see a patient in my office and tell them that they need a transplant when they clearly are somebody that's not going to qualify. So some of the absolute contraindications are malignancies within the last two years, chest wall or spinal deformities, non-adherence. Obviously if we have patients that are not going to take their medications, not going to do what we asked them to do, those are patients that are not going to be eligible for transplant. Patients with inadequate social support, substance abuse within the last six months, or untreatable organ dysfunction.

Relative contraindications, on the other hand, are age greater than 65. And I put in there that this is program-specific because across the country you will see varying degrees of at what age certain centers will use as their cutoff for transplant. are these patients critically ill? Are they requiring ECMO, for example? Do they have certain colonization of certain organisms? Do they have obesity? That can significantly impair their ability to recover from transplant? Do they have other medical problems that have not been optimized, like hypertension, diabetes, gastroesophageal reflux disease, obstructive coronary artery disease, just to name a few?

So we'll move on to Skill Building and Feedback Part Two.

[0:59:16]

John Giacona: Excellent. Thank you so much Brian.

[0:59:22]

So, coming back to another patient case. So this is Michael. He's a 56 year old man. His chief complaint: increased fatigue and dyspnea with routine activities for the past four months. He reports worsening exertional shortness of breath, as well as mild ankle swelling and reduced stamina at work. He also reports adherence to his current therapy. He is currently on macitentan, tadalafil and selexipag. Past medical history: idiopathic pulmonary arterial hypertension, WHO Group one diagnosed two years ago, and he also has a comorbidity of hypertension. On physical exam he has mild lower extremity edema, accentuated P2, mild right ventricular enlargement, and some recent blood work showed NT-proBNP of 880, which is up from 520, and his six minute walk is 295, which is down from 340.

[1:00:19]

So with Michael in mind, based on his findings, what is the most guideline concordant next step?

1. Continue current triple oral therapy and reassess in 6 mo
2. Add an activin pathway modulator (sotatercept) to optimize therapy
3. Switch from PDE-5 inhibitor to sGC stimulator
4. Reduce selexipag dose and repeat echocardiogram

Excellent. Thank you guys for answering.

So the question is when to escalate and turning risk into action. So in Michael, he's having persistent symptoms, elevated NT-proBNP, yet he's on triple oral therapy. He's considered intermediate high risk, which Brian and Lauren would probably indicate that he needs escalation of his therapy. He's obviously, because of this progressive disease, having ongoing vascular remodeling and right ventricular strain as shown by his NT-proBNP.

So what can we do to address these? We can add sotatercept for persistent symptoms or incomplete risk reduction to help get him to lower risk. It's important again to reassess every 3 to 6 months your patient's symptoms, six minute walk, NT-proBNP and functional class. Monitoring CBC for hemoglobin increase or telangiectasia and other side effects. And then importantly as a sort of mainstay for all of these patients is using team based approach. APPs, pharmacists, nursing, getting as many people involved, especially their patients’ care providers and their families to help guide, titrate and assess any adverse events that may happen from the medications. And reinforcing patient education on injection technique and follow up adherence, are all crucial in order to help our patients get, lower risk and better symptom management.

[1:02:29]

And so with that in mind, I'll ask Brian and Lauren to join again, and kind of tell us what their thoughts are for this patient. You know, for example, we can start by when do you guys consider introducing sotatercept for a patient who's already on triple therapy?

Lauren Eyadiel: I think really, in this case, our patient is demonstrating that not only is he not getting better, he's getting worse. Right? So, as with all disease, if you had a patient who came into your clinic with diabetes, and their A1c was going up, right, we wouldn't necessarily say we're good with the current amount of insulin, we're good with your current antihyperglycemic regimen, right? Like, we would get that patient on an escalated therapy. and so in his case, you know, I really think that patients who are having both diagnostic data that is worsening as well as ongoing reduction in quality of life and exertional symptoms, I really think that any of those things should be a trigger to really think about sotatercept.

in addition, I think even if your patient feels okay, if their hemodynamic profile, if their biomarkers, any of those things are going in the wrong direction, then we need to tell them that that's kind of our warning sign, right? Like that's the yellow flag before the red flag. Therefore, we want to escalate therapy before we get on a bad trajectory. What do you think, Brian?

Brian Rose: So I agree. You know, sotatercept in this instance is being thought of as is a fourth agent. Because it's a novel pathway that is really kind of looking at pulmonary arterial hypertension from a different angle, if you will, at least anecdotally, I introduce this sometimes a little bit earlier. You know, this sometimes is a third agent, as opposed to being a fourth agent. But in this patient's instance, I absolutely would advocate for a fourth agent here because of that clinical worsening. This is a patient that the yellow flag has gone up. this is a patient that, if we don't get a handle on this, I mean, they're ultimately going to die, and have a very, very poor trajectory moving forward. this is also a patient that I would want to discuss with one of the tertiary facilities potentially in one of the transplant clinics to start maybe talking about, especially if this if it was a patient that would be deemed suitable to having that evaluation.

again, these are tough cases. these are very tough cases. and being able to have that open discussion with the patient, with their family, and saying, look, we really have to figure out why things are not going forward.

I also have a pretty low threshold to to relook at their hemodynamics. so if I have a patient who, let's say they were relatively stable for a while and then all of a sudden we kind of have some clinical worsening and I'm looking at potentially elevating or escalating therapy, you're not wrong to redo their hemodynamics with right heart catheterization and really see what's going on.

and, you know, lastly, I'll say this really highlights the need for multidisciplinary approach here. This is a patient that really is not always managed by one individual provider. This is a patient that I would take to my larger group, to my colleagues that do pulmonary hypertension, both in cardiology, pulmonary. You know, is this a patient that also has like a connective tissue problem? Am I pulling in the rheumatologist? And having a multidisciplinary discussion on the back end and say, hey, you know, patient X is not doing well. we need to look at this as a team and really make a decision about their care.

John Giacona: Thank you both for that. That's that's very good. Very insightful. so I do have a couple of questions off this slide here that I'm really interested. How do you all approach managing adverse events, side effects and things of that nature? Do you guys have regular coordination with nursing or pharmacy teams to to check in on labs or monitoring at home? How do you guys approach that?

Brian Rose: Yes. So nursing is key. so my patients know my nurse and, you know, that's a constant line of communication. we also utilize clinical pharmacy to really help with that as well. and are able to co-manage, these patients, which which is of great benefit.

John Giacona: Excellent. That just shows how multidisciplinary we really need to be with addressing these issues. So thank you guys both for that.

[1:08:18]

So for the audience we'll move on to poll seven. So after everything we heard, how would you respond to a patient starting sotatercept who asks, why do I need another therapy if I'm already taking three?

1. This new medication targets a different pathway to help your current medicines work better
2. Because your symptoms have worsened, adding more therapy is our only option
3. Your current treatments aren’t strong enough, so we need something new
4. This is standard care for everyone with your condition

Excellent.

[1:09:06]

Moving to poll number eight. Take a moment to reflect on what this case brought up for you. What's one area you'd like to strengthen in your pulmonary arterial hypertension care?

1. Earlier identification of patients needing escalation
2. Improved AE management and patient education
3. Incorporating novel agents (eg, sotatercept) into treatment plans
4. Enhancing shared decision-making and adherence support

Perfect. Thank you all for staying engaged with our polling questions.

[1:10:00]

So now we'll move to Fundamentals Part Three with Lauren Eyadiel covering novel agents and four-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 four pillars of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction. So we can think of these as kind of four pathways. We're going to be targeting four 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 two 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 six minute walk distance, reduced risk for clinical worsening – very important to our patients. They probably care far less how far they can walk in six 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 six 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 three trial looking at patients who were already on therapies and their primary endpoint was six 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 six minute walk has plateaued, and she reports occasional nosebleeds and mild dizziness. She's on a four-drug regimen: macitentan, tadalafil, selexipag and sotatercept. Her past medical history: she has pulmonary arterial hypertension Group one, diagnosed three 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 six minute walk is 310, which has been stable.

[1:25:15]

So with Carla in mind, we'll move to poll number nine. 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]

Let’s Discuss: Sustaining Stability and Managing AEs in Patients With Advanced PAH

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 four-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 six 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 four-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 four-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 six 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 four-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 four 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 one, 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 four-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 four 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 one.

[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 two, high mortality risk. So pulmonary hypertension associated with left sided heart disease, in this case this patient has HFrEF, is classified as group two. We need to remember that pulmonary hypertension associated with pulmonary disease is group three. 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 two. 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 three, 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 three risk, the three 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 three 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 versus a PAH physiology. And in that case, our only ability to figure out the difference between those two 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 four 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 two disease or they have group three 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.

John Giacona: Excellent. Thank you both. So I will take us into the wrap up session. So thank you both again for a great presentation. you guys gave us your wisdom and your expertise. And I know that all the participants are very, very thankful. so I'll move into some announcements.

[2:03:26]

and so here is a link to go online for more coverage of pulmonary arterial hypertension. There’s a clinical thought expert commentary and additional CME at that link.

[2:03:40]

And some other announcements. So don't forget to complete the program evaluations. the program evaluations are required for you to receive credit for today's presentation. You can access them via the resource link. that's in the resource section of the player.

We're going to take a short break. so it's 12:04 p.m. eastern. there's a non-CME educational session that will start at 12:10 p.m. eastern time. and another note is that we will be switching rooms for the next presentation, and sometimes this can result in a reset of your audio settings. So if you cannot hear, be sure to check that the video speaker is turned on and refresh the player. and then if you continue to have issues, please click the request support at the bottom of the screen.

And with that being said, we'll see you in the next room for the next presentation.

[END OF TRANSCRIPT]