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[Video title: US-DS-1231 PAHI Advancing PAH Care: An Overview of the 2022 Treatment Guidelines]

[Voiceover]

Welcome to the Advancing PAH Care video series. This series includes key opinion leaders who discuss new information in the 2022 ESC/ERS treatment guidelines for pulmonary hypertension and how these recommendations can be incorporated into clinical practice in the US.

Some of the topics to be covered in this series include risk stratification, the right heart beyond pressure, ESC/ERS treatment algorithms, and individualized patient care.

The focus of this video is to provide a high-level overview of the key changes in the 2022 PAH treatment guidelines with regard to PAH care and treatment.

With support from UT, the PAH Initiative provides nonbranded, disease education for the PAH Community. The Initiative worked with PAH experts to identify the content for this program.

[Dr. Jean Elwing]

Welcome. My name is Dr. Jean Elwing and I'm a professor of medicine and the Director of the Pulmonary Hypertension program at the University of Cincinnati. And I'm joined today by Dr. Scott Visovatti. Scott, welcome.

[Dr. Scott Visovatti]

Thanks, Jean. I'm Scott Visovatti. I'm an Associate Professor of Medicine and the Director of the Pulmonary Hypertension program at the Ohio State University. I'm also a cardiologist.

So, Jean, let's give a bit of an overview on how these guidelines were developed. They were developed in Europe by a multidisciplinary group. You and I probably practice a bit differently here in the United States, as do many of the practitioners who are listening in to this video series.

And so let's talk about some of those major themes that we'll hear about throughout the rest of this series.

We now approach pulmonary arterial hypertension as a hemodynamic condition and therefore it requires a hemodynamic definition. It's important to talk about how risk assessment at baseline and at follow-up is incorporated into recommendations about treatment decisions.

It's also critical to touch on the critical symbiosis between a local practitioner and a referral to a PH center and how this combination of expertise works in a patient's advantage.

So, Jean, the hemodynamic definition of pulmonary arterial hypertension has been debated for many, many years, including since the last world symposium. What are your thoughts about the implication of this new definition?

[Dr. Jean Elwing]

This is a very hotly debated topic. So, as we remember, we defined pulmonary arterial hypertension as a mean pulmonary pressure of 25 or greater with a wedge of 15 or less and that PVR greater than three. But we learned through big datasets that those individuals that had that mean pulmonary pressure in that what we used to call borderline range, 20-25, had increased risk of poor outcomes and mortality.

And now when the group assessed the data in this new ERS/ESC guideline s, they found that

even those patients that had that lower mean pulmonary pressure, that greater than 20 pressure, if they had a high resistance in their pulmonary vascular circuit – even when it was over two – they had worse outcomes. So, they proposed a new definition.

But they didn't stop there. They also looked at exercise. And you know we have been looking at exercise for so many years, trying to find really what we would use as a cutoff. And they proposed a mean pulmonary pressure change over cardiac output slope of greater than three millimeters of mercury as an abnormal finding.

So, where are we gonna take that? I'm not sure yet. But we will need to be able to study that group of patients further, see how they do over time, and maybe determine if they would need treatment at some point.

But currently, the only people we really recommend treatment in general to are people that meet the traditional, the older definition, because that's what we used in all of our clinical trials. You know that.

So, those other individuals with that lower mean pressure, with the lower PVR, they are the people that really we want to see in expert centers. We want to evaluate. We want to see what the trajectory of their disease is and then understand when we need to offer treatment and when it's appropriate.

So another area of the guidelines which I wanna ask you about is risk assessment. So very important. And how are you incorporating that and how do you view that in light of the new guidelines.

[Dr. Scott Visovatti]

Never before has risk assessment been woven throughout the entirety of guidelines. Very, very important. Important to assess risk at baseline, which we've done. Equally important to reassess patients frequently, generally every three to six months, with risk reassessment at that time as well. Our goal being to drive risk to the low-risk category. And only with frequent reassessment is that possible.

Risk also helps fuel our approach to treatment, escalation of therapy based on risk. Critically important.

So, Jean, could you give us a brief overview of how risk assessment helps dictate treatment options in the new guidelines?

[Dr. Jean Elwing]

So with our new guidelines, the 2022 ERS/ESC guidelines, we're seeing patients, evaluating, diagnosing them based on our new hemodynamic definition. And then risk assessing. We wanna know severity of illness from the get-go.

And those patients that are low or intermediate risk, we'll start them on two oral therapy. And those individuals who are on the high risk, we're going to treat them as aggressively as we possibly can with our oral therapies in addition to a parenteral prostacyclin.

But we're not gonna stop there. We're gonna reassess with the 4- strata model, as you mentioned, looking at walk distance, BNP, and functional class, and then see where they fall. Are they really getting to that low risk? And if we are, then we're happy. We're gonna hold tight.

If we're in that low-intermediate, we're either gonna change medications or add medications. And if we're anything high – high-intermediate or high risk, we either need to progress increasing our parenteral prostacyclin or add one.

So, really helpful in giving us a nice framework. Now, do we have to use this 4-risk strata? Of course not. We can use REVEAL. We could use a French scoring system. But we have to do something. We are doing our patients an injustice if we don't reassess them.

Scott, another area that the guidelines stress is collaborative care in expert centers. How do you apply that to what we're doing in the US?

[Dr. Scott Visovatti]

In Europe, by and large, it's sort of a spoke and hub system where patients are evaluated locally but then all referred to a major center where expert opinion can be leveraged and administered.

Things are a little bit different, as you know, in the United States, where we have very good folks who are practicing pulmonary hypertension in local centers.

There are huge benefits to having a patient evaluated at a PH center. Certainly, this takes more account how complex PAH is, not just the diagnosis, but we have more treatment options now than ever. And it's important to make sure we find the right fit for the right person. In other words, not every medication or every combination approach is right for each individual.

Jean, could you summarize some of the key takeaways of our discussion today?

[Dr. Jean Elwing]

So, we talked about how pulmonary arterial hypertension is ever evolving.

Diagnosis and care has evolved. New medications, new risk assessment strategies. But the most important thing is that we continue to evolve and learn additional things, how to positively impact our patients.

And, really, we have to leverage, as you mentioned, the accredited expert centers and the local physicians and work together for best outcomes.

So, we’ve covered only a small bit of what was stressed in the guidelines, but some very important points. And we invite everyone to join for future videos about the new updates from the guidelines from 2022 ERS/ESC.

So Scott, thank you so much for joining me. It was a pleasure to talk with you about the guidelines.

[Dr. Scott Visovatti]

Thank you, Jean. I always learn something sitting with you, listening to you. Really appreciate your input.

[Voiceover]

Thank you for watching. This program is part of a series of videos about how PAH management has evolved in recent years.

Topics covered in this series include the importance of hemodynamics, the role of risk assessment, the PAH treatment algorithm, and considerations for the treatment of PAH.

For more information on PAH, please visit: [ResourcesForPAH.com]

[Video title: Advancing PAH Care: The Role of Risk Stratification]

Welcome to the Advancing PAH Care video series. This series includes key opinion leaders who discuss new information in the 2022 ESC/ERS treatment guidelines for pulmonary hypertension and how these recommendations can be incorporated into clinical practice in the US.

Some of the topics to be covered in this series include risk stratification, the right heart beyond pressure, ESC/ERS treatment algorithms, and individualized patient care.

With support from UT, the PAH Initiative provides nonbranded, disease education for the PAH Community. The Initiative worked with PAH experts to identify the content for this program.

Hi, I’m Ray Benza. I’m a professor of medicine at the Icahn School of Medicine at Mount Sinai New York City. I’m also the network director for the Pulmonary Vascular Disease Program at Mount Sinai Heart. And I have the pleasure today of being joined by my colleague and long-term friend, Dr. Vallerie McLaughlin, to discuss risk stratification in the context of a video series on the evolving management of pulmonary arterial hypertension. Val?

Ray, thanks so much. It’s a pleasure to be here with you today. I’m Vallerie McLaughlin. I’m a cardiologist and endowed professor of medicine at the University of Michigan, where I also direct the Pulmonary Hypertension Program. I’m really excited to be here today to talk about risk stratification with my dear friend, Ray.

Now, Ray and I have been doing pulmonary hypertension for a long, long time and there’s been a lot of progress in patient care. And a lot of progress in what we’ve learned about risk stratification, including so many sentinel publications that Ray has led from the REVEAL Study.

Now, when we think about risk assessment, we really need to concentrate on objective, multi-parameter risk assessments. We never rely on any one variable in assessing a patient’s risk. PAH is a complex disease; we really need a big picture of the patients.

The risk scores help us provide a consistent objective method to follow the patients over time. Really, much better than assessing one thing like functional class, or relying on gestalt. Just the eyeball test. And it helps us establish treatment goals.

We have very well-established data now that tells us, our goal should be to get a patient to low-risk status. We know that their prognosis is going to be much better if we get them there. And using risk assessment tools can help clinicians alter the treatment strategies, if a patient is not at low risk. And follow-up assessments need to be done regularly.

Every single encounter with a patient is an opportunity for risk assessment and adjustment of therapy. So Ray, why don’t we start out by talking about what risk stratification tells us about the patient prognosis and treatment goals?

Well, it can tell us quite a bit. And I would love to remind everyone that this whole evolution of risk stratification really stemmed from the work that you did such a long time ago. And published in that beautiful article in JACC, where the first risk table was published. And I always remember that table, looking at it and saying to myself well, it is better to use more than one variable at a time. Because it really paints a better picture of how a patient is gonna do with this disease.

Particularly, because it’s such a progressive disease. And I think that was one of the clues that helped me derive the original Reveal Risk Score. So, I thank you for that.

You’re most welcome.

So, risk stratification as we know, helps us predict both mortality and morbidity in patients of pulmonary arterial hypertension. And all the contemporary risk equations and calculators were derived from registry data.

From large cohorts of patients that we followed in the United States, or in Europe, including those in REVEAL in the US or COMPERA, the Swedish Registry, or the French Registry in Europe. And all of these have been used to estimate survival. And it’s important to understand that the products that came from these registries, or these risk tools that evolve from these registries, have some key differences that reflect the area of the world where they were derived from.

So with that being said, how do the patient characteristics of these registries, in your mind, apply to the patients that you see in practice?

Yeah, I think it’s a great question, right? Because we think of PAH and sometimes we think of the clean PAH that we enroll in clinical trials and that’s a very clean population. But it’s not what we see every day. And so, the registries really reflect more real-world data. The REVEAL Registry is a US registry, so it really is reflective of the patients that you and I see every day.

The French Registry, they actually are a lot tighter on their entry criteria and in many ways, it looks more like a clean-cut Group 1 PAH population. They have some heritables, they have some drug and toxin induced.

The COMPERA registry actually is older and with a lot more co-morbidities than what we see in the US. So, they’re actually three very different registries.

So, thanks for going through those individual characteristics of those registries. I think that’s important for the audience to recognize. But let’s continue.

Risk status is important in setting goals of treatment and establishing treatment and for monitoring plans. And determining when treatment adjustments may be needed. The ESC and ERS guidelines recommend a goal of low-risk status for all patients of pulmonary hypertension. And I know that I practice that, and I treat to low risk.

Patients at low risk have the highest survival rates at five years. And even those in intermediate risk, we have to remember that their survival is less than 95%. That’s really important so, just because someone is intermediate risk doesn’t mean we can leave them alone. That’s actually a very important group that we need to focus on and to drive them to low risk. Because a stable intermediate risk doesn’t mean they’re risk free. They are still at very high risk of death. So, getting those clinically stable intermediate risk to low risk is key.

And so, I wanna make sure that people understand the difference between clinical stability and low risk, it’s not the same thing. We want to treat to low risk.

It’s really essential also, I think, to avoid underestimating risk in this population. Pulmonary hypertension is a rapidly progressive, deadly disease. You don’t wanna make a mistake with that first discrimination and that first calculation of their risk. Because if you do, you won’t use the same intensity for that initial therapy as you would, and someone can get hurt by that.

We need to use these comprehensive risk assessment tools that have very good discrimination.

So Val, how would you describe how the treatment guidelines characterize baseline risk assessment?

Yeah, sure, this is really, really critical. Remember, when we’re first meeting a patient and making a diagnosis, we’re doing a very thorough evaluation. We have more data at that time than we probably have at any other time. And so, we can do a comprehensive risk assessment that includes everything we do in clinic like hall walk, labs, and such. But also echo, right heart caths, sometimes MRI. We have a lot of information. And so, going back to that risk stratification table, the low, intermediate, high.

It’s been interesting to see what’s been added in the ESC/ERS guidelines this year. So, there’s some new information about TAPSE, PAPSE, about right heart function. So, the TAPSE divided by the pulmonary systolic pressure gives us an indicator of RV-PA coupling, which we think is very, very important in pulmonary hypertension. There’s some additional MRI parameters added.

And so, really it warms my heart to see more indicators of right heart parameters in the risk stratification table. And Ray, you and I are cardiologists. We are very passionate about the right ventricle. Tell me your thoughts about these additional parameters?

Yeah, I think they’re invaluable. And do you know all the contemporary stratification schemes that we’ve developed, we always knew we were gonna have to add additional factors.

We have advanced so much in what we can do now with our imaging parameters that we get much better quantitative information from them. And I think that needs to be incorporated into our risk stratification tools. Because if you think about it, all really the variables that we have in all these scores really describe how the right ventricle is faring in the face of this very high afterload that is characteristic of this disease. So, why not have the most direct assessment of the right ventricle in imaging parameters.

Yeah, absolutely. Now, it doesn’t mean if you don’t have one parameter, that you can’t calculate a risk score. You still do it. But I do think it’s important to have all that data at baseline. And remember, low-risk status is the treatment goal, and we have to reassess risk every time we see the patient.

The intermediate-risk group is a wide range. It has a one-year mortality between 5 and 20 percent. So, that’s a really wide range. And it really emphasizes why the goal is low risk.

So Ray, you’ve really made so many important contributions to the literature with REVEAL. We’ve learned so much from the work that you’ve done. Why don’t you tell us a little bit about the REVEAL risk scoring methods and describe how the ESC/ERS updates align with the approach that you took in REVEAL.

Yeah, thank you. I think that’s a really important thing for people to understand that these algorithms are very similar. It’s the way that the multi-variables were put together where the biggest differences are.

In REVEAL, we used more of a statistical approach, where we used statistical weighting of the variables. So that, we know how one variable relates to the other variable very tightly. And that allowed us to develop algorithms with very high discrimination. Meaning that, we’re very likely to depict how a patient will live or if a patient will die, using these statistical modeling that we did. But the parameters are very similar, and many of them are in the European Risk Table.

So Ray, that’s a really great description and of course, it’s wonderful to have all that data at baseline and do the full comprehensive assessment. Now, let’s talk a little bit about how you use REVEAL 2 in follow up of patients, right? Because that’s really critical too. The goal is getting to low-risk status. So, tell me about how you incorporate that into the care of the patients?

One of the things that we were taking into consideration, when we did derivations of the REVEAL 2.0 score is, we had to take that into context of a very clinical, busy environment.

And so, we developed an abridged form of REVEAL 2.0 called REVEAL Lite. And abridged in meaning that we are utilizing only the changeable variables in this scoring system, as opposed to REVEAL 2.0 which had immutable risk factors in it like gender and age and the type of pulmonary hypertension.

But you only use the changeable risk factors. The vital signs, the renal functions, natriuretic peptide levels, the walk distance, and the functional class when you make that determination. So, REVEAL Lite 2 provides an accurate discrimination between risk with fewer variables than REVEAL 2.0 does.

And then I mentioned earlier, the 2022 guidelines present a similar model in the four-strata model. And I’d like to ask you, this model which was derived in part from REVEAL Lite. How do you think that fits in to our overview and how we approach the patient’s risk status?

So, when we think about how the ERS/ESC guidelines initially did risk, there were only three risk strata. We had variables that were low, intermediate and high risk and you calculated the score based on the variables that you had, low, intermediate, high.

So, that intermediate risk group is big, in terms of percentage. And big in terms of how we might approach treatment. So, the group from COMPERA looked at this and said, maybe there’s some way to discriminate this a little bit more. And so, they took their registry, over 1, 600 patients, and they divided them into four groups, rather than three. Low, intermediate-low, intermediate-high and high. And they used cut points derived from various registries for six-minute hall walk, functional class, and biomarkers.

So, the five-year survival between those intermediate-low and intermediate-high groups is 67% versus 47%. It’s a big difference. So, I think it’s really practical in terms of explaining things to patients, and in terms of making treatment decisions.

Now, REVEAL took a little different approach to that. Can you tell us about that?

Yeah, thanks. That’s a really key piece to really understand about the way REVEAL is supposed to be used. REVEAL is a continuous scoring system.

But using it as a continuous measure, where you have a score from 1 to 21, you can get a really nice separation of the various risk levels within that intermediate risk. It’s always been there. And it’s a good thing to recognize that you can get that level of discrimination in that intermediate group, using the continuous scoring system of REVEAL.

Let’s change gears a little bit.

So, can we talk a little bit about some of the other aspects you consider, when you decide what to do, how to manage your patients with pulmonary arterial hypertension?

Sure, I think that’s a really great direction to go in. I think we need to remind ourselves that our treatment goal is to achieve low risk for as many patients as we can do.

Because we’ve demonstrated better survival is associated with this low-risk status. And that’s my goal, that’s your goal and that’s what we should be teaching all of our colleagues who treat these patients in the community.

All risk tools have advantages and disadvantages and none of them can perfectly predict prognosis.

So, there is better need for integration of other tools into these parameters.

Particularly, imaging variables, so that we can better reflect on prognosis and make better predictions. So, these are a couple of my suggestions. So, Dr. McLaughlin, is there anything that you would like to add to this?

I think we feel both, very passionately that we are dedicated to taking care of PAH patients. But we want to work with our local docs. And it really takes a village to take care of the PAH patients. And then the other thing I wanna acknowledge is all the people that help us do this.

Yeah, those are really valuable points. So, I wanted to thank you, Dr. McLaughlin for sharing your incredible experience and providing your perspectives on how risk stratification can be useful in clinical decision making, at diagnosis, and throughout treatment.

The next video in this series, and you might wanna watch that, really builds on the story that we’ve created by focusing on right heart dysfunction, as an important indicator of disease status and patient prognosis.

In the meantime, I’d like to rehash some of the key points that we made on this talk today. And to leave our audience with some important caveats. First is that, comprehensive risk stratification is an essential part of patient management. Early and frequent risk assessment provides a timely indicator of treatment response and whether adjustments to treatment plans are really needed. As we mentioned earlier, every opportunity to risk stratify is an opportunity to help a patient get the treatment that they need.

That these treatment modifications should be based on objective risk stratification results, not just on clinical gestalt. And PH requires a proactive management scenario. It’s an entire village. So, collaborating with PH specialists and experts can really ensure that patients are optimally treated.

So, I wanna thank you again for being here with me today and it’s so great seeing you back here at the University of Michigan.

Ray, thank you so much. I always learn something every time I talk to you, and I really enjoyed our conversation today. Thank you.

Fantastic.

Thank you for watching. This program is part of a series of videos about how PAH management has evolved in recent years.

Topics covered in this series include the importance of hemodynamics, the role of risk assessment, the PAH treatment algorithm, and considerations for the treatment of PAH.

For more information on PAH, please visit: ResourcesForPAH.com.

[Advancing PAH Care: Understanding the Right Heart Beyond Pressure]

Welcome to the Advancing PAH Care video series. This series includes key opinion leaders discuss new information in the 2022 ESC/ERS treatment guidelines for pulmonary hypertension, and how these recommendations can be incorporated into clinical practice in the US.

Some of the topics to be covered in this series include risk stratification, the right heart beyond pressure, ESC/ERS treatment algorithms, and individualized patient care

With support from UT, the PAH Initiative provides nonbranded, disease education for the PAH Community. The Initiative worked with PAH experts to identify the content for this program.

I'm Dr. Paul Forfia, a cardiologist and professor of medicine and co-director of the Pulmonary Hypertension Right Heart Failure and CTEPH Program at Temple University Hospital in Philadelphia, and I am joined today by my partner, Dr. Anjali Vaidya.

Hi, I'm Dr. Anjali Vaidya, also professor of medicine and cardiologist at Temple University Hospital in Philadelphia, co-director of the Pulmonary Hypertension Right Heart Failure and CTEPH Program.

In this program, we're going to discuss right heart parameters, echocardiography and PAH, how these findings impact care decisions, and how echocardiographic findings are implemented into the updated ESC/ERS guidelines.

Dr. Vaidya, when we think about echocardiography, what are some of the echo findings that you think about when you're suspecting a diagnosis of PAH?

When I think about the views on an echo, one of the most helpful is that apical four chamber, sort of that money shot for pulmonary hypertension. And what we're looking for on this view is really evidence of the size, shape, structure, and function of the right heart parameters.

If the RV to LV ratio is enlarged, greater than one, that's very suspicious for pulmonary arterial hypertension.

Speaking of chamber size, the right atrium can also be assessed in size there which can be helpful down the line, even in our risk assessment. We're looking for the presence of a pericardial effusion in that view, which can also be a sign of very advanced disease and high-risk assessment in PAH.

And then, we're also looking for things like right ventricular hypertrophy, which is a sign of chronic afterload to the right ventricle, and then, an open RV apex, that angle of the RV apex being open rather than narrow. And that specifically is a marker of elevated pulmonary vascular resistance.

Now, other views on the echo that are also very helpful, the parasternal short axis to the mid cavity of the LV where you're looking for that septal flattening, that D-shaped septum, and that's what's traditionally described as septal flattening, reflective of RV pressure overload, but of course, what we know is it's really specific to afterload or that elevated pulmonary vascular resistance that you would see in PAH.

The other thing on echo that's really helpful on that initial diagnostic assessment is the pulse-wave Doppler in the right ventricular outflow tract, and of course, as you know, we're looking for that notching, or that reduced acceleration time, both of which are very predictive of a high PVR in PAH.

Now, all of that describes looking at the pictures directly, the images for echo, but you can also use routine echo reports to predict hemodynamics and help in the diagnosis of PAH, as well. So, there's something called VEST, the Virtual Echo Screening Tool, that we published years ago looking at routine parameters on echo and coming up with a simple score to predict if the pulmonary hypertension is due to left heart congestion, pulmonary venous hypertension where we would expect things

like an enlarged left atrium, an elevated E to E prime ratio, and numeric quantification to predict left heart congestion, and the absence of septal flattening. The flip side on a VEST score would be features that would give you a positive score, such as a normal left atrial size that the presence of septal flattening and a low E to E prime. And a positive VEST score is extremely predictive of pulmonary arterial hypertension.

So, echo can be used a lot in the initial diagnosis of PAH. In addition to echo, though, how do you use right heart catheterization in your diagnostic assessment of pulmonary arterial hypertension, but then, also, over time in your risk assessment?

Sure, so as we know, in order to make a formal diagnosis of pulmonary arterial hypertension, it is required that we obtain a full hemodynamic interrogation through invasive right heart catheterization and this allows us to measure pulmonary artery pressure, right atrial pressure, left atrial pressure, cardiac output, and then, derive pulmonary and systemic vascular resistance.

And so, when we think about how we use right heart catheterization at the baseline diagnosis, the things that I'm most interested in, how high is the PVR and how affected is the cardiac index, and how elevated is the right atrial pressure?

It's not surprising to know that on serial assessment PVR, cardiac index, and right atrial pressure are also very important to follow in patients serially on therapy. In fact, one of the most important parameters to see on follow-up hemodynamic assessment of a patient is what their cardiac index is on PAH medical therapy. This is far more prognosticating than even their baseline cardiac index is.

Dr. Vaidya, how do you use echocardiography to serially assess patients once a diagnosis of PAH has been made?

So, on the echo, we're looking at RV function. TAPSE, for example. We're looking at more extreme metrics that represent really severely decompensated right heart, so when the right heart is chronically congested and impaired in function and you have impairment of venous and lymphatic drainage via the coronary sinus, you can develop that transudative pericardial effusion.

So right atrial size actually has been shown to be predictive of risk in pulmonary arterial hypertension. To some extent, we're looking for reversal of some of those other diagnostic features, like improvement of that septal flattening, for example, and the overall improvement in RV morphology. But importantly, not just the assessment of the right heart on echo, it’s worth talking about the frequency of use of echo in the risk assessment in PAH.

So, we've learned over the years, and the guidelines, the ESC/ERS guidelines, also emphasize this; that echo should be used more frequently than it previously had thought to be. And so, at least every three to six months of using echo in risk assessment for PAH. And we've learned that frequent monitoring with echo actually improves our ability to accurately risk-assess patients

Now, in addition to the echo and the hemodynamics, in terms of the risk assessment in PAH, how do you incorporate both of those things in conjunction with some of the other important clinical parameters such as six-minute walk distance, functional class, or NT-pro BNP?

In order to best answer that question, I'd like to go back to thinking about the hierarchy of living systems and I think about organs, organ systems, and organisms. And so, the organ that's affected in PAH at the outset of disease is the lung and the lung circulation. And as that lung circulation is diseased and the pulmonary vascular resistance goes up, that affects the right side of the heart. That's your organ system. Right? It's the lung and the heart.

And so, I think of that as the leading indicator of the disease, and then I think about things that stem from that and happen later.

What can happen next? Your BNP is going up. What can happen thereafter are things that are a bit more pathophysiologically removed from those kind of core pathophysiologic changes, like a person is saying, "I'm more short of breath when I'm walking". Their functional class will rise. Their six-minute walk distance may go down. Ultimately, if those abnormalities persist, a patient may actually transition into having clinical right heart failure. You'll start to see fluid retention and even the patient may become hospitalized from de-compensated right heart failure.

And so, I like to think of the cardiac imaging findings as a leading indicator, and then, some of those more further removed parameters as lagging indicators. As you know, one of the key goals in the management of PAH is to actually get the right side of the heart to as close to normal in size and function as possible.

So, that's a really nice summary and actually ties into what we've often said about take a look at the heart to see what's happening in the lungs, which of course is then a predictor for what would happen to the patient entire. So, we've talked about a lot of components today of the right heart, and just to summarize, initially really looking at the echocardiogram to use parameters to help make the diagnosis of pulmonary arterial hypertension.

We've talked about the hemodynamics that are really important to support that diagnosis, and then, shifting gears into risk assessment, we've taken a bit of a deeper dive into looking at how the echocardiogram can represent markers of risk from the right heart and also how you use those complementary hemodynamic parameters to help predict risk in PAH over time.

And so, it's important to partner with our sonographers and our technologists to ensure that they’re able to obtain high-quality comprehensive echocardiography to make these assessments that we discussed, and it's important for the physicians to know that if we don't have access to that kind of echocardiography expertise, then, per the guidelines, it really would be very important to refer patients to accredited centers of pulmonary hypertension expertise who can then have access to that quality of echo.

And so, we've had a wonderful conversation talking about pulmonary hypertension and the right side of the heart and how it's been incorporated into the most recent ESC/ERS guidelines, and we're really delighted to partner with our colleagues who are continuing that conversation of how to use the ESC/ERS 2022 guidelines in the clinical care of pulmonary arterial hypertension.

Thank you for watching. This program is part of a series of videos about how PAH management has evolved in recent years.

Topics covered in this series include the importance of hemodynamics, the role of risk assessment, the PAH treatment algorithm, and considerations for the treatment of PAH.

For more information on PAH, please visit: [ResourcesForPAH.com].

[Video title: Advancing PAH Care: The 2022 Treatment Algorithm]

Welcome to the Advancing PAH Care video series. This series includes key opinion leaders who discuss newinformation in the 2022 ESC/ERS treatment guidelines for pulmonary hypertension, and how these recommendationscan be incorporated into clinical practice in the US.

Some of the topics to be covered in this series include risk stratification, the right heart beyond pressure, ESC/ERS treatment algorithms, and individualized patient care.

With support from UT, the PAH Initiative provides non-branded, disease education for the PAH Community. The Initiative worked with PAH experts to identify the content for this program.

I’m Dr. Franck Rahaghi, chair of pulmonary and critical care at the Cleveland Clinic in Florida, and thedirector of pulmonary hypertension program. I’m joined here by my colleague, Dr. Mandras.

I’m Dr. Stacy Mandras,the medical director of the pulmonary hypertension program and a transplant cardiologist at Advent Health in Orlando.

In today’s discussion, we will review the updated treatment algorithm that was published in the ESC/ERS treatment guidelines released in 2022.

Highlights from the guidelines include clarified treatment goals, strength in need for proactive, risk-basedapproach to treatment plans, the recommendation to use baseline and frequent follow-up risk assessments, an expanded risk assessment approach to include right heart parameters, and lastly, added guidance for patients with cardiopulmonary comorbidities.

So, Franck, with those key points in mind, let’s talk broadly about the PAH treatment approach before weexplore specifics around the treatment algorithm. What are your thoughts?

Yeah, so, I think one of the hallmarks of this version of the guidelines is actually frequent risk assessment. In the past, we used to focus on patients’ functional class and symptoms, and really, truly, risk assessment is a much better way to determine where the patient is in their evolution and what do they need next?

And again, another approach that we’re gonna take is not just be happy with necessarily the lower risk, but actually look for actual clinical improvement and having clinical improvement in mind.

So, let’s get into some specifics, Stacy. What do the guidelines recommend for initial management?

So, baseline risk assessment is recommended at diagnosis, and options include either the ESC/ERS 3-strata method, or, like we use in my practice, the REVEAL 2.0, and these are validated risk assessment tools that give us a much more comprehensive idea of whether the patient falls into a low, intermediate risk, or high risk, and treatment options depend on where they fall.

Most patients, it’s recommended, start on combination therapy up front. We learned from the AMBITION trial that patients who are started on combination ERA PDE5 do better than patients who are started on monotherapy with either one alone.

The guidelines recommend as initial therapy that patients who are low or intermediate risk are started on this combination of the ERA and PDE5. That said, patients who have severe hemodynamic impairment, either by echo or hemodynamics with the right heart cath invasive data, despite being intermediate risk, these patients should be considered for parenteral prostacyclin as part of their upfront combination therapy.

For high-risk patients, these patients truly should be offered parenteral prostacyclin upfront, either IV orsubq. It’s a conversation that you have to have with your patient, as there may be reasons why some patients are better candidates for one or the other.

And then lastly, patients who have certain cardiopulmonary comorbidities, like hypertension, obesity, these patients may also be considered for monotherapy upfront, but these are patients that you need to monitor closely.

So, with this overview of initial therapy recommendations, let me ask, Franck: in what ways does your follow-up management approach either align or differ with the guidelines?

Sure so, actually, to a great degree, they do align. So, it’s really important to have treatment goals, which we already had discussed involve getting the patient to low-risk status within a year or as soon as possible, frequent risk assessment, usually every three months seeing the patients, and you know it’s really important to be aggressive.

It’s kind of akin to the golden hour of sepsis, where you have a limited time to get the patient better.Studies have shown that if you don’t get them to low-risk status within a year, they will have poor outcomes. And that’s why we sort of use the risk assessment frequently, and in the follow-up, we now use the four-strata risk assessment.

In the past, and using, for instance, REVEAL 2.0, we sort of, in our minds, used to divide them in the sort of the low-intermediate and high-intermediate, and here, now, the criteria have been formalized for that, because we know that the low-intermediate, as you explained, and the high-intermediate have a differing way of following the patients.

Now, in addition, the guidelines have suggested, and we believed in it, that you have to also consider rightheart parameters.

As an example, I have a patient, I had a patient that was low risk, technically, but had a really dilated right ventricle, and this young woman with two kids, I figured that if something happens to her, she has no reserves. So, even though she was at low risk, technically, I escalated her care so that the right ventricle would shrink, and indeed, that’s what happened. So, an example of how to incorporate the right heart parameters on top of the guidelines.

And then, again, treatment follow-up is key, once you start something, to go back and check and see where the patient is clinically and where their risk are, so that you could escalate or continue the care.

The next question is, how do you determine when and if to make changes in the treatment plan, Stacy?

So, as you said, everything is based on trying to achieve a low-risk strata. So, if I see patients on follow-up, even on the very first follow-up, if I don’t see them improving from intermediate or high risk coming down toward low risk or achieving low risk, then we have to escalate therapy.

If at baseline they’re low risk and they maintain low risk at follow-up, we maintain their current regimen. If they were at increased risk, whether it’s intermediate or high risk, and they achieve low risk at follow-up, they stay on the therapy that they’re on.

If they’re intermediate-low risk, I would argue that is not good enough. I think most of us would argue, that is not good enough. Every patient should, if possible, achieve low-risk status, and so if they come onfollow-up and they’re intermediate-low risk, then those patients deserve some type of treatment escalation,

either transitioning from the PDE5 to the guanylate cyclase stimulator or addition of some form of prostacyclin therapy, whether it’s oral, IV, subq, or in the US, inhaled, which is not available in Europe, but for us offers a nice additional tool in our arsenal, as it tends to be verywell tolerated and demonstrates improvement in six-minute walk and functional capacity.

For patients who are at intermediate-high risk, those are patients, again, who should be escalated, and in that stance, I would say those are patients who should be offered parenteral prostacyclin. Again, they have a choice between IV or subq, and that’s a conversation that has to happen between the provider and the patient.

Sometimes there are other things that go into play, things like support, distance from the treatment center,etc. So, again, this is very much individualized therapy, and that includes, for patients who have thecardiopulmonary comorbidities that we discussed earlier, these patients need to be followed very closely,frequent follow-up is important, patients are seen sometimes every three months, our sicker patients may befollowed every one to two months.

So, we’ve gone through a lot of information here, Franck. Thank you so much for all of your insight. Would you please summarize some of the key points that we’ve covered?

Well, Stacy, thank you for your brilliant comments and your perspective. So, basically, if I want to summarize it, I would say that pulmonary arterial hypertension management requires proactive and routine monitoring and risk assessment and goal-oriented therapy based on the risk, and with the objective of gettingthe patient to low risk within the first year.

Thank you for joining us today for this discussion. The discussion on the treatment algorithm is only part of a series of videos that we encourage you to check out, so, with that

Goodbye…Goodbye

Thank you for watching. This program is part of a series of videos about how PAH management has evolved in recent years.

Topics covered in this series include the importance of hemodynamics, the role of risk assessment, the PAH treatment algorithm, and considerations for the treatment of PAH.

For more information on PAH, please visit: [ResourcesForPAH.com]

[Video title: Advancing PAH Care: Considerations for Individualized Care]

Welcome to the Advancing PAH Care video series. This series includes key opinion leaders who discuss new information in the 2022 ESC/ERS treatment guidelines for pulmonary hypertension and how these recommendations can be incorporated into clinical practice in the US.

Some of the topics to be covered in this series include risk stratification, the right heart beyond pressure, ESC/ERS treatment algorithms, and individualized patient care.

With support from UT, the PAH Initiative provides non- branded, disease education for the PAH Community. The Initiative worked with PAH experts to identify the content for this program.

[Dr. Dan Lachant]:

Hello and welcome. I’m Dan Lachant. I’m a pulmonologist and Assistant Professor at the University of Rochester Medical Center. I’ve been treating patients with pulmonary hypertension since 2017 at our nationally accredited center along with my mentor, Jim White. I have both a clinical and research focus in pulmonary hypertension and I’m joined by my colleague, Dr. Sophia Airhart, to discuss real-world approaches for managing patients with pulmonary arterial hypertension.

[Dr. Sophia Airhart]:

Thank you. Dr. Lachant. I’m Sophia Airhart, I’m Medical Director of Heart Failure and Pulmonary Hypertension at St. Alphonse Regional Medical Center and Adjunct Assistant Professor at University of Utah, who we collaborate closely with. I’ve been an advanced heart failure cardiologist for five years and have a strong passion for treating and recognizing pulmonary arterial hypertension.

Today, Dr. Lachant and I will discuss how updates in the 2022 ESC/ERS treatment algorithm can be applied to clinical practice, and the importance of individualizing treatment plans. As you know, these patients are complex and they require a team approach for best outcomes. And that’s why we’re here, as a cardiologist and pulmonologist, discussing PH and daily clinical practice.

The guidelines focus initially on early identification of pulmonary hypertension in the community, as well as really triaging these patients who are high risk to a center of excellence.

With regard to initial drug therapy, three strata, multi- parametric model is used that estimates prognosis in one year mortality and guides treatment with the goal of achieving a low-risk status within the first year of therapy.

Early close follow-up is also recommended every three to six months, and when a shorter four strata model is used, it really focuses on functional class, six-minute walk distance, NT-proBNP. As we know, it’s not black and white.

Dr. Lachant, what are some of the key factors you consider when managing these patients?

[Dr. Dan Lachant]:

Those are all great points that you just highlighted, Dr. Airhart.

The good news is that with new treatment strategies and medications, the outcomes have improved, and I think a lot of that’s due to frequent follow-up that you described.

Another important point to consider when treating patients with pulmonary arterial hypertension is the comorbidities associated with it and that's where being at an expert center really helps patients. So, whether somebody has scleroderma, cirrhosis, GI bleeding – we have specialists who are well aware of pulmonary arterial hypertension, as well as the medication side effects And also developing strong support systems is extremely important. We provide patients with an emergency number so that they can contact us 24/7 if they have an emergency

And finally, the biggest thing that helps these patients is just joining the Pulmonary Arterial Hypertension Association support group system.

Networking with patients and families who have been through this journey is extremely valuable and can really help provide reassurance for these patients.These are just some of the factors I think about when managing patients with PAH. Dr.

Airhart, is there anything else you would like to add? [Dr. Sophia Airhart]:

You bring up a lot of really important points and I would like to reiterate those as well, but I start with generic lifestyle recommendations as well as the importance of exercise.

So, with regard to lifestyle recommendations, I recommend limiting fluid intake to less than two liters a day and salt to less than two grams a day, but clearly it’s going to be patient dependent. I think exercise training is really important. It helps people sleep better, it decreases dyspnea, and it improves their exercise tolerance.

And are these patients able to maintain medications schedules? You had mentioned maybe in health therapy it’s better for patients, is it more convenient for them to be on BID therapy, can they handle TID therapy or is continuous therapy more conducive to their life? And so, asking all those questions to really find out who they are and how they can best support them is important.

Oftentimes, after diagnoses, these patients go online and it can be very overwhelming and they come back to your clinic the next day and they ask, “Am I gonna live? How long am I gonna live?” And I think that that is a doorway to have the conversation of risk stratification in pulmonary hypertension and how that informs treatment and why we do what we do in terms of lab monitoring and frequent six- minute walk tests so they can be a partner in their care.

Also, when patients present at higher intermediate risk or aren’t doing the way we hoped

We talk about escalating to parenteral therapy, I usually integrate conversations about, you know, being considered for lung transplant because I don’t want that conversation to take patients by surprise and oftentimes, they need to prepare.

So, there are a lot of nuances in PH care. Dr. Lachant, as a PH expert, what is your perspective on the role of PH centers and managing these patients?

[Dr. Dan Lachant]:

That’s another great point you brought up about lung transplantation that ties in nicely about PH centers and experts who treat this.

What we wanna do is develop a co- management strategy.

The other thing is we also don’t want to take ownership of their patients. We like a collaborative approach, especially in patients where it’s difficult for them to travel. We like having an option locally for them to be able to still see another provider, have frequent check-ins, stagger visits

The Pulmonary Hypertension Association makes it easy for patients to find centers across the country so if they want they can reach out.

And given where we are with the advances of telemedicine, I think all patients should have at least one interaction with a pulmonary hypertension center and from there, they can decide what’s important to them, what the center thinks, what their local physician thinks in terms of who should take ownership of some of their more advanced therapies – do they need advanced therapies? But that first, initial interaction is extremely important for all patients.One important factor in patient care is how to best manage concurrent cardiopulmonary comorbidities. Dr. Airhart, can you talk about how the guidelines recommend managing patients with these comorbidities and how these recommendations align with your current approach?

[Dr. Sophia Airhart]:

Yeah, really great question. So, when I have a patient in front of me, it’s rare that I have a patient just with PAH. Usually they have other chronic medical conditions. And so, the first question I ask myself is, is their PH due to their other medical conditions or is this PAH with comorbidities?

Well, the guidelines recommend more cautious monotherapy in patients who have cardiopulmonary comorbidities as well as more close monitoring, particularly because we know these patients with comorbidities have poorer response to PAH medications and a greater likelihood of discontinuing medications due to side effects, as well as a lower chance of reaching a low- risk status and a higher mortality risk.

Because these patients are at higher risk of side effects, we discuss side effect management proactively as we do in the PAH population and I know you do in your population, so really they can be more likely to tolerate therapy and therapy escalation because their other big risk is that these patients be undertreated.

We know that PAH is a progressive incurable disease, and we don’t wanna undertreat this higher risk population, so that’s why frequent follow- up, as well as aggressive side effect management is essential.That’s my approach as a cardiologist, but Dr. Lachant, I’d love to hear your thoughts from a pulmonology perspective on this complex patient population.

[Dr. Dan Lachant]:

From a pulmonary perspective or a pulmonologist perspective, the two tests I really like to look at are pulmonary function tests and CT imaging. Most patients have had these checked at some point and really what I’m looking for is do they have any airways disease.

So, depending on what those two tests show, we kind of decide with the patient collaboration of is this somebody who I’m concerned medications will disrupt their VQ matching and make their oxygenation worse? And if that’s the case and they wanna feel better, we typically admit these people to the hospital for

24-48 hours, make sure their oxygenation doesn’t get worse, then we send them home and follow them up generally in three to four weeks.

And some of our other patients where structural lung disease is less of a concern, we follow a general strategy that you described where we contact them, they keep in contact with a specialty pharmacy, they send us updates, and we generally see them within three months to make sure we’re headed towards that low-risk status.

[Dr. Sophia Airhart]:

Thank you Dr. Lachant for sharing your experience and insights on the treatment guidelines and how we really need to layer in individualized care plans. We covered a really wide range of topics that require specialized approach. What are your key takeaways from our discussion today?

[Dr. Dan Lachant]:

Thank you, Dr. Airhart. I learned a lot from you especially how you view things from a cardiology perspective and just hearing your experience was very eye-opening and enlightening

[Dr. Sophia Airhart]:

Yeah, I think those are great take- home points. Another thing I would add is that early recognition is really important and it’s important to collaborate with everyone out there to recognize this patient population because they’re not all in highly dense areas and the earlier we recognize pulmonary hypertension, the earlier we can treat pulmonary hypertension and the better patients do. So, thank you everyone for joining us today. It’s been a great conversation. Please check out the other videos online as well in the series. VOICEOVER OUTRO:

Thank you for watching. This program is part of a series of videos about how PAH management has evolved in recent years.

Topics covered in this series include the importance of hemodynamics, the role of risk assessment, the PAH treatment algorithm, and considerations for the treatment of PAH.

For more information on PAH, please visit: ResourcesForPAH.com

Guidelines can help guide treatment choices, but selecting the final treatment should be based on the individual patient situation and needs and not just following an algorithm.

The most important thing I took away was frequent follow-up is the biggest thing, especially for starting monotherapy. We wanna make sure that patients are actually improving and we’re not just settling for status quo. And co-managing patients with PH centers has many benefits and like I said before, I think all patients should have at least one evaluation with a PH center to make sure everything is the way it should be.

[Video Title: The Echo in PAH: Right Heart Imaging In Clinical Practice]

I'm really excited to continue this conversation today.

Thank you so much.

Dr. Ryan nicely took us through the pathophysiology of pulmonary

arterial hypertension followed by the treatment goals in pulmonary arterial hypertension. This is a huge topic.

We're going to transition now into focusing, in a little more detail,

on the imaging and clinical practice in pulmonary arterial hypertension.

The emphasis of course, being on echocardiography. This is a critical component of patient care in PAH as a screening tool. It can be very helpful, if a patient is suspected to have pulmonary hypertension to evaluate the probability of PAH.

Echo is not sufficient alone, but wow, it can tell us a lot more than

I think was previously appreciated, and we'll talk about how to do that.

And then of course, as a monitoring tool, meaning once

someone already has a diagnosis of PAH, the monitoring is really

critical, and it should be done with high frequency to identify

early recognition of a patient's clinical status that's declining.

So, the Echo really is a highly available and helpful noninvasive

assessment that can give us information truly on the hemodynamic

right ventricular burden that measures RV structure and function.

So, it's a first-line screening tool, and it really can help

predict if a pulmonary vascular resistance is elevated.

It can take it a step further and give us really direct clues to

discriminate between pulmonary venous hypertension or PVH that's

WHO Group II or left-sided filling pressure is being elevated.

That's what Dr. Ryan referred to when the wedge pressure is elevated and

discriminate between that versus PH due to pulmonary vascular

disease, which is when that pulmonary vascular resistance is

elevated in the context of normal left heart filling pressures.

So, there are quite a few clues. This slide very nicely shows one that is really kind of prominent to the eye.

So, this is the apical 4-chamber view of the echocardiogram.

You can see the focus on the right side of the heart being the very

large chamber on the picture, on the left of your screen, which

is PH due to pulmonary vascular disease, or what would represent PAH.

And you can see here that the right ventricle is bigger than the left

ventricle, but specifically I want to bring your focus to the apex

of the right ventricle itself.

And you can see that first of all, the right ventricle is forming the

apex of the entire heart, but more specifically, the angle of the

right ventricular apex is wide open.

And, when you see that red line sort of measuring the diameter in the

apical 4-chamber of the heart, and it's measuring close to the apex of

the heart, that red line is truly almost as wide as the dimension of

the base of the right ventricle. You could even argue that they're about equal.

Now in contrast, the Echo on the right side of your screen is

pulmonary venous hypertension.

The pulmonary pressures may be equally high in both of these hearts,

but the patient on the right side of your screen has high pulmonary

pressure is not on the basis of a high pulmonary vascular resistance.

Instead, it's on the basis of high left-sided filling pressures,

and it looks vastly different. The apex of the right ventricle is normal here. It is narrow, the apical angle, relative to the base of the right ventricle, which has a much broader dimension.

So, the base-to-apex ratio in somebody with a normal pulmonary

vascular resistance or a right ventricle that has not been

chronically exposed to a high after load, that base-to-apex ratio remains

high, certainly greater than one, even greater than one and a half.

And this was studied and published in our group a few years ago,

in contrast to those again, with pulmonary arterial hypertension

on the left, where that base-to-apex ratio is much lower. The apical dimension is much wider. So, if that base-to-apex ratio is less than one and a half,

or even more simply stated, you look at that heart and the apex

of the right ventricle is wide open, you're immediately thinking

this is an elevated PVR, and you're going down that road of

urgent hemodynamic assessment.

Let's take that step further and kind of add to our toolbox now, of

clues that can give us a sense to predict if this is pulmonary arterial

hypertension, pulmonary vascular disease, PVD, or left heart disease.

This is the Echo score paper that we published about 10 years ago now.

And this is a culmination of work looking at several different Echo

Doppler parameters that represent the right heart, hemodynamics,

the left heart, size, Doppler features, and it's simplified here.

These were the parts of the score that were most predictive of the hemodynamic profile. And it's a very simple score. This warrants looking at the Echo pictures directly.

I'm going to start with the features on the top of the table,

which represent what the most common scenario is in all of our

clinical practice, which is left heart failure, WHO Group II,

pulmonary venous hypertension.

So, the features that would help you predict that when you're looking at

Echo pictures are features that correlate with high filling pressures on the left side of the heart.

So, all the cardiologists know that when you're looking at an Echo that

transmitral-to-tissue Doppler ratio, that E-to-E prime, if it's elevated,

this is a well-established marker of high left heart filling pressures.

Of course, all of our pulmonary colleagues who are experts in pulmonary hypertension know this as well.

And this has become a really helpful tool that all of us can recognize.

So, when the E-to-E prime is high or greater than 10, that predicts

high left heart filling pressures. This would be more consistent with pulmonary venous hypertension or WHO Group II PH.

Similarly, when a patient is presenting with shortness of breath,

dyspnea, and it's on the basis of pulmonary hypertension that you're

seeing is elevated on the Echo, if their left atrium is enlarged, that

also would correlate with pulmonary venous hypertension, which is

literally left atrial hypertension.

So very simply, very early on when you're looking at an Echo,

you're looking at left atrial size and that E-to-E prime ratio.

If they're enlarged or elevated, you're already thinking

this is more likely to be pulmonary venous hypertension.

Now, the flip side to that is what gets us really excited in the context

of pulmonary arterial hypertension. You have a patient who has shortness of breath.

Their pulmonary pressure is estimated on Echo, but again, that doesn't

tell you what's really wrong with the patient—you have to look further.

So, when you look at that and you see that the left atrium is

normal in size, that sort of tells you that, wow, this patient can't

have pulmonary hypertension on the basis of left atrial hypertension.

If their left atrium is small.

So that's already a clue that this may be more likely a pulmonary

vascular disease problem. Now, the other parameter exists in the pulse wave Doppler in the RV outflow tract.

And what we're talking about here is when you eject out of your RV

outflow tract through the pulmonic valve in systole, and you have a

high afterload, a high pulmonary vascular resistance, you get a

reflected wave back into your RV outflow tract before that pulmonic

valve closes at the end of systole. When that happens, that reflected wave back causes an indentation or a notch in that pulse wave Doppler profile. And that also correlates with a rapid peak at acceleration. So, a shortened acceleration time.

So, the flip side of pulmonary venous hypertension on an Echo report would

be features of pulmonary arterial hypertension, a high pulmonary

vascular resistance, meaning a notch in the RV outflow tract, or a reduced

acceleration time in the context of a normal or small left atrium.

So, let's put that into a little bit more perspective. Let me show you some more data about how that pans out.

The score, if it's positive is highly suggestive, again, of

pulmonary arterial hypertension, pulmonary vascular disease, and

you really need to move quicker for hemodynamic assessment.

You'll see that when the score goes from negative to positive, that wedge

pressure falls, the transpulmonary gradient increased, and the pulmonary

vascular resistance increased.

Now, a simpler way to look at this, if you don't have access to the

actual direct Echo images is what we call the virtual Echo screening tool.

This is a paper we published in 2020, looking at just the routine

Echo reports that can help predict the hemodynamic profile and

pulmonary arterial hypertension.

For all of our colleagues and friends who may not have easy, readily

accessible pictures to look at, just look at your routine Echo report.

Look at that E-to-E prime that's automatically populated

into the report when our technicians obtain it.

If you don't have the tissue doppler, E prime just look at that E velocity.

You can use 90 centimeters per second as a cutoff.

Look at the qualitative description of left atrial size if it's

at least moderately enlarged.

Look at that presence of the D-shaped septum, the interventricular

septal flattening that correlates with RV pressure overload.

We've all been taught this. Please remind yourself and your trainees that, that's specific to high resistance, it's not just pressure. So, when you see the D shaped septum and the left atrium is

normal or only mildly enlarged, and that E-to-E prime is low, or

that transmitral E velocity is low.

You get positive points for all of those, and that all correlates with

pulmonary arterial hypertension, or pulmonary vascular disease.

Those 3 parameters, very simply on a routine Echo report in VEST can identify patients with WHO Group 1 PAH. That's the graph on the left of your screen. You can see it's highly discriminatory to distinguish

between Group 1 and Group 2 PAH, as opposed to kind of the tempting

downfall of relying too heavily on the PA systolic pressure.

And you can see when doing that in the same cohort of patients with

pulmonary hypertension, there's a little ability to discriminate at all

between WHO Group 1 and WHO Group 2.

So positive VEST score has a higher sensitivity and specificity for

WHO Group 1, pulmonary arterial hypertension than simply PASP.

And so any patient with a VEST score that's greater than zero should be

referred really quickly for right heart cath to complete an additional

PAH evaluation and the goal here to recognize patients sooner and

really get them to their accurate diagnosis, much faster than our

current standard, unfortunately, which is up to two and a half or 3

years and waiting for patients to already be Functional Class 3 or

4, the imaging can show improvement in therapy and deterioration before

patients really clinically worsen.

So, we've talked about this kind of graph before where the pulmonary

pressures go up and you start to see these other changes on Echo.

The RV wall starts to thicken end diastolic volume increases.

And we start to uncouple the right ventricle in the pulmonary artery

and really worsen our contractility efficiency in that coupling.

And with that maladaptation, you see in the blue line, that

cardiac output really falls on the basis of a reduced stroke volume.

So, these are some of the morphologic metrics that are indicative of a

significant remodeling from PAH.

To put some of these concepts together—there’s that open RV apex,

that apical widening that you see on the left side of the screen.

RV hypertrophy is a sign of chronic remodeling—when the

RV wall is greater than 0.5 centimeters in thickness.

The RV-to-LV ratio, which is seen really nicely here in the apical

4-chamber, it should be less than kind of two-thirds or so, 0.6, 0.7.

When you measure the dimension at the base of the ventricles,

just above the valve plane, and that RV is greater than LV,

that's a right ventricle that's at least moderately enlarged.

The presence of the pericardial effusion gets a lot of attention in

PAH, and it's critically important to recognize, but unfortunately, we

can't rely solely on this because it is a marker of late disease.

So, it does correlate with mortality.

And the reason that a pericardial effusion happens in PAH is because

it represents impaired venous drainage into the right side

of the heart, which happens via the coronary sinus, very large

thin-walled venous structure that runs through the posterior AV groove

alongside the circumflex artery.

When you have such chronic and severe congestion and pressure

elevation in the right heart, it impairs that venous drainage from the

coronary sinus into the right heart.

As such, it then leads to a transudative effusion that builds

up as a representation of this.

It's what I call RV pitting edema, but it's not actually

the effusion that's dangerous, it’s that the effusion is a

marker of severity of disease.

Now the right atrial area has also been shown to correlate with outcome

and mortality and so you can get this sense here when it's measured in end

atrial diastole, that area is greater than 18, that’s a really high risk.

In the parasternal short axis. This is that septal flattening in systole is key. And just a reminder, when you see that D-shaped septum in

systole, it's not just for all versions of high pressure.

You won't see that as commonly or at all when PH is purely on

the basis of pulmonary venous hypertension, but when the pulmonary vascular resistance is high, you will see that. So that can be really significant and notable. TAPSE is a marker on Echo of right heart function. It stands for a tricuspid annular plane systolic excursion.

It is a measurement of longitudinal contraction of the right ventricle,

which in native hearts that have not been operated on, represent

70 to 75% of RV contraction.

So, while there are some limitations in this measurement, it's been

shown to be the most kind of reproducible with inter-rater reproducibility and reliability.

It's quite simple and easy to obtain and can be obtained

quite quickly in measurement.

So, it's really been a valuable thing to monitor serially.

This is a paper our group published a few years ago, showing that

if you achieve a normal TAPSE or TAPSE greater than 2 centimeters

on pulmonary hypertension medical therapy at 1 year, your survival is much greater than if you did not achieve that.

And I think it's really important to emphasize here that it's not the

RV function or the TAPSE at initial diagnosis that's the most predictive.

It's how you respond to therapy and really being progressive with therapy

to try to achieve this goal of a TAPSE greater than 2 in this study

that predicted mortality at 1 year.

So, in summary, there are a lot of concepts to go over today

that we discussed, but a really important goal and concept is

that we're trying to achieve near normalization of the right heart.

However, the right heart performance can be measured, those are the

parameters we are trying to generally achieve to achieve a

low-risk status for our patients and improve long term survival in PAH.

So, we're evaluating the structure and function of the right heart.

This is needed at the time of diagnosis and frequently throughout treatment.

We want to frequently monitor this and supplement it with our kind of

integrated Echo Doppler assessment to help inform our treatment decisions.

It might guide us to be more proactive and progressive in our

treatment escalation, than if we solely relied on Functional

Class and 6-minute walk.

We know that these changes to the right heart can often occur

before the subjective changes, or the functional capacity may

definitively change, and we certainly see that time and time

again in our clinical practice.

And it's really important to note that while patient symptoms are so

important for them and for us, if we wait for them to worsen before

we adjust their treatment regimen, we may miss an opportunity to

improve their functional impairment.

So, I'll stop there with this topic of discussion and really

grateful to have the opportunity to discuss all of this. Thank you.

Dr. Raymond Benza:

Welcome to the Pulmonary Arterial Hypertension Initiative podcast. This podcast is sponsored by and the presenters are being compensated by United Therapeutics. In this series of podcasts, we will talk about how PAH treatment guidelines and risk calculation drive treatment decisions in pulmonary arterial hypertension, as well as their own experience in treating our patients with PAH. My name is Dr. Raymond Benza. I'm a practicing cardiologist in the state of Ohio and currently serve as the division director for Cardiovascular Medicine at the Ohio State University. And I have the pleasure of being with one of my longtime colleagues, Dr. Vallerie McLaughlin.

Dr. Vallerie McLaughlin:

Hi Ray. It’s great to be here. I’m looking forward to this podcast. I am also a cardiologist and endowed professor at the University of Michigan, and I direct the Pulmonary Hypertension Program here.

Dr. Raymond Benza:

Thanks Val. In today's program, we will be discussing the importance of risk assessment and pulmonary arterial hypertension management. According to the PAH treatment guidelines, risk assessments should be driving our initial therapy choices as well as any changes in therapy. So let's get started. So Val, can you describe to me what risk assessment is all about in pulmonary arterial hypertension?

Dr. Vallerie McLaughlin:

Yeah. Ray. I think that we as cardiologists have really incorporated risk assessment into really many different diseases. We use different scores for NSTEMIs and STEMIs, and CHA2DS2-VASc for AFib. We live this, this is really something that is important to objectively care for patients. And over the years, we have learned about the important parameters that are prognostic in patients with pulmonary arterial hypertension. We've learned from many databases that have included thousands of patients, the parameters that assess a patient's risk or the severity of their illness and what their likelihood is of having an event over time. I think the multiparameter approach is really critical because this is a very complex disease and there are many different predictors, including how the patient is feeling, whether or not their right ventricle is failing, what their symptoms are like, syncope, how dyspneic they are, what their Functional Class is. Those are all clinical assessments of the patients. Echo has not been incorporated as much as I would like to see it.

We are really just more recently getting savvy about quantitating right ventricular function. So if you look at the registries, the Echo parameters that are included most often include right atrial area and the presence of a pericardial effusion. I think we both know how that right ventricle function is really critical in terms of the outcomes of PAH patients. And then of course, hemodynamics are important. They define the disease and also reflect the function of the right ventricle. And so when we talk about a multiparameter risk assessment, we're looking at many of those different parameters and trying to assess whether we think our patient is at low, intermediate, or high risk over the ensuing years. And we learned from each registry that no matter what the treatment is, if we can get a patient to a low-risk status, their 5-year mortality is very minimal and that should be our goal for the patients to reassess their risk and to drive them into that low-risk status. Ray, is this your approach as well?

Dr. Raymond Benza:

It is my approach. And I think you really eloquently described the available nuances that we take into consideration when we do these assessments of risk, including very importantly, the multiparameter approach. We never hang our hat on just one variable. And I also wanted to really emphasize the piece about imaging because, as we’ll talk about it a little bit later, many of the contemporary tools that we have lack sophisticated imaging parameters as part of them. And I think the tools that we have and that we use and that we will describe later, have to be really used in conjunction with some of these other newer things that are coming out that we think are important, but achieving low risk and using the multiparameter approach, I think of the 2 salient issues that I really would like our practicing clinicians to take away from this.

Dr. Vallerie McLaughlin:

Yeah. I agree. Let’s talk about how often we should be performing those risk assessments. What’s your approach to that?

Dr. Raymond Benza:

I think at least at baseline is probably one of the most important parts of risk stratification. Really, when a patient comes to your clinic for the first time, they may not have been on therapy. They’re just newly diagnosed. They’re really assessing their baseline risk; it’s very, very important. Not only for the treatments that we decide to place them on, but also for the patient’s information and their own means to plan their lives for the next year or 2. And then after that initial assessment, and I think at minimum, every 3 to 6 months, we should be evaluating our patients, but I’d like to get your opinion on a more detailed approach and maybe peaking at a patient every time we see him in our clinic. What do you think about doing risk assessments even in our routine clinic?

Dr. Vallerie McLaughlin:

Oh, Ray. I think that’s really key. I do that every single time I see a patient, I think pretty much every encounter we have with a patient, it’s an opportunity to assess their risk and consider whether or not we’ve gotten them into that low-risk status because that’s where we want them. So we can look forward and have confidence that they’re going to do well. So Ray, there are lots of ways to assess risk. Maybe we should go on and talk about some of those methods and you were really the genius behind the REVEAL risk calculators. Why don’t I talk about the ERS approach, ESC approach, and the French approach. And you talk about REVEAL, if that’s okay with you?

Dr. Raymond Benza: That’s perfect Val. Dr. Vallerie McLaughlin:

Yeah. The ESC and ERS guidelines published in 2015, this table, the very famous table. Green, yellow, red stoplight sort of table about a number of different prognosticators in pulmonary arterial hypertension and cut points that put them at low, intermediate, or high risk. Most of these are derived from registry data. Some of them are derived from gestalt, right? Like syncope is really a gestalt thing and an observation that we’ve made, but not really included in registries. So the important determinants include Functional Class. So we know patients who have Functional Class 4 symptoms do very, very poorly and Functional Class 1 and 2 do well, and Functional Class 3 sort of in the middle. We have discussed hall walk already, the exercise tolerance, objective exercise tolerance is something that’s very important and that can tell us about a patient’s prognosis. So greater than that sort of magic 440 number, patients do well, less than the mid-100 patients do poorly.

The Echo data and well, this is different; something I actually would like to talk to you about. The Echo data in all of these is really very limited. The presence of a pericardial effusion, which has been published a few times and the size of the right atrium—that’s really the data that we have from registries that go into these scores. And I think that’s a bit of a pity actually and personally, when I do an Echo on a patient, I go look at that right ventricle. It really is very meaningful to me and, I think, anyone who has experience in this disease. I think that it’s unfortunate that many registries don’t have a quantification of right ventricular function. Not all Echo labs quantify right ventricular function. And so really we have very limited imaging of the right ventricle in any of these risk scores, but I think it’s so, so important. And I guess sort of in my head, I incorporate that when I see patients as well. I just thought maybe you’d want to comment on that, Ray, before we move on.

Dr. Raymond Benza:

Oh no, I agree with you 100%, Val. I think all the tools that we have developed were developed in eras when imaging wasn’t as prominent as a known risk player in prognosticating. And I agree with you that as these risk scores and equations evolve, that I would love to see more imaging data in the scoring systems. And I think the important thing about that is if you really look at the spectrum on how a patient evolves or progresses with PAH, we have changes in pressure that then lead to changes in the right ventricle. And these changes can occur very early, even before many of the other symptoms or variables that are accounted for in these 3 scoring systems happen. So it even might add a level of greater sophistication and predictability for early decompensation by including these imaging parameters, entities, contemporary scoring systems that we have.

But ultimately, I think that it’s the combination of these things that are important, as you mentioned earlier, the ESC and ERS guidelines and even the French method, which use a number of variables that are within the guidelines. There are some differences between the calculators that we have developed in REVEAL, but I was curious if you might want to go into a little bit more about some of the French methodology for calculating risks before I went into what we do with REVEAL.

Dr. Vallerie McLaughlin:

Yeah, for sure. In fact, let me just make a couple more comments on ERS/ESC. So we talked about the syncope, right ventricular failure, Functional Class, hall walk or cardiopulmonary exercise testing PCO2 is listed. Biomarkers are also included, BNP less than 50, NT-proBNP less than 300. Very good prognostic indicators puts the patient in a low risk. Whereas if the BNP is greater than 300 or NT-proBNP is greater than 1400, that puts the patient in a higher risk. And then of course, hemodynamics are also important in terms of risk. And we’ve known for many years, and this point is emphasized in the risk assessments. It’s not what the pulmonary artery pressure is. It is how the right ventricle is coping with that pulmonary artery pressure. So, right atrial pressure, cardiac index, and SvO2 are the hemodynamic parameters that are most predictive. So, that’s the ERS/ESC approach.

Now the French approach, which I really like, is very simple. They took a different approach. They basically said, these are the 4 factors that are most important to us. And it has to do with being in Functional Class 1 or 2, having a hall walk over 440, having a cardiac index greater than 2.5, and a right atrial pressure less than 8. And so those are the 4 factors using the invasive French approach that they look at. And if you have 3 or 4 of those 4 factors, your prognosis is very good. Whereas if you have less than that, the prognosis is quite poor.

And then when they had a subgroup of patients that also had biomarkers and they can incorporate the BNP or NT-proBNP, when you put that into the multivariate analysis, the right atrial pressure and cardiac index falls off. And so the noninvasive French is really just Functional Class, hall walk, and biomarkers. And at least for me, that’s something I do in clinic every time I see a patient. I have all 3 of those parameters every time I see a patient. So that’s the noninvasive French approach. Ray, you want to tell us about REVEAL?

Dr. Raymond Benza:

Yeah. Thanks Val. So REVEAL calculators are in essence, very similar to the ESC/ERS guidelines and the French method in that they both use very similar variables. And that’s good because that tells us that all the contemporary risk stratification scoring and systems that we use are complimentary. And we could feel safe using them because many of the variables are shared. REVEAL takes it just a little bit further down kind of the statistical pathway, than the guideline or French method in that REVEAL methodologies are really derived from very standardized statistical modeling. And very importantly, that the variables that are used in these scoring systems are weighted against each other so that you know the relative importance of one variable versus another. For example, the Functional Class may be more or less important than an NT-proBNP level. So it kind of gives you a way to really summate the risk with a little bit more sophistication than some of the European methods.

So REVEAL Lite 2 is the derivation of an earlier model called REVEAL 1.0, and what REVEAL 2.0 did is, it took a lot of the same variables that we had found in the original REVEAL 1.0 calculator, which contains both demographic vital signs and other more objective measurements and add it to that hospitalization and the risk that is imparted by recent hospitalization for pulmonary hypertension and heart failure. It gave us a more objective means of measuring renal function, which we know comorbidities are very important part of risk stratification and renal function is one of the very important ones that have been highlighted and uses a GFR and then set of a subjective assessment of renal insufficiency. And also changes some of the scoring points and actually adds a more of a dynamic nature to the changeable risk factors like BNP and the 6-minute hall tests.

So it takes those variables and then weights them, and you can calculate a score that very nicely discriminates between low, intermediate, and high risk. Now, the difference between REVEAL 2.0 and REVEAL 2.0 Lite is just the number of variables that’s required to make the calculation. The parent score, which is the REVEAL 2.0, scores 13 variables that are associated with it. And these contain some immutable risk factors. The factors that don’t change over time, like a patient’s type of pulmonary hypertension that they have and their gender and age, even though age does change the risk points, here it is a kind of a combination of age and gender. And then it has a number of easy-to-discern variables, including vital signs like low blood pressure or high heart rate combined with the Functional Class NT-proBNP levels in which there are several cut points, and 6-minute walk distance, which also has several cut points.

And then add to that the Functional Class and Echo estimates of pericardial effusion that you mentioned earlier, and then hemodynamics, which include importantly, the right atrial pressure and the pulmonary vascular resistance. And then REVEAL Lite, takes the parent calculator and really strips it down to the easily obtainable, changeable variables that you can assimilate in each clinical encounter. Very similar to the French method in that it uses vital signs, Functional Class, the hall walk test, the NT-proBNP levels, and the vital signs. But the big difference, as we mentioned earlier, is that these factors continue to be weighted against each other, such that the discrimination index with these more statistically derived methods are a little bit higher than those that don’t incorporate weighting. Well, I hope those descriptions of the algorithm and calculators were helpful to the audience, but I’d like to ask Dr. McLaughlin, if she has any further opinions or statements that you wanted to make about the formal risks calculations that we make?

Dr. Vallerie McLaughlin:

I think that was a really elegant discussion of how REVEAL was developed. And one thing I want to highlight is the difference between 2.0 and 2.0 Lite, including the nonmodifiable risk factors. I think when we have nonmodifiable risk factors in a risk calculator, it’s an excellent way to predict prognosis. In fact, I think there’s probably nothing more accurate at actually predicting prognosis than REVEAL 2.0. But sometimes when we think of driving people to low risk, we get a little challenged because there are so many nonmodifiable risk factors in it that, sometimes our patients are going to be at very high risk, no matter what we do. And that I think is one of the things that we’ve discussed over the years about using calculators and driving patients to the low-risk status. And I think REVEAL 2.0 Lite very nicely addresses that issue and really includes the risk factors that you can treat with our medical therapies and have success at trying to drive patients into a low-risk status.

I think that’s a really important differentiation and in fact, REVEAL 2.0 Lite and French are very similar with the exception of the additional parameters of vital signs and kidney function. I think we’ve discussed 4 different tools and they’re all very good. They’re all very meaningful. If you get into low-risk status with any of those tools on therapy, no matter what the therapy is, the patient’s prognosis is good and that’s what we’re looking for—to improve the patient outcomes. And so that leads us to the next discussion point. We have this really wonderful data from all of these risk calculators that show if we can get them to low risk, they do well. So let’s talk a little bit about why it’s so important to use a formal risk calculator rather than just gestalt. Do you have any comments on that, Ray?

Dr. Raymond Benza:

Yeah. Thank you Val, for pointing that out. I think that is really important. And as we mentioned earlier in the talk, these tools are very complimentary to each other, and I think that can be used together—a more formalized, detailed risk assessment with REVEAL 2.0, perhaps at baseline and maybe at a year. And then when you’re doing the peak of patient, like you mentioned earlier, watching them at each one of their clinical visits, maybe that’s the time where you can implement the French method or REVEAL Lite. To get those on the fly risk assessments, just so that you make sure that you are actually plotting the trajectory correctly. Clinical gestalt, they think can really mislead us in certain circumstances. Now we even have a recent study that compared clinical gestalt and the formal risk calculation, and by reviewing patient’s charts from clinicians who treat patients with PAH. And both clinical gestalt and the calculated risk were aligned in less than half of the 365 charts that they examined.

I found that very surprising; 80% of the patients that are estimated to be low risk by clinical gestalt were actually reassigned to a higher risk category after formal risk calculation. That’s really important because underestimating risk is where patients can really be hurt because that’s where you wouldn’t use as an intensive mode of therapy, as opposed if they were really low risks. So that’s a really important thing is just not to miss the intermediate or high-risk patients by utilizing a less nuanced way of predicting risk. And I think there have been other studies that looked at formal risk calculation in these earlier patients functional two class patients.

And I believe a retrospective chart analysis of 153 Functional Class 2 patients who were either on mono- or dual combination therapy. And more than half of the Functional 2 patients were classified as intermediate or high risk when their risk was calculated. So again, these are patients whom if we use the single variable of assessment like Functional Class or even clinical gestalt, we would have underestimated their risk and perhaps not put them on the intensity of therapy that the patients deserved to be on.

Dr. Vallerie McLaughlin:

I think those are great points, Ray, and I think we always have to have some common sense, some gestalt in medicine, but this is an example where risk calculators are helpful. But I might point out Functional Class, as we’ve talked about, is subjective. Maybe a patient sounds Functional Class 2 because they’ve limited their activities so much that they don’t get short of breath. A really skilled historian can try to dig that out, but sometimes patients just adapt. And it also leads to the next topic of discussion is relying too much on one thing such as Functional Class. I mean, for many years before we had all of these additional tools and all of the additional data about BNP and what have you, Functional Class was the holy grail and it’s something that’s easy. It’s inexpensive, we do it every single time we see a patient. But it’s not enough, is it?

Dr. Raymond Benza:

No, it’s not. And it’s like you said, we were both weaned on Functional Class, as cardiology fellows. And it’s been ingrained into the way that we evaluate our heart failure patients, but it is, the bottom-line, subjective. It really relies on patient input, their memory, and even their honesty at some point. And so this subjective evaluation really has to be weighted and thought of in a different manner. The formal risk assessment is objective. We’re talking about multiple parameters. Some that are objectively measured, but not subjectively measured like hemodynamics or vital signs or pericardial effusion on an echo or an NT-proBNP level. So, balancing these subjective with objective factors I think is very good, but I don’t want to short come the Functional Class because even despite its subjective nature and every risk calculator and every assessment we have done, it’s always peaked its head as something that is important. It may not be as discriminatory as the others, but it certainly remains important.

Dr. Vallerie McLaughlin:

Yeah, no question. Now, some people who are critics of this say, “Oh my gosh, it takes so much time. You have a limited amount of time with a patient appointment and epic or the electronic medical record makes it all so complex. I don’t have the time to do this over the course of a visit.” And I think that’s really not a very good excuse to do something that is so important and so prognostic for a patient. A French invasive or noninvasive is really 4 or 3 variables. It really doesn’t take that much time. And Ray, I know that you’ve actually gone to a lot of trouble trying to develop apps to make the REVEAL calculation easy as well.

Dr. Raymond Benza:

Yeah. So, there are apps that are currently available. There are websites that are available that can calculate the risk for you. We've made a lot of headway in some of the EMRs in programming them to calculate risk on the fly. So I think the nature of the calculation is getting easier and easier for practitioners to perform. But like you mentioned, doing a risk calculation using REVEAL Lite 2 or the French method, that can be done in less than 30 seconds. So it really is very, very easy to do. In my practice, my nurse coordinators calculate the risk before I even walk into the room. And so it's readily available for me to talk with the patient about and discuss and make critical decisions on.

Dr. Vallerie McLaughlin:

Yeah. Ray, I think you've contributed so much to this area. It's really been a delight to have this conversation with you. I think to wrap up, we've really emphasized that formal risk calculations are important to help us monitor our patients and choose the appropriate therapy for them. So it's been such a pleasure and this concludes our first PAH Initiative podcast. Please join us next time when we will discuss initial therapy choices based on risk calculation.

If you would like more information on risk assessment, PAH treatment guidelines, or to use an online risk calculator, please visit pahinitiative.com/hcp.