Pulmonary Arterial Hypertension Podcast

Pulmonary Arterial Hypertension Risk Stratification

Vallerie McLaughlin, MD; Ioana R. Preston, MD

Disclosures

July 21, 2022

This transcript has been edited for clarity.

Vallerie McLaughlin, MD: Hello and welcome to this Medscape InDiscussion on pulmonary arterial hypertension (PAH). Our topic today is the very important one of risk stratification. My guest today is Dr. Ioana Preston from Tufts University. I’m Dr. Vallerie McLaughlin from the University of Michigan. Ioana, thank you so much for joining me.

Ioana Preston, MD: Thank you, Val, for having me.

McLaughlin: Ioana, tell me a little bit about your journey into PAH before we get started with risk stratification.

Preston: It started almost 20 years ago. As a physician and a pulmonologist, I grew along with the pulmonary hypertension (PH) field and learned how to diagnose patients with PH. Initially, they were always very, very sick and end stage. But over the years, we’ve learned to identify patients who are not end stage, who are at risk for PH, and in whom we can make a big difference with the treatments we have available today.

McLaughlin: That leads us beautifully into our topic of risk stratification. We’ve learned so much about risk stratification over the past 5-10 years. A lot of what we know has come from registries, and there have been a number of equations and prediction models that now guide us in our management of patients through the basis of the guidelines. Let’s talk about some of these risk stratification tools and some of the registries that led to this. Can you summarize what we learned from the US REVEAL Registry?

Preston: Absolutely. The REVEAL Registry is probably the largest database of patients with PAH that we have to date. It’s a US-based registry of over 3500 patients with PAH. We’ve learned that certain parameters being collected in our everyday clinic visits and also some invasive parameters explain how severe the disease is and how much improvement are we making with our therapies. And they predict the probable outcome at 1 year for our patients.

McLaughlin: Right. And REVEAL first came up with an equation that was very complicated. It included about 14 variables, some of them modifiable and some of them nonmodifiable, like etiology of PH, gender, or age. Those variables were refined in REVEAL 2. And then more recently, there is a much more user-friendly REVEAL Lite 2 tool that takes into account 6 variables we get in clinic every single day.

Preston: Val, you are absolutely right. REVEAL Lite 2 is a very useful and easy to use tool with every clinic visit. The REVEAL Lite 2 is the most updated version of a risk score calculator that we have. And it includes only noninvasive parameters such as systolic blood pressure or heart rate at rest, a walk test, and so on. Using the BNP or NT-proBNP, the clinician can put it all together and calculate it very easily into a score.

McLaughlin: That’s right. Let’s talk a little bit about the European models now. There’s a couple I’d like to touch on. One is based on that very famous green, yellow, and red table in the ESC/ERS guidelines, which goes through a number of indicators of risk—functional class, hall walk, biomarkers, and the like—and categorizes them under low risk, which means the variables are good and the patient is likely to do well, or intermediate risk or high risk. And there have been a couple of papers from Germany, primarily from the COMPERA registry and the Swedish PAH Register, which used this as the basis of modeling, assigning one point for low risk, two points for intermediate risk, three points for high risk; dividing by the number of variables measured; and rounding to the nearest integer to get low, intermediate, or high risk. A lot of the variables are the same as REVEAL in terms of biomarkers, walk, and the like. There’s not any of the nonmodifiable variables in that model. Then there’s the most simplistic of them all, the French model. Do you want to summarize the French model, Ioana?

Preston: The French model has four variables and one of them is invasive. But in the abbreviated version, the French model has only three noninvasive parameters. If all three parameters—functional class, BNP/NT-proBNP, and 6-minute walk test—are within the green zone, you have really good numbers for that particular patient. Then, that patient is at low risk. It’s not as granular in patients who are not low risk. It gives you a green flag in folks who are really well controlled, but the rest of them are not very well defined. So, this model has pluses and minuses.

McLaughlin: They all have pluses and minuses; that’s a great point. And they have become the basis of our treatment algorithm. Our treatment algorithm starts with some background therapies and whether or not a patient might be appropriate for calcium channel blockers, which is a small proportion of patients. For the overwhelming majority of patients, our first step in treatment depends on what risk level they are. If they’re at high risk, we recommend very aggressive therapy with combination therapy with parental prostacyclins. If they are at intermediate or low risk, we recommend less invasive therapies; often, we start with dual oral therapy. But I think the magic—the importance of risk assessment—is really in that next step. Ioana, do you want to review the next step on how the goal is getting to low risk?

Preston: Yes, absolutely. The risk scores are so important because they have been validated, not for baseline prediction of survival, but as you mentioned previously, they are very good for assessing survival in response to therapy. We know our goal is to make our patients with PAH drop down to as low of a risk score as possible. These tools are very handy in our clinic visits because they do predict, and they have been validated to predict response to therapy.

McLaughlin: I think this is the most important step in the algorithm. I just met a woman yesterday who was so sick we directly admitted her to the hospital for urgent start. She looks at me and she’s like, “What’s my prognosis? How long am I going to live?” I don’t even answer that question at baseline anymore. I always tell a patient it really depends on how they respond to therapy. You can have someone who is very sick when you meet them, and if they respond to therapy and get to the low-risk status, their prognosis is going to be excellent.

Preston: Absolutely. And that is because of two very important key points. First of all, we do have effective therapies that have an impact on the outcome of our patients. And then also, we have these risk scores that evaluate how well these patients respond to the therapies we’ve chosen. If they haven’t responded well enough, we can modify, switch, adapt, or add therapy to improve their risk score because this is how we’re going to make them better.

McLaughlin: I think that’s a really great point. Now, one of the limitations of the risk tools we’ve talked about so far is that the intermediate-risk group is really big, right? Risk stratification is supposed to separate people into risk groups that can help guide management. Certainly, for high-risk patients, it’s very clear. For low-risk patients, it’s very clear. But if you look at registries, about 70% of the patients fall into the intermediate-risk group. It really is not very granular if you look at that. I was always thinking, well, this is on the lower end of intermediate, or this is on the higher end of the intermediate. In my mind, I treated those patients differently. But we now have some very good data that help us divide that very large group of intermediate-risk patients into intermediate low and intermediate high. Do you want to tell us about some of these recent publications?

Preston: There are recent publications from Europe (Wu et al, Dardi et al, Sonnweber et al) that are helping us become more granular within this gray or intermediate zone. Think about a patient who is intermediate risk on dual oral therapy and not doing well enough. When do we decide? Do we add an oral agent? Maybe we add a prostacyclin oral or inhaled agent? Or, does that patient need infusion therapy because they’re on the higher end of intermediate risk but not quite high risk where we know exactly what we need to do. I think the recent papers trying to divide the intermediate group into low-intermediate and high-intermediate risk stratification will help us better guide our treatment approaches and additional therapy in the near future and today.

McLaughlin: And it’s very simple. It’s the same three variables that are in the French noninvasive risk score. It is functional class, 6-minute hall walk and a biomarker, which is either BNP or NT-proBNP. But there are different cut points for the biomarkers and for the hall walk to help delineate patients. I think the most important thing is what you said about an intermediate-risk patient, Ioana. If someone is still intermediate, are they on the low end of intermediate where we feel safe with either an oral or inhaled prostacyclin pathway agent? Or, are they at the high end of intermediate risk where we need to use a parenteral prostacyclin? You’ll also see that there’s more movement once we start therapy. You’ll see more people change groups. I think another really important point is that you can see the differences in the survival curves, and being at intermediate low is not as good at being low.

Preston: Absolutely. We have moved in the past years from evaluating and stratifying patients by NYHA functional class—which we used to do as the main guidance of how aggressive our therapy should be—to using these risk calculators and taking into account different parameters that give us the pieces of the puzzle of how PH impacts the bodies of our patients.

McLaughlin: Ioana, we’re both singing the praises and citing the importance of risk stratification. But it’s not perfect, of course. Tell me what you think the limitations are of our current risk stratification tools?

Preston: I’m a pulmonologist. You are a cardiologist. However, I do acknowledge the importance of right ventricular function, shape, size, and how it performs in relationship to the pulmonary vasculature. None of our risk-scoring systems have included the performance of the right ventricle, which is actually the ultimate key player for the survival of our PAH patients. As clinicians, we are looking at risk scores that are very helpful tools to predict how our patients do. However, I think we need to include a form of right ventricle assessment in collaboration with these scoring systems.

McLaughlin: I could not agree more. Looking at that echo and looking at that right ventricle is very impactful. Sometimes you see patients who maybe will never get to functional class I or II because they’re older or deconditioned or what have you, but they have normal right ventricles. Even if they’re not at low risk, I worry less about them if their right ventricle is normal.

Preston: Yes, absolutely. For example, I just saw a patient of mine with idiopathic PAH that I diagnosed 15 years ago. She’s 81 years of age now, and she is telling me she’s more fatigued. She cannot do as much. She cannot move as much. But her physical exam shows normal cardiac function, and her echo shows an almost normal right ventricle function, which she hadn’t had, of course, 15 years ago when I diagnosed her. So I know her limitations are not due to her PH, but arthritis and other conditions.

McLaughlin: I think that’s a really important point; a limitation is looking at that right ventricle function. Then also, as you mentioned, there are other conditions that could contribute to a functional class or a low hall walk score. And the hall walk is a limitation as well; for the cutoff, 440 meters is the magic number. It’s not really a magic number and whenever I have someone do a hall walk, I look not just at the number that they achieved but also what is predicted for their age and height. I have so many little old ladies with scleroderma who are never, ever, going to get to 440. Probably what is predicted for them is 360. They are always going to look higher risk than they really are. And again, right ventricle function is very helpful then. It works on the flip side too. What if I have a 20-year-old, 6-foot man with heritable PAH and he walks 445 meters? You know what? I’m really not happy with that. He probably should walk 700. So, there are still some limitations to the risk stratification system we have.

Preston: Absolutely. It is unfortunate that our 6-minute walk test validation and also the scores we’ve used have not incorporated the predicted distance for a patient’s age and height. In the future, we may think of modifying this tool, which is so easy to use in clinic, to better and more accurately reflect what a particular patient’s normal level should be.

McLaughlin: Let me ask another question, Ioana. We’ve talked about the most recent tools. They really focus on functional class, hall walk, biomarkers, and then of course the REVEAL Lite 2 also has systolic blood pressure, heart rate, and renal function. Hemodynamics are not in any of these. Are repeat hemodynamics important as we follow our PAH patients?

Preston: I think they’re crucial, but maybe not for every patient, especially if they’re doing well. The REVEAL noninvasive 2.0 Lite does not have hemodynamic parameters included. However, the REVEAL 2.0, which is a bit more extensive, does have a couple of hemodynamic parameters. As clinicians, the way we use these noninvasive tools can be increased. Our understanding of the disease can be augmented by echocardiography and looking at right ventricle function as well as repeat hemodynamics to better understand what the flow or cardiac output is, and what the SVO2 is. Sometimes even at rest, the hemodynamics may be very similar to before, but if you exercise these patients, they may not be able to augment a cardiac output as well as before. That tells us in a more subtle way that the disease has progressed. So I think hemodynamics still plays a very important role in understanding the severity of disease at a certain point.

McLaughlin: I absolutely agree. We still do repeat right heart catheterizations on a large proportion of our patients but not necessarily everyone. Certainly, we do them on the people who are very sick when we first meet them. We want to repeat hemodynamics to make sure we’ve had enough of an improvement. And for anyone on a parenteral prostacyclin, we get a repeat right heart catheterization. If someone is not feeling well, they’re not at low risk, and we’re debating what type of therapy to add—sometimes the hemodynamics are important, as well. Ioana, just practically, when you see patients in the clinic, tell me how you approach risk stratification, how you document it, how you explain it to patients, and how it impacts your practice.

Preston: Once my patients are used to coming to our PH clinic and have a clear understanding of their disease, they know how to report and what to report to me—how they’re feeling, if they have any symptoms that have progressed, and if they have any side effects from the medications we’ve started. We’ve coached them before we started them on the medication on what to expect if they develop any side effects. They know they have to come with sneakers on because we’re going to do a walk test. And they’re very excited, and they want to show they’re doing well. If they don’t want to do it, that’s a good signal for me as a clinician that they’re not doing very well. Indirectly, I have a lot of information by whether they want to do the walk test or not. Then we do blood tests. We want to make sure they’re not anemic, and that their liver function test results are in check. Once in a while, we check their thyroid function, and so on. It’s a whole assessment, and within that, we incorporate the risk score stratification. At Tufts Medical Center, we just rolled over to a new electronic medical system, and we are incorporating a risk stratification to be calculated with every visit.

McLaughlin: We have the same thing. We have created on the back end in the flow sheets where we can just enter the functional class, the biomarker, the hall walk, blood pressure, heart rate, and creatinine clearance. And then we have a smart phrase. The end of the note will have their risk scores by both the 4-strata method and REVEAL 2 Lite for the most recent visit. It really is very easy to do in practice because it is part of what we do every single time we see a patient. We talk to them, we get their functional class, we do a hall walk, and we draw their blood. Ioana, this has been a great conversation on risk assessment. I want to end by asking you your vision. It’s really an exciting time in PAH. Tell me what excites you most about what we’re going to see in the next 5 years?

Preston: Yes, it is a very exciting time. There are many new drugs being tested today in different forms, formulations, and delivery systems, from the inhaled therapies—we have not been very aggressive in using these in PAH until recently—to subcutaneous to oral therapies. Most important are the different pathways that hopefully will add to the armamentarium of our current therapies. The second most important is that we’ve learned that during clinical trials, we need to involve our patients and use their input to develop a trial end point and understand what’s most important for them. We can focus on both of these points.

McLaughlin: Ioana, it was a pleasure talking to you today about this very important topic of risk stratification in PAH. I really appreciate your time and your insights.

Preston: Thank you, Val. Always a pleasure to talk to you.

Resources

Pulmonary Arterial Hypertension

REVEAL Registry: Registry to Evaluate Early and Long-term PAH Disease Management

Predicting Survival in Pulmonary Arterial Hypertension: Insights From the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL)

Predicting Survival in Patients With Pulmonary Arterial Hypertension: The REVEAL Risk Score Calculator 2.0 and Comparison With ESC/ERS-Based Risk Assessment Strategies

Development and Validation of an Abridged Version of the REVEAL 2.0 Risk Score Calculator, REVEAL Lite 2, for Use in Patients With Pulmonary Arterial Hypertension

REVEAL Lite 2 Risk Calculator

Brain-Type Natriuretic Peptide (BNP)

2015 ESC/ERS Guidelines for the diagnosis and Treatment of Pulmonary Hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT)

Risk Assessment in Pulmonary Arterial Hypertension

A Comprehensive Risk Stratification at Early Follow-up Determines Prognosis in Pulmonary Arterial Hypertension

Risk Assessment, Prognosis and Guideline Implementation in Pulmonary Arterial Hypertension

Risk Assessment in Pulmonary Arterial Hypertension

Regular Risk Assessment in Pulmonary Arterial Hypertension - A Whistleblower for Hidden Disease Progression

A Pragmatic Approach to Risk Assessment in Pulmonary Arterial Hypertension Using the 2015 European Society of Cardiology/European Respiratory Society Guidelines

Risk Assessment in Precapillary Pulmonary Hypertension: A Comparative Analysis

Diagnostic and Predictive Value of Right Heart Catheterization-Derived Measurements in Pulmonary Hypertension

Scleroderma

COMPERA 2.0: A Refined 4-Strata Risk Assessment Model for Pulmonary Arterial Hypertension

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