Robert Frantz, MD - phaware® interview 533

Dr. Robert Frantz breaks down the key metrics behind risk stratification—functional class, six-minute walk distance, and brain natriuretic peptide levels—and explains how they shape treatment plans. He also explores the role of echocardiography, right heart catheterization, and cutting-edge therapies in improving patient outcomes.

This Special Edition Episode Sponsored by: Johnson & Johnson

I'm Dr. Bob Frantz. I'm a cardiologist at the Mayo Clinic in Rochester, Minnesota, and Co-Director of the pulmonary hypertension clinic there. I have been working there on staff since 1990, so actually many decades of time of seeing patients with pulmonary arterial hypertension and seeing their therapies evolve. 

Today, we're going to talk a little bit about risk stratification and pulmonary arterial hypertension. I had the privilege to be a member of the Task Force on Risk Stratification at the Seventh World Symposium on Pulmonary Hypertension in Barcelona. This brought experts together from around the globe including patient representation in order to talk about the different risk stratification systems, how they can be utilized, and both discussing their use in clinical practice and also as tools and research protocols, as well.

I would say that we had a very vigorous discussion at those meetings, because there are different risk stratification tools. Some people might say, "Well, if I have a really expert pulmonary hypertension provider, why do they need some risk calculator to plug in some numbers about me to say you're low risk, intermediate or high risk or whatever?"

I'd say that's true to an extent, but there's a sense to which we all acknowledge that, number one, everybody seeing a PAH patient might not be a world expert. Number two, it is sort of objective and can be tracked over time and can avoid conscious or unconscious bias that can come into our thought process for whatever reason. Even things like, well, we like our patients, we want them to be doing well. It's hard to talk about maybe your prognosis is not as good as we would hope. Then, we might actually underestimate the severity of their disease because we're trying to be positive and optimistic.

I feel like for me, who has been doing this for many years, I feel like, "Okay, I'm just going to objectify this set of information so that I'm keeping myself honest about where this person really is in terms of an objective risk calculator that might be a little different from how I'm viewing them today."

The thing about risk calculators, they're used in many disease states in order to try to quantify prognosis with regard to risk of hospitalization or mortality. We know a couple of things. One, if you don't have very many of the components of the risk calculator, then it doesn't work very well. One thing we agreed on at the World Symposium is that there are various risk calculators, but key components are Functional Class I, II, III or IV. "Are you asymptomatic or are you short of breath at rest?" Functional Class III would be if you go up a flight of stairs you get breathless. That's one metric. So, that is one component because the more advanced your Functional Class, the more concerned we should be about you.

The other thing is six-minute walk distance, like how far can you walk in six minutes? That is quite closely related to prognosis. That's why it's important for patients to be doing those six-minute walks and trying during that time to walk about as far as they think they can in that six minutes, even if they have to rest or stop a couple of times, because it's a reproducible way of assessing whether they're getting better or worse or about the same.

The third component is brain natriuretic peptide or N-terminal pro-brain natriuretic peptide, which is a mouthful, but it's basically a protein made by the heart that is released to try to help our kidneys dump fluid and salt, so kind of what we call a counter-regulatory hormone, that if the pressure is going up inside the heart, in the right atrium and things, we release more of this to help the kidneys get rid of fluid and salt. We use it as a prognostic marker. You can, as a patient, know what your BNP level is next week and you could have it checked again in three or six months and might follow that over time with the idea that if that value is rising, that might be of some concern. If it's dropping, that might be reassuring.

The thing about that particular metric is that there's two assays. One is called BNP, just brain natriuretic peptide, and the other is N-terminal pro-brain natriuretic peptide. Different hospitals and systems might use the different assays. It's important to know which one is being done, because otherwise a person could be rather concerned that the level's changing dramatically. It's just actually a different assay depending where you had it done. The NT-proBNP circulates at levels that are four to eight times the BNP, so they're very different metrics.

I think the bottom line is the risk calculators that include a variety of things that include the REVEAL risk calculators 2.0 and what we call 2.0 Light and the European calculators, which are things like COMPERA and COMPERA 2.0 have some differences, but all of them include functional class, six-minute walk distance and brain natriuretic peptide levels, and may include other things that are things like in for REVEAL 2.0 is heart rate where if your heart rate's high and your blood pressure is low, that's concerning. So high heart rate over 96 beats per minute or low blood pressure sort of in a way that would be of concern also would go into that risk calculator. In the REVEAL 2.0, if you have renal impairment, so that when you see these calculations being done, you can think about what's in the calculator.

When we think about that risk calculation, baseline when people are first diagnosed, are you low risk, intermediate risk or high risk? Almost everybody, even if they're both low and intermediate risk are getting an endothelin receptor antagonist and a phosphodiesterase 5 inhibitor, what we call dual therapy. If they're high risk, they may be getting IV or subcutaneous prostanoids plus an endothelin blocker plus a phosphodiesterase 5 inhibitor, what we call upfront triple therapy. The precision of that risk estimate just has to get your provider in the ballpark that they're going to provide you at least dual therapy or maybe triple therapy.

The goal of the risk calculator is to try to get patients to low risk if possible, a good six-minute walk distance, a good functional class, not being out of breath going up a flight of stairs, having a natriuretic peptide level that's normal or low as opposed to high and rising. These risk calculators are especially useful when patients come back, because then they're already on some treatment, and is that treatment actually working or not?

Patients and family members might get frightened that they're in a high risk or intermediate risk category, but need to recognize that the important thing in a way is when they come back in three to six months, is that risk lower now, are the therapy's working? So, redoing that risk calculation and saying, "Oh, the six-minute walk distance is a hundred meters farther and your brain natriuretic peptide level is significantly lower, and now you're not short of breath on stairs. We're feeling like you're now in a low risk category. Let's stay with these two drugs we're using." Or, "Actually things aren't quite where we want them to be."

The beauty of the risk calculator, in a way, is its objectivity. Sometimes the patient will say, "Doc, I don't know you that well. Do I trust you, you're really expert about this? You really want me to add another drug? Is that just because you want to be aggressive or do I really need it?"

Having an independent risk calculation that says, "Yes, actually you're still at intermediate risk for a bad outcome," can sometimes empower patients to understand that it's just not me as a provider saying I think they should do this or that. Any group of experts would say, "This person is still at intermediate risk. They would benefit from additional therapy and it may be worth putting up with some side effects to reduce the risk."

The other way we use these risk calculators sometimes can be in clinical trials as a secondary outcome measure, that is, is your risk calculated score improving on average with therapy or not? The other way we can use them is that if we have a set of patients who went into a randomized clinical trial of a PH therapy, we can characterize those patients by low, intermediate or high risk. Then, at the end of the trial can look and see which patients benefited the most. Then, when I'm seeing a patient in a clinic and I'm saying, "Should I apply this drug from this clinical trial in this clinical situation? How does my patient compare to the patients who did or didn't respond to the therapy?"

An example of that would be that analysis in the GRIPHON Trial, which is the study of selexipag, which is an oral IP receptor agonist as therapy for pulmonary arterial hypertension. On average, there was benefit in the patients who received the drug, but the patients who are actually at highest risk going in maybe benefited somewhat less. Maybe those patients actually would've been better off just going on to an IV or subcutaneous continuous prostanoid therapy as an even more aggressive therapy. We might say people at lower to intermediate risk, adding the selexipag could be very useful. If they're at high risk, then probably they'd be better off to go with even a more potent therapy. That kind of information can help us understand how to personalize our treatment for our patients based on the risk category.

General consensus was that you should be reassessed clinically and with regard to risk at three months after making a treatment decision, because most of the therapies that we give are going to be effective or not as effective as we like within that timeframe. Then, at that three month point, there'll be a reassessment, and then maybe a slightly different direction. Then, another three months later should be assessed again, and continue that every three month kind of recheck until a person is at low risk or on all the therapies we have available. If they're stable and on the therapy we think is optimal, then we might back off to every six months.

I think that the issue of reimbursement and coverage of medications is one that we all deal with on a regular basis. I would say that the clinical decision to add another therapy generally isn't going to be second guessed based on a person's risk categories or something like that. If the clinician thinks another drug is appropriate, then, usually, that will be accepted. It may be that there could be some pushback where if we say they're at high risk, they need IV or sub-Q continuous prostanoid and they're not yet on an endothelin receptor blocker, which is an easier oral agent that maybe the insurance companies say, "Well, you should be adding that, and they have to fail that before they go to the continuous infusion."

We might say, "They're too sick to do that now. We need to move to this other therapy now and can talk later about whether to add or subtract or something later." There can sometimes be that where if you're sort of leapfrogging ahead because they are not on aggressive enough therapy, there could be some pushback that you haven't tried something simpler. You have to say, "Look, in my judgment, we can't go simpler. We need to go with a more aggressive program." So, that can sometimes be an issue.

This World Symposium tends to meet about every five years. It's only one forum for our discussions about optimal strategies. There are many other forums that can include consensus documents that different scientific groups put together like the pulmonary or the cardiology societies and position papers that people might write, or just best evidence-based recommendations from a set of experts that might get published. So, there can certainly be updates to these things.

I think that one component of the World Symposium Review on Risk Calculation included a couple of things for saying directions we need to go with this. One includes that there's not very much echocardiographic guidance in the risk calculators, partly because there wasn't very much echocardiographic information in the registries that resulted in development of these calculators. So, if you don't have that information in there, it's hard to incorporate it.

One of the recommendations was that in addition to using these risk scores, we should also be keeping track of echocardiography in terms of how the right side of the heart is behaving, how big are the chambers, how impaired is the function of right ventricle, how much is the tricuspid valve on the right side of the heart leaking, and use that as supplemental information to our risk score.

You might have somebody who's young and they've otherwise been pretty healthy, and they still can walk quite far on a six-minute walk and maybe their BNP level isn't very high, but when you look at their echo, the right ventricle is quite severely impaired. That might be something where you say, "Well, I don't think the risk calculation is actually taking to account what's happening with this patient's right ventricle as fully as I would like. So, we're going to incorporate that right heart ventricular function information, into our decision-making and that the onus is on the community to continue to try to develop better and more widespread utilization and metrics for what the right heart is doing in terms of performance." That's one thing that the field is going to continue to work on. It's like, "What on the echo should I be looking at that tells me that they should have more therapy?"

The other thing has to do with hemodynamics and right heart catheterization. From the echo, we get estimates of pressure. We might get some estimate of the flow of the heart and cardiac index, but it varies in accuracy across centers and patients. There is the understanding that in situations where we're not sure which way to go, where sort of some low and some intermediate and maybe some high-risk features, that repeating a right heart catheterization in order to get very objective, accurate information about the cardiac output and the right atrial pressure and the cardiac index and things can be useful. Especially, as we start to have developed drugs coming along like sotatercept or Winrevair, which is this anti-proliferative that's scavenging growth factors in the blood, given as an injection every three weeks, that may lower the pulmonary pressure and lower the resistance, that repeating right heart catheterization and seeing how much better are things in that objective way might help us, especially if we're trying to make decisions about backing off on one of the other therapies.

We know our prostanoids, the infusions, the inhaled drugs, the oral therapies, that prostanoid class of drug has the greatest side effect burden, and is maybe most hard for patients in terms of quality of life and having to deal with that. If some of our anti-proliferative therapies are successful enough, maybe we can reduce the burden of our therapies by reducing that prostanoid or maybe in some situations even taking it away. But if you're going to be doing that, you need to be really sure where things stand and maybe a risk calculator, and how far people can walk and their functional class isn't quite enough to be sure about that. Especially now, we're talking about backing off on other therapies for improving quality of life and burden of the therapies, repeating a right heart catheterization to know where we really are could be very useful.

Another thing I'd say about risk calculators is number one, they can be incorporated into electronic medical records. So then, that is living in that electronic record and can be flow charted like, "Okay, this patient's REVEAL risk score was 9 three months ago and now it's 7." I can see that difference and I can track it.

The other thing is that there are apps. If a person just Googles, “pulmonary hypertension risk calculator,” it can take you to a website that has all the different risk calculators. A patient could do that themselves if they wanted to, if they have that information. So it could be sometimes somewhat empowering if they choose to do so. Go there and say, "Hey, what's my REVEAL 2.0 Light risk score after this last visit," if my provider didn't tell me or didn't calculate it?

It always needs to be put in the context of the patient. I think that was another message from our debates at the World Symposium about this, is that this is one modality to assess risk. It has to be put in the context of the echo, the human dynamics, patient goals, where we're talking about patient-centric medicine. So we could say, "Oh, you're at intermediate risk, we should add a prostanoid." Then, the patient has to do some thinking about that, "Am I willing to take on that side effect burden to try to reduce these risk characteristics, or will it help me feel enough better that it's worth the side effect burden?"

We can get caught up in this objectification of risk and things, but realize this is a person sitting in front of us with different goals, and maybe we're not engaged in a way where we really understand what they're looking for. If we're mono-focused on reducing risk and adding more drugs, maybe we're not really meeting the patient where they are in terms of their journey.

I always like what Rino Aldrighetti, the former head of PHA used to say, "Every patient has the opportunity and the ability to fight this disease as much or as little as they choose to do."

We have to accept that, that we might be all in, "Do this, do this, do this." Is that really where our patient is? So, I think that's the other message, taking it back and being patient-centric, "Here's the information. Let's talk, what are our joint goals here?"

Thanks so much for listening. My name is Dr. Bob Frantz, and I'm aware my patients are rare.

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