Pulmonary Arterial Hypertension Podcast

The 2022 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension With First Author, Marc Humbert

Vallerie McLaughlin, MD; Marc Humbert, MD, PhD

Disclosures

October 20, 2022

This transcript has been edited for clarity.

Vallerie McLaughlin, MD: Hello. I'm Dr. Vallerie McLaughlin from the University of Michigan. And welcome to this edition of Medscape InDiscussion series on pulmonary arterial hypertension. Today, I'm really excited to discuss the new European Society of Cardiology (ESC) and the European Respiratory Society (ERS) guidelines on pulmonary hypertension, and I'm so honored to have my guest, Dr Marc Humbert, professor of respiratory medicine at University of Paris-Saclay and director of the French Pulmonary Hypertension Network. Marc, welcome to InDiscussion.

Marc Humbert, MD: Hello, Vallerie. Good to be with you.

McLaughlin: So, Marc, let's just get things started. Tell me just a tiny bit about what drew you into the area of pulmonary hypertension.

Humbert: I was a student in the pulmonary hypertension field when I was very young because I was a young resident with Professor Simonneau. It was very impressive to work with such a giant of pulmonary hypertension. I was immediately interested and he asked me to develop some translational research in the field. It was a great opportunity.

McLaughlin: It was. And what a superstar you have become, Marc. You're the first author on these guidelines. Congratulations. This is just a fantastic document, the first set of guidelines since 2015. And really, kudos to you for all the work you and the entire committee put into this.

Humbert: Thank you very much. It was teamwork.

McLaughlin: Absolutely. So, Marc, let's just start out with pulmonary hypertension and pulmonary arterial hypertension. There's a lot of discussion about this and distinction. And I think the central illustration of these guidelines puts it all in perspective. Do you want to just spend a moment on that?

Humbert: The central illustration was really important when we built the guidelines and the big messages we wanted to handle. Clearly, pulmonary hypertension is not rare. It affects a lot of people worldwide, but most of the people have what we call group 2 and group 3 pulmonary hypertension, meaning that they have a heart or lung condition, which explains mostly the pulmonary hemodynamic disturbances. Beyond that, you have group 1 and group 4, which are rare but which are really the focus of a lot of research, with a lot of dedicated strategies and treatment. I think this central illustration makes the whole story simple and indicates that we have a very unique way to classify these conditions with a purpose. We want to offer a solution to the patients when they present with pulmonary hypertension; classify them; and, at the end of the day, offer them management.

McLaughlin: Absolutely. And I think the central illustration really helps. Even as a cardiologist who specializes in pulmonary arterial hypertension, I would say that most of the new patients that I see have group 2 or group 3 disease.

Humbert: Indeed. It's the same for me as a respiratory doctor. Obviously, we are here to help them and to indicate how to best treat them. And some of the patients will in turn have group 1 or group 4 disease, where we have more specialized approaches.

McLaughlin: Marc, let's move on to one of the more controversial, or at least one of the more discussed, changes in the guidelines. That is the change in the hemodynamic definition of pulmonary hypertension and pulmonary arterial hypertension. Do you want to summarize that for the audience?

Humbert: The mean pulmonary artery pressure, measured by right-heart catheterization, has always been estimated as abnormal by defining pulmonary hypertension > 25 mm Hg in previous world symposium proceedings and guidelines. But in 2018 and now in the 2022 Pulmonary Hypertension Guidelines of the European Society of Cardiology and the European Respiratory Society, we have decided to reestablish the real upper limit of normal. And thanks to a systematic analysis of hemodynamic databases, it has become very clear (and it was already known) that the mean pulmonary artery pressure is usually around 14 mm Hg, with a standard deviation of 3. So the upper limit of normal is 20 mm Hg. Clearly, any value strictly above 20 mm Hg defines pulmonary hypertension.

Then you have to measure, of course, the wedge pressure to see if it is pre- or post-capillary, and you have to measure the pulmonary vascular resistance to see if there is a pulmonary vascular component in this elevation of pulmonary pressure. So I think this hemodynamic definition puts very strongly evidence-based information in the spotlight.

McLaughlin: And lowering the pulmonary vascular resistance from 3 to 2, that's based on many observational studies showing that patients with a mean pulmonary artery pressure (PAP) > 20 mm Hg, and even a pulmonary vascular resistance (PVR) > 2 but < 3, don't do as well. So there are some data to suggest that those patients have a worse prognosis, although some of those patients are group 2, group 3; they're from large databases, correct?

Humbert: Indeed. And we put that in the central figure. We put the relationship between mean PAP and PVR with long-term outcomes and mortality. Very importantly, it doesn't mean that we have enough evidence to offer specific treatments to the people right above the new cutoff. But it also indicates that there is room for research and for new evidence.

McLaughlin: I think that's the critical point. And you do again emphasize that when you come to the treatment algorithm, it really applies to patients with a pulmonary vascular resistance > 3.

Let's move on to some of the tiny changes that were made in the classification. Do you want to briefly summarize those?

Humbert: The classification has been very helpful for the community because we grouped together patients who have a similar pathophysiology and mechanism and, at the end of the day, management. So you'll remember group 1, group 2, group 3, group 4, and group 5. The big difference for group 1 is that we consider that group 1 pulmonary arterial hypertension can be subdivided into idiopathic, heritable, and associated conditions or associated exposure to drug and toxin. In addition, there is a subgroup with features of venous and or capillary involvement, with a red flag indicating that these patients may be less prone to respond to specific therapy. But I would say that group 1 PAH has not been changed much. We have maintained all the information, and the guidance for future management of these patients is broadly the same as in 2015.

McLaughlin: The calcium-channel blocker patients have changed a little bit, and those are really a very special group of patients, right?

Humbert: In group 1 idiopathic PAH, we have decided to indicate that there is a subgroup of patients who are acute responders to vasodilators and who may be in turn long-term responders to calcium-channel blockers. So this has been put in the classification, not as a distinct subgroup, but as a subgroup of idiopathic PAH. But we indicate as well that some patients with heritable forms of PAH and some patients with associated forms with drugs and toxins might respond to vasodilators. This is a subtle change. And when we discuss treatment, any patients with group 1 idiopathic, heritable, or associated with drug PAH will need to be tested acutely with nitric oxide, for example.

McLaughlin: Thanks for that clarification, Marc. And so the rest of the classification?

Humbert: The rest of the classification is very straightforward, It's mostly the big picture of group 2 pulmonary hypertension associated with left heart disease, where we have the patients with heart failure and the patients with valvular heart disease and heart failure with either preserved ejection fraction or mildly reduced ejection fraction.

Then we have group 3 pulmonary hypertension, associated with lung disease and hypoxia. In these patients, you have the obstructive lung disease, restrictive lung disease, and all of the disease associated with hypoventilation syndrome, et cetera. And high altitude, of course.

Then there is the quite rare but so important group 4 pulmonary hypertension, associated with pulmonary artery obstruction, mostly a chronic thromboembolic pulmonary disease with pulmonary hypertension. In this category, we have a lot of management possibilities with drugs, with interventions, and with surgery. So that's a unique group.

And then group 5 remains a group with unclear or multifactorial mechanisms, which have to be further explored.

McLaughlin: Great. Let's move on to the diagnosis. There are a lot of great illustrations regarding symptoms, signs, and diagnostic workup, and they make a really important point to fast-track patients who have a high likelihood of severe pulmonary hypertension to an expert center. Do you want to highlight some key changes with that?

Humbert: What you just said is really important. First, we have a diagnostic algorithm for unexplained shortness of breath or suspicion of pulmonary hypertension. And as you just said, when there are signs of severity or when PAH or CTEPH (chronic thromboembolic pulmonary hypertension) is highly suspected, there is always a fast-track possibility to expert centers. That being said, most people in the community with shortness of breath will not have pulmonary hypertension, or they will have pulmonary hypertension due to a common cause and with less severe symptoms. So we have a stepwise approach.

Step one is at the general practitioner level. We will look for a common cause of shortness of breath, and then there will be a focus on heart and lung assessment, which will be done certainly in partnership with a specialist. And echocardiography is super important. As you always say, Val, it's more than TR (tricuspid regurgitant) jet velocity. It is a fantastic field, very complex and a lot of expertise in the cardiology field. And in the guidelines, there is a beautiful figure showing all the diverse changes you can find on echocardiogram.

Then when the process has been achieved, the patients will be sent to an expert center for a comprehensive workup if the pulmonary hypertension probability is high or moderate. So we have a stepwise diagnostic algorithm. It's very, very difficult to summarize in a few sentences, but it is structured and it shows also the importance of the multidisciplinary partnership between a cardiologist, a pulmonologist, and some other specialists.

McLaughlin: I think that was a beautiful summary, and one of the things I like most about this section of the guidelines is the way that it frames echocardiography. Because you're right: Every time I lecture, I always explain it's more than just the TR velocity, it's more than just the pulmonary artery pressure. And there is a beautiful figure that goes over some of the other signs on echo that we look for — both 2D signs and other Doppler signs that might influence us one way or another. Then, a beautiful flow diagram that helps you decide the probability of pulmonary hypertension by putting together both that TR velocity and the other signs that you see. I think that's a gorgeous part of the diagnostic algorithm. I know it might be very basic, but I think it was really important to highlight the parts that the important measurements that need to be made on a complete right-heart catheterization.

Humbert: Indeed. The hemodynamic measures have been very, very clearly explained, and the whole list of measured and calculated parameters have been described in great detail. And we insisted a lot, because we are always very sorry when the patient undergoes right-heart catheterization and they are missing values. When you decide to do it, you have to do it right and you have to do it completely.

McLaughlin: Absolutely. I have the same frustrations.

Let's go on to risk assessment. Your group in Paris has been one of the leaders in contributing to all the refinements that have been made in risk assessment. Can you summarize some of the variables that have been added to the risk table, as well as the recommendations for risk assessment as we diagnose and treat patients?

Humbert: In risk assessment, risk stratification is so important. Obviously, many people have worked on that worldwide, both in Europe and the United States. In the European guidelines, we have a table which is important, which has been really refined over time. We have now at baseline three major categories of low risk, intermediate risk, and high risk. Then at follow-up, we have refined the intermediate risk strata as low-intermediate and high-intermediate risk. Because we all know that at least 70% of patients were in the intermediate-risk category with different long-term outcomes between them. So at baseline, the three strata are very similar to what we used to have in 2015, but we have added some information. Of course, you have clinical factors, you have exercise indications, you have also very important biomarkers like BNP (brain natriuretic peptide), but also imaging — not only echocardiography but also cardiac magnetic resonance of the heart. So this is very important and we also have the hemodynamic information.

What is novel in terms of echocardiography parameters? We added one parameter, which is the TAPSE/PASP ratio (tricuspid annular plane systolic excursion and pulmonary arterial systolic pressure). It is interesting to measure. It is not always available in the reports, and we will advocate for that. In the CMR (cardiac magnetic resonance), we have a series of information that has been highlighted in the guidelines. And in the hemodynamic parameters, we have added the stroke volume index, which really indicates the strength of the heart, and when it is altered, it means a lot in terms of outcome. So there has been refinement in the risk stratification table.

McLaughlin: That sets us up to talk about treatment, because really, at the heart of the treatment algorithm is risk. Why don't you summarize some of the changes that have been made in the treatment algorithm as well?

Humbert: In the treatment algorithm, of course, we always start with assessment of the acute vasodilator response in idiopathic, heritable, and drug-associated pulmonary hypertension. Then, when the patients are nonresponders, they have to be risk-stratified in three strata; high, intermediate, or low risk. When they are high risk, it is really important to consider maximum combination therapy with three drugs, including a parenteral prostacyclin, a phosphodiesterase type 5 (PDE5) inhibitor, and an endothelin receptor antagonist (ERA). For the patients with low or intermediate risk, we advocate for initial oral combination therapy of an ERA and a PDE5 inhibitor. This is for most of the patients we see without major cardiopulmonary comorbidity.

McLaughlin: Great. We had a little bit of conversation about this. I do think there is some leeway in those guidelines even if you don't fall into the high-risk category, but you have advanced hemodynamics — maybe what some people would categorize as the intermediate high-risk patients. You may consider more aggressive therapy in those patients as well.

Humbert: Indeed. We fully agree with that. The evidence is less strong, less robust, and by definition in guidelines we are constrained, of course, by evidence. So I would say that there is a subgroup of intermediate risk with red flags, and these patients are usually characterized by altered hemodynamics and very often fast onset of symptoms, and they are sometimes quite young with a familial background. But you're right: The guidelines are indicative, and you can be intermediate high-risk at baseline and be a good candidate for maximal combination therapy. We have not yet put the fourth stratum at baseline owing to insufficient evidence, but it will come with time.

McLaughlin: The other thing that the guidelines have changed a little bit, and you alluded to this, is this group of patients who may have other comorbidities and to start perhaps a little slower on them. We see those so commonly in clinical practice now. Do you want to comment on that?

Humbert: You have patients who are a little bit old — over 65 or 70 — with several risk factors for heart failure with preserved ejection fraction, or they have a smoking history and a very low diffusing capacity for carbon monoxide (DLCO). These patients might be less easy to treat. They may tolerate the drugs less well. It could be a good idea to go a little bit less rapidly. It doesn't mean that we will not combine treatment. It means that in many of these patients, we will consider a stepwise approach with initial monotherapy and then consider adding sequential combination therapy depending on the tolerability and the efficacy of the first-line therapy. Obviously, this is also work we have to perform and maybe have some studies dedicated to these patients.

McLaughlin: Right. Then I think for me, the most important part of the treatment algorithm is the importance of reassessing patients — reassessing risk and trying to escalate therapy to get them to a low-risk status. This is where you bring in the four risk strata categorization to make these subsequent treatment decisions.

Humbert: Exactly. Regular reassessment is mandatory. These patients should reach the low-risk strata. Some patients with comorbidity may reach only the intermediate low-risk category. It might be acceptable in some patients. But really, as you said, risk assessment should be done at each visit. And we want to have a very clear assessment of the patients. In the fourth stratum, we have privileged noninvasive tests. It doesn't mean that we don't do right-heart catheterization. We do it very often. But with the noninvasive fourth strata, with functional class walk distance and biomarker BNP or NT-proBNP, we can have a good sense of what's going on and whether or not it's time to upgrade the treatment.

McLaughlin: Do you want to highlight some of the new changes with respect to group 4 pulmonary hypertension for the audience?

Humbert: Group 4 is really the group of pulmonary hypertension with a high speed evolution right now. Thanks to multidisciplinary teams with surgeons, radiologists, interventional cardiologists, and PH specialists, we can offer multimodality approaches in this very treatable group of pulmonary hypertension.

In the guidelines right now, first, the screening approach based on VQ (ventilation-perfusion) lung scan is very emphasized. It's always a mistake not to consider group 4 PH as a possible cause of pulmonary hypertension. Then, when it is possible, you have to image the lung vessels with CTPA (CT pulmonary angiography) or angiography. Then when the diagnostic is confirmed, you have different approaches. Surgical cases should be considered for surgery for sure, and nonsurgical cases should be considered for medical therapy and balloon primary angioplasty. In the guidelines, we have shown that it might be a good idea to always consider the full spectrum of treatment options in patients who may benefit from one, two, or three treatment approaches.

McLaughlin: Marc, this was a really wonderful summary. Thanks to you for everything that you, your center, and the committee have done in pulmonary hypertension. I wish I could sit here and talk to you about this all day. Let's wrap up. I want to ask you, looking into the future, what are you most excited about in the area of pulmonary arterial hypertension?

Humbert: Thank you, Val, for your very kind comments. Working in an international group with you and others, it's really a privilege. In the future, we have to understand very well the mechanisms of each group of pulmonary hypertension. So in group 1, we have to understand better how to reverse pulmonary vascular remodeling and maybe obtain groundbreaking innovations for treatment based on novel treatment approaches. And then for group 2 and group 3, I think the community has to organize itself in order to produce good-quality data to tell us whether or not the drugs we use for PAH should be used in these other groups of PH. So that was my look to the future.

McLaughlin: Great. Marc, thank you so much. It was a privilege to discuss this with you today. Congratulations again on this very important document, and to the audience, I hope you enjoyed this as much as I did. Thank you.

Humbert: Thank you very much.

Resources

Pulmonary Arterial Hypertension

2022 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension

Pulmonary Arterial Hypertension Risk Stratification

Pulmonary Function Testing

Pulmonary Angiography Technique

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