Pulmonary Arterial Hypertension Podcast

Identifying and Navigating Challenging Clinical Scenarios in Pulmonary Arterial Hypertension

Vallerie McLaughlin, MD; Oksana Shlobin, MD


August 25, 2022

This transcript has been edited for clarity.

Vallerie McLaughlin, MD: Hello, and welcome to this InDiscussion Medscape podcast on pulmonary hypertension (PH). We're here today to talk about some challenging clinical scenarios in pulmonary hypertension. I'm Vallerie McLaughlin from the University of Michigan, and I'm joined by my good friend and colleague, Oksana Shlobin, from Inova Fairfax Hospital. Welcome, Oksana.

Oksana Shlobin, MD: Thank you for having me.

McLaughlin: Oksana, before we get into some of the scenarios that I wanted to discuss today, tell everyone a little bit about your journey into pulmonary hypertension.

Shlobin: I actually started my career as a lung transplant physician. I also did quite a lot of work in interstitial lung disease (ILD) while I was in training at Johns Hopkins. When I came to Inova Fairfax, I joined an advanced lung disease program, and as a part of this program, I had to start taking care of PH patients. And as I did, I really became fascinated by pulmonary hypertension; I really enjoyed learning more about it, learning about the physiology of this disease. And I really like taking care of the PH patients.

McLaughlin: That's great, Oksana. We enjoy having you in the pulmonary hypertension community, and your background is exactly what makes you perfect for the first challenging scenario that I want to talk to you about. And that is, what's group 1 and what's group 3 pulmonary hypertension? I think we run into this most often in patients with connective tissue diseases like scleroderma, and they're often very, very dyspneic and they have some ILD, they have some pulmonary hypertension. Sometimes it's hard to tease out what's what. What's your approach diagnostically to helping determine what type of pulmonary hypertension you think such a patient has?

Shlobin: These patients can be very, very tricky. Sometimes we have patients who have known ILD and we don't know that they have pulmonary hypertension when they initially come to see us. And sometimes patients present with a diagnosis of pulmonary hypertension. But then there is ILD that has been undiagnosed or underappreciated. So they come in different varieties. But having said that, these patients, as I mentioned, can be very challenging and their initial presentation sometimes can help you determine what their predominant pathophysiology is. So again, if patients come in and they have very significant ILD — very significant fibrosis, for example — and a little bit of pulmonary hypertension, they fall into more of the group 3 category. And if they have very significant pulmonary hypertension, just with a little bit of ILD, then they sort of fold into more of a group 1 pathophysiology. Unfortunately, it's very rare that it's actually this way, right? I think a lot of us have patients who have a fair amount of ILD and a fair amount of pulmonary hypertension. And you're right — when you knock out their parenchyma and then knock out their pulmonary vasculature, these patients can get very short of breath, very symptomatic with really any exertion or any exercise or any activity, and they can be very difficult to deal with. So if we have a patient with ILD, we monitor their full pulmonary function tests and their diffusion capacity, and on a periodic basis. Normally we get that every 3-6 months, and the diffusion capacity starts dropping out of proportion to the forced vital capacity. For example, in pulmonary function tests, that can be one of the things that you can look at to say, oh, maybe they're developing pulmonary vascular disease — if patients are desaturating more on their 6-minute walk test or they're walking a shorter distance than they used to, either the distance or more desaturation with the same distance or more desaturation with the shorter distance. So this change in 6-minute walk test parameters can be an important clue. Sometimes we'll look at the pulse rate recovery as well. If the pulse rate recovery starts changing, starts dropping, that's an important clue that they're developing pulmonary hypertension. And I also look at their CT scans. Obviously the heart is not very reliably assessed by CT scan, but for example, the pulmonary artery is pretty easily measured. So if you see a dilation in the pulmonary artery, especially the PH where the ratio starts going in the wrong direction, their pulmonary artery is more dilated. That's a clue that someone is developing pulmonary hypertension.

McLaughlin: Oksana, that's a lot of really good advice. So, you're following someone for ILD. These are the things that make you worry about PH — the reduction in diffusing capacity, for example. Or you're following someone for PH and this should make you start thinking about ILD and more desaturation. What about a newly diagnosed patient who comes to you and has moderate ILD on CT scan and moderate PH on echo? How do you put that patient together?

Shlobin: In a setting of connective tissue disease, I assume that both of them are very important components and they have to be addressed. So if their ILD appears to be more inflammatory, then I will always give them some treatment for ILD. If they really have a lot of inflammatory changes on their CT scan and you treat it and make it better, often their pulmonary hypertension will get better, which makes sense. Now, if you have a patient with more of a fibrotic disease, there is really no treatment that you can give for patients with fibrotic disease that's going to make this fibrosis go away. So for those patients, I would normally start them on an antifibrotic therapy to delay progression of the disease and to address the pulmonary hypertension, and start treating their pulmonary hypertension at the same time.

McLaughlin: That leads to the next section. Treatment might be a little tricky, right? We always have this concern about worsening V/Q mismatch in someone with fibrotic lung disease in whom we want to use PH therapies. Tell me what your approach to that is.

Shlobin: We have not had this experience in our center. Or I have not really noticed that there is really worsening desaturation with activity when pulmonary hypertension therapy is started. Looking at all of the major studies of therapies that were useful or not useful in patients with group 3 PH — sometimes small studies and sometimes bigger studies — that really has not been supported. So this concern of worsening V/Q mismatch is more theoretical, I think, instead of something that happens in reality. We monitor the 6-minute walk tests very regularly to make sure that patients are being oxygenated with activity as the treatment is started for pulmonary hypertension. But again, we have not had this experience of someone who becomes much more hypoxemic with treatment of pulmonary hypertension.

McLaughlin: Are there any pulmonary arterial hypertension (PAH) meds that you are more reluctant to use in someone with ILD?

Shlobin: Yes. And that really comes from our experiences with non–connective tissue disease group 3 patients with ILD, and specifically endothelin-receptor antagonists (ERAs) and riociguat. There were several studies that used a number of ERAs, and also the RISE-IIP study with riociguat, that were stopped for futility and sometimes for worse outcomes. And so I usually try not to go to one of those classes of drugs while treating these patients.

McLaughlin: I think this is an area where what you were talking about earlier — is it group 1 or is it group 3? — is really, really important, because if I have someone who I really think is group 1 PAH, their right ventricle is big and dysfunctional, their PVR (pulmonary vascular resistance) is 12. They have real-deal group 1 PAH and they have some ILD. You have to weigh risks and benefits, right? Sometimes I am more liberal with PAH therapies. And then even if there's a little bit of data on ERAs in ILD, I might say that the potential benefits in that type of patient outweigh the risks. Whereas in a patient with more ILD, bad fibrosis on CT, maybe their right ventricle is not dysfunctional, their mean PA pressure is 32 and their PVR is 4.2, and they have some PH, I might treat their PH, but I would be very reluctant to use an ERA or riociguat in that situation.

Shlobin: I think it's very nicely summarized, and we definitely approach our patients in a similar manner. I do have to say that in the context of connective tissue disease, we do try to be much more aggressive than in patients who have ILD-associated pulmonary hypertension without connective tissue disease. We try to really steer toward a similar approach in treatment for patients with ILD due to connective tissue disease. So, a similar approach like we would use in group 1 patients — with small caveats.

McLaughlin: Are you ever reluctant to use a parenteral prostacyclin in such a patient?

Shlobin: No. We have definitely used IV prostanoids because they're a little bit easier to titrate. And I think you see the negative effect on hypoxemia, for example. If it was to occur quicker in patients who have significant fibrosis in a setting of scleroderma, rheumatoid arthritis, mixed connective tissue disease, patients with myositis-associated ILD often have pulmonary hypertension. We actually very rarely see it without ILD in the setting of myositis. So we tend to treat that much more aggressively and we use IV prostanoids quite often in those patients if, hemodynamically or from the right ventricular standpoint, this is what you would do in group 1 patients.

McLaughlin: Right. I think that's the key. If the patient really has advanced hemodynamics, if they really look like group 1 disease, we treat them even if they have some ILD there. It's those people who are more in the middle, who have more modest hemodynamics and maybe could be group 3 for whom we tend to be a little more reserved with some of the more aggressive pulmonary hypertension therapies. One last question about the connective-tissue disease patients before we move on to the next challenging scenario, and that is pulmonary veno-occlusive disease (PVOD), which is really challenging to manage too. Sometimes we see PVOD in our scleroderma patients, for example, and sometimes we even uncover it with our PAH therapies. So, tell me what your words of wisdom to the audience are for when you should suspect PVOD and how you might alter your therapy when you think someone has PVOD.

Shlobin: Again, monitoring for exertional hypoxemia is very important. It's this hypoxemia assessment. Sometimes if PVOD is really a predominant factor in the setting of an ILD, that can be quite dramatic. People can get much more hypoxic, and if they are on your floor or in the ICU, you would notice it very, very quickly — not even with exertion but even at rest. And normally we would see a change in their CT scan. So if they have a baseline fibrosis, then there is going to be some more of the gross centrilobular ground-glass infiltrates and nodules. And then often in retrospect, you'd go back and you would say, oh my gosh, look at these mediastinal lymph nodes that were there that maybe we underappreciated in the past. So I think looking for this worsening hypoxemia is the clue, both acutely and with more of the outpatient assessment. But if PVOD is present, you'll see it pretty quickly when you start therapy, especially IV therapy. Now, I do have to say that we have had patients who I think have a PVOD component. It really became obvious with very aggressive PH therapy. Then we had to back off and then we instituted inhaled therapy or inhaled and oral therapy, and they seemed to sort of settle down. I think that the thing to remember with PVOD is that it's not only present on the venous side; it really is a continuum across the pulmonary vasculature. And so sometimes if you treat pulmonary hypertension, but maybe a little bit less aggressively, they may not get really hypoxemic and you may alter the hemodynamic to stabilize it.

McLaughlin: You have to find a happy medium, right? There's really no therapy for PVOD, and these patients are quite symptomatic. And so, as you said, sometimes too much PAH therapy makes them a lot worse, but sometimes a more modest amount of pulmonary hypertension therapy makes them a little bit better. They often are still symptomatic, but of course, sometimes we have to bring transplant into the discussion as well, because there's really no other treatment, frankly, for PVOD.

Shlobin: Absolutely. Patients with connective tissue disease, pulmonary hypertension, and ILD have the worst prognosis in comparison to people just with PH or patients with connective tissue disease–associated ILD. So this transplant workup needs to be in the equation very early on. I would definitely encourage a referral to a transplant center or calling your transplant team to weigh in and see whether a particular patient would be a transplant candidate potentially.

McLaughlin: It was great to get your perspective on the ILD. I know that this is what you spend a lot of your life doing, but another common and very clinically challenging scenario are those patients with what is probably group 2 pulmonary hypertension but combined pre- and post-capillary pulmonary hypertension. And I'm a cardiologist. I see these patients every single time I'm in clinic, and probably you as a pulmonologist see these patients too. People recognize that left ventricular (LV) systolic dysfunction can cause pulmonary hypertension. They don't send them to us. But when the LV squeeze is normal and the PA pressures are high, they send them to us and the patients are often quite symptomatic. Tell me what your approach to those patients is.

Shlobin: I will send them back to cardiology. No, I'm kidding. But you're absolutely right. We see those patients quite a lot. They constitute probably the largest proportion of patients that get referred to us. As far as the approach to treatment, I feel that most of the time the patients come to us, they're definitely underdiuresed. Diuretics can go a long way. And often patients come back just with increase of diuretics and say, "Oh my God, I feel so much better." They can pack in so much extra fluid. And it's not very obvious. It's not like those patients come in and they have 3+ edema. I mean, by the time they have 3+ edema, they have horrible biventricular failure, but often they don't seem to be that fluid-overloaded on exam. So assessing the fluid status is very important, and frequently you have to do a heart catheterization, either with a fluid challenge or with exercise, to really demonstrate what happens when the LV is working hard with exertion, to prove that they need to be diuresed better or more adequately.

McLaughlin: That's what I refer to when I see these patients; I refer to the bread-and-butter medicine — the things that people don't pay as much attention to as they should but which make a big difference. So, volume status is critical: making sure you adjust diuretics, making sure you counsel them on sodium restriction, making sure their blood pressure is well controlled. These patients often have concomitant sleep apnea, so, making sure that's controlled. There is some new literature, and it was just added to the heart failure guidance, about the role of SGLT2 inhibitors in these patients as well. I think there's a lot to go after with these patients. The thing that's really important to remember is that treating the underlying cause is critical. And as opposed to what data we have with ILD, there are actually no data with any PAH-specific therapy in patients with group 2 disease that show that it's helpful, and some data that suggest that these therapies may be harmful.

Shlobin: Right. That's absolutely correct, Val. Looking for things like sleep apnea is very, very important. A lot of those patients have sleep apnea and most of the time it's undiagnosed and definitely undertreated. We have started using SGLT medications in combination with diuretics and [spironolactone] in this patient population. I do think that at least our early experience is very positive. So we definitely have been doing that.

McLaughlin: Oksana, I'm just thinking, as I talk to you, about how I long for the days when I started doing this 30 years ago, when 90% of what we saw in clinic was the straightforward 55-year-old woman with IPAH. But we don't see those very much anymore. We see these patients with the group 2 and 3 causes that we've been talking about that are really, really challenging. But rather than look back, let's look forward. Tell me what you are most excited about in the area of pulmonary hypertension in the next 5 years.

Shlobin: I think I'm most excited about what a lot of other pulmonary hypertension clinicians probably are excited about: the class or classes of medications that may change pathology of the disease on a more cellular, molecular level and may even reverse the disease. Some people refer to them as disease-modifying agents. I don't know whether that's the correct terminology or not, but they are classes of medications that may actually alter the disease itself — not only dilate the vasculature, but actually treat the disease and maybe even reverse it. I think this is something that would be very exciting. And I know we have some literature that there may be some of those drugs on the horizon.

McLaughlin: I think that's right. I think a lot of folks are excited about having novel mechanisms of action. We attacked the same three pathways for 20, 30 years. It's exciting to have a new pathway. Well, Oksana, thank you so much for joining me and for sharing your wealth of knowledge, particularly about those patients who also have ILD.

Shlobin: Val, thank you for having me. This was a lot of fun.

McLaughlin: It was great. And thanks to the audience for joining us.


What Is Pulmonary Hypertension?

What Are the WHO Clinical Classifications of Pulmonary Hypertension?

Interstitial Lung Disease: Pathophysiology and Genetic Predisposition

What Is the Role of Pulmonary Function Testing in the Evaluation of Restrictive Lung Disease?

What Is the Six-Minute Walk Test (6mwt) in Pulmonary Function Testing?

Respiratory Failure-V/Q Mismatch

Efficacy and Safety of Riociguat in Patients With Symptomatic Pulmonary Hypertension (PH) Associated With Idiopathic Interstitial Pneumonias (IIP) (RISE-IIP)

Pulmonary Veno-Occlusive Disease

Sodium-Glucose Cotransporter 2 Inhibitors: An Overview

Treatment Approach to Connective Tissue Disease-Associated Interstitial Lung Disease

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