Activity Transcript

Sandhya Murthy, MD: We know that the treatment of pulmonary artery hypertension -- or PAH -- is driven in large part by assessment of the patient's mortality risk. And in many cases, the latest evidence-based treatment algorithm will guide us as we try to provide the most effective care possible. But to say that managing PAH can be challenging is an understatement. Patients have a wide response to therapies, and there's a lot of clinical heterogeneity in how the disease evolves over time.

We're also seeing an increasing number of aging patients with multiple comorbidities who have significant precapillary pulmonary hypertension and exhibit hemodynamics consistent with PAH, or group 1 pulmonary hypertension (PH). But do these patients have "true PAH," or another type of PH in the classification schema?

These are the types of challenging cases that we'll be discussing today.

Hello and welcome to season 6 of CME-TV: Contemporary Topics in Pulmonary Hypertension. I'm your host, Dr Sandhya Murthy -- cardiologist and associate professor at Albert Einstein College of Medicine in New York.

Today we'll be visiting with the esteemed Professor of Cardiovascular Medicine, Associate Chief Clinical Officer of Cardiovascular Services, and Director of Michigan Medicine's Pulmonary Hypertension Program, Dr Vallerie McLaughlin. I can think of no better an individual to guide us on today's topic of… "Approaching Challenging Cases in the PAH Clinic."

Vallerie, thank you so much for joining us.

Vallerie V. McLaughlin, MD: Thank you for the very kind introduction.

Dr Murthy: Do you find that one of the major challenges in treating PAH is the heterogeneity and phenotypic diversity that you encounter in clinical practice?

Absolutely -- there's incredible diversity now. Long gone are the days when we saw mostly young women with very clear-cut primary PH. Over the past few decades, the phenotypic makeup has shifted almost entirely.

How many patients would you say still have the classical presentation of PAH?

Dr McLaughlin: The COMPERA registry looked at almost 850 patients with newly diagnosed idiopathic PAH and identified 3 distinct phenotypes. The data were pulled from 2009 to 2019, so they used the older diagnostic criteria for mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR), but differentiation between the phenotypes still applies.

Cluster 1 was the classic presentation -- mostly female, median age in the mid-40s, no comorbidities, and were, primarily, never smokers. This phenotype accounted for 1 out of every 8 cases. Only around 13% total.

Nearly 36% fell into Cluster 2, described as the "left heart phenotype." This group was almost entirely older women, with a median age of 75. They had risk factors for heart failure with preserved ejection fraction, such as hypertension, obesity, diabetes, and coronary heart disease -- and they had precapillary pulmonary hypertension. And around one-third had a history of atrial fibrillation.

The remaining half -- or 52% of patients -- then fell into Cluster 3, referred to as the "cardiopulmonary phenotype." This group was predominantly male, with a median age of 72. Their diffusing capacity of the lungs for carbon monoxide (DLCO) was less than 45% of the predicted value, and they had a significant smoking history as well as various risk factors for left heart disease.

Dr Murthy: So these phenotypes are very different from each other. What were the prognostic implications?

Dr McLaughlin: As you might expect, outcomes for patients with the cardiopulmonary phenotype were poor. Their survival rate in the registry was 42% at 5 years. And they were less likely to achieve low-risk status, either because they respond less well to treatment or because they discontinue treatment.

Dr Murthy: Is there any way to predict how well a patient will respond to treatment?

Dr McLaughlin: Only in broad strokes. We can anticipate that certain patient types may be more challenging, but there's nothing at the individual level that will tell us in advance who is going to respond to what.

For example, patients with multiple risk factors for diastolic heart failure are more likely to get fluid overloaded on endothelin receptor antagonists (ERAs). So we usually start them on a phosphodiesterase-5 (PDE5) inhibitor and then add an ERA later on if it's needed. But you have to keep a close watch on their volume status. Or we may consider inhaled prostacyclins for pulmonary patients. But to answer your question, no, there's really nothing we can do in advance to predict a patient's response to treatment.

We just have to monitor how they're doing. Bring them back to the clinic to reassess their symptoms, their hall walk, their biomarkers, and echo. And then adjust their medications as necessary.

Dr Murthy: Whereas systemic sclerosis -- or scleroderma -- was once viewed as a skin condition. It's now recognized as a multisystem disease characterized by fibrosis, excessive collagen deposition in the skin and internal organs, chronic inflammation, autoimmune dysregulation, and microvascular endothelial dysfunction.

Up to 19% of people with systemic sclerosis may develop PAH, and around half will die within 3 years. This, to me, is the very definition of a challenging case.

So, Vallerie, do you see many patients with PAH with systemic sclerosis?

Dr McLaughlin: Absolutely. We have a large population of patients with scleroderma at our center. And treatment can be difficult.  These patients invariably have many other symptoms that accompany their scleroderma, particularly musculoskeletal symptoms. And they often have gastrointestinal (GI) issues that make it difficult to tolerate medications.

In general, their prognosis is worse than it is for many other patients. And whereas some of them have clearcut group 1 PAH, others have connective tissue disease-related interstitial lung disease (ILD). And sometimes they have both.

Dr Murthy: How do you decide initial treatment when there's such a wide variation in their underlying disease?

Dr McLaughlin: If they have more clearcut group 1 PAH, we approach their treatment the same way we would treat idiopathic PAH -- usually with an upfront endothelin receptor antagonist and PDE5 inhibitor. We do a telehealth visit at 1 month to check in and assess side effects. And then we reassess in 3 to 4 months.

Patients with interstitial lung disease tend to be older and have multiple comorbidities. They also tend to have risk factors for heart failure with preserved ejection fraction (HFpEF). Ultimately, there can be multiple causes for their dyspnea and PH, which makes treatment more challenging.

Dr Murthy: I suspect that a patient having 2 very complex disease processes, occurring simultaneously, complicates every aspect of their disease management. How does it affect their assessment in particular?

Dr McLaughlin: That's a great question. And, yes, risk assessment of patients with scleroderma can be more challenging due to their musculoskeletal symptoms and frequent comorbidities.

Most do not do well on hall walks. So, they'll appear to be at intermediate-high or high risk. This makes their echo extremely important. Because if their right ventricular (RV) function is normal, it's probable that other causes -- like musculoskeletal limitations -- are contributing to their symptoms.

Dr Murthy: Pulmonary fibrosis is another fibrotic disease with a similar pathophysiology to systemic sclerosis. Does that condition also complicate the treatment of PAH?

Dr McLaughlin: We're seeing a lot of patients with pulmonary fibrosis because inhaled treprostinil is Food and Drug Administration (FDA)-approved for PH in the setting of pulmonary fibrosis. This is based on the results of a single randomized clinical trial showing an improvement of 31 meters in 6‐minute walk distance compared with placebo.

But, the main challenge is that both pulmonary fibrosis and PH can cause shortness of breath. And inhaled treprostinil is probably only going to help with what's directly related to the pulmonary hypertension.

Dr Murthy: So, someone with severe fibrotic lung disease and mild PH may not benefit very much from inhaled treprostinil. Is that correct…?

Dr McLaughlin: That's right. Conversely, if you have someone with more modest lung disease and significant PH -- a pulmonary artery (PA) pressure of, say, 40 -- that's the type of patient who is likely to benefit much more from inhaled treprostinil.

One thing to remember in patients with pulmonary fibrosis, however, is that many of them are older and have risk factors for diastolic heart failure as well. So, it's vital that we start out with a good diagnosis, which means we need to obtain an accurate right heart catheterization.

If we confirm that they have PH in addition to pulmonary fibrosis, inhaled treprostinil is the only FDA-approved therapy. And if they don't respond adequately to that medication, we may need to consider other more investigative approaches.

Dr Murthy: As initial oral drug therapy for the treatment of idiopathic PAH without cardiopulmonary comorbidities, guidelines recommend upfront combination therapy with an endothelin receptor antagonist and a PDE5 inhibitor.

For patients who don't achieve or maintain low-risk status on this combination, an oral prostacyclin receptor agonist is often added, or the PDE5 inhibitor could be switched to a guanylate cyclase stimulator. But if their condition continues to worsen after that, the best course of action gets a little…fuzzy.

What is your approach when you have a patient with group 1 PAH who has been escalated to triple oral therapy, but their symptoms are still getting worse?

Dr McLaughlin: That's usually when we have the hard conversation about initiating a parenteral prostanoid. These can be lifesaving therapies, but some patients resist taking them.

Dr Murthy: And why is that?

Dr McLaughlin: When I first started treating PAH, parenteral prostanoids were the only effective treatment, and all of our patients went on intravenous (IV) therapy. But now that we have so many other oral medications, patients want to stay on those rather than starting a parenteral prostanoid.

So sometimes, even when patients' symptoms are getting worse, they resist parenteral therapy until their disease has become quite advanced. In some instances, they wait until it's too late, and there has been too much remodeling for us to reverse it. If they wait until they have a pulmonary vascular resistance (PVR) of, say, 20 before the parenteral is started, they're not going to do as well as they would have if one had been started earlier.

And sometimes patients who don't respond to dual or triple therapy may be candidates for clinical trials. Quite a few promising studies are underway with agents targeting new disease pathways in PAH. Sotatercept is furthest along in development. It's a fusion protein that acts by rebalancing deficient BMPR2 signaling. Seralutinib is an antiproliferative agent that targets the platelet-derived growth factor (PDGF) cascade and increases BMPR2 expression. And rodatristat is a tryptophan hydroxylase (TPH) inhibitor targeting excess serotonin production in the vascular endothelial cells.

Dr Murthy: Is there any way to make the conversation about initiating parenteral therapy go more smoothly?

Dr McLaughlin: When patients keep resisting parenteral therapy, I sometimes find that it's helpful for them to talk with another patient who's already on a pump. I can recommend parenteral therapy from a medical perspective, but in some cases, it carries a lot more weight coming from another patient with shared experience.

Dr Murthy: And that's when you send in…a Mary, right?

Dr McLaughlin: Exactly. That’s when we throw a Hail Mary.

Mary: Did I hear my name?

Dr Murthy: Mary! What a nice surprise. Could you tell us a little about how you approach mentoring other patients with PAH?

Mary: Yes, absolutely! Hello everyone! My name is Mary Eisemann. I've had PAH for about 8 years. And I've been mentoring people with newly diagnosed PAH for about 5 of those years now.

When I mentor, I give it to people straight. They really, really need to know the seriousness of having PAH. I can't stress that enough. But on the flip side, they need to hear that there's hope. I might say something like, "Look at me. I'm on an IV. And going on it was very scary. But here I am today. I'm mobile. I exercise every day. I'm able to work and be with friends, go out to dinner...talk to you." You can't guarantee them the same results. But there's hope.

The other thing that every person with PAH needs is a practical understanding of their medications, regardless of what they're taking. They need to know what to expect and how to manage potential challenges.

In my case, I needed to know how to take a shower with an IV. I had to get a removable wand installed in my shower since you can't get the catheter site wet. And a hook to hang the pump up in its case. Those are the things people need to know.

The PH nurses and pharmacists are wonderful, and they can share in detail what they've learned from other patients. And they can explain the side effects of treatment from top to bottom. But, sometimes, hearing it from another patient is what's really needed.

Dr Murthy: Well said, Mary. Thank you for sharing. Your timing was impeccable.

Mary: I just knew it would be. I'll let you get back to whatever you're doing. Bye-bye.

Dr Murthy: She's wonderful.

Alright, let's see. Are there any other challenging treatment scenarios that we haven't yet covered…? What about patients with diastolic dysfunction? How do you approach managing their PAH in the clinic?

Dr McLaughlin: There is no specific PAH therapy approved for use in patients with group 2 PH due to diastolic heart failure. And existing PAH therapies should NOT be used for these patients. They're not associated with any consistent clinical benefit, and they can actually worsen the patient's condition.

Dr Murthy: And why is that?

Dr McLaughlin: Causing vasodilatation and increasing venous return to a stiff left ventricle can end up raising left heart-filling pressures even further and induce pulmonary edema in the patient.

Dr Murthy: What can we do for these patients?

Dr McLaughlin: Group 2 patients are typically older women who have hypertension, diabetes, obesity, and other cardiometabolic comorbidities. And there's a lot that can be done to manage these conditions. But it's not a magic solution. And they may not like, for example, taking their diuretic. Because it makes them have to use the bathroom often. But this is what it is. It's about treating the underlying problems and getting them involved in preserving their health through diet, exercise, and medication adherence.

Dr Murthy: Do you think there is any possibility that we will see a medication for treating PAH -- specifically -- in this group?

Dr McLaughlin: Anything's possible. But we're still at least several years out. There's an ongoing clinical trial called CADENCE, which is evaluating the fusion protein, sotatercept, in patients with PH due to HFpEF. The results from that study are expected in 2026.

Dr Murthy: How about patients with group 1 PAH and a low DLCO?

Dr McLaughlin: We generally use the same therapies for these patients as we do for those with idiopathic PAH, but they tend not to respond as well. And then there are the patients with heritable PAH. They typically have more aggressive disease. So, I think the key with this group is to proactively screen at-risk individuals to identify them early, and then treat them aggressively, including escalation to parenteral prostacyclin therapy when necessary.

Dr Murthy: Regardless of whether we -- as clinicians -- consider a case to be more clinically challenging or not, a PAH diagnosis -- for the patient -- affects every part of their life. The inherent complexity of the disease and its treatment is best managed by an interprofessional and multidisciplinary team, including the patient themself. But I suspect that taking a holistic and collaborative approach to manage challenging cases like we've been discussing makes a world of difference.

Vallerie, how does working with an interprofessional team help to optimize care in these challenging scenarios?

Dr McLaughlin: The primary care professional -- whether that's a physician, physician assistant, or nurse practitioner -- plays a pivotal role in PAH, especially as a lot of patients have several comorbidities. Similarly, pharmacists and nurses can improve overall care by making sure that those other conditions are not overlooked.

So, for example, making sure that the patients with diastolic dysfunction are volume optimized and their blood pressure is controlled -- emphasizing sodium restriction, finding out whether they're taking their diuretics, and checking whether they're on other medications that might be beneficial, such as an SGLT2 (sodium-glucose cotransporter 2) inhibitor.

And then, when patients need to be escalated to parenteral prostanoid therapy, it's really important to make sure that the whole patient care team is familiar with its benefits, how to optimize the process, and how to manage the side effects.

Dr Murthy: Are there any technologies that you find help to improve the interaction between patients and the wider care team?

Dr McLaughlin: Yes, a lot of clinics are finding that virtual visits can improve both the quality and efficiency of care.

At our center, we use a virtual care platform that monitors patient-generated data, biometrics, outcomes, and symptoms data, which are all integrated into the medical record. The platform provides patients with highly personalized dialogue and can, in some cases, alert us to the need for specific follow-up or interventions. Those tasks can then be assigned to the most appropriate member of the interprofessional team.

Generally, the platform allows us to communicate more with our patients and get better control over things like volume.

Dr Murthy: Wonderful. Well, Vallerie, thank you for sharing your insights with us.

Dr McLaughlin: It's always a pleasure talking with you, Sandhya.

Dr Murthy: And thank you, as always, for watching. Please continue to answer the questions that follow and complete the evaluation for your CME and CE credit. And be sure to check back for the next episode on Contemporary Topics in Pulmonary Hypertension -- "Connecting the Dots in CTEPH: Advancing Diagnosis and Treatment." Goodbye for now.

This transcript has not been copyedited.