Pulmonary Arterial Hypertension Podcast

Diagnosis and Treatment of Chronic Thromboembolic Pulmonary Hypertension

Vallerie McLaughlin, MD; Richard Channick, MD

Disclosures

September 22, 2022

This transcript has been edited for clarity.

Vallerie McLaughlin, MD: Hello, everyone, and welcome to this Medscape InDiscussion podcast. Today we're talking about chronic thromboembolic pulmonary hypertension (PH). I'm Vallerie McLaughlin, professor of medicine at the University of Michigan. And I'm so excited to be joined today by Richard Channick, who's a professor of medicine and director of the Acute and Chronic Thromboembolic Disease Program at UCLA. Rich, great to have you here.

Richard Channick, MD: Pleasure to be here, Val.

McLaughlin: Rich, tell me a little bit about your PH journey.

Channick: I'm one of those who has been involved in this field for quite a while, over 30 years now. Even as a fellow in San Diego, we had a very busy PH and chronic thromboembolic pulmonary hypertension (CTEPH), program as we'll talk about. That's where I did my training and stayed there for a couple of decades, and then was involved in some of the early clinical trials in pulmonary hypertension, as well as helping grow the CTEPH program there. And then I went to Boston — Mass General — to start a similar program there. I was there for about 9 years and I've been at UCLA a little over 3 years, and I'm still very heavily involved in all aspects of PH, certainly including chronic thromboembolic disease.

McLaughlin: You're one of the pioneers in chronic thromboembolic disease. Can you tell the audience a little bit about the pathophysiology, the epidemiology of CTEPH?

Channick: It's a very fascinating disease process in terms of how it develops and to admit that there is a lot we don't know about it. But very simply, it's presumably an acute pulmonary embolism (PE) or emboli that, for reasons we're not entirely sure of, doesn't completely resolve, whereas many people get an acute PE and don't even know about it. You may see resolution of that clot, either most of it or all of it. But in these patients that doesn't happen. Then the clot starts to organize and become chronic, and that probably occurs after about 8-12 weeks. In other words, what you have left about 8 weeks after an acute pulmonary embolism, that's what you're going to have. And then the process goes from there. So it's basically like scar tissue forming inside the vascular bed, leading in some cases to PH. And whether a patient gets PH really depends on a variety of factors: how extensive the clot is, maybe other processes that cause remodeling of the vasculature, with the end result being obstructive lesions in patients with PH. And that's really what the term CTEPH refers to.

McLaughlin: It's a tough diagnosis to make, right? You and I are used to seeing it because patients get sent to us with a suspicion of that. But it's kind of referred to as the Great Masquerader. Patients have very nonspecific symptoms — dyspnea, fatigue. Some of them may not give a history of an acute PE. Let's talk a little bit about the diagnostic evaluation of these patients. Can you take me through that?

Channick: Absolutely. And you're entirely correct that many of these patients don't get diagnosed sometimes for long periods of time. There may be a variety of reasons for that. We're showing between probably 1 and 2 years' delay in diagnosis. And as you very well know, Val, you could say that about other forms of PH as well, where the symptoms are typically nonspecific: progressive exercise intolerance, shortness of breath, fatigue, sometimes very vague symptoms. You mention that many of these patients don't give a clear history of an acute PE, although presumably they had it. And it's been estimated that between 30% and maybe even as high as 50% of patients don't have that history. So when we're thinking about a patient who's more likely to have CTEPH, the first rule is that as part of the workup for any patient with PH, you want to consider CTEPH. And equally as important is how we follow up patients after an acute PE to ensure that they get resolution of their symptoms. If they've had, for instance, evidence of right ventricular dysfunction, then that goes away. So another hat I wear is in the acute PE world where we've developed this concept of pulmonary embolism response teams (PERT), which is a very organized, multidisciplinary group of people that takes care of patients with acute PE and then, importantly, follows them up.

McLaughlin: This is a great topic, the PE response teams. I think one important contribution the PERT teams have made is to help delineate acute from chronic PE when a patient comes in to a hospital with worsening shortness of breath. Because I've got to tell you, a lot of times we see people come in with worsening shortness of breath and they get called acute PE but it's clearly chronic; when you look at the CT you see chronic changes in the pulmonary vasculature, you see right ventricular enlargement. That does not happen with an acute PE. Can you tell me a little bit more about that?

Channick: Absolutely. We've seen exactly the same phenomenon as well, that what's often labeled as acute PE is actually chronic or maybe acute on chronic. And without the so-called PERT team, a patient may have been mismanaged and not recognized as having CTEPH. As you allude to, there are some typical radiographic findings that distinguish acute from chronic — the appearance of the clot for instance, being more eccentric in the vessel in a patient with chronic disease vs acute; the development of bronchial arterial collaterals that you may see on the CT, a so-called mosaic perfusion pattern where there's this geometric heterogeneity in the perfusion and in the lung shadows on the CT scan. We're also obviously taking a history, and with some of these acute PE cases that we get called for, you do talk to the patient and they've been short of breath for a month or more. That clearly suggests something more chronic.

McLaughlin: Right. And then the other aspect is what the right heart looks like. In a normal person who has an acute PE, their right heart may dilate, but it's not thick and hypertrophied. They may generate a PA (pulmonary artery) pressure of 45. They don't generate a PA pressure of 90. So there's a lot to the heart imaging on CT as well as echo, and really in terms of going back to CTEPH, oftentimes the echo is what leads to further evaluation of PH and then the consideration of CTEPH as an etiology. Whenever I give a lecture on this topic, I always say a patient with unexplained dyspnea and PH on the echo needs a V/Q (ventilation/perfusion) scan to rule out CTEPH because you don't want to miss that diagnosis. And in reality, V/Q scans aren't done that much anymore; everyone relies on spiral CTs. Tell me why the V/Q scan is the study of choice to rule out CTEPH.

Channick: That's a great point and I certainly echo your comment about how V/Q scans are often not done as frequently. They certainly have been replaced with CT scanning for the acute PE, based on very good data showing how reliable, how sensitive and relatively specific they are for acute PE. For chronic, it's a different story. And some of these data go back a decade or more, really showing that V/Q is very, very sensitive at excluding chronic thromboembolic disease. In other words, a normal nuclear perfusion scan with, very, very high reliability will rule out that diagnosis. CT scanning is a little bit of a mixed bag. Now, certainly CT scans have come along and advanced. And they're very sensitive in some cases for finding things on them. But I still see cases where very good radiologists have missed small irregularities in a segmental vessel, let's say. They don't look like acute PE with intraluminal thrombus and the radiologist missed it. The perfusion scan, on the other hand, clearly showed you a decrease or an absence of perfusion in that area. So as a functional test showing where the flow is going, I still think it's the best test. Now, it's not the most specific test. A normal perfusion scan excludes CTEPH but a "positive" perfusion scan showing defects doesn't rule it in. You need confirmatory testing.

McLaughlin: Sure. Every single year, big centers like yours and mine and UCSD, we find patients with operable disease that was missed on CT. So I really want to emphasize that point. I do want to ask one follow-up question about the V/Q scan. In the COVID era, we've had a lot of sites be concerned about doing the ventilation portion. Tell me what you think about a Q-only scan in the setting.

Channick: We all had the same problem. In fact, they were forbidden from doing ventilation scans for a very long period of time. Some places may still forbid it because it's an aerosolizing procedure in the COVID era. And so all we were doing was perfusion scans. There are some pretty good data that in patients without any underlying lung disease, like COPD or pulmonary fibrosis, and a clear chest radiograph, the perfusion scan is adequate and gives essentially the same information as doing the ventilation scan. So I think it's okay in those cases.

McLaughlin: Great. That's good to hear. So we've got the patient with dyspnea. We've got the patient who has evidence of PH on their echo. We've got the sensitive but nonspecific V/Q scan or maybe a CT scan that's got some findings. We need to do that confirmatory test. So that's the right heart catheterization and the pulmonary angiogram. And keeping in mind that these patients are often sick, they've got a high pulmonary vascular resistance. You're going in there, you're giving them a dye load. Tell me some of your highlights of the important aspects of safely approaching a pulmonary angiogram in such patients.

Channick: This is something that we've obviously addressed over decades now — doing right heart catheterizations and pulmonary angiogram in patients with, in many cases, very severe PH. The one thing I would say before things like that is that we still do CT scanning even though, as you say, it doesn't rule it out. But the CT scan actually does give you a lot of additional useful information. It looks for some of the mimics of CTEPH, like tumors either in or surrounding the pulmonary artery, things like fibrosing mediastinitis with calcification around the pulmonary artery, vasculitis of the pulmonary artery. So we do get that information. And also it'll tell us whether there's a very, very proximal clot blocking the main pulmonary artery; that may affect what you do with the invasive part of it or the right heart catheterization.

McLaughlin: Those are great points, Rich.

Channick: So we simply do a right heart cath in the standard way, which is a very, very safe, low-risk procedure, and then the pulmonary angiography where we do a conventional digital subtraction angiogram, which is just two shots — one in the right and one in the left. Position of the catheter is important. Not to get too technical, but one of the things I've learned is that the catheter has to be put out far enough so it doesn't kick back. You really want to get good resolution in the lower lobe vessels where a lot of the disease is. So we position that catheter correctly, usually just past the upper lobe take-off. And typically it's a standard injection of between 20 and 30 mL of contrast on each side. We recommend biplane imaging, ideally because the lateral view will give you additional information about the lower lobe vessels. So by doing both the anterior actually on the left, we do a little LAO (left anterior oblique) 20° — not to get too technical. But in the lateral view, we're able to get very good imaging of all those lower lobe vessels and it is safe. And again, it's with limited contrast; with the modern catheters that are usually side injections, it's very, very rare to see any kind of safety issue.

McLaughlin: Right. One of my favorite things about the CTEPH program and caring for these patients is that it's really a team-based sport. There are a lot of important members of this team. So we've now taken this patient through the workup. We have a V/Q, we have an echo, we have a CT, we have a pulmonary angiogram. As you said, most of the patients get all of those things. And then we have to sit down as a team and talk about the patients to figure out what the best therapy is for them, and the team members are multiple. It's the PH team, it's cardiology, it's pulmonary. We often have our radiology colleagues — you know, imagers — and the surgeon, the interventionalists who may do balloon pulmonary angioplasty (BPA). So tell me about how that's evolved over the years and who's involved in your team now, and how you discuss the patients after they've had their diagnostic evaluation.

Channick: It's really nice to have this multidisciplinary team where everybody brings their expertise and perspective and we decide the best treatment options. And especially now that there are multiple treatment options, I think what we always say is that the default approach is the surgical approach. We'll talk about the surgery, pulmonary thromboendarterectomy. But that's the procedure that in many ways we're hoping the patient will be a candidate for, because that's extraordinarily effective and with very long term data showing the benefit of a pulmonary thromboendarterectomy.

McLaughlin: I mean, let's talk about that, Rich. You've participated in the care of patients who have undergone that surgery for decades. We always kind of have the mantra that if the patient has favorable anatomy, has surgical anatomy, we need to at least think about surgery for them. There are a few reasons why a patient with surgical anatomy might not be a good candidate for surgery. But if they are, we usually give the surgeon what we might call the right of first refusal, but it is a complex surgery. Can you briefly summarize the surgery for the audience?

Channick: Sure. It's actually an amazing surgery. It's a pulmonary thromboendarterectomy. So they go into each pulmonary artery and then where you get to it is through a median sternotomy, which is a standard approach for other heart surgeries. The patient goes on cardiopulmonary bypass. Then they isolate each pulmonary artery and they make an incision first on the right, main pulmonary artery, and then they have to find what we call a dissection plane. So they typically make a small incision in the back of that pulmonary artery and start dissecting, using blunt dissection. And if you think about it, they've got to get out to every branch that they can that may be occluded. As it turns out, sometimes the disease starts very proximally, but sometimes there's minimal disease proximally. And it's only as you get further and further out that you get into some of the occlusions, the chronic occlusions, that really have formed like a cast of the pulmonary vascular tree. So that dissection plane and how they do that is very delicate in some ways and requires a lot of expertise to do that. To have a bloodless field, you need to put the patient under circulatory arrest, so-called profound hypothermia, where they get cooled to about 18 °C and then have periods of complete circulatory arrest where they turn off the pump. So the patient has no EEG activity. They're essentially brain-dead during upwards of 20 minutes at a time on each side. So it's a race against the clock, in some ways, to get out all of that material. But you want to do a complete endarterectomy as well.

McLaughlin: Yeah, it is an incredible surgery. And when they can get those tails, when they can really extract that material, you can have great results. Of course, during the rewarming time, you can do whatever else you need, if the patient needs a bypass or a tricuspid ring or closure of a PFO (patent foramen ovale) or what have you. So it's really a wonderful surgery. But it may not cure everyone. There are some patients who may have persistent pulmonary hypertension afterwards. And based on some of the data from the UK databases, we've been doing what we call risk stratification at 6 months — repeating echo, V/Q, right heart cath to see what those hemodynamics are like. Because if they have persistent PH, they don't do as well and we might not think about other things, such as BPA in some cases or medical therapy. So I think it's important to keep that in mind. But we've both seen people, just day and night, get back to normal with that surgery. BPA is picking up a lot of steam. Do you want to tell the audience about that?

Channick: Absolutely. And just to make one other point, I think the fact that we do see residual PH in some patients really underscores the complexity of this disease. I always say this is not just about mechanical obstruction from clot. If it were, then you'd take out the clot and the pressures, everything, would be normal. But what we’ve learned is that there's actually a fair amount that goes on behind the scenes, if you will, where you're getting remodeling, microscopic arteriopathy, that can develop as a result of these chronic thromboembolic lesions. And in some patients, there's more microvascular disease or small vessel disease than in others. It's a fascinating area of research to figure out why some patients develop more of this remodeling of the vasculature that may contribute to the residual hypertension. And we'll talk about that as it may relate to medical therapy for PH after their surgery or in inoperable patients.

In the middle zone we have BPA, which has emerged as a pretty good treatment for many patients who have disease that is felt to be not operable in location, where you can go in and, using small balloons, relatively low pressure, do multiple dilations and open up flow to these vessels. It's a procedure that was done many decades ago that fell into disfavor due to a high complication rate. But then a couple of Japanese groups really modified the procedure and made it safer with smaller balloons, maybe cross-sectional imaging to look at the size of the vessels so you don't overdilate. They published a very large case series which has really brought BPA back. There are many centers in this country that are doing BPA, including both of ours.

McLaughlin: Right. And again, it requires some coordination. Often it takes three or four or five or six sessions to be able to target all the areas that you would like to target. But the hemodynamic results can be quite impressive. And then lastly, Rich, you mentioned medical therapy, and that's sometimes used in patients with residual CTEPH after an intervention or in some patients who may not be candidates for any sort of revascularization. Do you want to just touch on that?

Channick: Yes. It makes a lot of sense. As we know, microscopically and pathologically the vascular lesions look very similar to in patients with so-called group 1 PAH, for which many medications are approved. Several studies and trials have looked at the various PAH therapies to see if they could apply to these patients — we're talking about with CTEPH. One drug in particular, riociguat, which is a guanylate cyclase stimulator, is also proven in PAH and has been proven to be effective in those patients with residual PH after surgery or inoperable CTEPH. So that drug is FDA approved for use in that setting and, based on its benefit on 6-minute walk distance, also has hemodynamic effects. There are other drugs that we use for PAH that are also being studied and, in some countries, also approved for CTEPH. And then there are other trials that are going on. So I think, again, it makes sense. There's a strong rationale and we're certainly pretty aggressive, as you are, about considering medical therapy in patients with persistent pulmonary hypertension.

McLaughlin: Right. And of course, the other therapy we can't overlook is that these patients require lifelong anticoagulation; there really aren't a lot of randomized controlled trials there. Do you have a preference for one thing vs another, Rich?

Channick: Great question. We're always feeling the pressure to use the newer direct-acting oral anticoagulant (DOAC) drugs and new anticoagulants because they are much easier to use and don't require monitoring. Historically, of course, we've always used warfarin, and I think the consensus is still that we use warfarin, at least in the early stage after surgery. There's some evidence, although it's debated for sure, that there may be a little higher recurrence rate of acute PE in these patients who are on a DOAC vs warfarin. So I think we're evolving there as we get more and more real-life data. Right now, our approach is to do 6 months of warfarin following surgery and then consider switching. Certainly if a patient is having trouble maintaining a therapeutic INR (international normalized ratio), then we'll switch earlier.

McLaughlin: Yeah, we do 6 months for sure and then consider switching. Unless, of course, they had some sort of hypercoagulable state and then we're a little bit more firm about coumadin, sometimes even with a higher INR range — but again, not a lot of RCT data there. Rich, this has been a great conversation. You've been around the block and have a wealth of knowledge in CTEPH. I want you to look into the next 5 years and tell me what is really exciting you about the likely happenings in the arena of PH.

Channick: Thanks for that opportunity. I'm old enough to remember when there were no treatments. I was a fellow when IV epoprostenol was just first being studied, and now to have over a dozen approved therapies in PH… While working on three pathways we had a little lull, but now we're clearly in this surge, this crest of new studies and new therapies. So I think that the exciting thing is that 5 years from now, I almost guarantee that we're going to have a new list of therapies, new pathways, and we're going to push things forward. I think it's awesome.

McLaughlin: Great. Well, Rich, thanks for joining me today.

Channick: Thank you.

Resources

Pulmonary Hypertension

Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Pulmonary Embolism

Determinants of Diagnostic Delay in Chronic Thromboembolic Pulmonary Hypertension: Results From the European CTEPH Registry

Pulmonary Embolism Response Teams: Purpose, Evidence for Efficacy, and Future Research Directions

V/Q Scan

Multidetector Computed Tomography for Acute Pulmonary Embolism

Pulmonary Thromboendarterectomy

Dynamic Risk Stratification of Patient Long-term Outcome After Pulmonary Endarterectomy: Results From the United Kingdom National Cohort

Balloon Pulmonary Angioplasty in Chronic Thromboembolic Pulmonary Hypertension

Balloon Pulmonary Angioplasty as a Treatment in Chronic Thromboembolic Pulmonary Hypertension: Past, Present, and Future

Pulmonary Arterial Hypertension Clinical Presentation

Riociguat

Long-term Clinical Value and Outcome of Riociguat in Chronic Thromboembolic Pulmonary Hypertension

Riociguat Prescribing Information

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