Treating CTEPH: Surgery, Medication or Balloon Angioplasty?

Podcast Transcript

Raed Dweik, MD:

Hello, and welcome to the Respiratory Exchange podcast. I'm Raed Dweik, chairman of the Respiratory Institute at Cleveland Clinic. This podcast series of short, digestible episodes is intended for healthcare providers and covers topics related to respiratory health and disease. My colleagues and I will be interviewing experts about timely and timeless topics in the areas of pulmonary, critical care, sleep, infectious disease, and related disciplines. We will share information that will help you take better care of your patients today, as well as the patients of tomorrow. I hope you enjoy today's episode.

Gustavo Heresi, MD:

Hello, and welcome, everybody. My name is Gustavo Heresi. I'm a pulmonologist at the Cleveland Clinic, where I am the section head for pulmonary vascular disease in the relation of pulmonary medicine, and it is my pleasure today to have Dr. Alice Goyanes, one of our pulmonary hypertension experts with special interest in chronic thromboembolic pulmonary disease, which is the topic at hand today.

Chronic thromboembolic pulmonary hypertension is a special type of pulmonary vascular disease. It is currently classified as group four pulmonary hypertension, and it is particularly relevant to diagnose because among the types of pulmonary hypertension, chronic thromboembolic pulmonary hypertension, or CTEPH as we call it for short, has really specialized dedicated treatment options that can really improve the situation in ways that, for other forms of pulmonary hypertension, may not be that relevant. So, we're going to focus on treatment options, but before we do that, Alice, I was hoping that you can set the stage a bit for this conversation and tell us about how do you think about CTEPH, how do you make this diagnosis?

Alice Goyanes, MD:

Thank you so much, Gustavo, for that nice introduction, and I'm looking forward to our conversation today. So, CTEPH, I think that patients arrive at this diagnosis kind of from two different sources. So, one way that patients arrive at this diagnosis is if they have a history of a pulmonary embolism, and then there's incomplete resolution of the thrombus, which then results in the patient having ongoing symptoms, presenting to their doctor, getting an echocardiogram which suggests pulmonary hypertension, and then the patient goes forward and gets a series of imaging studies that confirm chronic thromboembolic disease.

The other way that patients arrive at this diagnosis is if they are actually starting with a pulmonary hypertension diagnosis and then the pulmonary, if they get referred to a pulmonary hypertension center as part of the initial workup for pulmonary hypertension, we actually will screen all of those patients for CTEPH. And the reason for that is that actually about 30% of patients that end up with a CTEPH diagnosis don't actually have a confirmed history of an acute pulmonary embolism event. So, that's sort of the two ways that patients start undergoing the workup for this disease

Once you're in the process of being worked up for CTEPH, the way the diagnosis is made is when a combination of, as I mentioned, imaging that confirms that there's chronic thromboembolic disease, as well as hemodynamic data confirming pulmonary hypertension. It's the combination of the two that help a patient confirm having a diagnosis of CTEPH.

The imaging modalities, I'll just briefly list out because a lot of the time we use all of those to help us make treatments decisions, is typically a combination of some type of imaging modality documenting profusion limitation, meaning that there's abnormal blood flow in certain sections of lung where there's obstruction. And the types of imaging modalities that can support that classically is a ventilation profusion scan. You can also see limitation of blood flow in other imaging modalities that we use, such as dual-energy profusion weighted imaging, one, CT scans for looking at the parenchymal phase of a pulmonary angiogram. But classically, patients come to us with a ventilation profusion scan that's abnormal, showing areas of lung that are receiving air that are not receiving blood. And then, we confirm the location and degree of the obstruction either, as I mentioned, with a CT pulmonary angio or with a digital subtraction angiography of the pulmonary arteries.

Once we've worked through all of those imaging modalities, that's how you confirm that there's chronic thromboembolic disease-causing profusion limitation in the lung. And that combined with the hemodynamic measurements that are obtained during a right heart catheterization are how patients arrive at a diagnosis of CTEPH.

Gustavo Heresi, MD:

That's wonderful. Thank you. Obviously, it is a somewhat complex diagnostic evaluation process that definitely requires accurate and hemodynamic measurements and precise imaging to pull that together. So, that's really wonderful. Now, once we are confident that we're dealing with chronic thromboembolic disease leading to pulmonary hypertension or so-called CTEPH, tell us a bit about what comes to mind in terms of treatment. What is the first thing that you think about in terms of helping these patients?

Alice Goyanes, MD:

Yeah, absolutely. So, this is a very rewarding patient population to be able to take care of because there's a lot of things that we can do for them. So, the first and sort of, I would even say, gold standard of treatment consideration for CTEPH is to determine if they're a candidate, though, for a pulmonary endarterectomy. So, pulmonary endarterectomy is a, you know, as I describe it to my patients, it's a large open-heart surgery typically done with a midline sternotomy in which a cardiothoracic surgeon goes into the pulmonary arteries and dissects out the chronic thromboembolic material that's adherent to the intima of the pulmonary arteries. It requires that a patient be able to tolerate a circulatory arrest in cardiopulmonary bypass, and it also requires that the surgeon be able to physically reach the chronic thromboembolic material. There are some patients that this material is very easily accessed, and you can see it very easily on CT scan, and then there are some patients where the disease is more distal, and that can be a more challenging treatment decision.

Patients who get selected and ultimately go for pulmonary endarterectomy surgery, the key thing for determining how they're going to do is if there's a dramatic reduction in their pulmonary pressures as a result, uh, within the first couple of hours to days, as a result of the surgical extraction. So, outcomes are definitely significantly tied to the delta decrease that you get in pulmonary vascular resistance. So, patient selection becomes very important under those circumstances, and that's one of the reasons that the guidelines really highlight making a decision about cervical candidacy in a highly experienced, high-volume CTEPH center.

Gustavo Heresi, MD:

That's great. You mentioned something at the beginning, that this is rewarding condition because we frequently see really good results with the operation with pulmonary endarterectomy, both short term and long term. Right? Which is why this is the, sounds like it's the treatment of choice. And I always think about this as, if you have CTEPH and you can get operated, you should get operated, right? But I'm sure we also deal, and I know we also deal with the folks that cannot get operated. Right? So, I wonder if you can tell us a little bit about why some people may not qualify for the surgery, and then we can talk a bit more about what else can be done if surgery's not an option.

Alice Goyanes, MD:

Absolutely, yeah. I always, when I'm teaching my fellows about this, I always tell them that this is, you know, really where we kind of earn our paychecks in the CTEPH realm is making this decision, because it's a very complex and big one in terms of who gets to, who's a good candidate and who may not benefit potentially. So, some of the things that can impact somebody's surgical candidacy, there's sort of the anatomic factors that have to do with the thrombotic burden. There's sort of weighing the proportion of hemodynamic insult versus thrombotic burden, and I'll explain what I mean by that in a couple minutes. And then there's sort of medical comorbidities that would just make anybody, making getting through cardiopulmonary bypass, the circulatory arrest medically prohibitive in terms of the risk-benefit ratio.

So, the anatomic factors that I'll take into account are if the chronic thromboembolic disease is so distal out into the lungs that it is, it would be challenging for the surgeon to physically reach that. If you're a CTEPH surgical center of excellence, you should be able to offer surgery that can extract thrombotic material up to the subsegmental level of the pulmonary arteries. So, that's sort of the benchmark that's been set, although, you know, different centers have different levels of comfort with that degree of extraction, and so there may be, you know, some types of patients that are, you know, candidates to get this surgery at a high-volume center with a surgeon who's very comfortable, with a lot of experience with the surgery, but they may not be a candidate to get it at a lower volume center that's kind of just getting their program off the ground, for instance. It's one of the reasons that the guidelines say that when you have surgical operability discussion, that if you actually get turned down at one center, that you should get a second opinion at another, and a second CTEPH center to make sure that there is concurrence. So, anatomic considerations in terms of whether the thrombotic burden is too far distal in the lungs to reach is sort of one particular consideration.

The other consideration that kind of goes along with anatomy or distribution of blood clots is the hemodynamic insult in the lungs in proportion to the amount of disease our surgeon thinks they're gonna get out. So, for instance, there are some patients that sort of present with much more of a idiopathic pulmonary arterial hypertension phenotype compared to a CTEPH phenotype. What I mean by that is that they may have significant elevations in their pulmonary vascular resistance and only one or two segments of lung potentially impacted by a chronic thromboembolic insult. And if that's the case and our surgeon thinks they're only going to be able to intervene on one or two small segments of lung, you may not expect to get that nice decrease in pulmonary vascular resistance post-op, which is so closely tied to good outcomes and survival. So, under those circumstances when the degree of pulmonary hypertension is out of proportion to the clot burden is kind of how I phrase it. We tend to encourage patients to pursue a different type of combination of treatments, which I'll talk about in just a minute.

The other just last category of patients that I mentioned with you know, patients with medical comorbidities that would make circulatory arrest in cardiopulmonary bypass not a great risk-benefit ratio. So, there's not very many absolute contraindications to this potential surgery from a medical comorbidity standpoint. Decompensated cirrhosis is one of them. Obviously, patients that have metastatic cancer or another condition that's gonna limit their lifespan would be another reason why you wouldn't pursue something like a large open-heart surgery. And then, you know, age is not an absolute contraindication, but it does sort of, you know, factor into our risk-benefit ratio decision-making.

So, for those patients that are, you know, either have medical contraindications to pursuing surgery or they have a balance of more pulmonary hypertension versus thrombotic burden, we do have a lot of other options for them, um, to help improve their symptoms and their quality of life.

Gustavo Heresi, MD:

If I may, before we proceed with that, I was... You were actually talking about this, I'm thinking that these decisions are very complex, right? So, there's the aspect of the technical inoperable patient, right, the clot is too far out, the surgeons will not get it. Then the aspect of the imbalance between clot burden and severity of pulmonary hypertension. And then the aspect of surgical candidacy, right? Like, okay, maybe the clot is reachable, maybe you feel good about pulmonary pressures coming down after the operation, but the patient has liver cirrhosis, so, uh, multiple comorbidities that make the patient not a surgical candidate. So, you know, I was, as I'm listening to this very eloquent description, I'm thinking, maybe we should share with the audience how we make these decisions, right? Because again, going back to the point of, we always think about surgery first, right? How do we make these decisions? We, you and I, are lung doctors. So, I wonder if you can tell the audience a little bit about the multidisciplinary team approach about, you know, how we decide about treatment.

Alice Goyanes, MD:

Yeah, absolutely. So, this is... Multidisciplinary decision-making about operability is a fundamental cornerstone of CTEPH care. What a multidisciplinary discussion actually is, it is comprised of sort of many different groups of specialists coming together to review a patient's medical history, clinical presentation, and imaging. So, the fundamental, you know, key players in that discussion are having a CTEPH radiologist available to review the imaging with you. In our particular institution, we're very lucky that our radiologist is also one of our interventional radiologists who helps with a surgical intervention called m- angioplasty. You need whichever pulmonary hypertension specialist is bringing the patient to the, to the committee. So, whether that's a pulmonologist or a cardiologist, whoever's the PH center expert in that particular institution. And then your CTEPH surgeon also needs to be available and participating in this particular discussion. And with those three groups of expertise sort of all coming together to talk about a given patient-

Gustavo Heresi, MD:

Hmm.

Alice Goyanes, MD:

... that's how we come up to a consensus about what the best plan is for a particular patient.

Gustavo Heresi, MD:

Yeah.

Alice Goyanes, MD:

We often have, you know, our colleagues from vascular medicine and sometimes hematology joining in with us to talk about particularly challenging cases. And we often consult with those folks if there's sort of special medical conditions that would make, you know, either surgery or the other modalities of treatment, you know, more challenging under those circumstances. That the multidisciplinary discussion is comprised of the sort of those three groups of specialists primarily and bringing each of their perspective to the conversation to help make the best decision for the patient.

Gustavo Heresi, MD:

Thank you. I thought that was really important to emphasize because those conversations are key to the care of a lump of these patients. And some of these conversations can be relatively short because, with experience and expertise and time to when basically kind of know what to do, but some of these conversations can be quite challenging (laughs) and long.

Alice Goyanes, MD:

Well, and you know, I'll also point out that having a robust multidisciplinary team implemented is, you know, has, at least what we saw when we looked at it, our practice over the course of the past 10 years is tied with way, much, much improved outcomes for patients.

Gustavo Heresi, MD:

Yeah.

Alice Goyanes, MD

So, it's absolutely a cornerstone of care for this patient population.

Gustavo Heresi, MD:

Wonderful. Now, getting back to, all right, so we have this nice conversation, and the team concludes that surgery's not a good option. So, tell us a little bit about what treatment options are out there for patients that are not good surgical candidates.

Alice Goyanes, MD:

Absolutely. So, under those circumstances, typically patients receive two other kinds of treatment options if they're not a surgical candidate. Most of the time what we start with is getting the patient started on vasodilator therapy. So, in the United States the only FDA-approved medication that we have for CTEPH is Riociguat, which is a soluble guanylate cyclase stimulator which helps promote nitric oxide availability in the pulmonary vasculature and promote vasodilation. In the clinical trial that supported this medication getting started, patients had improvement in PVR as well as improvement in exercise capacity. And it received FDA approval just under a decade ago for this particular disease.

So, our practice generally is, once we know somebody's not a surgical candidate, if their PVR is above three Wood units, which used to be the definition of precapillary pulmonary hypertension, till the most recent guidelines came out a couple years ago which moved the PVR definition a little bit lower. So, if their P-... All the clinical trials were done for patients with a PVR greater than three. So, for that patient population, we'll get them started on Riociguat and titrate up to the highest tolerated dose.

Most of the time we don't necessarily have to add any other vasodilator therapies in then before we then refer the patient for this treatment regimen called balloon angioplasty. Under select circumstances, we will sometimes consider other vasodilators which have been demonstrated to help improve hemodynamics, but when they've done large clinical trials, it's been harder to see the improvements of exercise in the past few and the quality of life. So, regardless, typically, Riociguat is sort of the fundamental vasodilator that we work to get all our patients on because it has the best highest quality evidence of benefit.

Once they're titrated and tolerating Riociguat, then we refer them for something called balloon angioplasty. Balloon angioplasty is an interventional radiology procedure which can target some of the medium- and smaller-sized blood vessels that have clots in them. It's not appropriate for very large blood vessels and it's not appropriate for complete occlusions of the blood vessels because the way the procedure physically works is that the interventional radiologist basically performs a right heart catheterization, then goes into the pulmonary vasculature, threads a wire into the blood vessel where there's chronic thromboembolic disease, and then inflates a small balloon over that wire to push the chronic thromboembolic disease to the sides of the blood vessel. If you can kind of picture what tree roots going through a water pipe look like, that's sort of the best type of morphology to be treated with balloon angioplasty. So, again, sort of generally pushing the blood clots to the sides of the blood vessel and then that improves distal flow from where the obstruction was previously.

When patients undergo balloon angioplasty, we can typically treat a couple of segments of lung at a time. You can't do the entire lung at once because there's, you know, an amount of intravenous contrast that gets used and then also exposure to fluoroscopy, 'cause they use that for performing, you know, isolating the blood vessel that they're gonna focus on. And so, the patient comes back for repeated treatment sessions that are typically spaced out over the course of, you know, months to a year. So, when a patient's undergoing balloon angioplasty I always kinda counsel them that, you know, "This is gonna be a little bit of a longer term relationship, compared to surgery, which is you get everything fixed at once and then you have a much bigger recovery at that period of time."

The outcomes for balloon angioplasty, if we've been getting more and more data about this over the course of the past five or six years as people have been publishing some of their experiences. The sort of most robust data and registries for this particular procedure and condition of Okinawa, Japan, and their five-year outcome data suggests that the sustained improvement in pulmonary pressures that you get with balloon angioplasty, that it, that it is sustained. So they get an initial drop and then they, you know, report that they have ongoing stability of the improvement in the mean pulmonary pressure afterward. So, it's a really nice thing to be able to offer patients that may not be able to take on a huge open-heart surgery.

Gustavo Heresi, MD:

Yeah, that's wonderful, and certainly a welcome addition to the treatment around there right until, say, more than 15 years ago or so, surgery was really the only thing that we could offer. With the availability of FDA-approved medication in the form of Riociguat, I think change improved significantly for a lot of people, and now, and more recently in the last probably 10 years or so, the availability of balloon pulmonary angioplasty has really lifted expectations dramatically and outcomes. And some recent data from the international CTEPH registry is looking at inoperable cases and achieving survival rates closer to what you achieve with PTE, with pulmonary endarterectomy in the operable cases. So, it very exciting treatment. Which brings me to the next question, which is, how do we put these treatment options together, right? Or do we put them together? You started mentioning and alluding to this a little bit because you told us that usually for the inoperable patient, we start with medical therapy first in the form of Riociguat, and then we follow that up with balloon pulmonary angioplasty. So we're combining medical therapy that addresses the microscopic vasculopathy with a balloon procedure that addresses the mechanical component. So obviously, that's already sort of multi-modality therapies, but where our patients are retreating these days, where we combine two or even three of this treatment options first.

Alice Goyanes, MD:

Yeah, wonderful thing to discuss here because I think there's a lot of different kinds of patients coming to see us at a CTEPH center. And everybody's journey and outcome can be slightly different depending on where the anatomic burden of their disease is and what their response is to the initial intervention that we do. So, when a patient undergoes PTE surgery, our p-... I'm sorry, pet- pulmonary endarterectomy, excuse me, we typically don't make decisions about whether there's residual pulmonary hypertension until we've allowed them a period of time to recover from surgery. You know, in the immediate post-operative period we're measuring how much mean pulmonary pressures are coming down, but there's a lot of other things that could potentially be affecting your mean pulmonary pressure when you're recovering from a sternotomy. You know, you may have-a little bit of diaphragm dysfunction and your lungs may, you know, need to be diureced if a patient has, is coming to us with a certain amount of obesity and you're just looking at the mean pulmonary pressure, you don't know what the left atrial pressure is or the transpulmonary or transpleural pressures are.

So, you know, we don't typically... As long as we get a nice decrease in mean pulmonary pressure post-op, we reserve the decision about whether someone is gonna have residual pulmonary hypertension after CTEPH for a right heart catheterization that gets done sometime between three and six months after surgery when the patient's had a chance to recover a little bit.

So, at that three- to six-month right heart catheterization, and our practice is at six months, is that everybody gets a right heart catheterization to assess whether there's been normalization of pulmonary pressure at this point, that point, or whether there's residual pulmonary hypertension which is, you know, most classically defined as a mean pulmonary pressure greater than 25, back when, you know, people were looking at outcomes for these, this particular patient population. And what they found when they looked at these outcomes is that if somebody had a residual, had a large degree of residual pulmonary hypertension with a mean pulmonary pressure in the high 30s s- three to six months after surgery, that there potentially was a difference in survival compared to people who had mean pulmonary pressures that were lower post-op. So, there was a signal for a difference in survival if they had residual PH with a PVR greater than five, and most people were actually getting started on vasodilator therapy in this retrospective study when their PVR was between three and four.

Our practice generally is that if somebody has residual pulmonary hypertension and their PVR is greater than four, we recommend starting vasodilator therapy with the thinking being that even if the surgeon extracted everything that he could see, that that particular patient probably has a degree of what we call microscopic vasculopathy. Microscopic vasculopathy is what happens to the arterials and the capillaries potentially, that when they change as a result of having experienced an alteration in the, uh, blood flow through the lungs. So if you think back to the original diagnosis of CTEPH and you think about how there's gonna be some sections of lung that are not getting any blood, and then there's some sections of blood that are getting almost all the cardiac output now, if a patient lives with that for a long period of time, what can happen is that distal to the obstructions or distal to where out- the overflow is happening, the microscopic vasculature starts to change and remodel. That will not be addressed with surgery, but that is addressed with pulmonary vasodilators. So if a patient has residual pulmonary hypertension after we've extracted everything that we can reach as a surgical team, we then typically introduce pulmonary vasodilators to treat an element of microscopic vasculopathy.

Now, there are also some patients that, you know, they had not only an element of microscopic vasculopathy, but they also may have had one or two segments of lung that our surgeon just could not get a full extraction from. And so, after we get patients ramped up on their vasodilator therapy, we always then ask if there are any small- or medium-sized blood vessels that would be a good target for the balloon procedure after that. So, we have some patients that they'll go for PTE, they come back, they've improved, but they have some residual pulmonary hypertension. If there's enough residual hyper- pulmonary hypertension or if they're short of breath, we get them started on vasodilator therapy and then we target some of the smaller blood vessels with BPA. So, they really get the full spectrum of treatment.

There are some patients that get surgery and medication. There are some patients that get medication and balloon angioplasty. There are some patients that just need surgery. And then, you know, there's a very rare circumstance where we have a patient who has a very hard time tolerating vasodilator therapy, and they may just get balloon angioplasty. So, there's really a full spectrum of combinations of interventions we can offer these folks.

Gustavo Heresi, MD:

That's great really well said, Alice. Thank you. I think that sort of describes very nicely how fortunate we are that we have so many options for our patients these days. Some of them may get all of them, some of them may get one. But I think it's really important to understand that these are not easy decisions, so complex. These people need to be seen in expert centers, work closely with their local doctors, establish that relationship. So, for people listening to this conversation, reach out to your closest, friendliest, expert CTEPH PH center (laughs), 'cause as we were talking about in the beginning of this conversation, we can help these patients. Very, very dramatically lives can change, transplant gets avoided, people live long and healthy lives after one or more of these interventions. So it's really an exciting era to live in because, uh, we can really help patients with this terrible condition all at once. So, Alice, thank you so much. I wonder if you have any closing thoughts. I think this was really nice. I enjoyed the conversation. I don't know if you have any final messages to our audience.

Alice Goyanes, MD:

No, I mean, I think you just summed it up really well, Gustavo, that we're happy to help and we love taking care of these patients, and, you know, please reach out to your nearest CTEPH center if you have any concerns. 'Cause making the diagnosis can be hard, and then the decisions about treatment modalities, it really takes a whole team to kind of come up with the best plan for these patients, and- and that's really what we love to do at these types of CTEPH centers and institutions.

Gustavo Heresi, MD:

Wonderful. Thank you so much, Alice. I enjoyed our conversation, but, and I'm sure our audience did. Have a nice day. Thank you.

Alice Goyanes, MD:

Thanks a lot.

Gustavo Heresi, MD:

Thank you.

Raed Dweik:

Thank you for listening to this episode of the Respiratory Exchange podcast. For more stories and information from the Cleveland Clinic Respiratory Institute, you can follow me on Twitter @RaedDweikMD.