The Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Program at University of Michigan Health

Can you give us an overview of CTEPH and the program at the University of Michigan?

Dr. Val McLaughlin, Director, Pulmonary Hypertension Program: Chronic thromboembolic pulmonary hypertension (CTEPH) is rare. We think that it affects 3% or 4% of patients who have had acute pulmonary embolism (PE) and it is difficult to diagnose. Symptoms are insidious and include a lot of nonspecific symptoms such as dyspnea that are part of the workup of any patient with PH who is referred.

Some patients develop PH because this chronic, organized thrombus essentially blocks the pulmonary vasculature.

For many years, the treatment was surgical. Pulmonary endarterectomy is a rare operation, and in fact, there are a limited number of centers that do it. A decade ago, Jonathan Haft, our cardiac surgeon, developed an interest in CTEPH. He visited the University of California at San Diego several times and started treating patients at University of Michigan Health. Dr. Haft’s experience has grown such that right now we are probably at a medium-range volume.

Some countries don’t have the cardiac surgery resources available to treat these patients, and as a result, in Japan, researchers pioneered the balloon pulmonary angioplasty (BPA) procedure as an alternative to surgery, developing their techniques over the past 5-7 years. We started looking at BPA for patients who don’t have the proximal disease more appropriate for surgery but who still have significant PH. Many of our team members have gone to Japan to learn BPA. As a result, our program has evolved into one of the premier CTEPH programs, and we offer a range of services, from an expert surgeon to an interventional cardiologist who can do BPA, to our very experienced PH team. The University of Michigan has one of the biggest pulmonary hypertension centers in the country.

Dr. Haft, can you tell us more about what is involved in performing a pulmonary endarterectomy?

Dr. Jonathan Haft: A pulmonary endarterectomy is very different than a pulmonary embolectomy, which is a surgical procedure performed for patients that have massive acute pulmonary emboli. When you are operating on patients for CTEPH, typically there is no fresh clot. All of the thrombus is now organized and covered with vascular endothelium, so the operation requires an endarterectomy, removing it from within the wall of the pulmonary artery. It involves dissection of these organized thrombi into the distal segmental and often, sub-segmental, branches. Access is done through a sternotomy, which allows exposure to both the right and the left pulmonary arteries and has to be performed under intermittent periods of hyperthermic circulatory arrest to eliminate the bronchial effluent flow, which would obstruct our view.

Patients that have CTEPH have been suffering from this condition for a long time. It can be quite debilitating and limiting in terms of the quality of their life. For many of these patients, surgical treatment can be largely curative, so it is a rewarding procedure to offer. Dr. Stuart Jameison in San Diego developed the surgery. I had a chance to learn from his surgical program and their multidisciplinary processes and took that information back to Michigan. We have performed several hundred pulmonary endarterectomies now and believe that we are improving the quality of life for many of these patients.

What is the typical medical therapy pre and post surgery?

Dr. Jonathan Haft: A growing number of patients are coming to us on pulmonary hypertension-specific vasodilators. We will typically resume these medications after surgery, but the hope is that in the majority of patients, we will be able to eventually liberate them from these medications. Medical treatment of CTEPH is reserved for patients who are not surgical candidates or patients who have recurrent or persistent PH after surgery. We encourage PH specialists in the community to refer these patients to an experienced CTEPH program for assessments of surgical accessibility before initiating PH-specific vasodilator therapy.

Dr. Aggarwal, can you tell us more about balloon pulmonary angioplasty (BPA)?

Dr. Vikas Aggarwal, Director, Pulmonary Vascular Interventions: BPA originated in Japan, as Dr. McLaughlin noted, and is a percutaneous interventional procedure. We access the pulmonary artery branches through the femoral vein, pass a wire across to where we think the blockage is located, and then use a balloon catheter, similar to what we do in other parts of the body, to dilate and relieve the blockage. Patients typically do not experience a recurrence where the balloon dilatation has not been durable, so there has not been a need as yet for something like a stent.

In Japan, the majority of the patients with CTEPH are treated with BPA. Their first major publication¹ regarding BPA was in 2012 and details one center’s experience with 68 patients who were treated from 2004 to 2011. More than 10 centers in Japan now do BPA and they are doing a very high volume. We are learning that if you can relieve the obstruction in CTEPH patients, they do well. The efficacy of the procedure is being established, but Japanese centers are also showing that this is a fairly high-risk vascular space for intervention, because the pulmonary arteries are very tortuous and friable. Since 2016, when the BPA procedure started to be performed in the U.S., we have seen this procedure grow from 1 to 3 centers, to now close to 20 centers, and the volumes similarly have grown. The University of Michigan started doing BPA in 2018. We did 3 procedures in the first year and now we perform close to 100 procedures per year.

Most patients end up needing anywhere from 4 to 6 sessions of BPA, and we treat one part of the lung at a time. Once a patient is selected for pulmonary angioplasty, we see the patient in clinic, clearly discuss the evolving nature of the procedure and the risks, and give the patient an expectation as to how many treatment sessions they might need. We come up with what we call a pulmonary angioplasty calendar, which is highly organized. Our protocol is to do 2 procedures 1 week apart, and then give the patient 2 or 3 weeks off. In the off weeks, patients are seen in the PH clinic. The patient might undergo a hall walk to see how they are doing, allowing us to evaluate the need for more procedures on an ongoing basis. We bring them back to do 2 more procedures and again give them a few weeks off. It takes up to 3 and a half months for patients to cycle through a full pulmonary angioplasty calendar. This is another example of how it takes a village. You need a whole team, and the other team members who play important roles are the staff and nurses that work in the cath lab. BPA is a whole different beast. Staff underwent a lot of training for the pre-procedure workup and post procedure care for patients undergoing BPA. The cath lab team is used to giving aspirin to every patient, but BPA patients don’t need aspirin. CTEPH is not coronary disease. Just a small example, but that is the process.

We do want to highlight that CTEPH is also a disease where patients often travel long distances for treatment. We and our team will work with the patients who are coming from out of state and from long distances, and we work with their local doctors in order to take patients through the process in the most seamless fashion possible. We are located in Ann Arbor, a college town in the Midwest that is located close to the Detroit airport and highly geographically accessible.

Dr. Val McLaughlin: There is a learning curve and a comfort level required in treating CTEPH patients. We want to emphasize that a team-based approach to the decisions for patients is critical, because not everyone is a good candidate for BPA. Dr. Victor Moles organizes our multidisciplinary conferences to review the patients.

Dr. Victor Moles, Associate Director, Pulmonary Hypertension Program: CTEPH is a rare disease. It is also a very multidisciplinary disease in the sense that you need input from different physicians, including surgeons, interventional cardiologists, clinicians, and radiologists, who can help you determine what exactly the patient has and where the disease is located. The pulmonary vasculature is very diverse and is full of vessels. Understanding exactly where the lesions are situated is not easy. In the past, treatment of CTEPH might have been easier, in the sense that you had only one option, a pulmonary endarterectomy, but now we have several options: pulmonary endarterectomy, balloon pulmonary angioplasty, and medical therapy. The challenge is in understanding exactly what disease the patient has, where it is situated, and which treatment option offers the greatest benefit to the patient. We approach these challenging patients as a team, discuss them in a multidisciplinary clinic, and then decide the best treatment option for each patient. The range of patients who may benefit from a BPA procedure is evolving over time. In the past, we would only select patients who had very distal lesions, because the smaller the vessel, the more difficult it is for a surgeon to reach, but the easier it would be for a catheter to reach. We now have learned that there are special cases that can also benefit from BPA, such as patients who have had prior surgery but still have PH, patients who have unique anatomy, or patients with selective blockages where the thrombus is not all throughout the lungs, but in focal areas.

Dr. Val McLaughlin: We can think of the blood vessels in the lungs like a tree, and if someone has proximal disease in the trunk or the big branches or even the next-level branches, it is best treated surgically, but sometimes the disease extends into some of the smaller branches, and try as they may, sometimes surgeons can’t get the tails of the thrombus extending into those very small branches. If someone has surgery, they may come out with normal hemodynamics, but sometimes they come out with some persistent PH, either because of small-vessel vasculopathy in the capillaries, or because sometimes the surgeon just can’t dissect down into some of those smaller vessels. As a result, there can be an opportunity to further improve the patient with BPA after surgery.

Can you share more about the types of imaging used for diagnosis?

Dr. Victor Moles: Every patient who we suspect may have pulmonary hypertension (and CTEPH is a form of PH) will first need an echocardiogram. Then every patient undergoes a ventilation-perfusion (VQ) scan, which is a nuclear medicine test and is the most sensitive test to rule out blockages. The VQ scan evaluates how well perfused and well ventilated the lungs are. Patients who have CTEPH will have normal ventilation, but with areas that don’t have normal perfusion. If we suspect that the patient has CTEPH, it is confirmed with a right heart catheterization and pulmonary angiography. Computed tomography (CT) pulmonary angiography scans are also growing in use and offer more information about exactly what kind of lesions the patients have and whether the lungs are normal, which also affects the choice of therapy.

Dr. Prachi Agarwal, Director, Cardiothoracic Radiology: The most sensitive technology we have available for CTEPH is VQ imaging or ventilation perfusion nuclear medicine scans. CT plays a role when a nuclear medicine scan is positive, because not all cases that are positive on nuclear medicine necessarily have CTEPH — there are definitely other entities that must be considered. These are interesting and challenging cases, because perfusion can be altered by mechanisms other than CTEPH. We have seen cases of pulmonary artery sarcomas and vasculitis, which can mimic the findings of CTEPH on a nuclear medicine scan. The newer-generation dual energy CT scans provide not only anatomical information regarding the pulmonary arteries, but also perfusional information for the lungs. Think about dual energy CT as a nuclear medicine study, but now adding anatomical information. It is quite a helpful complementary technique and we use it in many of our patients to, first, confirm the diagnosis of CTEPH or find other alternative causes. Second, we use it to evaluate whether this patient is accessible for surgery, because it can define the proximal extent of disease. What CT doesn’t do very well is identify the very distal disease, but that disease will not be surgically resectable regardless. Pulmonary angiograms are basically a “luminogram”, so you are opacifying the vessel but you are not seeing the wall. You are seeing only the contrast and sometimes you might not be able to tell if the disease extends more centrally. CT affords a better look at the wall and allows us to pick up proximal disease. The distal disease can be harder to see and that is one caveat with CT. Diagnosis is challenging because the abnormalities can involve the vessels and it can be difficult to see more distally. That is where the expertise comes in, to be able to tell if it is CTEPH or whether there are alternative causes for PH. We have seen cases where the patients have had shunts in the heart as a contributing cause to PH. In cases of CTEPH, the surgeon wants to know how far proximally the disease extends, as well as the disease burden, which helps them plan the procedure.

Can you walk us through the multidisciplinary team meetings for these patients?

Dr. Victor Moles: We meet periodically and have a standardized process for presenting patients so that they already have undergone necessary testing. We have information on whether patients have PH and if it is CTEPH, and at the meeting, we discuss what level of disease is present. We review echocardiograms, CT pulmonary angiograms, right heart cath and pulmonary angiograms, and discuss which pathway is most appropriate. We consider whether the disease is proximal, if the patient would benefit from a pulmonary endarterectomy, or maybe if it is actually more distal disease and a BPA might be more appropriate. Other factors that play a role include whether the patient already had a pulmonary endarterectomy or a BPA, or if other comorbidities are present that would make either of these two procedures high risk and therefore the patient would do best on medical therapy.

Dr. Jonathan Haft: A number of factors go into our collective decision making. The first and most important is the patient and their symptoms. Does the patient have physical, functional limitations affecting the quality of their life in which we think some type of intervention is likely to improve their quality of life? The second important element is the patient’s functional status and capacity for recovering from surgery and making it through an operation or any other therapy. We also consider unique anatomic aspects, along with how much clot burden is present and whether it is considered surgically accessible. Surgical accessibility is something that can only be determined through experience, knowing how far distal you can identify the organized thrombus and remove it, and it has been a moving target at our own institution as we have gained additional experience. Lastly is the degree of PH. How much obstructive burden does the patient actually have? And are they likely to benefit from an aggressive treatment like surgery?

What is the timeframe from once a patient might be identified as having CTEPH to actually receiving treatment, whether surgery, BPA, or medical therapy?

Dr. Victor Moles: We see patients that are coming from many different places, so distance can be a factor. Getting all the appropriate testing on an outpatient basis, such as a VQ scan, echocardiogram, a right heart cath and pulmonary angiography, can take a few weeks. Timing then depends on what treatment is selected, and also depends on the urgency of having a particular test or procedure done. Right now we have two patients who are in their twenties that were admitted early last week, and are already having their procedure done inpatient. Sometimes patients are less symptomatic. They have a milder form of the disease, and then we take our time in making sure that we discuss and go through all the appropriate testing and scheduling.

Dr. Val McLaughlin: Another reason why coordination between the teams is important is that it takes time for the pulmonary vasculature to remodel. Continuously following the patient and making sure they meet certain goals is important. Patients also all need lifelong anticoagulation.

Dr. Victor Moles: When patients have a pulmonary endarterectomy, they may feel better sooner, because it is a single procedure where most of the disease is taken care of. With BPA, it is more like a journey that takes several sessions. After six months, we reevaluate by doing a heart catheterization, and if the patient is still not feeling optimal, if they feel symptomatic and the right heart catheterization shows that there is still PH, we may decide to revisit their case. What we expect is a slow process where the patient may feel better over time. There is the possibility that the PH returns. Sometimes an acute pulmonary embolism occurs. Sometimes it is just disease progression, which is why we follow CTEPH patients long term. Other patients do well over time and we follow them on a yearly basis, ensuring their bloodwork and echocardiograms don’t change significantly.

What advice would you give to centers who might be considering a CTEPH program?

Dr. Val McLaughlin: Just because you can, doesn’t mean you should. CTEPH patients are complex and require a multidisciplinary approach. Interventional cardiology never makes a decision to do a BPA without a PH specialist having evaluated the patient and without a specialized surgeon having looked at the films to see if the disease treatment could be surgical. If I could send one message, it is that CTEPH is a complex disease that absolutely requires a multidisciplinary approach. The surgeon, the interventionalist, and the pulmonary hypertension experts need to discuss each patient individually to decide what is best for each case. Our clinical care coordinators also attend our meetings and are an important part of the team.

Dr. Vikas Aggarwal: All the pieces have to be put together. You can’t do BPA outside of a CTEPH program. You need expertise in PH and cardiothoracic surgery, with a surgeon comfortable with endarterectomy. We have talked here about pulmonary angioplasty, but a key aspect for interventionalists is pulmonary angiography. You cannot do angioplasty without first doing a good job at angiography, meaning a good understanding of the pulmonary anatomy, learning from your radiology colleagues, and then you also have to be comfortable with taking care of a complication. You must to be comfortable with coiling, and you need a hospital system that has the necessary support, so that if a patient gets sick and needs to be placed on extracorporeal membrane oxygenation (ECMO), it is available.

Dr. Val McLaughlin: The treatment of CTEPH is a process. It is not like a coronary angioplasty or aortic stenting where it is one and done. The other important point involves the difference between acute and chronic. People can come in with “acute PE” that is actually CTEPH.

Dr. Victor Moles: As the field of CTEPH is evolving, the field of acute pulmonary embolism is also evolving and growing. Although these are not new medical conditions, we are still learning more, even over just the past few years. Many patients may come to the hospital feeling short of breath, and one of the tests routinely done is a CT angiogram of the pulmonary arteries. If there is an obstruction, if you are not familiar with the idea that clots can be either acute or chronic and how to differentiate them, you can fall into this idea that all clots are acute, which may lead to treatment options that may not be the most appropriate for every patient. Clots in the pulmonary arteries can be chronic. Sometimes acute and chronic clots look very different. Sometimes they look similar and it is difficult to piece together, but that is where the expertise of your team helps. In this multidisciplinary approach, the radiologists play a key role in this process.

Dr. Prachi Agarwal: Having an integrated team that works together is the most important aspect; people should look at imaging together, because sometimes we are all working in different silos. A radiologist may report something, but unless you have face-to-face conversations, it can be hard to get messages across. Having the technology to do dual energy CT scans and incorporating the appropriate imaging protocols is essential. I also want to emphasize the importance of developing local expertise to interpret scans and understand the clinical ramifications.

Dr. Jonathan Haft: Patients with CTEPH complain of dyspnea and exertional intolerance, and CTEPH is far less common than the myriad of other conditions that can cause dyspnea and exertional intolerance. CTEPH patients will often have a substantial delay in their diagnosis. Their dyspnea and exertional intolerance are attributed to some other condition and while they are treated appropriately for that condition, in fact the diagnosis of CTEPH is delayed. A focus on awareness of CTEPH is first, and second, a focus on proper assessment. If you identify a patient with exertional intolerance, dyspnea, and evidence of pulmonary hypertension, usually the next test is a VQ scan to identify evidence of mismatched defects suggesting CTEPH. CT scanning is very sensitive for acute pulmonary embolism, but it is inferior to VQ scanning in identifying patients that have CTEPH. We do encourage the use of a VQ scan if you have a patient with PH and without some other clear explanation. If you have a patient where you suspect CTEPH, please refer them to a center that has experience in surgical, catheter-based, and medical management of CTEPH before initiating medical treatment. 

Reference

1. Mizoguchi H, Ogawa A, Munemasa M, Mikouchi H, Ito H, Matsubara H. Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv. 2012 Dec; 5(6): 748-755. doi: 10.1161/CIRCINTERVENTIONS.112.971077