A closer look at chronic thromboembolic pulmonary hypertension

As a rarer form of pulmonary hypertension, chronic thromboembolic pulmonary hypertension, or CTEPH, often receives less attention than other pulmonary vascular diseases. However, it remains the only type of PH that may be cured by surgery.

“When a diagnosis of PH is made, it is important that clinicians do consider and look for CTEPH since it is one of the few forms of PH that is potentially curable,” Aaron Waxman, MD, PhD, director of the Pulmonary Vascular Disease Program and a pulmonologist in the division of pulmonary and critical care at Brigham and Women’s Hospital, told Healio. “However, I do use the word curable a little hesitantly because these patients will still be on some sort of medical therapy — specifically anticoagulation — for the rest of their lives and some may also need pulmonary vasodilators over time.”

Aaron Waxman

During an interview with Healio, Waxman discussed important issues related to CTEPH, including the actual incidence of CTEPH, diagnostic criteria, the current treatment options and areas that require further research.

Healio: What is the prevalence of CTEPH?

Waxman: We probably do not know the actual answer. The original studies based on autopsy estimated the incidence of CTEPH to be approximately 1% to 3% overall and about 0.1% to 0.5% in those patients who survive an acute pulmonary embolism. In the United States, more than half a million people — at least that we know of — survive an acute PE while the annual number of new CTEPH cases in the U.S. ranges from 500 to 2,500, so we are likely underestimating the true frequency of CTEPH. Notably, in a recent longitudinal, prospective study looking at symptomatic CTEPH in patients who had an acute PE, the cumulative incidence of CTEPH post-PE was around 4%.

The other problem is the misdiagnosis or underdiagnosis of CTEPH, which is likely due to nonspecific symptoms and a variable disease course. In fact, most of the patients we see do not present with a clear, acute event. They often present with slowly progressive shortness of breath.

Healio: How is CTEPH usually diagnosed?

Waxman: It is diagnosed in the same way as many forms of PH. Patients present with the nonspecific symptom of shortness of breath or exertional intolerance. An echocardiogram, which is often part of the workup, is probably the first step as far as screening.

The traditional diagnostic criteria for CTEPH are based on a combination of imaging and hemodynamics that specifically should and need to be obtained through right heart catheterization. The current definition of PH based on the most recent updates are a mean pulmonary artery pressure (PAP) of 20 mm Hg or greater with a normal pulmonary capillary wedge pressure and a pulmonary vascular resistance (PVR) of 3 Wood units or greater.

In addition to those hemodynamics, imaging is fundamental. Generally, if you are using ventilation/perfusion scintigraphy, you want to see mismatched perfusion defects. CT scans with pulmonary angiography, or CT angiography, will show clear findings, especially if there is proximal disease. MRI is also being used more often. The gold standard, however, remains conventional pulmonary angiography, which can be done at the time of right heart catheterization.

Overall, diagnosis boils down to a combination of imaging that demonstrates persistent endovascular filling defects or clot and hemodynamics.

Healio: Is surgery still the preferred treatment option for most patients with CTEPH?

Waxman: In the right patient, pulmonary thromboendarterectomy (PTE) is the only potentially curative therapy. In light of that, yes, PTE is considered first-line treatment.

Some patients, though, are really not suitable candidates for PTE. These include patients who have had persistent PH after surgery or those who require a bridge because they are too sick to undergo surgery. In these patients, pulmonary arterial hypertension-specific therapy, specifically pulmonary vasodilators, is often considered and administered. It is important to note that PAH-specific therapy is not curative and its effects, in some cases, are relatively modest.

However, PTE is a big operation and a very involved surgery. Although mortality associated with the surgery has decreased dramatically — now less than 2% in experienced centers — patients may not be operative candidates, partially due to personal choice but more often due to the anatomic distribution of disease. We are always looking for those patients who have more proximal disease that is easily accessible in the OR, while those patients who have very distal disease may not be the best candidates. This is largely dependent on the experience of the surgeon.

In addition to the extent of disease, we must also consider comorbidities because as these patients become sicker, more comorbidities, including cardiac disease, are often present. Therefore, the decision that a patient’s disease is inoperable should only be made after an extensive, comprehensive evaluation at a center with experience in the management of CTEPH.

Healio: Is the number of centers with experience in PTE limited?

Waxman: There are definitely a limited number of centers with experience, but the definition of experience is a moving target. All patients used to have to go to San Diego where the procedure originated to get the operation, but now, every major city in the U.S. probably has an experienced center. Still, it is important for the patient to ask the surgeon how many cases they do in a year. Somewhere between 20 and 30 cases per year is probably a good number.

Healio: What are the treatment options for patients with inoperable CTEPH?

Waxman: Balloon pulmonary angioplasty (BPA) has gained a lot of interest and is probably being increasingly utilized in patients who are not candidates for surgery or who choose not to undergo surgery. Beyond angioplasty, there is a role for pulmonary vasodilator therapy.

Healio: What does the research say about BPA?

Waxman: Percutaneous BPA does promise hemodynamic and functional benefits for patients with CTEPH who are inoperable or who have persistent disease after surgery. In contrast to conventional angioplasty, such as that used for peripheral artery disease or coronary artery disease, BPA is done with undersized balloons over guidewires. The idea is to exclusively break up intraluminal webs and bands without dissecting the medial vessel layers. Often, we will go in and do a small region of the lung and then repeat sessions over time to expand where we have done the work as well as to improve hemodynamics.

Currently, registry data support the role for BPA, confirming that it results in substantial reduction in mean PAP and PVR and, likewise, there is an increase in cardiac index in patients who have undergone the procedure. It is important to note that the hemodynamic effects may not be seen immediately during the procedure but develop over the next several days to weeks and can even be charted out over a couple of months post-procedure.

Additionally, functional class does improve and seems to improve consistently. The vast majority of patients appear to achieve functional class I or II after BPA and studies have also shown substantial improvements in 6-minute walk distance and brain natriuretic peptide (BNP). However, not every patient has normalization of right ventricular function.

Recently, there was a randomized controlled trial — the RACE trial — that compared riociguat (Adempas, Bayer) with BPA in patients who were deemed inoperable. The researchers included 124 patients who were randomly assigned in a 1:1 fashion to BPA or riociguat. At 6 months after the procedure, PVR decreased by 60% in patients who underwent angioplasty vs. 32% in those who received medical therapy, which was a highly statistically significant difference. There were also a number of secondary endpoints in the study, including PAP, right atrial pressure, NT-proBNP and functional class — all of which showed greater improvements in the angioplasty group. There was not a substantial increase in, or a significant difference in 6-minute walk distance between the two groups. Of course, BPA comes with potential side effects or adverse events that were also more predominant among patients who received angioplasty, but they often were not significant.

However, it is important to recognize that there are complications with BPA, including hemoptysis, potential wire injuries, vessel dissections, vessel rupture and bleeding into the pulmonary parenchyma or the pleural space. One of the more common complications is reperfusion pulmonary edema. While this most often is easily managed, it underscores that BPA is not a procedure without risk.

Healio: Where does riociguat fit into the treatment landscape?

Waxman: This is an interesting issue because riociguat, which is a soluble guanylate cyclase stimulator, works very well as a pulmonary vasodilator. It is important to remember that before riociguat came along, we used all of the available pulmonary vasodilators just as we would for PAH in CTEPH. The key thing to remember here, though, is that a specific trial was done to see if riociguat was beneficial in patients with CTEPH, and because of that clinical trial, riociguat is recognized as “the treatment.” However, treatment is really about finding what works best for the patient, so even though riociguat is FDA-approved for CTEPH, the other pulmonary vasodilators have an important role in managing these patients as well.

Healio: Are there any other medical therapies being studied or in the pipeline for CTEPH specifically?

Waxman: I do not know about any specific clinical trials per se. As I said, many of us have been using the other pulmonary vasodilators all along in CTEPH, both before and since riociguat, and the standard approach really is combination therapy, so we are often combining riociguat or one of the other pulmonary vasodilators with something else.

Healio: What areas in CTEPH require further research?

Waxman: We need more research in diagnosis and treatment, but the pathogenesis of the disease itself is still not clear. We always say that CTEPH is the result of unresolved PE, but when you see what we remove in the OR, it’s not clot; it’s fibrotic tissue that’s integrated with the intima of the vessel. This does make you wonder whether there are different forms of CTEPH. Yes, there are probably a good number of CTEPH cases that arise from unresolved clot, but there may also be some cases that reflect just very hyperproliferative pulmonary vascular remodeling and fibrosis. There is still room for better understanding of why people get this disease, which may in turn open the door to new treatments.

Additionally, it would be nice to know for sure what combinations of drugs are important for managing patients who have a poor outcome from surgery or who are not able to undergo surgery. In terms of BPA, more data are always helpful, especially with regards to improving outcomes and reducing complications.

For more information:

Aaron Waxman, MD, PhD, can be reached at abwaxman@bwh.harvard.edu.