Issue: May 2018
May 09, 2018
9 min read

Pulmonary hypertension requires multidisciplinary approach for diagnosis, treatment

Issue: May 2018
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Hospitalizations for pulmonary hypertension have increased from 1980 to 2002, resulting in 200,000 hospitalizations for the condition as a primary or secondary diagnosis during that time. Accurate diagnosis and optimal treatment for pulmonary hypertension is paramount for all health care professionals involved in the management of these patients. Patients with pulmonary hypertension are often treated by cardiologists, pulmonologists or a combination of both. At some centers, fellows may train an extra year in pulmonary hypertension, but formal fellowship training does not currently exist.

“Pulmonary hypertension is a condition that physicians learn about to varying degrees during internal medicine training as well as general pulmonary or cardiology fellowship,” Paul Forfia, MD, director of the Pulmonary Hypertension/Right Heart Failure and Pulmonary Thromboendarterectomy Program at the Lewis Katz School of Medicine at Temple University, told Cardiology Today. “There are virtually no dedicated fellowships specific to pulmonary hypertension, and no board certification in pulmonary hypertension.”

Over time, awareness and knowledge of pulmonary hypertension and how it affects the heart has grown in the cardiology community.

Over the yearstime, awareness and knowledge of cardiologists have been learning more about pulmonary hypertension and how it affects the heart has grown in the cardiology community.

“There’s a lot of excitement in the field because, although we’ve helped these patients enormously and improved their outcomes and made it more of a chronic disease, we’re now looking toward pathways that are not vasodilatory pathways,” Mardi I. Gomberg-Maitland, MD, MSc, FACEE, professor of medicine at Virginia Commonwealth University in Maryland and director of the Right Ventricular Failure and HF with Preserved Ejection Fraction unit at Inova Fairfax Heart and Vascular Institute in Virginia, said in an interview.

Robert P. Frantz, MD, FACC, from Mayo Clinic, said cardiologists and pulmonologists are working together closely to optimize diagnosis and treatment of pulmonary hypertension.
Robert P. Frantz, MD, FACC, from Mayo Clinic, said cardiologists and pulmonologists are working together closely to optimize diagnosis and treatment of pulmonary hypertension.

Source: Ben Hanson/Mayo Clinic. Printed with permission.

Despite a wealth of current research and a number of new drugs approved in recent years, patients and cardiologists still face obstacles regarding the diagnosis and treatment of pulmonary hypertension.

“The patients who suffer with this condition, in my mind, are heroes,” Robert P. Frantz, MD, FACC, director of the pulmonary hypertension clinic and professor of medicine at Mayo Clinic, told Cardiology Today. “They’re remarkable people ... who need to have attention to their disease that can get overlooked when we’re so focused on other, more common problems.”

Challenges of pulmonary hypertension

Pulmonary hypertension is classified by WHO into five groups: pulmonary artery hypertension, left-heart related, lung/hypoxia related, chronic thromboembolic pulmonary hypertension (CTEPH) and other pulmonary arterial/multifactorial disease. There are multiple pathological drivers of PAH, including abnormal proliferation, inflammation, metabolism, neurohumoral, oxidative stress and dysregulation of vascular tone.

Raymond L. Benza, MD, FACC
Raymond L. Benza

Although the groups appear to be distinct, one of the major issues that heath care providers face is distinguishing between types of pulmonary hypertension.

“The reason why that’s so critical is that some of the therapeutics that we use to treat one form of pulmonary hypertension could be deleterious in other forms,” Raymond L. Benza, MD, FACC, professor of medicine and program director of advanced HF, transplant, mechanical circulatory system and pulmonary hypertension at Allegheny Health Network in Pittsburgh, told Cardiology Today.


Guideline-based algorithms are recommended to accurately identify in which group a patient belongs, and that information can help distinguish what type of therapy a patient needs. Without proper tools and knowledge, it commonly takes more than a year to diagnose a patient with pulmonary hypertension, Victor F. Tapson, MD, FCCP, FRCP, professor of medicine, director of clinical research for the Women’s Guild Lung Institute, director of the venous thromboembolism and pulmonary vascular disease research program, and associate director of the pulmonary and critical care division at Cedars-Sinai, said in an interview.

A high level of expertise in pulmonary hypertension is not particularly common, including among well-trained cardiologists and well-trained pulmonologists,” Forfia said. “You could imagine how difficult it could be for patients when they’re short of breath and it ultimately turns out to be related to pulmonary hypertension, and the health care providers that they’re seeing are not knowledgeable about the condition itself.”

Proper evaluation of pulmonary hypertension requires achieving the best possible understanding of both the context in which it is occurring and its severity. This includes carefully seeking out any associated heart or lung diseases and systemic disorders that may help to explain the pulmonary hypertension.

Incorrect identification or classification of pulmonary hypertension can have devastating consequences. For example, patients with PAH or CTEPH who are not treated may develop right HF that can lead to death. These patients also have increased risk for hospitalizations for right ventricular failure, which can increase the risk for mortality up to 50%.

Nonspecific symptoms of pulmonary hypertension can severely affect a person’s life, and some of these include shortness of breath, exercise intolerance, fainting, palpitations, feeling lightheaded and chest discomfort.

Victor F. Tapson, MD, FCCP, FRCP
Victor F. Tapson

Another challenge is access to medication. Although many medications to treat PAH have been shown to be effective, they are also expensive, even with programs available to partially reduce the cost.

“It can be a difficult disease, causing severe symptoms,” Tapson said. “Until a patient is on an appropriate treatment regimen, they can be symptomatic, which is a huge challenge.”

Available treatment options

Once a patient is diagnosed with pulmonary hypertension, there are many treatment options available based on the type of condition and the underlying disease (see Table below for selected medical therapies).

PAH is treated with medications belonging to one of three classes: endothelin receptor antagonists, nitric oxide pathway drugs and prostanoid therapies.

Table. Selected drugs approved by the FDA to treat pulmonary hypertension

“Generally, everyone agrees that therapy should be managed on a risk-associated basis, meaning that higher-risk patients get the higher combinations of drugs and the more invasive medications, the intravenous prostacyclins,” Benza said. “The less ill patients possibly can get away with double oral concentrations and maybe in some cases monotherapy.”

When operable, patients with WHO group 4 pulmonary hypertension, which is related to CTEPH, should be treated with pulmonary endarterectomy, which involves the removal of chronic thromboembolic material from the pulmonary arteries. Balloon pulmonary angioplasty is another promising treatment option, particularly for patients who are not candidates for open thromboendarterectomy or have residual disease and symptoms despite prior endarterectomy.

When surgical and interventional options are not available or not sufficient, patients with WHO group 4 pulmonary hypertension are treated with medical therapies including riociguat (Adempas, Bayer Healthcare), which is the only FDA-approved treatment for CTEPH. Macitentan (Opsumit, Actelion) may be approved for this indication in the future, Benza said. In the MERIT-1 study published in The Lancet in October, macitentan was well-tolerated in patients with CTEPH. Although riociguat has been shown to be effective for treatment of WHO group 4 pulmonary hypertension, it is expensive, so careful patient selection is important, experts said.

Selexipag (Uptravi, Actelion) is a prostacyclin receptor agonist approved in 2015 that was shown to effectively treat patients with PAH, including many patients already receiving a phosphodiesterase type 5 inhibitor and an endothelin receptor antagonist, in the GRIPHON trial published in The New England Journal of Medicine in 2015.

Treating patients with group 3 or 4 pulmonary hypertension requires multiple approaches.

“The sickest people with PAH need to be started on parenteral prostanoid therapy,” Tapson said. “Sometimes we use substantaneous prostanoid therapy, and then we strongly consider adding a second drug subsequently.”

In the AMBITION trial, which was published in NEJM in 2015, patients with PAH who were treated with an upfront combination of ambrisentan (Letairis, Gilead) and tadalafil (Adcirca, United Therapeutics) had a decreased risk for clinical-failure events compared with those who were treated with monotherapy.

The role of cardiologists

Paul Forfia, MD
Paul Forfia

Whether a pulmonologist or a cardiologist cares for a patient with pulmonary hypertension varies from center to center, although cardiologists have assumed a much larger role in care over the past 10 years. At least half of the major pulmonary hypertension programs in the U.S. listed by the Pulmonary Hypertension Association are either cardiology or combined cardiology/pulmonary centers, Forfia said.

“We should not think of pulmonary hypertension as a condition that belongs to a particular specialty,” Forfia said.

According to Benza, the cardiologists’ experience in managing right HF lends credence to the greater role with pulmonary hypertension.

However, there are instances where a pulmonologist may be better suited to primarily care for a patient with pulmonary hypertension, such as those with group 3 pulmonary hypertension, as it is related to respiratory diseases.

Regardless of the type of pulmonary hypertension, cardiologists and pulmonologists can work together to care for these patients, and there are centers across the country that utilize health care providers from both areas. One example is Frantz’s pulmonary hypertension clinic.

“In our pulmonary hypertension clinic, we deliberately over time have both pulmonologists and cardiologists staffing the clinics so that patients got the best of both worlds,” Frantz said.


Further research

Research continues into the diagnosis and treatment of pulmonary hypertension.

Ralinepag (Arena) is an oral, next-generation, selective IP receptor agonist that has shown promising results in a phase 2 study, and a phase 3 study is under development.

Pyruvate dehydrogenase kinase inhibitors, used in treating cancer and other diseases, are also being considered as a pulmonary hypertension treatment, Tapson said, noting that similar potential could be seen with certain tyrosine kinase inhibitors.

In addition, he said, tocilizumab (Actemra, Genentech), a monoclonal antibody against the interleukin-6 receptor currently approved for treating rheumatoid arthritis, is being tested as a treatment for PAH, as is rituximab, a generic chimeric monoclonal antibody against the protein CD20 currently used to treat certain cancers and autoimmune diseases.

A potentially simpler way to deliver inhaled treprostinil with a dry powder inhaler is also entering phase 3 clinical trials.

Implantable hemodynamic monitors have been shown benefit in congestive HF and could also be applied to patients with pulmonary arterial hypertension. This allows health care providers to have daily touch points with their patients’ hemodynamics.

The pathways involved in pulmonary vascular disease are also not well-understood. Frantz and colleagues at multiple centers across the United States are currently looking at various forms of pulmonary hypertension and performing genomic, proteomic and metabolomic analyses to learn more about the pathways, as part of the NIH-funded Pulmonary Vascular Disease OMICs consortium.

Monitoring the right ventricle when following patients can be a critical tool, but figuring out how to do so is necessary. Experts told Cardiology Today there is a need for proper risk stratification with tools such as algorithms to help identify the presence and type of pulmonary hypertension; this can potentially be done through echocardiography, right heart catheterizations or another technique, and a major focus on echocardiography can help prevent patients from having to undergo right heart catheterizations as frequently.

Another focus area moving forward is expanding the medication landscape for pulmonary hypertension. Although there are currently three classes of drugs, it would be beneficial to find other novel pathways that impact the disease, elicit remodeling of the pulmonary arteries and right ventricle and reverse the proliferative process, Frantz and others said.


“The holy grail in pulmonary hypertension is trying to identify drugs that will prevent scarring and proliferation of the lung vessels so that they stop thickening and obstructing or even reverse that by favoring what we call apoptosis or programmed cell death so that the cells would actually regress instead of staying in the way. That has been slow-going,” Frantz said.

Experts said research is needed on treatment of patients with WHO group 2 and group 3 pulmonary hypertension, especially since most patients present with these kinds of conditions at clinics. The medications available to treat WHO group 1 pulmonary hypertension have generally not been effective or have even been harmful in patients with group 2 and 3 pulmonary hypertension.

Tapson and colleagues at Cedars-Sinai including Eduardo Marban, MD, PhD, and Michael I. Lewis, MD, are currently working on new research on therapies, including bardoxolone, an anti-inflammatory medication, as well as stem cell-type therapy with cardiosphere-derived cell therapy.

“We’d love to see new therapies get us to the point where we don’t need parenteral therapies, and maybe not even inhaled therapy,” Tapson said. “Perhaps diagnostic testing will be advanced to the point that we no longer need right heart catherization. And we’d like to avoid lung transplantation, which can be necessary occasionally in patients with severe pulmonary hypertension.”

Mardi I. Gomberg-Maitland, MD, MSc, FACEE
Mardi I. Gomberg-Maitland

The area of pulmonary hypertension is currently evolving, and research in progress could one day lead to vast improvements in treatment.

“In pulmonary vascular disease, there are current and emerging genetic data that should enable us to prioritize better targets and drug development,” Gomberg-Maitland said. “The field is moving very quickly.” – by Darlene Dobkowski

Disclosures: Benza reports he received research grants from Actelion, Belleraphone, Liquidia and United Therapeutics. Frantz reports he consults for Arena Pharmaceuticals and St. Jude Medical; serves on the steering committee, data and safety monitoring board and adjudication committee for United Therapeutics and is on the steering committee for Actelion Pharmaceuticals. Forfia reports he consulted for Bayer and United Therapeutics. Gomberg-Maitland reports she received Inova Health System from Actelion, AADi and United Therapeutics and consults for Actelion, Acceleron, Bayer, Complexa, Janssen, St. Jude/Abbott, Merck and United Therapeutics. Tapson reports he received research support from Actelion, Arena, Riata and United Therapeutics and consults for Actelion, Riata and United Therapeutics.