Healio Interview

Disclosures: Tonelli reports no relevant financial disclosures.
May 10, 2021
5 min read

Risk stratification, improved therapies important in PAH


Healio Interview

Disclosures: Tonelli reports no relevant financial disclosures.
You've successfully added to your alerts. You will receive an email when new content is published.

Click Here to Manage Email Alerts

We were unable to process your request. Please try again later. If you continue to have this issue please contact

For physicians, pulmonary artery hypertension poses many challenges, including the need for greater awareness and better therapies, according to an expert who spoke with Healio.

Fortunately, as the field evolves, researchers and physicians are closing gaps in care by learning more about how best to approach evaluation and treatment of patients with PAH. In an interview, Adriano Tonelli, MD, pulmonologist at the Cleveland Clinic, discussed the use of updated risk stratification strategies, the promise of novel therapies, the importance of early diagnosis and more.

Pulmonary hypertension

Healio: How can clinicians improve the diagnosis of PAH?

Tonelli: Educating physicians so that they are more aware of the condition is key to improving diagnosis. This can be improved by having medical societies as well as the Pulmonary Hypertension Association disseminate knowledge about the disease and increase awareness among physicians. Also, having more information online is beneficial. If patients can find information online from reputable resources, they can talk to their physicians to see if the symptoms that they are experiencing could be related to pulmonary hypertension.

Then, as physicians get started on treatment, we want to follow guidelines and we want to get the right treatment for every patient. In terms of pulmonary hypertension, there are a variety of conditions that can cause an increase in pressure and we do not have treatments available for some of them, so we have to be careful which patients we treat. For the ones whom we do treat and who are indicated for treatment, we want to be proactive, follow them closely, add medications or increase doses as necessary and, at the end, achieve the best outcome possible.

Healio: How do you manage patients with different severities of PAH?

Tonelli: We used to stratify patients based on WHO functional class 1 to 4, with class 4 being the worst. These patients are practically unable to move without shortness of breath, whereas class 1 patients are able to perform most activities. Based on functional class, we decided which treatment would be best, with more aggressive treatments — IV therapy and subcutaneous therapies — for class 3 or 4 patients and oral treatments for class 1 or 2 patients. But now, things have changed.

Because division into four classes is not enough to stratify patients at risk for dying with pulmonary hypertension, new methodologies have emerged. There is the French risk stratification approach and the Registry to Evaluate Early and Long-Term PAH Disease Management risk calculator (REVEAL 2.0). Based on REVEAL 2.0, we define patients at low-, medium- or high-risk, depending on the risk for dying. The low-risk category includes patients with a 1% to 5% chance of dying within 1 year; the medium-risk category includes patients with a 5% to 10% chance of dying within 1 year; and the high-risk category includes patients with a greater than 10% chance of dying within 1 year. Once we have a patient in one of those buckets, then we decide on treatments.

Now, based the results of the AMBITION study, the majority of patients are started on two oral medications. However, if a patient is in the high-risk category, then we need to consider parenteral therapies, such as IV or subcutaneous therapies.

The other push is to follow these patients very frequently to get them into the low-risk category as soon as we can. If that is not achieved, the newer medications are added or doses are increased to achieve the low-risk category, with the idea that patients will have a lower risk for dying in the following year. This is why treatment has become more aggressive than in prior years. Now, we not only look at functional class, but we also look at a bunch of other parameters, such as 6-minute walk distance, NT-proBNP and echocardiographic determinations, to better assess everything, move the patient to a low-risk category and get them close to normal. That is what we want — to get patients to survive as long as they possibly can.

Healio: What are the greatest areas of unmet need in PAH?

Tonelli: The greatest unmet need by far is improved survival. Despite multiple therapies, patients with PAH continue to die. There are registries that show that half of patients have a median survival of 7 years. Certainly, that is less than ideal, and we need better treatments. This is where disease-modifying agents, such as sotatercept (Acceleron Pharma), come into play. Disease-modifying agents work in the disease process, hopefully causing a backward remodeling of the vessel. In PAH, the vessels narrow with time, so if the medication can make that process of proliferation go away and the vessels increase in size again, the ventricle will be in a better shape and able to pump blood forward, leading to improvement for the patient. Disease-modifying agents are essential in the field and will help fill the most important unmet need at the moment, which is improved survival in these patients and getting them as close to normal as we can.

Another unmet need pertains to diagnosis. Although physicians are more aware than ever about PAH, there is still a delay in diagnosis and patients could have been treated sooner, potentially affecting outcomes. So, early diagnosis is also an important goal here.

Healio: What were some of the highlights presented in PAH at conferences last year?

Tonelli: The American Thoracic Society International Conference 2020 had abstracts on many areas of pulmonary hypertension, mostly pertaining to risk stratification — how to risk-stratify patients so we can then offer the best available treatment options. In general, the higher the risk, the more aggressive the treatment, but risk evaluation is essential. So, the risk scoring systems that we have were tested in different databases and different types of patients, with the research generally supporting the use of currently used methodology such as the French risk stratification approach and REVEAL 2.0. But obviously, new ways of assessing risks were presented as well, some of which are very promising.

In terms of treatment, most of the studies presented were focused on dual vs. triple combination therapy. There were also a lot of studies on switching medications — from IV to orals or from orals to IV — regarding prostacyclin analog treatment. There are also other interesting novel therapeutic pathways, but those are mostly in animal studies or very early human studies and need more time to develop so we can see the utility and clinical applicability.

Healio: What are some of the recent advances in treatment of PAH?

Tonelli: There are new and exciting results from several studies, some of which were presented in a virtual format at the ATS 2020 meeting, and those include three main studies: PULSAR, TRITON and INCREASE. PULSAR is a study looking at a new disease-modifying agent called sotatercept (Acceleron Pharma). TRITON tested whether two medications are better than three medications when starting treatment for patients with PAH. INCREASE — which is also very exciting — tested whether inhaled treprostinil (Tyvaso, United Therapeutics) could benefit patients with interstitial lung disease and PAH. This was an area of unmet need, as there were no treatments for this group of patients.

There are a few other developments in the field. One major advance is a new subcutaneous pump (Remunity, United Therapeutics) that simplifies the treatment of patients with subcutaneous treprostinil (Remodulin, United Therapeutics) with a smaller pump with prefilled cassettes. There is another medication called ralinepag, which is a receptor antagonist for prostacyclin, that is currently being tested with interesting results in a phase 2 study. It is a promising and long-acting, very selective medication, but we obviously need results from a phase 3 study, which is underway.

Editor’s note: The FDA approved inhaled treprostinil for treatment of pulmonary hypertension associated with ILD on April 5.