New European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines for diagnosis and treatment of pulmonary hypertension have lowered the cutoff for defining pulmonary hypertension and tweaked the diagnostic algorithm so that the diagnosis is made earlier.

The chairpersons, Marion Delcroix, MD, PHD from ERS and Stephan Rosenkranz, MD, from ESC presented the guidelines at the European Society of Cardiology (ESC) Congress 2022 and the document was simultaneously published online in the European Heart Journal.

“Pulmonary hypertension is not a rare condition, since it affects approximately 1% of the global population and approximately 10% of the elderly population,” said Rosenkranz, Cologne Cardiovascular Research Center, Cologne, Germany, in the guideline overview session. 

With the new guidelines replacing the 2015 version, “we really help the physician to better diagnose and to diagnose earlier,” Delcroix, from University Hospitals of Leuven, Belgium told theheart.org | Medscape Cardiology in an interview.

Pulmonary hypertension is still classified into five groups:

• Group 1, pulmonary arterial hypertension

• Group 2, pulmonary hypertension associated with left heart disease

• Group 3, pulmonary hypertension associated with chronic lung disease

• Group 4, chronic thromboembolic pulmonary hypertension (CTEPH), often with a history of pulmonary embolism

• Group 5, pulmonary hypertension with unclear and/or multiple causes

“One of the most important proposals from the 6th World Symposium on Pulmonary Hypertension (WSPH) was to reconsider the hemodynamic definition of PH,” the authors write.

“We lowered the cutoff value for defining pulmonary hypertension” from 25 mm Hg to 20 mm Hg, Delacroix said, “because there was evidence that the abnormal values were lower than we thought initially, and also that from a mean pressure of more than 20 mm Hg, we already have an impact on the prognosis of patients.”

Any increase in pulmonary arterial pressure represents an increased afterload for the right heart and is associated with earlier mortality, Rosenkranz noted.

However, this lower cutoff “does not yet translate into new therapeutic recommendations,” the guideline states, since the efficacy of pulmonary arterial hypertension therapy in patients with mean pulmonary arterial pressure (mPAP) of 21-24 mm Hg is unknown.

This was one of the confusions about the guidelines that was brought up at a “Meet the Task Force” session at the ESC meeting, Delacroix said.

“Pulmonary arterial hypertension is now defined by mPAP >20 mm Hg,” she clarified, “but treatment is only recommended where we have evidence of efficacy, which means mPAP >25 mm Hg.”

Three Steps to Diagnose the Patient

When assessing patients with suspected pulmonary hypertension, Rosenkranz said, “it is of utmost importance to perform a proper diagnostic workup and to consider the clinical classification of this condition, because the therapeutic strategies within these five groups are fundamentally different.”

The new diagnostic algorithm for patients with suspected pulmonary hypertension or unexplained dyspnea has “been completely restructured,” he noted, “and it follows the path of the patient in the medical system.”

The writing task force “worked on the diagnosis of pulmonary hypertension,” Delcroix said, so that clinicians could make it earlier.

The diagnosis is made in the following three steps, presented in an algorithm:

• Step 1 : Contact with the general practitioner. The GP needs to be aware that there are some rare forms of shortness of breath and can “perhaps already think of pulmonary hypertension for a patient who has bad clinical signs, already has heart failure signs, and who could be sent directly to a pulmonary hypertension center,” Delcroix said. “If there are warning signs or when pulmonary arterial hypertension or CTEPH are suspected, the patient should get a fast-track referral to a pulmonary hypertension center,” Rosenkranz stressed.

• Step 2: Detection by echocardiography. The “regular GP sends the patient with shortness of breath to a cardiologist or a respiratory physician,” Delcroix said, based on the suspected cause. The patient gets a more comprehensive lung or heart assessment, with rapid cross referral to a cardiologist or pulmonologist, as needed, Rosenkranz said.

• Step 3 : Confirmation with right heart catheterization in a pulmonary hypertension center. If the patient probably has intermediate or high-risk pulmonary hypertension, then he or she should be referred to a pulmonary hypertension center for a comprehensive diagnostic workup and invasive assessment, as needed, Delcroix said.

Echocardiography is the key noninvasive test to assess patients with pulmonary hypertension, said Rosenkranz, and the new guidelines provide much more detailed guidance for right heart imaging.

The gold standard in the hemodynamic assessment of pulmonary hypertension is right heart catheterization, he noted, and this is recommended to confirm the diagnosis of pulmonary hypertension and especially pulmonary arterial hypertension or CTEPH and to support treatment decisions (Class I recommendation).

Patient Treatment and Risk Stratification

The guidelines classify patients as having low, intermediate, or high mortality risk at 1 year, Delcroix said, where patients in the high-risk group have >20% risk of death within 1 year.

“This three-strata risk classification assessment in [pulmonary arterial hypertension] has been refined after being validated in multiple registries,” the guideline states.

“We help make the closer link between risk classification and the therapy,” Delcroix added. “When these patients are high risk we really need to start with maximum therapy, which is usually two oral drugs plus one intravenous drug.”

“Probably the most important point” concerning therapy, she said, is that it needs to be evaluated at 3-6 months after initiation, to see if it needs to be adjusted.

“At follow-up, a four-strata risk-assessment tool is now proposed based on refined cutoff levels for World Health Organization functional class (WHO-FC) 6-minute walking distance (6MWD), and N-terminal pro-brain natriuretic peptide (NT-proBNP), categorizing patients as low, intermediate–low, intermediate–high, or high risk,” the guidelines state.

Patients who remain low risk stay on the same therapy. Patients who are intermediate–low risk receive a small adjustment in oral therapy, and patients who are intermediate–high risk or high risk get an intravenous drug or are referred for lung transplantation, Delcroix explained.

Because of the aging population in Western countries, she noted, clinicians are seeing more patients with pulmonary hypertension who are older than 65 or 70 and have multiple comorbidities including lung disease or HF (most often HF with preserved ejection fraction).

It is very difficult to know if these patients have a primary pulmonary vascular disease or if it is secondary to their heart or lung disease, she said, so these patients should be seen in pulmonary hypertension centers.

The medications for pulmonary hypertension are the same as those in 2015, Delcroix noted. It’s always one of three pathways, she said: The endothelin receptor antagonists for one pathway, the phosphodiesterase-5 (PDE₅) inhibitors and guanylate cyclase stimulators for the nitric oxide pathway, and the prostacyclin receptor agonist for the third pathway.

“But what we know better, is how to use them,” she said. “For example, we know when we can add a third drug. We know when we better switch from one phosphodiesterase-5 inhibitor to a guanylate cyclase stimulator, which is a bit more efficient.”

Potential New Drugs Available Within Months?

“Pulmonary arterial hypertension remains an incurable condition with a high mortality rate, despite use of [drugs] mainly targeting imbalance of vasoactive factors,” the guidelines state.

The vasodilators that are used now to treat pulmonary hypertension dilate the pulmonary vascular vessels and make it easer for the heart to pump blood through the lungs, Delcroix noted, but new drugs in development target the thick vessel walls.

“We are expecting new drugs that are in phase 3 trials,” she said, “and we probably will need an update of the guidelines within months.”  

Primary results from a phase 3 trial of ralinepag and a phase 3 trial of sotatercept are expected in December.

The guidelines were endorsed by the International Society for Heart and Lung Transplantation (ISHLT) and the European Reference Network on rare respiratory diseases (ERN-LUNG).

Delcroix discloses receiving institutional speaker, consultant, or steering committee fees from Acceleron, AOP, Bayer, Daiichi Sankyo, Ferrer, Inari, Janssen, MSD, and Pfizer, and receiving institutional research grants from Janssen. Rosenkranz discloses receiving speaker or consultant fees from Actelion, AstraZeneca, AOP, Bayer, Boehringer-Ingelheim, Janssen, MSD, and Vifor, and receiving institutional research grants from AstraZeneca, Bayer, and Janssen.

European Society of Cardiology (ESC) Congress 2022. Guideline overview presented August 26, 2022.

Eur Heart J. Published August 28, 2022. Full text

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