Experts Issue Guidance on Use of Oral PPAs, Like Uptravi, in Treating PAH

A consensus on the use of oral prostacyclin pathway agents (PPAs), like Uptravi (selexipag), as an add-on to standard therapies for certain types of pulmonary arterial hypertension (PAH) was announced by a 19-physician expert panel.

PPAs can be an adjunct therapy to standard vasodilator compounds — endothelin receptor antagonists (ERAs) and phosphodiesterase type 5 inhibitors (PDE-5 inhibitors) — in treating functional class (FC) II or III PAH patients. But differing recommendations as to the best timing and circumstances for their use are a source of confusion.

Treatment guidelines defined by the Prostacyclin International Expert Panel were described in the study, “Results of an Expert Consensus Survey on the Treatment of Pulmonary Arterial Hypertension With Oral Prostacyclin Pathway Agents,” published in the journal CHEST.

Funding for the Prostacyclin International Expert Panel was provided by Actelion Pharmaceuticals, which markets Uptravi. (Actelion is part of Johnson & Johnson.)

“Actelion is committed to helping healthcare providers improve outcomes for patients through greater understanding and management of PAH,” Siân Walker, MD, vice president and head of Medical Affairs at Actelion, said in a press release.

“We are proud to support the meaningful work being done by these frontline physicians who have been dedicated to advancing research, education and care of this progressive disease,” Walker added.

PDE5 inhibitors and ERAs are vasodilator compounds that lower blood pressure by inducing blood vessel widening and relaxation. These types of compounds are part of the panel of medications currently approved to treat PAH.

In addition, PPAs — medications that mimic the activity of prostacyclin, a molecule naturally produced in the body that also acts as a vasodilator — have also been approved to treat PAH.

“For adult patients with PAH and functional class (FC) II or III symptoms, guidelines recommend initial combination therapy with an ERA and PDE5i [inhibitor]. If a patient’s risk status is intermediate while receiving combination therapy, the European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines and the 6th World Symposium on Pulmonary Hypertension proceedings recommend escalation to triple therapy by adding an oral or parenteral PPA,” the study authors wrote.

However, the guidelines defined by the ESC/ERS differ from those defined by the American College of Chest Physicians (CHEST) regarding the clinical criteria that should guide the timing of when PPAs are started.

“The current gaps in information about the use of oral PPAs in patients with FC II or III symptoms combined with a dual ERA and PDE-5 inhibitor background therapy create ambiguity in prescribing practices and in managing these patients,” said Vallerie McLaughlin, MD, a cardiologist with a pulmonary hypertension specialty at the University of Michigan, and the study’s lead author of the study.

“While each patient faces a unique set of circumstances and struggles, we hope these consensus opinions provide a perspective into clinical scenarios when adding an oral prostacyclin pathway agent in those patients currently receiving an ERA and PDE-5 inhibitor as background therapy may be appropriate,” McLaughlin said.

The panel aimed to achieve consensus on clinical scenarios in which adding an oral PPA, like selexipag or treprostinil, should be considered to treat PAH.

Panelists ranked various factors generally used to make routine decisions regarding the initiation of oral PPAs, including patient hemodynamics (blood flow), number of hospitalizations due to PAH in the last six months, right heart function, levels of N‐terminal pro‐brain natriuretic peptide (NT-proBNP; a prognostic marker of pulmonary hypertension), and the six-minute walk distance (6MWD; a measure of exercise capacity).

These factors were then used to create different scenarios about patients with either idiopathic, heritable, and drug- or toxin-induced PAH (IPAH+ group), or with connective tissue disease-associated PAH (PAH-CTD). All these people would experience discomfort or shortness of breath while performing daily life activities (functional class II or III), and would be on an ERA and PDE-5 inhibitor as background therapy.

Panelists evaluated the different clinical scenarios by completing two rounds of surveys.

These surveys yielded a total of 14 consensus opinions, and included 13 scenarios in which experts agreed that selexipag should be added to compliment ERA and PDE-5 inhibitor background therapy.

Some of these scenarios included, for instance, patients with IPAH+ or PAH-CTD with functional class II or III symptoms and low-risk hemodynamic parameters, irrespective of hospitalization, right heart function, NT-proBNP levels, and 6MWD.

Panelists also agreed that parenteral prostacyclin therapy should be the treatment of choice for those with IPAH+ and PAH-CTD with high-risk hemodynamic parameters, regardless of other clinical factors.

Regarding treprostinil, “the median score for the use of oral treprostinil did not meet the predetermined threshold for a recommendation in favor of its use in any clinical scenario evaluated,” the authors wrote.

“In summary, this expert panel survey provides physicians with guidance for the use of oral PPAs in patients with FC II or III IPAH+ and CTD-associated PAH receiving dual oral ERA/PDE5i therapy,” they added.

These experts emphasized that these treatment guidelines are not meant to replace the assessment and clinical decision of a certified physician regarding a particular patient. Rather, they are meant as support guidelines.

“These consensus statements are intended to aid physicians in navigating treatment options and using oral PPAs in the most appropriate manner in patients with PAH … These expert opinions must be validated with rigorous prospective studies, and this document may serve as a template for future investigations,” the team concluded.

Actelion reports in the press release that the company played no role in the surveys or data analyses done for this study, and no company employees attended “the face-to-face meeting during which consensus statements were finalized.”

McLaughlin, the study’s lead author, reports having received research funding and consulting fees from Actelion.