Results of an Expert Delphi Consensus Survey on Clinical Scenarios Considered When Initiating Oral PPAs for PAH

Results of an Expert Delphi Consensus Survey on Clinical Scenarios Considered When Initiating Oral Prostacyclin Pathway Agents for Pulmonary Arterial Hypertension

Results of an Expert Delphi Consensus Survey on Clinical Scenarios Considered When Initiating Oral Prostacyclin Pathway Agents for Pulmonary Arterial Hypertension

    Results from an Expert Delphi Consensus Survey on clinical scenarios considered when initiating oral PPAs in the treatment of PAH.

    • Overview

      Results of an Expert Consensus Survey on the Treatment of Pulmonary Arterial Hypertension with Oral Prostacyclin Pathway Agents

      Vallerie V McLaughlin, MD, FACC, FCCP; Richard Channick, MD; Teresa De Marco, MD, FACC, FHFSA; Harrison W Farber, MD, FCCP; Sean Gaine, MD, PhD; Nazzareno Galié, MD; Richard A Krasuski, MD; Ioana Preston, MD; Rogerio Souza, MD, PhD; J Gerry Coghlan, MD; Robert P. Frantz, MD; Anna Hemnes, MD; Nick H Kim, MD; Irene M Lang, MD; David Langleben, MD; Mengtao Li, MD; Olivier Sitbon MD, PhD; Victor Tapson, MD; Adaani Frost, MD

      Funding was provided by Actelion to support the use of independent providers of Delphi methodology expertise and nominal group technique, survey creation, data analysis, medical communication, and meeting management. The authors were not paid an honorarium for their participation. Actelion played no role in the literature search and analysis, development of surveys used to gather consensus, or data analysis; and no Actelion employee was present at the meeting during which consensus statements were finalized. The manuscript was drafted, critically reviewed, and edited solely by the authors with support from an independent professional medical communications agency. Actelion Pharmaceuticals reviewed the final manuscript only to ensure accuracy of UPTRAVI® (selexipag) background information; no edits were made to the manuscript based on this review.

      Background: Treatment of pulmonary arterial hypertension (PAH) has evolved substantially over the past two decades and varies according to etiology, functional class (FC), hemodynamic parameters, and other clinical factors. The objective of PIXEL (Prostacyclin International Expert Panel) was to develop consensus opinions on clinical scenarios considered when initiating an oral prostacyclin pathway agent (PPA) to WHO FC II and III PAH patients on endothelin receptor antagonist (ERA) and phosphodiesterase type 5 (PDE-5) inhibitor background therapy.

      Methods: A systematic literature search was conducted using MEDLINE. The established RAND/University of California Los Angeles Appropriateness Method, which incorporates the Delphi method and the nominal group technique, was utilized to create consensus statements. Idiopathic, heritable, repaired congenital heart defect, and drug- or toxin-induced PAH was considered as one etiological grouping (IPAH+). The process was focused on the use of oral tresprostinil or UPTRAVI in patients with IPAH+ or connective tissue disease-associated PAH (CTD-PAH) and FC II or III symptoms receiving background dual ERA/PDE-5 inhibitor therapy.

      Results: The panel developed consensus opinions on clinical scenarios considered when initiating oral PPAs in adults with PAH. Thirteen of those clinical scenarios are ones where UPTRAVI was considered as a treatment option, and parenteral prostacyclin therapy was considered treatment of choice for IPAH+ and CTD-PAH patients with high-risk hemodynamics irrespective of other clinical factors.

      Conclusion: These expert opinions may serve as a template for future investigations, however, they must be validated with rigorous prospective studies.

      The PIXEL was not a consensus conference such as one held by a task force convened for the purpose of developing treatment guidelines. The results are not intended to be formal treatment guidelines or recommendations. The PIXEL opinions cannot replace assessment and/or critical decision-making by a qualified healthcare practitioner for an individual patient. These statements do not address all possible clinical situations, nor do these statements account for additional individual patient factors not specifically stated.

      Concomitant use of strong inhibitors of CYP2C8 (eg, gemfibrozil) with UPTRAVI is contraindicated.

      Pulmonary Veno-Occlusive Disease (PVOD)
      Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue UPTRAVI.

      Adverse reactions more frequent compared to placebo (≥3%) are headache (65% vs 32%), diarrhea (42% vs 18%), jaw pain (26% vs 6%), nausea (33% vs 18%), myalgia (16% vs 6%), vomiting (18% vs 9%), pain in extremity (17% vs 8%), flushing (12% vs 5%), arthralgia (11% vs 8%), anemia (8% vs 5%), decreased appetite (6% vs 3%), and rash (11% vs 8%).

      These adverse reactions are more frequent during the dose titration phase.

      Hyperthyroidism was observed in 1% (n=8) of patients on UPTRAVI and in none of the patients on placebo.

      CYP2C8 Inhibitors
      Concomitant administration with gemfibrozil, a strong inhibitor of CYP2C8, doubled exposure to selexipag and increased exposure to the active metabolite by approximately 11-fold. Concomitant use of UPTRAVI with strong inhibitors of CYP2C8 is contraindicated.

      Concomitant administration of UPTRAVI with clopidogrel, a moderate inhibitor of CYP2C8, had no relevant effect on the exposure to selexipag and increased the exposure to the active metabolite by approximately 2.7-fold.  Reduce the dosing of UPTRAVI to once daily in patients on a moderate CYP2C8 inhibitor.

      CYP2C8 Inducers
      Concomitant administration with an inducer of CYP2C8 and UGT 1A3 and 2B7 enzymes (rifampin) halved exposure to the active metabolite. Increase UPTRAVI dose, up to twice, when co-administered with rifampin. Reduce UPTRAVI when rifampin is stopped.

      Recommended Dosage
      Recommended starting dose is 200 mcg twice daily. Tolerability may be improved when taken with food. Increase by 200 mcg twice daily, usually at weekly intervals, to the highest tolerated dose up to 1600 mcg twice daily. If dose is not tolerated, reduce to the previous tolerated dose.

      Patients With Hepatic Impairment
      For patients with moderate hepatic impairment (Child-Pugh class B), the starting dose is 200 mcg once daily. Increase by 200 mcg once daily at weekly intervals, as tolerated. Avoid use of UPTRAVI in patients with severe hepatic impairment (Child-Pugh class C).

      Co-administration With Moderate CYP2C8 Inhibitors
      When co-administered with moderate CYP2C8 inhibitors (eg, clopidogrel, deferasirox and teriflunomide), reduce the dosing of UPTRAVI to once daily. Revert back to twice daily dosing frequency of UPTRAVI when co-administration of moderate CYP2C8 inhibitor is stopped.

      Dosage Strengths
      UPTRAVI tablet strengths:
      200, 400, 600, 800, 1000, 1200, 1400, and 1600 mcg.

      Please see full Prescribing Information.

      UPTRAVI® (selexipag) is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH.

      Effectiveness was established in a long-term study in PAH patients with WHO Functional Class II-III symptoms.

      Patients had idiopathic and heritable PAH (58%), PAH associated with connective tissue disease (29%), and PAH associated with congenital heart disease with repaired shunts (10%).


      1. McLaughlin V, et al. CHEST. 2019; DOI: 10.1016/j.chest.2019.10.043.

      ©2020 Actelion Pharmaceuticals US, Inc. All rights reserved. cp-120745v3 1220

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