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Selexipag is an oral selective agonist of the prostacyclin receptor approved to treat adults with pulmonary arterial hypertension (PAH). Selexipag is initiated at a dose of 200 μg twice daily (bid) and usually titrated up by 200 μg bid weekly (per label) or more slowly (e.g., every other week in real-world clinical practice) to the highest tolerated individualized dose (ID) ranging from 200 to 1600 µg bid. In the Phase 3 GRIPHON trial, selexipag delayed disease progression and reduced risk of PAH-related hospitalization compared with placebo; the effect was consistent across three prespecified ID groups: low (200-400 µg bid), medium (600-1000 µg bid), and high (1200-1600 µg bid). This study evaluated patient outcomes across selexipag dose ranges in real-world practice. Data were analyzed from 1186 US adult patients with PAH on selexipag from the Komodo closed-claims database (2015‒2022). Of these, 634 (53.5%) patients completed titration and reached their selexipag ID (43.8% high ID, 29.8% medium ID, 26.3% low ID). Subsequently, 72.4% of patients in the low ID group had dose adjustments compared with 61.9% (medium ID) and 34.5% (high ID; standardized mean difference 0.63). There were no significant differences in patient outcomes, i,e, persistence (time to discontinuation) and risk of all-cause and PAH-related hospitalization across ID groups. The findings in this diverse, real-world population of patients with PAH reinforced an individualized approach to the dosing scheme to maximize benefit-risk and achieve the highest tolerated dose with selexipag similar to findings from the GRIPHON trial and other studies., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Actelion Pharmaceuticals US, Inc., a Johnson & Johnson company, sponsored this study. Wenze Tang, Yuen Tsang, and Sumeet Panjabi are employees of Actelion Pharmaceuticals US, Inc. and may own stocks. The study sponsor was involved in all aspects of the research, including the collection of data, its analysis and interpretation, and approval of the final manuscript for publication. Charles D. Burger provided consulting services to Janssen, LLC., (© 2024 Actelion Pharmaceuticals US, Inc (a Johnson & Johnson Company). Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Pulmonary hypertension (PH) associated with chronic kidney disease (CKD) (PH-CKD) affects approximately 20%-40% of CKD patients and is associated with increased morbidity and mortality. PH and CKD are both pathophysiologically associated with nitric oxide (NO) deficiency. The NO pathway, an important therapeutic domain in pulmonary arterial hypertension (PAH), is an intriguing but unexplored target in PH-CKD. We sought to improve understanding of the clinical significance of the NO pathway in patients with PH-CKD by assessing the hemodynamic response to inhaled NO (iNO) during right heart catheterization (RHC). In this retrospective cohort study, patients with diagnosis codes of PH and stage IV/V CKD or end-stage renal disease and estimated glomerular filtration rate < 60 mL/min/body surface area who underwent RHC and hemodynamic drug study between July 2011 and June 2021 were eligible. Patients with mean pulmonary artery pressure (mPAP) > 20 mmHg and pulmonary vascular resistance (PVR) > 3 Wood units were included. The final cohort included 37 patients (45.9% female, mean age 72.5 ± 9.7 years). A total of 56.7% of the cohort (21/37) had precapillary PH, while 43.2% (16/37) had combined precapillary postcapillary PH (Cpc-PH). Median survival was 3.1 years after RHC. iNO was associated with a significant decrease in both mPAP and PVR. Hemodynamic changes in mPAP and PVR were similar in precapillary and Cpc-PH groups. Among a small subset ( n  = 14) who were subsequently treated with PAH-targeted therapy, treatment response was mixed and did not reveal significant benefit. Further studies are warranted to better define the potential role of PAH therapy in PH-CKD., Competing Interests: HMD has received research funding from Bayer Pharmaceuticals and has served on advisory boards and received consulting fees from Janssen. The other authors declare no conflict of interest., (© 2024 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Inhaled treprostinil is an approved therapy for pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease in the United States. Studies have confirmed the robust benefits and safety of nebulized inhaled treprostinil, but it requires a time investment for nebulizer preparation, maintenance, and treatment. A small, portable treprostinil dry powder inhaler has been developed for the treatment of PAH. The primary objective of this study was to evaluate the safety and tolerability of treprostinil inhalation powder (TreT) in patients currently treated with treprostinil inhalation solution. Fifty-one patients on a stable dose of treprostinil inhalation solution enrolled and transitioned to TreT at a corresponding dose. Six-minute walk distance (6MWD), device preference and satisfaction (Preference Questionnaire for Inhaled Treprostinil Devices [PQ-ITD]), PAH Symptoms and Impact (PAH-SYMPACT®) questionnaire, and systemic exposure and pharmacokinetics for up to 5 h were assessed at baseline for treprostinil inhalation solution and at Week 3 for TreT. Adverse events (AEs) were consistent with studies of inhaled treprostinil in patients with PAH, and there were no study drug-related serious AEs. Statistically significant improvements occurred in 6MWD, PQ-ITD, and PAH-SYMPACT. Forty-nine patients completed the 3-week treatment phase and all elected to participate in an optional extension phase. These results demonstrate that, in patients with PAH, transition from treprostinil inhalation solution to TreT is safe, well-tolerated, and accompanied by statistically significant improvements in key clinical assessments and patient-reported outcomes with comparable systemic exposure between the two formulations at evaluated doses (trial registration: clinicaltrials.gov identifier: NCT03950739)., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.A.B. has received funding from Janssen, Bayer, and Actelion for research and honoraria from United Therapeutics Corporation, Bayer, Janssen, AstraZeneca, Intuitive, and Boehringer Ingelheim for lectures, presentations, or speakers' bureau. C.D.B. has no conflict of interest. C.D. is an employee of United Therapeutics Corporation. S.V.D. has no conflict of interest. M.S.E. reports ongoing industry‐sponsored research with Acceleron, Merck, and United Therapeutics Corporation. K.A.E. has received fees from United Therapeutics Corporation for serving on a speakers' bureau and advisory boards; from J&J Actelion for serving on advisory boards; and from Acceleron for consulting services; and institutional research funding from UT and J&J Actelion. M.R.F. has no conflict of interest. S.J. has received research funding from United Therapeutics Corporation and Bellerophon Therapeutics and honoraria from Actelion and Bayer for speakers programs. J.M. has received speaker fees from United Therapeutics Corporation. M.M. is an employee of United Therapeutics Corporation. J.M.J. has no conflict of interest. H.I.P. has received honoraria from Acceleron, United Therapeutics Corporation, and Actelion‐Janssen for serving on advisory boards. G.V.R. has no conflict of interest. R.R.J. has received fees from United Therapeutics Corporation, Bayer, and J&J Actelion for consulting, serving on a speakers' bureau, and research funding. S.S. has served as a consultant for United Therapeutics Corporation, Acceleron, Actelion, and Bayer Pharmaceuticals; as an advisor and speaker for United Therapeutics Corporation, Actelion, and Bayer; and as clinical trial site PI for United Therapeutics Corporation, Actelion, Merck, Liquidia Technologies, Altavant Sciences, and Gossamer Bio; and has received research grant support from ACCP CHEST and United Therapeutics Corporation. T.G.S. has served as an advisor for Bayer Pharmaceuticals and Liquidia Technologies and as clinical trial site PI for United Therapeutics Corporation, Actelion/J &J, Liquidia Technologies, Bayer Pharmaceuticals, and Regeneron Pharmaceuticals. S.M.S. has no conflict of interest. P.S. is an employee of United Therapeutics Corporation. L.A.S. has received consulting fees from Gossamer Bio and has served as clinical trial site PI for United Therapeutics Corporation, Gossamer Bio, INSMED, Actelion, Liquidia, Merck, and Altavant Sciences., (© 2022 United Therapeutics Corporation. United Therapeutics Corporation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Dual combination therapy with a phosphodiesterase-5 inhibitor (PDE5i) and endothelin receptor antagonist is recommended for most patients with intermediate-risk pulmonary arterial hypertension (PAH). The RESPITE and REPLACE studies suggest that switching from a PDE5i to a soluble guanylate cyclase (sGC) activator may provide clinical improvement in this situation. The optimal approach to escalation or transition of therapy in this or other scenarios is not well defined. We developed an expert consensus statement on the transition to sGC and other treatment escalations and transitions in PAH using a modified Delphi process. The Delphi process used a panel of 20 physicians with expertise in PAH. Panelists answered three questionnaires on the management of treatment escalations and transitions in PAH. The initial questionnaire included open-ended questions. Later questionnaires consolidated the responses into statements that panelists rated on a Likert scale from -5 ( strongly disagree ) to +5 ( strongly agree ) to determine consensus. The Delphi process produced several consensus recommendations. Escalation should be considered for patients who are at high risk or not achieving treatment goals, by adding an agent from a new class, switching from oral to parenteral prostacyclins, or increasing the dose. Switching to a new class or within a class should be considered if tolerability or other considerations unrelated to efficacy are affecting adherence. Switching from a PDE5i to an SGC activator may benefit patients with intermediate risk who are not improving on their present therapy. These consensus-based recommendations may be helpful to clinicians and beneficial for patients when evidence-based guidance is unavailable., Competing Interests: Franck F. Rahaghi reports consultation, research, and speakership honoraria from Bayer and Janssen, consultation and speakership from United Therapeutics, and consultation fees from Acceleron. Vijay P. Balasubramanian reports a research grant from United Therapeutics and serves on a speakers bureau for Bayer. Robert C. Bourge reports research grant support to my institution from United Therapeutics and Bayer, and service on a Scientific Advisory Board at United Therapeutics. Murali M. Chakinala reports grants or contracts from Actelion/Janssen, Bayer, Medtronic, NIH, Reata, Liquidia, Phase Bio, Complexa, United Therapeutics, Altavant, Trio Health Analytics, Reata, Acceleron, Arena, and Gossamer; consulting fees from Altavant, Vaderis Therapeutics, Aerovate, Reata, VWave, and Arena; honoraria from Bayer, Gilead, Simply Speaking, WebMD, and United Therapeutics; support for attending meetings and/or travel from Actelion/Janssen, United Therapeutics, Bayer, Acceleron, Reata, and Gilead; participation on a Data Safety Monitoring Board or Advisory Board for Actelion/Janssen, Express Scripts, Phase Bio, Altavant, Gossamer, United Therapeutics, Bayer, Acceleron, and Liquidia; and leadership or a fiduciary role in the Pulmonary Hypertension Association and the Cure HHT Global Research and Medical Advisory Board. Michael S. Eggert reports research contracts with United Therapeutics (BREEZE and ADVANCE Outcomes), Acceleron, and Actelion. Jean M. Elwing reports grants from Actelion, Acceleron, Reata, United Therapeutics, Liquidia, Phase Bio, Complexa, Gossamer Bio, Bayer, Arena, Eiger, Akros, Bellerophon, and Lung LLC and consulting fees from United Therapeutics, Acceleron, Liquidia, Altavant, Bayer, Gossamer Bio, Actelion, Bayer. Jeremy Feldman reports consulting and giving talks for Bayer, United Therapeutics, and Jansen. Christopher King reports personal fees from Actelion, personal fees from Genentech, United Therapeutics, and Boehringer Ingelheim; has served on advisory boards for and is on the Speakers’ Bureau of Actelion, Boehringer‐Ingelheim Pharmaceuticals, and United Therapeutics. James R. Klinger reports that his institution receives research funding from United Technologies, service on a Steering Committee and a Clinical Outcomes Committee for Bayer, and a leadership role in the Pulmonary Hypertension Association. Stephen C. Mathai reports personal fees from United Therapeutics; participation on a data safety monitoring board or advisory board from United Therapeutics, Actelion, and Bayer, and leadership or a fiduciary role in the PCORI Rare Disease Advisory Panel and the World Symposium on Pulmonary Hypertension. John Wesley McConnell reports consulting fees from Actelion, Bayer, Gossamer, Altavant, and Liquidia; honoraria from Actelion, Bayer, Simply Speaking, Impact PH, and Reata, and participation on a data safety monitoring board or advisory board for Actelion, Liquidia, Gossamer, and Altavant. Harold I. Palevsky reports honoraria for serving on scientific advisory boards for Acceleron, Actelion/Janssen, PhaseBio and United Therapeutics, and serving on a DSMB for United Therapeutics. Ricardo Restrepo‐Jaramillo reports serving on speaker's bureau for United Therapeutics, Bayer, and Actelion. Zeenat Safdar reports serving on a speakers bureau, consultation and advisory boards for Actelion, United Therapeutics, Boehringer Ingelheim, Bayer, and Roche. Jeffrey S. Sager reports personal fees from Bayer pharmaceuticals, grants and personal fees from United Therapeutics, grants and personal fees from Janssen (J and J), and grants from Reata outside the submitted work. Namita Sood reports a speaking fee from Bayer. Roxana Sulica reports research grants from Bayer, United Therapeutics, Complexa, and Reata, and serves on advisory boards for Actelion, Bayer, United Therapeutics, and Reata. R. James White reports research grants from United Therapeutics, Reata, Bayer, Merck, and Janssen and consulting fees from Merck and Bayer. Nicholas S. Hill reports honoraria from Axon Research for this study; grants to his institution from Actelion, Bayer, Gilead, and United Therapeutics; consulting fees from United Therapeutics; and participation in Data Safety Monitoring Boards for United Therapeutics and Pfizer. All authors had access to the Delphi questionnaire analysis and data and participated in the review, revision, and approval of the content of the manuscript for submission. Charles D. Burger reports no disclosures or conflicts of interest., (© 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Compared to idiopathic pulmonary arterial hypertension (IPAH), patients with portopulmonary hypertension (POPH) have worse survival. Health disparities may contribute to these differences but have not been studied. We sought to compare socioeconomic factors in patients with POPH and IPAH and to determine whether socioeconomic status and/or POPH diagnosis were associated with treatment and health-care utilization. We performed a cross-sectional study of adults enrolled in the Pulmonary Hypertension Association Registry. Patients with IPAH (n = 344) and POPH (n = 57) were compared. Compared with IPAH, patients with POPH were less likely to be college graduates (19.6% vs. 34.9%, p = 0.02) and more likely to be unemployed (54.7% vs. 30.5%, p < 0.001) and have an annual household income below poverty level (45.7% vs. 19.0%, p < 0.001). Patients with POPH had similar functional class, quality of life, 6-min walk distance, and mean pulmonary arterial pressure with a higher cardiac index. Compared with IPAH, patients with POPH were less likely to receive combination therapy (46.4% vs. 62.2%, p = 0.03) and endothelin receptor antagonists (28.6% vs. 55.1%, p < 0.001) at enrollment with similar treatment at follow-up. Patients with POPH had more emergency department visits (1.7 ± 2.1 vs. 0.9 ± 1.2, p = 0.009) and hospitalizations in the six months preceding enrollment (1.5 ± 2.1 vs. 0.8 ± 1.1, p = 0.02). Both POPH diagnosis and lower education level were independently associated with a higher number of emergency department visits. Compared to IPAH, patients with POPH have lower socioeconomic status, are less likely to receive initial combination therapy and endothelin receptor antagonists but have similar treatment at follow-up, and have increased health-care utilization., (© The Author(s) 2021.)

In patients treated with macitentan (Opsumit®, Actelion Pharmaceuticals Ltd., Basel, Switzerland) for pulmonary arterial hypertension (PAH), prevention and/or effective management of treatment-related adverse events may improve adherence. However, management of these adverse events can be challenging and the base of evidence and clinical experience for macitentan is limited. In the absence of evidence, consensus recommendations from physicians experienced in using macitentan to treat PAH may benefit patients and physicians who are using macitentan. Consensus recommendations were developed by a panel of physicians experienced with macitentan and PAH using a modified Delphi process. Over three iterations, panelists developed and refined a series of statements on the use of macitentan in PAH and rated their agreement with each statement on a Likert scale. The panel of 18 physicians participated and developed a total of 118 statements on special populations, add-on therapy, drug-drug interactions, warnings and precautions, hospitalization and functional class, and adverse event management. The resulting consensus recommendations are intended to provide practical guidance on real-world issues in using macitentan to treat patients with PAH.

The primary aim was to explore the safety and tolerability of inhaled treprostinil when used in patients with pulmonary hypertension (PH) with concomitant chronic obstructive pulmonary disease (COPD). Patients with a diagnosis of pre-capillary PH (defined as pulmonary artery mean pressure of ≥ 25 mmHg and pulmonary artery wedge pressure or left ventricular end diastolic pressure of ≤ 15 mmHg) who were being initiated on inhaled treprostinil and had concomitant COPD (defined as FEV1/FVC ratio ≤ 70% with FEV1 ≥ 40% predicted) were considered for inclusion in this pilot study. Assessments included adverse events, physical exam, World Health Organization (WHO) functional class, 6-minute walk test (6MWT), modified Borg dyspnea score, and concomitant medication. At baseline and week 16 St. George's Respiratory Questionnaire (SGRQ), arterial blood gas (ABG), and pulmonary function test (PFT) were assessed. The median age was 65 years (age range, 56-80 years) and five patients (56%) were men. Among the nine patients, a majority had an increase in 6MWT from baseline to week 16 (median change, 19 m). Only three of the nine patients (33%) had an increase in A-a gradient at week 16 (median change, -7). There was no difference in any of the following: arterial blood gases, WHO functional class, 6MWT results, or SGRQ scores from baseline to week 16. There was a statistically significant decline in several of the PFT measures, including FEV1 (median change, -0.18 L; P  = 0.004; median change, -7% of predicted; P  = 0.016), FVC (median change, -0.23 L; P  = 0.027), and diffusion capacity for carbon monoxide (DLCO) (median change, -5% of predicted; P  = 0.023). The small number of patients limits firm conclusions; however, inhaled treprostinil did not seem to adversely impact oxygenation in the majority of the study patients with pre-capillary PH and COPD. While there may have an adverse impact on some pulmonary function parameters, the clinical significance is unclear.