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Summary Background INCREASE was a randomised, placebo-controlled, phase 3 trial that evaluated inhaled treprostinil in patients with interstitial lung disease (ILD) and associated pulmonary hypertension. Treprostinil improved exercise capacity from baseline to week 16, assessed with the use of a 6-min walk test, compared with placebo. Improvements in forced vital capacity (FVC) were also reported. The aim of this post-hoc analysis was to further characterise the effects of inhaled treprostinil on FVC in the overall study population and in various subgroups of interest. Methods In this post-hoc analysis, we evaluated FVC changes in the overall study population and in various subgroups defined by cause of disease or baseline clinical parameters. The study population included patients aged 18 years and older who had a diagnosis of ILD based on evidence of diffuse parenchymal lung disease on chest CT done within 6 months before random assignment (not centrally adjudicated). All analyses were done on the intention-to-treat population, defined as individuals who were randomly assigned and received at least one dose of study drug. The INCREASE study is registered with ClinicalTrials.gov, NCT02630316. Findings Between Feb 3, 2017, and Aug 30, 2019, 326 patients were enrolled in the INCREASE trial. Inhaled treprostinil was associated with a placebo-corrected least squares mean improvement in FVC of 28·5 mL (SE 30·1; 95% CI −30·8 to 87·7; p=0·35) at week 8 and 44·4 mL (35·4; −25·2 to 114·0; p=0·21) at week 16, with associated percentage of predicted FVC improvements of 1·8% (0·7; 0·4 to 3·2; p=0·014) and 1·8% (0·8; 0·2 to 3·4; p=0·028). Subgroup analysis of patients with idiopathic interstitial pneumonia showed FVC differences of 46·5 mL (SE 39·9; 95% CI −32·5 to 125·5; p=0·25) at week 8 and 108·2 mL (46·9; 15·3 to 201·1; p=0·023) at week 16. Analysis of patients with idiopathic pulmonary fibrosis showed FVC differences of 84·5 mL (52·7; −20·4 to 189·5; p=0·11) at week 8 and 168·5 mL (64·5; 40·1 to 297·0; p=0·011) at week 16. The most frequent adverse events included cough, headache, dyspnoea, dizziness, nausea, fatigue, and diarrhoea. Interpretation In patients with ILD and associated pulmonary hypertension, inhaled treprostinil was associated with improvements in FVC versus placebo at 16 weeks. This difference was most evident in patients with idiopathic interstitial pneumonia, particularly idiopathic pulmonary fibrosis. Inhaled treprostinil appears to be a promising therapy for idiopathic pulmonary fibrosis that warrants further investigation in a prospective, randomised, placebo-controlled study. Funding United Therapeutics Corporation.

Pulmonary hypertension (PH) is usually associated with a normal or decreased cardiac output (CO). Less commonly, PH can occur in the context of a hyperdynamic circulation, characterized by high CO (8 L/min) and/or cardiac index ≥4 L/min/m

The coronavirus of 2019 (COVID-19) disrupted delivery of healthcare. Patients with pulmonary hypertension (PH), especially pulmonary arterial hypertension (PAH), require significant resources for both diagnosis and management and are at high risk for decompensation due to disruption in their care. A survey consisting of 47 questions related to the care of patients with PH was designed by the American College of Chest Physicians 2020-2021 Pulmonary Vascular Disease (PVD) NetWork Steering Committee and sent to all members of the PVD NetWork, as well as the multiple other professional networks for PH. Participation was voluntary and anonymous. Responses were collected from November 2020 through February 2021. Ninety-five providers responded to this survey. The majority (93%) believe that care of PH patients has been affected by the pandemic. Sixty-seven percent observed decreased referrals for PH evaluation. Prior to the pandemic, only 15% used telemedicine for management of PH patients compared to 84% during the pandemic. Telemedicine was used most for follow up of selected low-risk patients (49%). While 22% respondents were completely willing to prescribe new PAH therapy via telemedicine, 11% respondents were completely unwilling. Comfort levels differed based on type of medication being prescribed. Over 90% of providers experienced disruptions in obtaining testing and 31% experienced disruptions in renewal or approval of medications. Overall, providers perceived that the COVID-19 pandemic caused significant disruption of care for PH patients. Telemedicine utilization increased but was used mostly in low-risk patients. Some providers had a decreased level of comfort prescribing PAH therapy via telemedicine encounters.

The INSPIRE trial was a Phase 3, open-label, multicenter trial (LTI-301) that enrolled patients with pulmonary arterial hypertension (PAH) ≥ 18 years of age who transitioned to Yutrepia from nebulized treprostinil (Transition) or added Yutrepia to prostacyclin naïve patients on ≤2 nonprostacyclin oral therapies. The objectives of the trial were to evaluate the safety and tolerability of Yutrepia (dry-powder formulation of treprostinil) in patients with PAH. The primary safety measures were the incidence of adverse events (AEs) and serious AEs. Exploratory efficacy measures were also assessed during the trial. Transition patients initiated Yutrepia at a dose comparable to their nebulized treprostinil dose while prostacyclin naïve patients received 26.5-mcg QID; up-titration in 26.5-mcg increments was permitted for both groups. A total of 121 patients were enrolled, of which 29 patients discontinued from the trial, with the most common reason being AEs. Eighty percent of the Transition group and 96% of the prostacyclin naïve group titrated to a dose ≥79.5 mcg QID at Day 360, respectively, with one patient achieving a dose of 212-mcg QID. The most common AEs were cough, headache, upper respiratory tract infection, dyspnea, dizziness, throat irritation, diarrhea, chest discomfort, fatigue, and nasopharyngitis. Most of these events were considered treatment-related though mild to moderate in severity and expected for prostacyclin therapy administered by inhalation. In an evaluation of exploratory efficacy measures, patients remained stable or improved over the 1 year of treatment. Yutrepia was found to be a convenient, safe, and well-tolerated inhaled prostacyclin treatment option for PAH patients.

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).

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease where the additional presence of pulmonary hypertension (PH) reduces survival. In particular, the presence of coexistent pulmonary vascular disease in patients with advanced lung parenchymal disease results in worse outcomes than either diagnosis alone. This is true with respect to the natural histories of these diseases, outcomes with medical therapies, and even outcomes following lung transplantation. Consequently, there is a striking need for improved treatments for PH in the setting of IPF. In this review, we summarize existing therapies from the perspective of molecular mechanisms underlying lung fibrosis and vasoconstriction/vascular remodelling and discuss potential future targets for pharmacotherapy. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc.

Pulmonary arterial hypertension is a progressive disease that can lead to right-sided ventricular failure and premature death. Tailoring therapy to individual patient’s needs, along with regular risk assessment, is integral for optimal outcomes in patients with pulmonary arterial hypertension. Results from the AMBITION trial support the use of upfront combination of tadalafil and ambrisentan. In a recent analysis of risk assessment in pulmonary arterial hypertension, abridged versions of the REVEAL 2.0 risk score were shown to be comparable to the full tools. In this report, we present a case series of the use of riociguat in upfront combination or sequentially, and the impact on risk scores as determined by the abridged REVEAL Lite 2.0 approach.

Pulmonary hypertension (PH) is a common complication of interstitial lung disease (ILD) and is associated with worse outcomes and increased mortality. Evaluation of PH is recommended in lung transplant candidates, but there are currently no standardized screening approaches. Trials have identified therapies that are effective in this setting, providing another rationale to routinely screen patients with ILD for PH.What screening strategies for identifying PH in patients with ILD are supported by expert consensus?The study convened a panel of 16 pulmonologists with expertise in PH and ILD, and used a modified Delphi consensus process with three surveys to identify PH screening strategies. Survey 1 consisted primarily of open-ended questions. Surveys 2 and 3 were developed from responses to survey 1 and contained statements about PH screening that panelists rated from -5 (strongly disagree) to 5 (strongly agree).Panelists reached consensus on several triggers for suspicion of PH including the following: symptoms, clinical signs, findings on chest CT scan or other imaging, abnormalities in pulse oximetry, elevations in brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP), and unexplained worsening in pulmonary function tests or 6-min walk distance. Echocardiography and BNP/NT-proBNP were identified as screening tools for PH. Right heart catheterization was deemed essential for confirming PH.Many patients with ILD may benefit from early evaluation of PH now that an approved therapy is available. Protocols to evaluate patients with ILD often overlap with evaluations for pulmonary hypertension-interstitial lung disease and can be used to assess the risk of PH. Because standardized approaches are lacking, this consensus statement is intended to aid physicians in the identification of patients with ILD and possible PH, and provide guidance for timely right heart catheterization.

Pulmonary arterial hypertension (PAH) is a chronically progressive fatal disease. A goal-oriented approach to achieve low risk status has been associated with improved survival. A variety of risk stratification tools are available, but use is low. We conducted a survey to assess potential reasons for under-utilization. We conducted a survey-based study of global PAH disease specialists with a goal of assessing risk assessment utilization and identifying modifiable barriers to use. The survey was designed by the American College of Chest Physicians’ Pulmonary Vascular Diseases (PVD) NetWork. Respondents were global members of the PVD NetWork and Pulmonary Hypertension Association. Survey invitations were sent electronically to all members. Participation was anonymous and no provider or patient level data was collected. Participants from four countries responded with the majority (84%) being from the United States. Our survey found suboptimal use of any risk stratification tool with 71/112 (63%) reporting use. A total of 85% of the respondents had more than 5 years of experience in managing PAH. REVEAL 2.0 and European Society of Cardiology/European Respiratory Society risk tools were the most commonly used. A total of 44 (65%) surveyed felt that use of risk tools led to change in PAH therapies. Only 6 (9%) felt they prompted additional testing or changed the frequency of follow-up. A total of 5 (7%) reported they prompted goals of care/palliative care discussions and 2 (3%) that they triggered lung transplant referral. The vast majority indicated that incorporation of risk tools into electronic medical records (EMR) would improve utilization. PAH risk assessment tools remain under-utilized. Most respondents were experienced PAH clinicians. More than one-third were not routinely using risk tools. Most felt that risk tools led to PAH therapy changes but few reported impacts on other aspects of care. The most commonly identified barriers to use were time constraints and lack of integration with EMR.

Risk stratification is an essential tool in the management of pulmonary arterial hypertension (PAH). These tools lack detailed echocardiographic assessment which plays a central role in clinical risk assessment in PAH. Thus, we aimed at assessing whether adding echocardiography-driven data to REVEAL Lite 2.0 (Registry to Evaluate Early and Long-Term PAH Disease Management) improves the assessment of risk stratification in PAH. A retrospective analysis of 134 consecutive patients between January 2016 and December 2019 was done. We identified patients who experienced a disease progression "event" defined by the initiation of intravenous (IV) or parenteral prostacyclin, transplant referral, or death due to PAH. All other PAH patients who did not experience an "event" during this period were included in the analysis as controls. Echocardiography and REVEAL Lite 2.0 were collected from 4 to 8 months before the event and compared with the control group to predict the risk of a disease progression event. One hundred and ten patients were included in the final analysis with 22 experiencing a disease progression event and 88 remaining stable during the study period. Different echocardiographic parameters were combined with REVEAL Lite 2.0 scores in both groups. The combination of REVEAL Lite 2.0 and the left ventricular end-diastolic (LVED) eccentricity index (as a continuous variable) had the highest area under the curve (AUC) of 0.87, which approached a significant difference with that of the REVEAL Lite 2.0 alone (

Background: INCREASE was a multicenter, randomized, double-blind, placebo-controlled, 16-week study that evaluated the safety and efficacy of inhaled treprostinil in patients with interstitial lung disease and associated pulmonary hypertension (PH-ILD). The study met its primary endpoint of change in peak 6-minute walk distance at Week 16. Methods: Pulmonary function testing and exacerbations of underlying lung disease were conducted as safety assessments. This current analysis assessed the effects of inhaled treprostinil on the forced vital capacity (FVC). Findings: 326 patients were randomized to inhaled treprostinil or placebo. Inhaled treprostinil was associated with placebo-corrected improvements in the FVC of 28·5 mL (95% CI -30·8-87.7, p=0·345) and 44·4 mL (95% CI -25·3-114·1, p=0·211) at Weeks 8 and 16, respectively. The associated percent predicted FVC improvements at Weeks 8 and 16 were 1·79% (95% CI 0·37-3·21, p=0·014) and 1·80% (95% CI 0·20-3·39, p=0·028), respectively. Patients with idiopathic interstitial pneumonia (IIP) demonstrated FVC improvements of 46·5 mL (n=129, 95% CI -32·55-125·5, p=0·247) and 108·2 mL (n=115, 95% CI 15·3-201·1, p=0·023) at Weeks 8 and 16, respectively. Patients with idiopathic pulmonary fibrosis (IPF) demonstrated FVC improvements of 84·5 mL (n=78, 95% CI -20·4-189·5, p=0·113) and 168·5 mL (n=70, 95% CI 40·1-297·0, p=0·011) at Weeks 8 and 16, respectively. Interpretation: In patients with PH-ILD, inhaled treprostinil resulted in improvements in FVC compared to placebo. This difference was most evident in patients with IIP and in particular, IPF. Inhaled treprostinil appears to be a promising therapy for IPF that warrants further prospective clinical study. Trial Registration: The INCREASE study (NCT02630316) is registered with ClinicalTrials.gov. Funding Statement: The INCREASE study was funded by United Therapeutics Corporation. Declaration of Interests: SDN has received research funding and consulting fees from United Therapeutics. He has received consulting fees from Boehringer-Ingelheim, Roche-Genentech and Galapagos. He is also on the speakers bureau for Boehringer-Ingelheim and Roche-Genentech. AW reports grants from United Therapeutics Corporation, during the conduct of the study. SR reports grants from United Therapeutics Corporation, during the conduct of the study; grants and personal fees from United Therapeutics, grants and personal fees from Janssen Pharmaceuticals, personal fees from Altavant Sciences, personal fees from Liquidia Technologies, Inc., personal fees from Insmed, Inc., personal fees from Bayer Pharmaceuticals, outside the submitted work. AC reports grants from United Therapeutics Corporation, during the conduct of the study. SJ reports grants from United Therapeutics Corporation, during the conduct of the study; grants and personal fees from Bayer Pharmaceuticals, grants from Bellerophon Therapeutics, grants and personal fees from Janssen Research and Development, outside the submitted work. HD reports grants from United Therapeutics Corporation during the conduct of the study; grants and personal fees from Actelion Pharmaceuticals, outside the submitted work. DZ reports grants from United Therapeutics Corporation, during the conduct of the study. SS reports grants from United Therapeutics Corporation, during the conduct of the study; personal fees and non-financial support from Bayer Pharmaceuticals, personal fees and non-financial support from United Therapeutics, personal fees and non-financial support from Actelion Pharmaceuticals, personal fees from Liquidia, personal fees from Altavant Sciences, from GSK, grants from ACCP CHEST ILD Research Grant, personal fees from Boehringer Ingelheim, outside the submitted work. CK reports grants from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics, personal fees from Actelion, personal fees from Boehringer Ingelheim Pharmaceuticals, personal fees from Genentech, outside the submitted work. LMG reports grants and personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, personal fees from Janssen and Janssen Pharmaceuticals, personal fees from Bayer Pharmaceuticals, outside the submitted work. PS reports personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, outside the submitted work. ES reports personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, outside the submitted work. LDE reports personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, outside the submitted work. AN reports personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, outside the submitted work. VFT reports grants from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics, outside the submitted work. Ethics Approval Statement: The study protocol was approved by the institutional review board at each participating site. The study was monitored by an independent data and safety monitoring committee and was conducted in accordance with the principles of Good Clinical Practice.

Over the last two decades treatment options have drastically improved for patients with pulmonary arterial hypertension (PAH). In the recent times, there is renewed interest in dry powder inhaler (DPI) based inhaled therapies in the treatment of PAH. PAH patients are well known to have respiratory and other muscle weakness either related to the disease itself or due to the underlying diseases like connective tissue disease (CTD). CTD PAH patients are at particular disadvantage as there is a concern if they have enough strength to press the buttons on the inhaler device, needed to pierce the drug capsule inside the device. Additionally, CTD PAH patients develop hand deformities making it difficult to use devices. To our knowledge, this is the first study to systematically examine the pinch force strength needed to pierce the capsule in DPI devices in patients with PAH. We enrolled 35 patients and our results showed that all PAH patients were able to generate enough pinch strength needed to pierce the capsule regardless of the etiology of PAH.

The 2015 European Society of Cardiology/European Respiratory Society treatment guidelines recommend frequent risk assessment in pulmonary arterial hypertension utilizing risk variables. Our objectives were: (1) to investigate the impact of inhaled treprostinil on risk stratification using the French noninvasive approach and REVEAL 2.0, and (2) to analyze the prognostic utility of both risk stratification methods in the predominantly New York Heart Association/World Health Organization functional class III/IV cohorts of TRIUMPH and BEAT. A post hoc analysis was performed to assess risk at baseline and follow-up at Week 12 in the TRIUMPH cohort (n = 148) and at Week 16, 21, and 30 in the inhaled treprostinil naïve placebo BEAT cohort (n = 73). Overall survival, clinical worsening-free survival, and pulmonary arterial hypertension-related hospitalization-free survival were all assessed in the pooled TRIUMPH and inhaled treprostinil naïve placebo BEAT cohorts based on risk group/strata at Week 12/16 follow-up. Inhaled treprostinil improved REVEAL 2.0 risk stratum (OR: 2.38, 95% CI: 1.09–5.19, p = 0.0298) and REVEAL 2.0 score (p = 0.0008) compared to placebo in the TRIUMPH cohort at Week 12. REVEAL 2.0 risk stratum and the number of low-risk criteria by the French approach improved at Weeks 16, 21, and 30 in the inhaled treprostinil naïve placebo BEAT cohort. Combining cohorts, REVEAL 2.0 risk stratification at follow-up was prognostic for clinical worsening-free, pulmonary arterial hypertension hospitalization-free, and overall survival, whereas the number of low-risk criteria was not. These post-hoc pooled analyses suggest inhaled treprostinil improves risk status and indicates that the REVEAL 2.0 calculator may be more suitable than the French noninvasive method for evaluating short-term clinical change in the New York Heart Association/World Health Organization functional class III/IV population.

Pulmonary arterial hypertension is a devastating progressive disease mediated by different pathophysiologic pathways that result in progressive increase in pulmonary vascular resistance along with right ventricular failure and eventually premature death. Despite significant advances in the understanding of the underlying mechanisms and development of a number of targeted therapies, pulmonary arterial hypertension remains a challenging condition with high morbidity and mortality. New therapies are being actively sought, and early recognition remains of paramount importance. In an effort to improve the detection and management of pulmonary hypertension, the 6th World Symposium on Pulmonary Hypertension came up with most recent statements in 2018. The goal of this review is to summarize some key updates from the proceedings of the Symposium pertaining to different aspects of evaluation and management of patients with pulmonary arterial hypertension.

The 2019 European Respiratory Society (ERS) International Congress, held in Madrid, Spain, had exciting sessions regarding the field of pulmonary vascular disease. The symposia related to the new ERS/European Society of Cardiology (ESC) Guidelines for the diagnosis and management of acute pulmonary embolism were well received, as were sessions on pulmonary hypertension related to lung disease, demonstrating the concept of pulmonary hypertension not being the rarity that it was previously thought to be. The use of risk stratification in relation to pulmonary arterial hypertension (PAH) was heavily featured and the scientific sessions informing the respiratory community of potential biomarkers and targets for future therapies were thought-provoking. This article discusses highlights of the 2019 pulmonary vascular disease sessions as a summary of current knowledge and practice. We have summarised the key points from the sessions pertaining to the new ERS/ESC Guidelines for the management of acute pulmonary embolism. We have also focused on prognostic factors and potential therapies in pulmonary hypertension related to interstitial lung disease. Relating to PAH, we have reviewed the symposia on risk stratification, along with the use of noninvasive measures and the sessions relating to biomarkers in PAH., This article aims to summarise research presented at #ERSCongress 2019: the new @escardio/@EuroRespSoc guidance on acute PE diagnosis and management, PH in relation to chronic lung disease, and advances in pulmonary arterial hypertension https://bit.ly/3bAUG0o

Patients with portal hypertension may develop pulmonary hypertension. The economic implications of these comorbidities have not been systematically assessed. We compared healthcare resource utilization and costs in the United States between patients with co-existing portal hypertension and pulmonary hypertension (pulmonary hypertension cohort) and a matched cohort of portal hypertension patients without pulmonary hypertension (control cohort). In this retrospective analysis, adult pulmonary hypertension and control patients were identified from the Optum® Clinformatics® Data Mart database between 1 July 2014 and 30 June 2018. All patients had ≥2 claims with diagnosis codes for portal hypertension; pulmonary hypertension patients had ≥2 claims with diagnosis codes for pulmonary hypertension; controls could not have pulmonary hypertension diagnoses or any claims for pulmonary arterial hypertension-specific medications. Controls were matched to pulmonary hypertension patients by age, sex, Charlson comorbidity index score, and liver diseases. We assessed 12-month healthcare resource utilization and costs. Each cohort included 146 patients. During follow-up, pulmonary hypertension cohort patients were more likely than controls to experience a hospitalization (51% vs. 32%, P = 0.0014) and an emergency room visit (55% vs. 41%, P = 0.026). The average annual total cost was higher in pulmonary hypertension patients than for matched controls ($119,912 vs. $81,839, P

In the past decade and a half, the introduction of new therapeutic agents has revolutionized the management of pulmonary arterial hypertension (PAH). These new treatment options have improved the quality of life and survival in PAH. With an armamentarium of options available, the identification of unique phenotypes can help practitioners choose tailored treatment regimens. Experts in other cardiovascular diseases, such as congestive heart failure and hypertension, have recommended race-specific treatments in their fields based on data highlighting variations in response to therapies. With this perspective, we review evidence supporting the hypothesis that ethnicity or race plays an important role in the management of PAH. Preliminary research suggests that races/ethnicities have differences in the presentation and outcome of PAH and could respond to PAH-specific medications with varying efficacy. Genetic, physiological, and anatomic differences exist between races, particularly regarding the structure and function of the right ventricle. Unfortunately, clinical trials have not adequately included minorities, and registry data often omit inclusion of this demographic information. Further studies are needed to characterize the role that ethnicity plays in the prevalence, presentation, outcomes, and optimal treatment of PAH.

Purpose PH associated with chronic lung disease (WHO Group 3 PH) has a poor prognosis compared with pulmonary arterial hypertension (PAH [WHO Group 1 PH]). OPUS and OrPHeUS provide real-world data on Group 1 and Group 3 patients initiating macitentan. This analysis aims to describe characteristics and clinical outcomes of macitentan-treated Group 3 patients, including those with interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD). Methods OPUS was a prospective, US, multicenter, observational drug registry (Apr 2014-Apr 2020; NCT02126943). OrPHeUS was a US multicenter chart review (Oct 2013-Mar 2017; NCT03197688). The data cut-off for these analyses was February 2020. ILD, COPD, and other non ILD/COPD Group 3 patients are descriptively compared with Group 1 idiopathic/heritable PAH (I/HPAH) patients. Results By February 2020, OPUS/OrPHeUS (N = 5549) included 361 Group 3 patients, of whom 143 (40%) had ILD, 119 (33%) had COPD, 99 (27%) had neither ILD nor COPD; and 4540 Group 1 patients, of whom 2462 (54%) had I/HPAH. Characteristics at macitentan initiation and follow up are shown in the table. Kaplan-Meier survival estimates (% [95% CL]) at 12 months were 88 (80, 93) for ILD, 81 (71, 88) for COPD, 90 (81, 95) for non ILD/COPD, and 91 (89, 92) for I/HPAH. In OPUS only, the number of patients who reported ≥1 adverse event was (n/N) 46/59 (78%) for ILD, 33/39 (85%) for COPD, 39/44 (89%) for non ILD/COPD, and 915/1204 (76%) for I/HPAH. Safety profiles were similar between groups. Conclusion In OPUS/OrPHeUS, 6.5% of patients were in Group 3. In general, COPD patients were older, more likely to be male, and a greater proportion were in WHO FC III/IV compared to ILD and I/HPAH patients. Rates of discontinuation due to an AE were higher in ILD and COPD patients than in non ILD/COPD and I/HPAH patients. A higher hospitalization rate and worse survival were observed in COPD patients at 12 months compared to the other subgroups. Safety was consistent with the known profile of macitentan.

Pulmonary hypertension (PH) is a chronic, progressive, life-threatening disease that requires expert multidisciplinary care. To facilitate this level of care, the Pulmonary Hypertension Association established across the United States a network of pulmonary hypertension care centers (PHCCs) with special expertise in PH, particularly pulmonary arterial hypertension, to raise the overall quality of care and outcomes for patients with this life-threatening disease. Since the inception of PHCCs in September 2014, to date 35 centers have been accredited in the United States. This model of care brings together physicians and specialists from other disciplines to provide care, facilitate basic and clinical research, and educate the next generation of providers. PHCCs also offer additional opportunities for improvements in PH care. The patient registry offered through the PHCCs is an organized system by which data are collected to evaluate the outcomes of patients with PH. This registry helps in detecting variations in outcomes across centers, thus identifying opportunities for improvement. Multiple tactics were undertaken to implement the strategic plan, training, and tools throughout the PHCC network. In addition, strategies to foster collaboration between care center staff and individuals with PH and their families are the cornerstone of the PHCCs. The Pulmonary Vascular Network of the American College of Chest Physicians believes this to be a positive step that will improve the quality of care delivered in the United States to patients with PH.

Summary of Objectives Significant advantages are associated with inhaled therapies for pulmonary arterial hypertension (PAH), including enhanced delivery of drug to the lungs at a lower overall dose, improved ventilation-perfusion matching, and decreased risk of systemic vasodilation and other systemic adverse effects. LIQ861 is an investigational, novel, dry-powder formulation of treprostinil (TRE) designed using PRINT® technology to enhance deep-lung drug deposition and enable delivery of TRE doses in 1 to 2 breaths per capsule 4 times per day while using a convenient dry-powder inhaler. The primary objective of the INSPIRE study is to evaluate the safety and tolerability of LIQ861 in PAH patients transitioning to LIQ861 from a stable dose of Tyvaso® (Transition Group) and those adding LIQ861 to therapy with ≤2 non-prostacyclin (PGI) oral agents (Add-on Group). Final results from INSPIRE will be presented. Methods INSPIRE is a phase 3, open-label, multicenter study that enrolled WHO Group I PAH patients classified as New York Heart Association (NYHA) functional class (FC) II-IV. Patients in the Transition Group received an initial dose of LIQ861 that was believed to be comparable to their Tyvaso® dose, while those in the Add-on Group initiated LIQ861 at a dose of 25 mcg capsule strength QID. LIQ861 dose increases in both groups were titrated in 25 mcg capsule strength QID increments to tolerance and symptom relief. Endpoints The primary endpoint is the incidence of treatment-emergent adverse events and serious adverse events at Month 2. Exploratory endpoints are changes from baseline through Month 2 in physician assessment of stability; six-minute walk distance; NYHA FC, N-terminal B-type natriuretic peptide levels; and patient-reported quality of life. An additional endpoint for the Transition Group is the proportion of patients maintaining a sustained transition through Month 2, with sustained transition defined as continued LIQ861 therapy after discontinuation of Tyvaso®, no interruptions in LIQ861 therapy for ≥7 days; and no treatment with any other PGI analog or PGI receptor agonist.

BACKGROUND Prior research has suggested that the prevalence and outcomes of pulmonary arterial hypertension (PAH) may vary by race or ethnicity. However, these studies have been limited by small sample size or methodological techniques relying on epidemiologic data. The purpose of this study is to evaluate the relationship between race/ethnicity and survival in a large U.S.-based prospective multicenter registry. METHODS Patients in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a 5-year observational study of Group 1 PAH, were categorized by race/ethnicity. Baseline hemodynamic characteristics, clinical characteristics, and medication use was described. The relationship between race/ethnicity and outcome was evaluated by Kaplan–Meier and Cox proportional hazards modeling techniques. Left-truncation analysis, which adjusted for time from diagnosis to study enrollment, was used to minimize the effect of survivor bias. RESULTS This analysis included 3,046 patients; 2,202 identified as white, 393 as black, 263 as Hispanic, 100 as Asian or Pacific Islander, and 88 as other. Unadjusted Kaplan–Meier survival analysis indicated that white patients had the lowest survival rates. After adjusting for variables of prognostic impact, race/ethnicity was no longer significantly associated with survival. Other results showed that black patients were more likely to have connective tissue disease–associated PAH, Hispanic patients were more likely to have portopulmonary hypertension, and Asian patients were more likely to have congenital heart disease–associated PAH. CONCLUSIONS Analysis of the REVEAL registry did not find race/ethnicity to be a significant predictor of mortality. This is the largest analysis to date evaluating the role of race/ethnicity on outcomes in PAH.

Epoprostenol, a synthetic prostaglandin I2 (PGI2) analog, has been the mainstay of treatment for severe pulmonary arterial hypertension (PAH) for the last two decades. Treprostinil, another synthetic prostaglandin analog, and selexipag, an oral selective Inositol Phosphate (IP) prostacyclin receptor agonist, have also been approved for treatment of PAH. Prostacyclin and its analogs cause a variety of side effects in patients with PAH; however, thyroid dysfunction is rarely reported. After treating an index case of thyroid dysfunction occurring after initiation of epoprostenol, we reviewed our databases of PAH patients treated with epoprostenol, treprostinil or selexipag to identify the occurrence of this association. We identified six cases of thyroid dysfunction in our cohort: five after initiation of an intravenous prostacyclin (epoprostenol) and one after initiation of an oral prostacyclin receptor agonist (selexipag). Four of the patients presented with hyperthyroidism and two with a large autoimmune goiter. Graves’ disease was seen in three patients, Hashimoto’s disease in two patients and thyrotoxicosis in one patient. Therapy with medications targeting the prostacyclin pathway is a potential risk factor for the development of symptomatic thyroid disease.

Background Accurate and regular risk assessment is important for evaluation and treatment of pulmonary arterial hypertension (PAH) patients, including those with functional class (FC) II symptoms, a population considered at low risk for disease progression. Risk assessment methods include subjective and objective evaluations. Multiparametric assessments include tools based on the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines (COMPERA and FPHR methods, respectively) and the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL; REVEAL 2.0 tool). To better understand risk status determination in FC II patients, we compared physician-reported risk assessments with objective multiparameter assessment tools. Methods This retrospective chart analysis included PAH patients with FC II symptoms receiving monotherapy or dual therapy. Physicians were surveyed (via telephone) to obtain an assessment of patient risk using their typical methodology, which might have been informed by objective risk assessment. Patient risk was then calculated independently using COMPERA, FPHR and REVEAL 2.0 tools. Factors associated with incongruent risk assessment were identified. Results Of the 153 patients, 41%, 46%, and 13% were classified as low, intermediate, and high risk, respectively, by physicians. Concordance between physician gestalt and objective methods ranged from 43%–54%. Among patients considered as low risk by physician gestalt, 4%–28% were categorized as high risk using objective methods. The most common physician factor associated with incongruent risk assessment was less frequent echocardiography during follow-up (every 7–12 months vs. every 3 months; p = 0.01). Conclusions More than half of FC II PAH patients were classified as intermediate/high risk using objective multiparameter assessments. Incorporating objective risk-assessment algorithms into clinical practice may better inform risk assessment and treatment strategies.