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Background Current clinical guidelines support use of parenteral prostacyclin therapy for patients with pulmonary arterial hypertension (PAH) at intermediate risk. The objective of this study was to assess parenteral prostacyclin therapy use among patients at intermediate risk according to the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) 2.0 four-strata risk assessment model. Methods This was a retrospective chart review and cross-sectional online survey of healthcare professionals (HCPs). Included patients were classified as intermediate-low or intermediate-high risk per COMPERA 2.0 between 2016 and 2020 (index visit), initiated on a parenteral prostacyclin any time following intermediate risk assessment, and had World Health Organization (WHO) Functional Class (FC), 6-minute walk distance (6MWD), and B-type natriuretic peptide/N-terminal pro B-type natriuretic peptide (BNP/NT-proBNP) assessments at index and first comprehensive follow-up visits (follow-up). Results A total of 139 HCPs (53% community-based, 47% Pulmonary Hypertension Care Center-based) participated in the survey and provided 350 patient records; among these, mean age (SD) was 54.1 (15.3) years and 52% were female. Median (IQR) time from parenteral prostacyclin initiation to follow-up was 3.0 months (2.0, 7.0). At parenteral prostacyclin initiation for the 280 patient records with available COMPERA 2.0 assessments, 62% of patients were intermediate-high risk, 33% were intermediate-low risk and 3% were low risk, improving to 38%, 53%, and 8%, respectively, at follow-up. Conclusions Improvements were seen for the individual COMPERA 2.0 risk calculator parameters and for several other clinical parameters. Findings from this study substantiate recent guidelines suggesting earlier use of this treatment in intermediate-risk patients with PAH. Clinical trial number Not applicable.

The objective of this analysis was to compare clinician‐based and formally calculated risk assessments by REVEAL Lite 2 and COMPERA 2.0 and to characterize parenteral prostacyclin utilization within 90 days of baseline in high‐risk patients. A multisite, double‐blind, retrospective chart review of patients with pulmonary arterial hypertension (PAH) was conducted with an index period of January 2014–March 2017. Patients were categorized into the “any PAH medication” or “prostacyclin‐enriched” cohort based on latest PAH medication initiated within the index period. Clinicians classified the patient's 1‐year mortality risk as “low,” “intermediate,” or “high” based on their clinical assessment. REVEAL Lite 2 and COMPERA 2.0 scores were independently calculated. Risk assessment congruency was evaluated. Parenteral prostacyclin use was evaluated within 90 days of baseline. Thirty‐two clinicians participated and abstracted data for 299 patients with PAH. At baseline, mean patient age was 52 years, 6‐min walk distance was 226 m, and most patients were WHO functional class II or III. Half of the patients (53%) were classified by clinician assessment as intermediate risk, while most were classified as high risk by REVEAL Lite 2 (59%) and intermediate‐high risk by COMPERA 2.0 (52%). Parenteral prostascyclins were underutilized in high‐risk patients, and not initiated in a timely fashion. Clinician‐assessed risk category was incongruent with tool‐based risk assessments in 40%–54% of patients with PAH, suggesting an underestimation of the patient's risk category by clinician gestalt. Additionally, there was a lack of timely prostacyclin initiation for patients with PAH stratified as high‐risk by either tool.

Performing longitudinal and consistent risk assessments for patients with pulmonary arterial hypertension (PAH) is important to help guide treatment decisions to achieve early on and maintain a low‐risk status and improve patient morbidity and mortality. Clinical gestalt or expert perception alone may over or underestimate a patient's risk status. Indeed, regular and continued use of validated risk assessment tools more accurately predict patients' survival. Effective PAH risk assessments are often underutilized even though many seasoned clinicians will attest to using these tools routinely. We present recommendations based on real‐world experience in varied clinical practice settings around the United States for overcoming barriers to facilitate regular, serial formal risk assessment. Expert advanced practice provider clinicians from mid to large‐size medical centers collaborated to formulate recommendations based on multiple discourses and discussions. Enlisting the help of support staff, such as medical assistants and nurses, to fill in available risk parameters in risk assessment tools can save time for providers and increase efficiency, as can technology‐based solutions such as integrating risk assessments into electronic medical records. Modified, abbreviated risk assessment tools can be applied to a patient's clinical scenario when all of a patient's data are not available to complete a more comprehensive assessment. Initial discussions regarding the overall meaning and prognostic importance of risk scores may assist patients to take on a more active role in terms of informed decision‐making regarding their care. A collaborative approach can help clinics establish consistent use of risk assessment.

Treprostinil is a prostacyclin analogue that targets multiple cellular receptors to treat pulmonary arterial hypertension (PAH). In certain scenarios, patients may require aggressive treprostinil titration. Several studies have demonstrated that higher doses of treprostinil lead to greater clinical benefit. Data supports successful transitions from parenteral to oral treprostinil; however, administration routes, transition duration, and transition setting vary in the real‐world. The EXPEDITE clinical trial (NCT03497689) prospectively studied whether rapid parenteral treprostinil induction can be used to achieve high doses of oral treprostinil (total daily dose: ≥12 mg) in prostacyclin naïve PAH patients. Parenteral prostacyclin induction may be more appropriate for patients who need to reach therapeutic dosing more urgently than longer titration durations reported with conventional de novo oral treprostinil initiation. This summary provides strategies utilized in EXPEDITE. Parenteral treprostinil was initiated at 2 ng/kg/min intravenously or subcutaneously; clinicians determined the frequency and dose increment of up‐titration. Two distinct transition schedules from parenteral to oral treprostinil were employed: rapid cross‐titration in an inpatient setting (median: 2 days) or gradual cross‐titration in an outpatient setting (median: 5 days). Patient status was closely monitored after transition; oral treprostinil dose was titrated to clinical effect and tolerability. Factors considered when individualizing dosing strategies included parenteral and oral treprostinil target doses, nursing support, patient education, medication counseling and adverse events management. EXPEDITE demonstrated the time to a therapeutic dose of oral treprostinil is significantly shorter when utilizing a short‐term parenteral induction strategy and may be suitable for patients requiring aggressive titration of oral treprostinil.

Treprostinil is a prostacyclin approved for the treatment of pulmonary arterial hypertension. Commercial data sets indicate that approximately 20–25% of patients are prescribed a higher dose than the maximum recommended dosage of nine breaths per treatment session (bps) (54 μg), four times a day (QID) and numerous studies have demonstrated the safety of doses >9 bps QID. This phase 4, retrospective analysis of specialty pharmacy records assessed the effects of inhaled treprostinil at doses >9 bps QID. Patients receiving inhaled treprostinil between September 2009 and June 2018 were included, and a random sampling of 5000 patients was selected for further analysis. Subjects were grouped based on the highest dose reached for ≥2 months within a rolling six-month window and were followed for up to three years. Of the total of 5000 patients analyzed, 28.5% received >9 bps QID. Survival rates were significantly higher in the >9 bps QID dosing group for years one, two, and three (P < 0.001). The time to transition to parenteral therapy was significantly longer for those at doses >9 bps (17.5 months) compared to doses ≤9 bps (9.5 moths; P < 0.0001). Drug persistence was also significantly higher for those taking >9 bps at years 1, 2, and 3 (P < 0.0001). Patients receiving inhaled treprostinil at doses >9 bps QID had a higher rate of survival and drug persistence over a three-year period, suggesting that higher doses may provide clinically relevant benefits while remaining tolerable.

Right heart (RH) structure and function are major determinants of symptoms and prognosis in pulmonary arterial hypertension (PAH). RH imaging provides detailed information, but evidence and guidelines on the use of RH imaging in treatment decisions are limited. We conducted a Delphi study to gather expert opinion on the role of RH imaging in decision‐making for treatment escalation in PAH. A panel of 17 physicians with expertise in PAH and RH imaging used three surveys in a modified Delphi process to reach consensus on the role of RH imaging in PAH. Survey 1 used open‐ended questions to gather information. Survey 2 contained Likert scale and other questions intended to identify consensus on topics identified in Survey 1. Survey 3 contained Likert scale questions derived from Survey 2 and summary information on the results of Survey 2. The Delphi panel reached consensus that RH imaging is likely to improve the current risk stratification algorithms and help differentiate risk levels in patients at intermediate risk. Tricuspid annular plane systolic excursion, right ventricular fractional area change, right atrial area, tricuspid regurgitation, inferior venae cavae diameter, and pericardial effusion should be part of routine echocardiography in PAH. Cardiac magnetic resonance imaging is valuable but limited by cost and access. A pattern of abnormal RH imaging results should prompt consideration of hemodynamic evaluation and possible treatment escalation. RH imaging is an important tool for decisions about treatment escalation in PAH, but systematically collected evidence is needed to clarify its role.

Treprostinil is a prostacyclin analogue approved for the treatment of pulmonary arterial hypertension. Apart from the inhaled formulation, there is neither a target dose nor a ceiling dose to guide clinicians using treprostinil; doses are individualized for each patient based upon tolerability and clinical improvement. Using combined data from the pivotal subcutaneous and oral treprostinil studies, we evaluated the effect of treprostinil dose on hospitalization and exercise capacity to better define the treprostinil dose–response relationship. Data from the pivotal subcutaneous and oral treprostinil studies were combined by converting oral doses to weight-based continuous doses (ng/kg/min) accounting for patient weight and bioavailability. Patients were divided into dose tertiles (lowest, middle, highest 33%) and retrospectively analyzed. Analysis 1 assessed the effect of dose on pulmonary arterial hypertension-related and all-cause hospitalizations. Analysis 2 evaluated the effects of dose on six-minute walk distance, Borg dyspnea score, and World Health Organization functional class. Results showed that, in Analysis 1, higher doses of treprostinil were associated with significantly longer times to first pulmonary arterial hypertension-related and all-cause hospitalization. In Analysis 2, there was a trend toward improvements in six-minute walk distance with higher doses. In patients with pulmonary arterial hypertension on systemic treprostinil therapy, higher doses were associated with significantly longer time to first pulmonary arterial hypertension-related and all-cause hospitalization. There was a trend toward improvements in six-minute walk distance. Collectively, these results underscore the importance of managing prostacyclin adverse events in order to achieve appropriate dose titration. Further studies are required to confirm these findings and to better characterize the dose–response relationship of treprostinil.

Real‐world dosing and titration of parenteral (subcutaneous, SC; intravenous, IV) prostacyclin, a mainstay of pulmonary arterial hypertension (PAH) treatment, is not always consistent with prescribing information or randomized trials and has yet to be adequately characterized. The current study describes real‐world outpatient dosing and titration patterns over time, in PAH patients initiated on SC or IV treprostinil. A longitudinal, cross‐sectional analysis of medication shipment records from US specialty pharmacy services between 2009 and 2018 was conducted to determine dosing and titration patterns of SC or IV treprostinil in the outpatient setting beginning with the patient's first shipment. The sample for analysis included shipment records for 2647 patients (IV = 1040, SC = 1607). Although more patients were started on SC treprostinil than IV, median initial outpatient IV treprostinil dose (11 ng/kg/min at month on therapy one [MOT1]) was consistently and statistically significantly higher than initial outpatient SC dose (7.5 ng/kg/min at MOT1; p < 0.01). However, the SC treprostinil dose acceleration rate (DAR) was more aggressive from MOT1 to MOT6, MOT12, and MOT24, leading to a higher dose achieved at later timepoints. All between‐group DAR differences were statistically significant (p < 0.001). This study provides evidence that real‐world prescribing patterns of parenteral treprostinil in the outpatient setting differs from dosing described in pivotal trials, with important differences between SC and IV administration. Although initial outpatient IV treprostinil dosing was higher, SC titration was accelerated more aggressively and a higher dose was achieved by MOT3 suggesting that factors specific to SC administration (e.g., site pain) may not limit dosing and titration as previously thought.

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.

Mortality in pulmonary arterial hypertension (PAH) remains high and referral to palliative or supportive care (P/SC) specialist services is recommended when appropriate. However, access to P/SC is frequently a challenge for patients with a noncancer diagnosis and few patients living with PAH report P/SC involvement in their care. A modified Delphi process of three questionnaires completed by a multidisciplinary panel (N = 15) was used to develop expert consensus statements regarding the use of P/SC to support patients with PAH. Panelists rated their agreement with each statement on a Likert scale. There was a strong consensus that patients should be referred to P/SC when disease symptoms become unmanageable or for end‐of‐life care. Services that achieved consensus were pain management techniques, end‐of‐life care, and psychosocial recommendations. Palliative or supportive care should be discussed with patients, preferably in‐person, when disease symptoms become unmanageable, when starting treatment, when treatment‐related adverse events occur or become refractory to initial intervention. Care partners and patient support groups were considered important in improving a patient's overall health outcomes, treatment adherence, and perception of care. Most patients with PAH experience cognitive and/or psychosocial changes and those who receive psychosocial management have better persistence and/or compliance with their treatment. These consensus statements provide guidance to healthcare providers on the “who and when” of referral to palliative care services, as well as the importance of focusing on the psychosocial aspects of patient care and quality of life.