BREEZE Optional Extension Phase: Long-term safety and efficacy of treprostinil dry powder inhaler (Tyvaso DPI) in pulmonary arterial hypertension.

Introduction: Pulmonary arterial hypertension (PAH) is a rare and progressive disease associated with significant morbidity and mortality. Prostacyclins, including treprostinil, are a mainstay of PAH treatment, particularly in patients with intermediate to high risk of death. Following the approval of treprostinil inhalation solution for PAH, treprostinil dry powder inhaler (DPI) was developed as a small, portable, low-maintenance device to improve patient experience.

Study Design and Rationale for the PHINDER Study: Pulmonary Hypertension Screening in Patients with Interstitial Lung Disease for Earlier Detection.

Introduction: A common complication of interstitial lung disease (ILD) is pulmonary hypertension (PH), which is associated with increased morbidity and mortality and worsened quality of life. In ILD, evaluating for PH is recommended prior to lung transplantation. However, this is not standardized or routinely performed in earlier stages of ILD, and guidelines lack an evidence-based approach for PH screening in this population.

Safety and pharmacokinetics of ralinepag, a novel oral prostacyclin receptor agonist.

Background: Ralinepag is an oral, potent, highly selective prostacyclin receptor agonist and is in development for pulmonary arterial hypertension. Ralinepag was formulated as an immediate-release (IR) capsule, later modified to an extended-release (XR) tablet to optimize administration for once-daily dosing.

Methods: This phase I study evaluated the pharmacokinetic (PK) profile and relative bioavailability of ralinepag XR.

Peak steps to measure ''capacity for activity'': Actigraphy in the ADAPT registry with oral treprostinil.

Pulmonary arterial hypertension (PAH) patients have low activity time. Actigraphy provides an objective quantification of movement outside of clinic visits (home, work, social activities). Summary actigraphy measures (total daily steps or activity time) have not been shown to increase after adding therapies in patients with PAH.

Treatment With Oral or Inhaled Treprostinil in Patients With Pulmonary Arterial Hypertension and Cardiovascular Comorbidities.

Background: An increasing number of patients with pulmonary arterial hypertension (PAH) have cardiovascular comorbidities. However, the effects of comorbidities on responses to PAH treatment are not well understood.

Research Question: Do cardiovascular comorbidities in patients with PAH influence the efficacy and tolerability of inhaled or oral treprostinil?

Study Design And Methods: All patients from phase 3 studies Clinical Investigation Into Inhaled Treprostinil Sodium in Patients With Severe Pulmonary Arterial Hypertension (TRIUMPH) (N = 235) and Phase III Clinical Worsening Study of UT-15C in Subjects With PAH Receiving Background Oral Monotherapy (FREEDOM-EV) (N  =  690) were included in this post hoc analysis and were classified as having 0, ≥ 1, or ≥ 2 cardiovascular comorbidities of interest based on patient medical history.

Parenteral prostacyclin utilization in patients with pulmonary arterial hypertension in the intermediate-risk strata: a retrospective chart review and cross-sectional survey.

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.

Congruency between clinician-assessed risk and calculated risk of 1-year mortality in patients with pulmonary arterial hypertension: A retrospective chart review.

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.

Practical management of oral treprostinil in patients with pulmonary arterial hypertension: Lessons from ADAPT, EXPEDITE, and expert consensus.

Background: Oral treprostinil is a prostacyclin analogue approved to treat pulmonary arterial hypertension (PAH) by delaying disease progression and improving exercise capacity. Higher doses of oral treprostinil correlate with increased treatment benefit. Titrations may be challenging due to common side effects of prostacyclin-class therapies.

Oral Treprostinil is Associated with Improved Survival in FREEDOM-EV and its Open-Label Extension.

Introduction: In the event-driven FREEDOM-EV trial, oral treprostinil delayed clinical worsening in patients with pulmonary arterial hypertension (PAH). Open-label extension studies offer additional data about tolerability, efficacy, and survival, especially for those initially assigned placebo. The aim of the current study was to determine if oral treprostinil changed survival when considering the parent and extension study, if treprostinil provides functional benefits for participants initially assigned to placebo, and if the benefits observed for those treated with treprostinil were durable.

Tyvaso DPI: Drug-device characteristics and patient clinical considerations.

Tyvaso DPI is a drug-device combination therapy comprised of a small, portable, reusable, breath-powered, dry powder inhaler (DPI) for the delivery of treprostinil. It is approved for the treatment of pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease. Tyvaso DPI utilizes single-use prefilled cartridges to ensure proper dosing.

Parenteral treprostinil induction for rapid attainment of therapeutic doses of oral treprostinil.

Rationale: Oral treprostinil slows disease progression and improves exercise capacity in pulmonary arterial hypertension; however, titration can be prolonged. Published data suggests prostacyclin-naïve patients achieve total daily oral treprostinil doses of about 6 mg by Week 16, while those on prior parenteral treprostinil reach higher doses at the same timepoint.

Objectives: EXPEDITE (NCT03497689), a single-arm, multicenter study, assessed the efficacy of rapid parenteral treprostinil induction to quickly reach higher doses of oral treprostinil for the treatment of pulmonary arterial hypertension.

Implementing the EXPEDITE parenteral induction protocol: Rapid parenteral treprostinil titration and transition to oral treprostinil.

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.

The heart of the matter: Right heart imaging indicators for treatment escalation in pulmonary arterial hypertension.

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.

Contemporary risk scores predict clinical worsening in pulmonary arterial hypertension - An analysis of FREEDOM-EV.

Background: Risk scores integrate clinical variables emphasizing symptoms, exercise capacity, and measures of cardiac strain to predict clinical outcome better than any single value in pulmonary arterial hypertension (PAH). Risk scores have demonstrated prognostic utility for outcomes in registries, and recent studies have suggested that they are also therapy-responsive in controlled trials.

Methods: FREEDOM-EV, a global, placebo-controlled, event-driven study, randomized 690 PAH participants 1:1 to oral treprostinil (TRE) or placebo.

Inhaled Treprostinil Dosage in Pulmonary Hypertension Associated With Interstitial Lung Disease and Its Effects on Clinical Outcomes.

Background: Pulmonary hypertension (PH) complicates the course of many patients with fibrotic interstitial lung disease (ILD). Inhaled treprostinil (iTre) has been shown to improve functional ability and to delay clinical worsening in patients with PH resulting from ILD.

Research Question: Do higher dosages of iTre have greater benefits in preventing clinical worsening and achieving clinical improvement?

Study Design And Methods: Post hoc analysis of the INCREASE study, a 16-week double-blind, randomized, placebo-controlled trial of iTre in patients with PH resulting from ILD.

Clinical application of risk assessment in PAH: Expert center APRN recommendations.

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.

Real-world dosing characteristics and utilization of parenteral treprostinil in the outpatient setting.

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.

An expert panel Delphi consensus statement on the use of palliative care in the management of patients with pulmonary arterial hypertension.

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 ( = 15) was used to develop expert consensus statements regarding the use of P/SC to support patients with PAH.

Survival and drug persistence in patients receiving inhaled treprostinil at doses greater than 54 µg (nine breaths) four times daily.

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.

Combination Therapy in Pulmonary Arterial Hypertension-Targeting the Nitric Oxide and Prostacyclin Pathways.

Pulmonary arterial hypertension (PAH) is a chronic and progressive disorder characterized by vascular remodeling of the small pulmonary arteries, resulting in elevated pulmonary vascular resistance and ultimately, right ventricular failure. Expanded understanding of PAH pathophysiology as it pertains to the nitric oxide (NO), prostacyclin (prostaglandin I) (PGI) and endothelin-1 pathways has led to recent advancements in targeted drug development and substantial improvements in morbidity and mortality. There are currently several classes of drugs available to target these pathways including phosphodiesterase-5 inhibitors (PDE5i), soluble guanylate cyclase (sGC) stimulators, prostacyclin class agents and endothelin receptor antagonists (ERAs).

A multicenter retrospective study of patients with pulmonary hypertension transitioned from inhaled to oral treprostinil.

Oral treprostinil has recently been shown to delay disease progression in patients with pulmonary arterial hypertension in a long-term outcomes study. The potential advantages of an oral formulation have resulted in patients transitioning from inhaled to oral treprostinil. The current study reports a retrospective analysis of patients who transitioned from treatment with inhaled to oral treprostinil.

Impact of inhaled treprostinil on risk stratification with noninvasive parameters: a post hoc analysis of the TRIUMPH and BEAT studies.

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.

Novel dose-response analyses of treprostinil in pulmonary arterial hypertension and its effects on six-minute walk distance and hospitalizations.

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.

EXPRESS: Long term study of oral treprostinil to treat pulmonary arterial hypertension: dosing, tolerability, and pharmacokinetics.

Oral treprostinil may be an option for low- and intermediate-risk patients with pulmonary arterial hypertension, a rare lung vascular disease. This open-label extension study collected data on participants who completed previously reported, placebo-controlled oral treprostinil studies. Eligible participants had completed the prospective parent studies and took increasing doses of oral treprostinil twice daily; some later transitioned to three times daily dosing.